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Sample records for 2nd generation tyrosine

  1. Using 2nd generation tyrosine kinase inhibitors in frontline management of chronic phase chronic myeloid leukemia

    PubMed Central

    Jayakar, Vishal

    2014-01-01

    Choices in medicine come with responsibility. With several TKI's (Tyrosine kinase inhibitors) available for front-line management of CML (Chronic Myeloid Leukemia), an astute clinician has to personalise, rationalise and take a pragmatic approach towards selection of the best drug for the ‘patient in question’. Though it is hotly debated as to which TKI will triumph, the truth of this debate lies in individualising treatment rather than a general ‘all size fits all’ approach with imatinib. I personally believe that the second generation TKI's will suit most patient clinical profiles rather than prescribing imatinib to all and I have strived to make a strong case for them in front line treatment of CML. Though Imatinib may remain the first line choice for some patients, my efforts in this debate are mainly geared towards breaking the myth that imatinib is the sole ‘block buster’ on the CML landscape PMID:24665456

  2. Early onset hypercholesterolemia induced by the 2nd-generation tyrosine kinase inhibitor nilotinib in patients with chronic phase-chronic myeloid leukemia.

    PubMed

    Rea, Delphine; Mirault, Tristan; Cluzeau, Thomas; Gautier, Jean-François; Guilhot, François; Dombret, Hervé; Messas, Emmanuel

    2014-07-01

    Despite a well-recognized clinical benefit of the 2(nd)-generation tyrosine kinase inhibitor nilotinib in patients with imatinib-resistant/-intolerant or newly diagnosed chronic myeloid leukemia, recent evidence suggests that nilotinib has a propensity to increase the risk of occlusive arterial events, especially in patients with pre-existing cardiovascular risk factors. Given the key role of lipids in cardiovascular diseases, we studied the plasma lipid profile and global cardiovascular risk prior to and during nilotinib therapy in a series of 27 patients in the setting of a prospective single center study. Data from a minimum 1-year follow up showed that nilotinib significantly increased total, low- and high-density lipoprotein cholesterol within three months. Consequently, the proportion of patients with non-optimal low-density lipoprotein cholesterol increased from 48.1% to 88.9% by 12 months, leading to cholesterol-lowering drug intervention in 22.2% of patients. The proportion of patients with low levels of high-density lipoprotein cholesterol decreased from 40.7% to 7.4% by 12 months. In contrast, a significant decrease in triglycerides was observed. Global cardiovascular risk worsened in 11.1% of patients due to diabetes or occlusive arterial events. Whether hypercholesterolemia was the main driver of occlusive arterial events was uncertain: a longer follow up is necessary to ask whether nilotinib-induced hypercholesterolemia increases long-term risk of atherosclerotic diseases. Nevertheless, given key atherogenic properties of low-density lipoprotein cholesterol, we conclude that when prescribing nilotinib, commitment to detect lipid disorders at baseline and during follow up is mandatory given their frequency, requirement for changes in lifestyle or drug intervention, and potential for long-term cardiovascular complications.

  3. 2nd Generation ELT Performance Specification Development

    NASA Technical Reports Server (NTRS)

    Stimson, Chad M.

    2015-01-01

    NASA Search And Rescue is supporting RTCA SC-229 with research and recommendations for performance specifications for the 2nd generation of emergency locator transmitters. Areas for improvement and methods for collecting data will be presented.

  4. 2nd & 3rd Generation Vehicle Subsystems

    NASA Technical Reports Server (NTRS)

    2000-01-01

    This paper contains viewgraph presentation on the "2nd & 3rd Generation Vehicle Subsystems" project. The objective behind this project is to design, develop and test advanced avionics, power systems, power control and distribution components and subsystems for insertion into a highly reliable and low-cost system for a Reusable Launch Vehicles (RLV). The project is divided into two sections: 3rd Generation Vehicle Subsystems and 2nd Generation Vehicle Subsystems. The following topics are discussed under the first section, 3rd Generation Vehicle Subsystems: supporting the NASA RLV program; high-performance guidance & control adaptation for future RLVs; Evolvable Hardware (EHW) for 3rd generation avionics description; Scaleable, Fault-tolerant Intelligent Network or X(trans)ducers (SFINIX); advance electric actuation devices and subsystem technology; hybrid power sources and regeneration technology for electric actuators; and intelligent internal thermal control. Topics discussed in the 2nd Generation Vehicle Subsystems program include: design, development and test of a robust, low-maintenance avionics with no active cooling requirements and autonomous rendezvous and docking systems; design and development of a low maintenance, high reliability, intelligent power systems (fuel cells and battery); and design of a low cost, low maintenance high horsepower actuation systems (actuators).

  5. 2nd Generation RLV Risk Definition Program

    NASA Technical Reports Server (NTRS)

    Davis, Robert M.; Stucker, Mark (Technical Monitor)

    2000-01-01

    The 2nd Generation RLV Risk Reduction Mid-Term Report summarizes the status of Kelly Space & Technology's activities during the first two and one half months of the program. This report was presented to the cognoscente Contracting Officer's Technical Representative (COTR) and selected Marshall Space Flight Center staff members on 26 September 2000. The report has been approved and is distributed on CD-ROM (as a PowerPoint file) in accordance with the terms of the subject contract, and contains information and data addressing the following: (1) Launch services demand and requirements; (2) Architecture, alternatives, and requirements; (3) Costs, pricing, and business cases analysis; (4) Commercial financing requirements, plans, and strategy; (5) System engineering processes and derived requirements; and (6) RLV system trade studies and design analysis.

  6. 2nd Generation Reusable Launch Vehicle NASA Led Propulsion Tasks

    NASA Technical Reports Server (NTRS)

    Richards, Steve

    2000-01-01

    Design, development and test of a 2nd generation Reusable Launch Vehicle (RLV) is presented. This current paper discusses the following: 2nd Generation RLV Propulsion Project, Overview of NASA Led Tasks in Propulsion, Gen2 Turbo Machinery Technology Demonstrator, and Combustion Devices Test Bed, GRCop-84 Sheet For Combustion Chambers, Nozzles and Large Actively Cooled Structures

  7. 2nd Generation RLV: Program Goals and Acquisition Strategy

    NASA Technical Reports Server (NTRS)

    Graham, J. Bart; Dumbacher, D. L. (Technical Monitor)

    2001-01-01

    The risk to loss of life for Space Shuttle crewmembers is approximately one in 245 missions. U.S. launch service providers captured nearly 100%, of the commercial launch market revenues in the mid 1980s. Today, the U.S. captures less than 50% of that market. A launch system architecture is needed that will dramatically increase the safety of space flight while significantly reducing the cost. NASA's Space Launch Initiative, which is implemented by the 2nd Generation RLV Program Office at Marshall Space Flight Center, seeks to develop technology and reusable launch vehicle concepts which satisfy the commercial launch market needs and the unique needs of NASA. Presented in this paper are the five primary elements of NASA's Integrated Space Transportation Plan along with the highest level goals and the acquisition strategy of the 2nd Generation RLV Program. Approval of the Space Launch Initiative FY01 budget of $290M is seen as a major commitment by the Agency and the Nation to realize the commercial potential that space offers and to move forward in the exploration of space.

  8. Refraction data survey: 2nd generation correlation of myopia.

    PubMed

    Greene, Peter R; Medina, Antonio

    2016-10-01

    The objective herein is to provide refraction data, myopia progression rate, prevalence, and 1st and 2nd generation correlations, relevant to whether myopia is random or inherited. First- and second-generation ocular refraction data are assembled from N = 34 families, average of 2.8 children per family. From this group, data are available from N = 165 subjects. Inter-generation regressions are performed on all the data sets, including correlation coefficient r, and myopia prevalence [%]. Prevalence of myopia is [M] = 38.5 %. Prevalence of high myopes with |R| >6 D is [M-] = 20.5 %. Average refraction is  = -1.84 D ± 3.22 (N = 165). For the high myopes, |R| >6 D, prevalence for the parents is [M-] = 25 %, for the 2nd generation [M-] = 16.5 %. Average myopia level for the high myopes, both generations, is  = -7.52 D ± 1.31 D (N = 33). Regression parameters are calculated for all the data sets, yielding correlation coefficients in the range r = 0.48-0.72 for some groups of myopes and high myopes, fathers to daughters, and mothers to sons. Also of interest, some categories show essentially no correlation, -0.20 < r < 0.20, indicating that the refractive errors occur randomly. Time series results show myopia diopter rates = -0.50 D/year.

  9. The 2nd generation VLTI path to performance

    NASA Astrophysics Data System (ADS)

    Woillez, Julien; Alonso, Jaime; Berger, Jean-Philippe; Bonnet, Henri; de Wit, Willem-Jan; Egner, Sebastian; Eisenhauer, Frank; Gonté, Frédéric; Guieu, Sylvain; Haguenauer, Pierre; Mérand, Antoine; Pettazzi, Lorenzo; Poupar, Sébastien; Schöller, Markus; Schuhler, Nicolas

    2016-08-01

    The upgrade of the VLTI infrastructure for the 2nd generation instruments is now complete with the transformation of the laboratory, and installation of star separators on both the 1.8-m Auxiliary Telescopes (ATs) and the 8-m Unit Telescopes (UTs). The Gravity fringe tracker has had a full semester of commissioning on the ATs, and a first look at the UTs. The CIAO infrared wavefront sensor is about to demonstrate its performance relative to the visible wavefront sensor MACAO. First astrometric measurements on the ATs and astrometric qualification of the UTs are on-going. Now is a good time to revisit the performance roadmap for VLTI that was initiated in 2014, which aimed at coherently driving the developments of the interferometer, and especially its performance, in support to the new generation of instruments: Gravity and MATISSE.

  10. Philips' 2nd generation Novallure LED candle lamp

    NASA Astrophysics Data System (ADS)

    Li, Yun; Pei, Zhigang; Yuan, Chuan; Jiang, Tan; Lu, Zhengsong; Wang, Yuqian; Duan, Xiaoqing; Xiong, Yan; Zhong, Hong; Liu, Ye

    2010-08-01

    Finding an energy efficient replacement of incandescent candle lamp has been a technical challenge. Compact fluorescent lamps, for example, can be miniaturized to fit the form factor of a candle lamp but they fail to reproduce its "sparkle" effect. Empowered by solid state lighting technology along with original optical design, Philips has successfully developed LED-powered candle lamps "Novallure" with great energy savings (2W power consumption with lumen output of 55 lumen) and the "butterfly" radiation pattern that mimics the sparkle effect from an incandescent candle lamp. With new high performance LED packages, novel under-cut prismatic optics and state-of-the-art electronic driver solution and thermal solution, we have developed a 2nd generation Novallure with breakthrough performance: a dimmable 2700K 136 lumen LED candle lamp with CRI 90.

  11. Super Boiler 2nd Generation Technology for Watertube Boilers

    SciTech Connect

    Mr. David Cygan; Dr. Joseph Rabovitser

    2012-03-31

    This report describes Phase I of a proposed two phase project to develop and demonstrate an advanced industrial watertube boiler system with the capability of reaching 94% (HHV) fuel-to-steam efficiency and emissions below 2 ppmv NOx, 2 ppmv CO, and 1 ppmv VOC on natural gas fuel. The boiler design would have the capability to produce >1500 F, >1500 psig superheated steam, burn multiple fuels, and will be 50% smaller/lighter than currently available watertube boilers of similar capacity. This project is built upon the successful Super Boiler project at GTI. In that project that employed a unique two-staged intercooled combustion system and an innovative heat recovery system to reduce NOx to below 5 ppmv and demonstrated fuel-to-steam efficiency of 94% (HHV). This project was carried out under the leadership of GTI with project partners Cleaver-Brooks, Inc., Nebraska Boiler, a Division of Cleaver-Brooks, and Media and Process Technology Inc., and project advisors Georgia Institute of Technology, Alstom Power Inc., Pacific Northwest National Laboratory and Oak Ridge National Laboratory. Phase I of efforts focused on developing 2nd generation boiler concepts and performance modeling; incorporating multi-fuel (natural gas and oil) capabilities; assessing heat recovery, heat transfer and steam superheating approaches; and developing the overall conceptual engineering boiler design. Based on our analysis, the 2nd generation Industrial Watertube Boiler when developed and commercialized, could potentially save 265 trillion Btu and $1.6 billion in fuel costs across U.S. industry through increased efficiency. Its ultra-clean combustion could eliminate 57,000 tons of NOx, 460,000 tons of CO, and 8.8 million tons of CO2 annually from the atmosphere. Reduction in boiler size will bring cost-effective package boilers into a size range previously dominated by more expensive field-erected boilers, benefiting manufacturers and end users through lower capital costs.

  12. Aging Studies of 2nd Generation BaBar RPCs

    SciTech Connect

    Band, H.R.; /SLAC

    2007-09-25

    The BaBar detector, operating at the PEPII B factory of the Stanford Linear Accelerator Center (SLAC), installed over 200 2nd generation Resistive Plate Chambers (RPCs) in 2002. The streamer rates produced by backgrounds and signals from normal BaBar running vary considerably (0.1- >20 Hz/cm2) depending on the layer and position of the chambers, thus providing a broad spectrum test of RPC performance and aging. The lowest rate chambers have performed very well with stable efficiencies averaging 95%. Other chambers had rate-dependant inefficiencies due to Bakelite drying which were reversed by the introduction of humidified gases. RPC inefficiencies in the highest rate regions of the higher rate chambers have been observed and also found to be rate dependant. The inefficient regions grow with time and have not yet been reduced by operation with humidified input gas. Three of these chambers were converted to avalanche mode operation and display significantly improved efficiencies. The rate of production of HF in the RPC exhaust gases was measured in avalanche and streamer mode RPCs and found to be comparable despite the lower current of the avalanche mode RPCs.

  13. The 2nd Generation Real Time Mission Monitor (RTMM) Development

    NASA Technical Reports Server (NTRS)

    Blakeslee, Richard; Goodman, Michael; Meyer, Paul; Hardin, Danny; Hall, John; He, Yubin; Regner, Kathryn; Conover, Helen; Smith, Tammy; Lu, Jessica; Garrett, Michelle

    2009-01-01

    The NASA Real Time Mission Monitor (RTMM) is a visualization and information system that fuses multiple Earth science data sources, to enable real time decisionmaking for airborne and ground validation experiments. Developed at the National Aeronautics and Space Administration (NASA) Marshall Space Flight Center, RTMM is a situational awareness, decision-support system that integrates satellite imagery and orbit data, radar and other surface observations (e.g., lightning location network data), airborne navigation and instrument data sets, model output parameters, and other applicable Earth science data sets. The integration and delivery of this information is made possible using data acquisition systems, network communication links, network server resources, and visualizations through the Google Earth virtual globe application. In order to improve the usefulness and efficiency of the RTMM system, capabilities are being developed to allow the end-user to easily configure RTMM applications based on their mission-specific requirements and objectives. This second generation RTMM is being redesigned to take advantage of the Google plug-in capabilities to run multiple applications in a web browser rather than the original single application Google Earth approach. Currently RTMM employs a limited Service Oriented Architecture approach to enable discovery of mission specific resources. We are expanding the RTMM architecture such that it will more effectively utilize the Open Geospatial Consortium Sensor Web Enablement services and other new technology software tools and components. These modifications and extensions will result in a robust, versatile RTMM system that will greatly increase flexibility of the user to choose which science data sets and support applications to view and/or use. The improvements brought about by RTMM 2nd generation system will provide mission planners and airborne scientists with enhanced decision-making tools and capabilities to more

  14. The 2nd Generation Real Time Mission Monitor (RTMM) Development

    NASA Astrophysics Data System (ADS)

    Blakeslee, R. J.; Goodman, M.; Hardin, D. M.; Hall, J.; Yubin He, M.; Regner, K.; Conover, H.; Smith, T.; Meyer, P.; Lu, J.; Garrett, M.

    2009-12-01

    The NASA Real Time Mission Monitor (RTMM) is a visualization and information system that fuses multiple Earth science data sources, to enable real time decision-making for airborne and ground validation experiments. Developed at the National Aeronautics and Space Administration (NASA) Marshall Space Flight Center, RTMM is a situational awareness, decision-support system that integrates satellite imagery and orbit data, radar and other surface observations (e.g., lightning location network data), airborne navigation and instrument data sets, model output parameters, and other applicable Earth science data sets. The integration and delivery of this information is made possible using data acquisition systems, network communication links, network server resources, and visualizations through the Google Earth virtual globe application. In order to improve the usefulness and efficiency of the RTMM system, capabilities are being developed to allow the end-user to easily configure RTMM applications based on their mission-specific requirements and objectives. This second generation RTMM is being redesigned to take advantage of the Google plug-in capabilities to run multiple applications in a web browser rather than the original single application Google Earth approach. Currently RTMM employs a limited Service Oriented Architecture approach to enable discovery of mission specific resources. We are expanding the RTMM architecture such that it will more effectively utilize the Open Geospatial Consortium Sensor Web Enablement services and other new technology software tools and components. These modifications and extensions will result in a robust, versatile RTMM system that will greatly increase flexibility of the user to choose which science data sets and support applications to view and/or use. The improvements brought about by RTMM 2nd generation system will provide mission planners and airborne scientists with enhanced decision-making tools and capabilities to more

  15. Production and verification of a 2nd generation clonal group of Japanese flounder, Paralichthys olivaceus

    PubMed Central

    Hou, Jilun; Zhang, Xiaoyan; Wang, Yufen; Sun, Zhaohui; Si, Fei; Jiang, Xiufeng; Liu, Haijin

    2016-01-01

    Clonal fishes are useful tools in biology and aquaculture studies due to their isogenicity. In Japanese flounder (Paralichthys olivaceus), a group of homozygous clones was created by inducing meiogynogenesis in eggs from a mitogynogenetic homozygous diploid. As the clones reached sexual maturity, meiogynogenesis was again induced in order to produce a 2nd generation clonal group of Japanese flounder. After 3 months, there were 611 healthy, surviving individuals. Twenty-four microsatellite markers, that covered all the linkage groups of Japanese flounder, were used to identify the homozygosity of the 2nd generation clones; no heterozygous locus was detected. This indicates that the production of a 2nd generation clonal group of Japanese flounder was successful. Restriction-site DNA associated sequencing at the genomic level also confirmed the homozygosity and clonality of the 2nd generation clonal group. Furthermore, these 2nd generation clones had a small coefficient of variation for body shape indices at 210 days of age and showed a high degree of similarity in body characteristics among individuals. The successful production of 2nd generation clones has laid the foundation for the large-scale production of clonal Japanese flounder. PMID:27767055

  16. 2nd Generation Reusable Launch Vehicle Potential Commercial Development Scenarios

    NASA Technical Reports Server (NTRS)

    Creech, Stephen D.; Rogacki, John R. (Technical Monitor)

    2001-01-01

    The presentation will discuss potential commercial development scenarios for a Second Generation Reusable Launch Vehicle. The analysis of potential scenarios will include commercial rates of return, government return on investment, and market considerations. The presentation will include policy considerations in addition to analysis of Second Generation Reusable Launch Vehicle economics. The data discussed is being developed as a part of NASA's Second Generation Reusable Launch Vehicle Program, for consideration as potential scenarios for enabling a next generation system. Material will include potential scenarios not previously considered by NASA or presented at other conferences. Candidate paper has not been presented at a previous meeting, and conference attendance of the author has been approved by NASA.

  17. Support to 2nd Generation RLV Propulsion Project Office

    NASA Technical Reports Server (NTRS)

    Lee, Thomas J.

    2002-01-01

    In this final report regarding support to the second generation RLV (Reusable Launch Vehicle) propulsion project office, a list of tasks accomplished is presented. During this period, Lee & Associates, LLC participated in numerous Systems Requirements Reviews (SRR) related to the Cobra development program.

  18. Characterization and calibration of 2nd generation slope measuring profiler

    NASA Astrophysics Data System (ADS)

    Siewert, Frank; Buchheim, Jana; Zeschke, Thomas

    2010-05-01

    High spectral resolution and nanometer sized foci of 3rd generation SR beamlines can only be achieved by means of ultra precise optical elements. The improved brilliance and the coherence of free electron lasers (FEL) even push the accuracy limits and make the development of a new generation of ultra precise reflective optical elements mandatory. Typical elements are wave front preserving plane mirrors (lengths of up to 1 m, residual slope errors ˜0.05 μrad (rms) and values of 0.1 nm (rms) for the micro-roughness) and curved optical elements like spheres, toroids or elliptical cylinder (residual slope error ˜0.25 μrad (rms) and better). These challenging specifications and the ongoing progress in finishing technology need to be matched by improved accuracy metrology instruments. We will discuss the results of recent developments in the field of metrology made in the BESSY-II-optics laboratory (BOL) at the Helmholtz Zentrum Berlin (HZB), by the use of vertical angle comparator (VAC) in use to calibrate the nanometer optical component measuring machine (NOM). The BESSY-NOM represents an ultra accurate type of slope measuring instruments characterized by an accuracy of 0.05 μrad (rms) for plane substrates and 0.2 μrad (rms) for significant curved surfaces.

  19. Automated CFD Database Generation for a 2nd Generation Glide-Back-Booster

    NASA Technical Reports Server (NTRS)

    Chaderjian, Neal M.; Rogers, Stuart E.; Aftosmis, Michael J.; Pandya, Shishir A.; Ahmad, Jasim U.; Tejmil, Edward

    2003-01-01

    A new software tool, AeroDB, is used to compute thousands of Euler and Navier-Stokes solutions for a 2nd generation glide-back booster in one week. The solution process exploits a common job-submission grid environment using 13 computers located at 4 different geographical sites. Process automation and web-based access to the database greatly reduces the user workload, removing much of the tedium and tendency for user input errors. The database consists of forces, moments, and solution files obtained by varying the Mach number, angle of attack, and sideslip angle. The forces and moments compare well with experimental data. Stability derivatives are also computed using a monotone cubic spline procedure. Flow visualization and three-dimensional surface plots are used to interpret and characterize the nature of computed flow fields.

  20. NASA 2nd Generation RLV Program Introduction, Status and Future Plans

    NASA Technical Reports Server (NTRS)

    Dumbacher, Dan L.; Smith, Dennis E. (Technical Monitor)

    2002-01-01

    The Space Launch Initiative (SLI), managed by the Second Generation Reusable Launch Vehicle (2ndGen RLV) Program, was established to examine the possibility of revolutionizing space launch capabilities, define conceptual architectures, and concurrently identify the advanced technologies required to support a next-generation system. Initial Program funds have been allocated to design, evaluate, and formulate realistic plans leading to a 2nd Gen RLV full-scale development (FSD) decision by 2006. Program goals are to reduce both risk and cost for accessing the limitless opportunities afforded outside Earth's atmosphere fo civil, defense, and commercial enterprises. A 2nd Gen RLV architecture includes a reusable Earth-to-orbit launch vehicle, an on-orbit transport and return vehicle, ground and flight operations, mission planning, and both on-orbit and on-the-ground support infrastructures All segments of the architecture must advance in step with development of the RLV if a next-generation system is to be fully operational early next decade. However, experience shows that propulsion is the single largest contributor to unreliability during ascent, requires the largest expenditure of time for maintenance, and takes a long time to develop; therefore, propulsion is the key to meeting safety, reliability, and cost goals. For these reasons, propulsion is SLI's top technology investment area.

  1. Second harmonic generation from tyrosine containing peptides

    NASA Astrophysics Data System (ADS)

    Nasir, M. N.; Bergmann, E.; Benichou, E.; Russier-Antoine, I.; Lascoux, N.; Jonin, Ch.; Besson, F.; Brevet, P. F.

    2013-10-01

    The Second Harmonic Generation (SHG) response from Tyrosine-containing peptides at the air-water interface is presented. First, the quadratic hyperpolarizability of the aromatic amino acid Tyrosine obtained by Hyper Rayleigh Scattering is reported, demonstrating its potentiality as an endogenous molecular probe for SHG studies. Then, the single Tyrosine antimicrobial peptide Mycosubtilin is monitored at the air-water interface and compared to another peptide, Surfactin, lacking a Tyrosine residue. Adsorption kinetics and polarization analysis of the SHG intensity for the peptide monolayers clearly demonstrate that the SHG response from Mycosubtilin arises from Tyrosine. Besides, it confirms that indeed Tyrosine can be targeted as an endogenous molecular probe.

  2. Systems Engineering Approach to Technology Integration for NASA's 2nd Generation Reusable Launch Vehicle

    NASA Technical Reports Server (NTRS)

    Thomas, Dale; Smith, Charles; Thomas, Leann; Kittredge, Sheryl

    2002-01-01

    The overall goal of the 2nd Generation RLV Program is to substantially reduce technical and business risks associated with developing a new class of reusable launch vehicles. NASA's specific goals are to improve the safety of a 2nd generation system by 2 orders of magnitude - equivalent to a crew risk of 1-in-10,000 missions - and decrease the cost tenfold, to approximately $1,000 per pound of payload launched. Architecture definition is being conducted in parallel with the maturating of key technologies specifically identified to improve safety and reliability, while reducing operational costs. An architecture broadly includes an Earth-to-orbit reusable launch vehicle, on-orbit transfer vehicles and upper stages, mission planning, ground and flight operations, and support infrastructure, both on the ground and in orbit. The systems engineering approach ensures that the technologies developed - such as lightweight structures, long-life rocket engines, reliable crew escape, and robust thermal protection systems - will synergistically integrate into the optimum vehicle. To best direct technology development decisions, analytical models are employed to accurately predict the benefits of each technology toward potential space transportation architectures as well as the risks associated with each technology. Rigorous systems analysis provides the foundation for assessing progress toward safety and cost goals. The systems engineering review process factors in comprehensive budget estimates, detailed project schedules, and business and performance plans, against the goals of safety, reliability, and cost, in addition to overall technical feasibility. This approach forms the basis for investment decisions in the 2nd Generation RLV Program's risk-reduction activities. Through this process, NASA will continually refine its specialized needs and identify where Defense and commercial requirements overlap those of civil missions.

  3. Systems Engineering Approach to Technology Integration for NASA's 2nd Generation Reusable Launch Vehicle

    NASA Technical Reports Server (NTRS)

    Thomas, Dale; Smith, Charles; Thomas, Leann; Kittredge, Sheryl

    2002-01-01

    The overall goal of the 2nd Generation RLV Program is to substantially reduce technical and business risks associated with developing a new class of reusable launch vehicles. NASA's specific goals are to improve the safety of a 2nd-generation system by 2 orders of magnitude - equivalent to a crew risk of 1-in-10,000 missions - and decrease the cost tenfold, to approximately $1,000 per pound of payload launched. Architecture definition is being conducted in parallel with the maturating of key technologies specifically identified to improve safety and reliability, while reducing operational costs. An architecture broadly includes an Earth-to-orbit reusable launch vehicle, on-orbit transfer vehicles and upper stages, mission planning, ground and flight operations, and support infrastructure, both on the ground and in orbit. The systems engineering approach ensures that the technologies developed - such as lightweight structures, long-life rocket engines, reliable crew escape, and robust thermal protection systems - will synergistically integrate into the optimum vehicle. To best direct technology development decisions, analytical models are employed to accurately predict the benefits of each technology toward potential space transportation architectures as well as the risks associated with each technology. Rigorous systems analysis provides the foundation for assessing progress toward safety and cost goals. The systems engineering review process factors in comprehensive budget estimates, detailed project schedules, and business and performance plans, against the goals of safety, reliability, and cost, in addition to overall technical feasibility. This approach forms the basis for investment decisions in the 2nd Generation RLV Program's risk-reduction activities. Through this process, NASA will continually refine its specialized needs and identify where Defense and commercial requirements overlap those of civil missions.

  4. Life Cycle Systems Engineering Approach to NASA's 2nd Generation Reusable Launch Vehicle

    NASA Technical Reports Server (NTRS)

    Thomas, Dale; Smith, Charles; Safie, Fayssal; Kittredge, Sheryl

    2002-01-01

    The overall goal of the 2nd Generation RLV Program is to substantially reduce technical and business risks associated with developing a new class of reusable launch vehicles. NASA's specific goals are to improve the safety of a 2nd- generation system by 2 orders of magnitude - equivalent to a crew risk of 1 -in- 10,000 missions - and decrease the cost tenfold, to approximately $1,000 per pound of payload launched. Architecture definition is being conducted in parallel with the maturating of key technologies specifically identified to improve safety and reliability, while reducing operational costs. An architecture broadly includes an Earth-to-orbit reusable launch vehicle, on-orbit transfer vehicles and upper stages, mission planning, ground and flight operations, and support infrastructure, both on the ground and in orbit. The systems engineering approach ensures that the technologies developed - such as lightweight structures, long-life rocket engines, reliable crew escape, and robust thermal protection systems - will synergistically integrate into the optimum vehicle. Given a candidate architecture that possesses credible physical processes and realistic technology assumptions, the next set of analyses address the system's functionality across the spread of operational scenarios characterized by the design reference missions. The safety/reliability and cost/economics associated with operating the system will also be modeled and analyzed to answer the questions "How safe is it?" and "How much will it cost to acquire and operate?" The systems engineering review process factors in comprehensive budget estimates, detailed project schedules, and business and performance plans, against the goals of safety, reliability, and cost, in addition to overall technical feasibility. This approach forms the basis for investment decisions in the 2nd Generation RLV Program's risk-reduction activities. Through this process, NASA will continually refine its specialized needs and

  5. Effects of Thermal Cycling on Control and Irradiated EPC 2nd Generation GaN FETs

    NASA Technical Reports Server (NTRS)

    Patterson, Richard L.; Scheick, Leif; Lauenstein, Jean-Marie; Casey, Megan; Hammoud, Ahmad

    2013-01-01

    The power systems for use in NASA space missions must work reliably under harsh conditions including radiation, thermal cycling, and exposure to extreme temperatures. Gallium nitride semiconductors show great promise, but information pertaining to their performance is scarce. Gallium nitride N-channel enhancement-mode field effect transistors made by EPC Corporation in a 2nd generation of manufacturing were exposed to radiation followed by long-term thermal cycling in order to address their reliability for use in space missions. Results of the experimental work are presented and discussed.

  6. VLT interferometer upgrade for the 2nd generation of interferometric instruments

    NASA Astrophysics Data System (ADS)

    Gonté, Frederic; Woillez, Julien; Schuhler, Nicolas; Egner, Sebastian; Merand, Antoine; Abad, José Antonio; Abadie, Sergio; Abuter, Roberto; Acuña, Margarita; Allouche, Fatmé; Alonso, Jaime; Andolfalto, Luigi; Antonelli, Pierre; Avila, Gerardo; Barriga, Pablo José; Beltran, Juan; Berger, Jean-Philippe; Bolados, Carlos; Bonnet, Henri; Bourget, Pierre; Brast, Roland; Bristow, Paul; Caniguante, Luis; Castillo, Roberto; Conzelmann, Ralf; Cortes, Angela; Delplancke, Françoise; Del Valle, Diego; Derie, Frederic; Diaz, Alvaro; Donoso, Reinaldo; Dorn, Reinhold; Duhoux, Philippe; Dupuy, Christophe; Eisenhauer, Frank; Elao, Christian; Fuenteseca, Eloy; Fernandez, Ruben; Gaytan, Daniel; Glindemann, Andreas; Gonzales, Jaime; Guieu, Sylvain; Guisard, Stephane; Haguenauer, Pierre; Haimerl, Andreas; Heinz, Volker; Henriquez, Juan Pablo; van der Heyden, P.; Hubin, Norbert; Huerta, Rodrigo; Jochum, Lieselotte; Leiva, Alfredo; Lévêque, Samuel; Lizon, Jean-Louis; Luco, Fernando; Mardones, Pedro; Mellado, Angel; Osorio, Juan; Ott, Jürgen; Pallanca, Laurent; Pavez, Marcus; Pasquini, Luca; Percheron, Isabelle; Pirard, Jean-Francois; Than Phan, Duc; Pineda, Juan Carlos; Pino, Andres; Poupar, Sebastien; Ramírez, Andres; Reinero, Claudio; Riquelme, Miguel; Romero, Juan; Rivinius, Thomas; Rojas, Chester; Rozas, Felix; Salgado, Fernando; Scheithauer, Silvia; Schmid, Christian; Schöller, Markus; Siclari, Waldo; Stephan, Christian; Tamblay, Richard; Tapia, Mario; Tristram, Konrad; Valdes, Guillermo; de Wit, Willem-Jan; Wright, Andrew; Zins, Gerard

    2016-08-01

    ESO is undertaking a large upgrade of the infrastructure on Cerro Paranal in order to integrate the 2nd generation of interferometric instruments Gravity and MATISSE, and increase its performance. This upgrade started mid 2014 with the construction of a service station for the Auxiliary Telescopes and will end with the implementation of the adaptive optics system for the Auxiliary telescope (NAOMI) in 2018. This upgrade has an impact on the infrastructure of the VLTI, as well as its sub-systems and scientific instruments.

  7. Emotional and Behavioral Disorders in 1.5th Generation, 2nd Generation Immigrant Children, and Foreign Adoptees.

    PubMed

    Tan, Tony Xing

    2016-10-01

    Existing theories (e.g., acculturative stress theory) cannot adequately explain why mental disorders in immigrants are less prevalent than in non-immigrants. In this paper, the culture-gene co-evolutionary theory of mental disorders was utilized to generate a novel hypothesis that connection to heritage culture reduces the risk for mental disorders in immigrant children. Four groups of children aged 2-17 years were identified from the 2007 United States National Survey of Children's Health: 1.5th generation immigrant children (n = 1378), 2nd generation immigrant children (n = 4194), foreign adoptees (n = 270), and non-immigrant children (n = 54,877). The 1.5th generation immigrant children's connection to their heritage culture is stronger than or similar to the 2nd generation immigrants, while the foreign adoptees have little connection to their birth culture. Controlling for age, sex, family type and SES, the odds for having ADD/ADHD, Conduct Disorder, Anxiety Disorder, and Depression diagnosis were the lowest for the 1.5th generation immigrant children, followed by the 2nd generation immigrant children and the foreign adoptees. The foreign adoptees and non-adopted children were similar in the odds of having these disorders. Connection to heritage culture might be the underlying mechanism that explained recent immigrants' lower rates of mental disorders.

  8. Enabling the 2nd Generation in Space: Building Blocks for Large Scale Space Endeavours

    NASA Astrophysics Data System (ADS)

    Barnhardt, D.; Garretson, P.; Will, P.

    Today the world operates within a "first generation" space industrial enterprise, i.e. all industry is on Earth, all value from space is from bits (data essentially), and the focus is Earth-centric, with very limited parts of our population and industry participating in space. We are limited in access, manoeuvring, on-orbit servicing, in-space power, in-space manufacturing and assembly. The transition to a "Starship culture" requires the Earth to progress to a "second generation" space industrial base, which implies the need to expand the economic sphere of activity of mankind outside of an Earth-centric zone and into CIS-lunar space and beyond, with an equal ability to tap the indigenous resources in space (energy, location, materials) that will contribute to an expanding space economy. Right now, there is no comfortable place for space applications that are not discovery science, exploration, military, or established earth bound services. For the most part, space applications leave out -- or at least leave nebulous, unconsolidated, and without a critical mass -- programs and development efforts for infrastructure, industrialization, space resources (survey and process maturation), non-traditional and persistent security situational awareness, and global utilities -- all of which, to a far greater extent than a discovery and exploration program, may help determine the elements of a 2nd generation space capability. We propose a focus to seed the pre-competitive research that will enable global industry to develop the necessary competencies that we currently lack to build large scale space structures on-orbit, that in turn would lay the foundation for long duration spacecraft travel (i.e. key technologies in access, manoeuvrability, etc.). This paper will posit a vision-to-reality for a step wise approach to the types of activities the US and global space providers could embark upon to lay the foundation for the 2nd generation of Earth in space.

  9. The New 2nd-Generation SRF R&D Facility at Jefferson Lab: TEDF

    SciTech Connect

    Reece, Charles E.; Reilly, Anthony V.

    2012-09-01

    The US Department of Energy has funded a near-complete renovation of the SRF-based accelerator research and development facilities at Jefferson Lab. The project to accomplish this, the Technical and Engineering Development Facility (TEDF) Project has completed the first of two phases. An entirely new 3,100 m{sup 2} purpose-built SRF technical work facility has been constructed and was occupied in summer of 2012. All SRF work processes with the exception of cryogenic testing have been relocated into the new building. All cavity fabrication, processing, thermal treatment, chemistry, cleaning, and assembly work is collected conveniently into a new LEED-certified building. An innovatively designed 800 m2 cleanroom/chemroom suite provides long-term flexibility for support of multiple R&D and construction projects as well as continued process evolution. The characteristics of this first 2nd-generation SRF facility are described.

  10. Characterization of γ and γ' phases in 2nd and 4th generation single crystal nickel-base superalloys

    NASA Astrophysics Data System (ADS)

    Zietara, Maciej; Neumeier, Steffen; Göken, Mathias; Czyrska-Filemonowicz, Aleksandra

    2017-01-01

    A Ni based single crystal superalloy from the 2nd generation, PWA 1484, and one from the 4th generation, PWA 1497, were comparatively studied by scanning electron microscopy, energy dispersive X-ray spectroscopy and nanoindentation technique in an atomic force microscope (NI-AFM) after high temperature creep deformation. During primary creep of both generations of superalloys, γ' precipitates start to coalesce and grow directionally. Further creep deformation leads to the topological inversion and coarsening of the rafted microstructure. The NI-AFM technique was used for measurements of the hardness of the γ and γ' phases in as-received and creep deformed samples in various conditions. The g matrix of the PWA 1497 superalloy is on average 0.8 GPa harder than that of PWA 1484 that can be explained by higher content of Re and Ru, since they partition predominantly to the matrix phase.

  11. STARS 2.0: 2nd-generation open-source archiving and query software

    NASA Astrophysics Data System (ADS)

    Winegar, Tom

    2008-07-01

    The Subaru Telescope is in process of developing an open-source alternative to the 1st-generation software and databases (STARS 1) used for archiving and query. For STARS 2, we have chosen PHP and Python for scripting and MySQL as the database software. We have collected feedback from staff and observers, and used this feedback to significantly improve the design and functionality of our future archiving and query software. Archiving - We identified two weaknesses in 1st-generation STARS archiving software: a complex and inflexible table structure and uncoordinated system administration for our business model: taking pictures from the summit and archiving them in both Hawaii and Japan. We adopted a simplified and normalized table structure with passive keyword collection, and we are designing an archive-to-archive file transfer system that automatically reports real-time status and error conditions and permits error recovery. Query - We identified several weaknesses in 1st-generation STARS query software: inflexible query tools, poor sharing of calibration data, and no automatic file transfer mechanisms to observers. We are developing improved query tools and sharing of calibration data, and multi-protocol unassisted file transfer mechanisms for observers. In the process, we have redefined a 'query': from an invisible search result that can only transfer once in-house right now, with little status and error reporting and no error recovery - to a stored search result that can be monitored, transferred to different locations with multiple protocols, reporting status and error conditions and permitting recovery from errors.

  12. A Plan for Advanced Guidance and Control Technology for 2nd Generation Reusable Launch Vehicles

    NASA Technical Reports Server (NTRS)

    Hanson, John M.; Fogle, Frank (Technical Monitor)

    2002-01-01

    Advanced guidance and control (AG&C) technologies are critical for meeting safety/reliability and cost requirements for the next generation of reusable launch vehicle (RLV). This becomes clear upon examining the number of expendable launch vehicle failures in the recent past where AG&C technologies would have saved a RLV with the same failure mode, the additional vehicle problems where this technology applies, and the costs associated with mission design with or without all these failure issues. The state-of-the-art in guidance and control technology, as well as in computing technology, is at the point where we can took to the possibility of being able to safely return a RLV in any situation where it can physically be recovered. This paper outlines reasons for AG&C, current technology efforts, and the additional work needed for making this goal a reality.

  13. RF SOI CMOS technology on 1st and 2nd generation trap-rich high resistivity SOI wafers

    NASA Astrophysics Data System (ADS)

    Kazemi Esfeh, B.; Makovejev, S.; Basso, Didier; Desbonnets, Eric; Kilchytska, V.; Flandre, D.; Raskin, J.-P.

    2017-02-01

    In this work three different types of UNIBOND™ Silicon-on-Insulator (SOI) wafers including one standard HR-SOI and two types of trap-rich high resistivity HR-SOI substrates named enhanced signal integrity high resistivity silicon-on-insulator (eSI HR-SOI) provided by SOITEC are studied and compared. The DC and RF performances of these wafers are compared by means of passive and active devices such as coplanar waveguide (CPW) lines, crosstalk- and noise injection-structures as well as partially-depleted (PD) SOI MOSFETs. It is demonstrated that by employing enhanced signal integrity high resistivity silicon-on-insulator (eSI HR-SOI) compared to HR-SOI wafer, a reduction of 24 dB is measured on both generations of trap-rich HR-SOI for 2nd harmonics. Furthermore, it is shown that in eSI HR-SOI, digital substrate noise is effectively reduced compared with HR-SOI. Purely capacitive behavior of eSI HR-SOI is demonstrated by crosstalk structure. Reduction of self-heating effect in the trap-rich HR-SOI with thinner BOX is finally studied.

  14. Immobilized High Level Waste (HLW) Interim Storage Alternative Generation and analysis and Decision Report 2nd Generation Implementing Architecture

    SciTech Connect

    CALMUS, R.B.

    2000-09-14

    Two alternative approaches were previously identified to provide second-generation interim storage of Immobilized High-Level Waste (IHLW). One approach was retrofit modification of the Fuel and Materials Examination Facility (FMEF) to accommodate IHLW. The results of the evaluation of the FMEF as the second-generation IHLW interim storage facility and subsequent decision process are provided in this document.

  15. Efficient 2(nd) and 4(th) harmonic generation of a single-frequency, continuous-wave fiber amplifier.

    PubMed

    Sudmeyer, Thomas; Imai, Yutaka; Masuda, Hisashi; Eguchi, Naoya; Saito, Masaki; Kubota, Shigeo

    2008-02-04

    We demonstrate efficient cavity-enhanced second and fourth harmonic generation of an air-cooled, continuous-wave (cw), single-frequency 1064 nm fiber-amplifier system. The second harmonic generator achieves up to 88% total external conversion efficiency, generating more than 20-W power at 532 nm wavelength in a diffraction-limited beam (M(2) < 1.05). The nonlinear medium is a critically phase-matched, 20-mm long, anti-reflection (AR) coated LBO crystal operated at 25 degrees C. The fourth harmonic generator is based on an AR-coated, Czochralski-grown beta-BaB(2)O(4) (BBO) crystal optimized for low loss and high damage threshold. Up to 12.2 W of 266-nm deep-UV (DUV) output is obtained using a 6-mm long critically phase-matched BBO operated at 40 degrees C. This power level is more than two times higher than previously reported for cw 266-nm generation. The total external conversion efficiency from the fundamental at 1064 nm to the fourth harmonic at 266 nm is >50%.

  16. Performance Evaluation of Electrochem's PEM Fuel Cell Power Plant for NASA's 2nd Generation Reusable Launch Vehicle

    NASA Technical Reports Server (NTRS)

    Kimble, Michael C.; Hoberecht, Mark

    2003-01-01

    NASA's Next Generation Launch Technology (NGLT) program is being developed to meet national needs for civil and commercial space access with goals of reducing the launch costs, increasing the reliability, and reducing the maintenance and operating costs. To this end, NASA is considering an all- electric capability for NGLT vehicles requiring advanced electrical power generation technology at a nominal 20 kW level with peak power capabilities six times the nominal power. The proton exchange membrane (PEM) fuel cell has been identified as a viable candidate to supply this electrical power; however, several technology aspects need to be assessed. Electrochem, Inc., under contract to NASA, has developed a breadboard power generator to address these technical issues with the goal of maximizing the system reliability while minimizing the cost and system complexity. This breadboard generator operates with dry hydrogen and oxygen gas using eductors to recirculate the gases eliminating gas humidification and blowers from the system. Except for a coolant pump, the system design incorporates passive components allowing the fuel cell to readily follow a duty cycle profile and that may operate at high 6:1 peak power levels for 30 second durations. Performance data of the fuel cell stack along with system performance is presented to highlight the benefits of the fuel cell stack design and system design for NGLT vehicles.

  17. Research on the 2nd generation biofuel BIOXDIESEL in aspects of emission of toxic substances in exhaust gases

    NASA Astrophysics Data System (ADS)

    Struś, M. S.; Poprawski, W.; Rewolte, M.

    2016-09-01

    This paper presents results of research of Diesel engines emission of toxic substances in exhaust gases fuelled with a second generation biofuel BIOXDIESEL, which is a blend of Fatty Acid Ethyl Esters obtained from waste resources such waste vegetable and animal fats, bioethanol and standard Diesel fuel. Presented results are very promising, showing that the emission of toxic substances in exhaust gases are significantly reduced when fuelling with BIOXDIESEL fuel in comparison with standard Diesel fuel.

  18. Second-generation inhibitors of Bruton tyrosine kinase.

    PubMed

    Wu, Jingjing; Liu, Christina; Tsui, Stella T; Liu, Delong

    2016-09-02

    Bruton tyrosine kinase (BTK) is a critical effector molecule for B cell development and plays a major role in lymphoma genesis. Ibrutinib is the first-generation BTK inhibitor. Ibrutinib has off-target effects on EGFR, ITK, and Tec family kinases, which explains the untoward effects of ibrutinib. Resistance to ibrutinib was also reported. The C481S mutation in the BTK kinase domain was reported to be a major mechanism of resistance to ibrutinib. This review summarizes the clinical development of novel BTK inhibitors, ACP-196 (acalabrutinib), ONO/GS-4059, and BGB-3111.

  19. An analytical benchmark and a Mathematica program for MD codes: Testing LAMMPS on the 2nd generation Brenner potential

    NASA Astrophysics Data System (ADS)

    Favata, Antonino; Micheletti, Andrea; Ryu, Seunghwa; Pugno, Nicola M.

    2016-10-01

    An analytical benchmark and a simple consistent Mathematica program are proposed for graphene and carbon nanotubes, that may serve to test any molecular dynamics code implemented with REBO potentials. By exploiting the benchmark, we checked results produced by LAMMPS (Large-scale Atomic/Molecular Massively Parallel Simulator) when adopting the second generation Brenner potential, we made evident that this code in its current implementation produces results which are offset from those of the benchmark by a significant amount, and provide evidence of the reason.

  20. Autocommander: A Supervisory Controller for Integrated Guidance and Control for the 2nd Generation Reusable Launch Vehicle

    NASA Technical Reports Server (NTRS)

    Fisher, J. E.; Lawrence, D. A.; Zhu, J. J.; Jackson, Scott (Technical Monitor)

    2002-01-01

    This paper presents a hierarchical architecture for integrated guidance and control that achieves risk and cost reduction for NASA's 2d generation reusable launch vehicle (RLV). Guidance, attitude control, and control allocation subsystems that heretofore operated independently will now work cooperatively under the coordination of a top-level autocommander. In addition to delivering improved performance from a flight mechanics perspective, the autocommander is intended to provide an autonomous supervisory control capability for traditional mission management under nominal conditions, G&C reconfiguration in response to effector saturation, and abort mode decision-making upon vehicle malfunction. This high-level functionality is to be implemented through the development of a relational database that is populated with the broad range of vehicle and mission specific data and translated into a discrete event system model for analysis, simulation, and onboard implementation. A Stateflow Autocoder software tool that translates the database into the Stateflow component of a Matlab/Simulink simulation is also presented.

  1. Contribution of ion beam analysis methods to the development of 2nd generation high temperature superconducting (HTS) wires

    SciTech Connect

    Usov, Igor O; Arendt, Paul N; Stan, Liliana; Holesinger, Terry G; Foltyn, Steven R; Depaula, Raymond F

    2009-01-01

    One of the crucial steps in the second generation high temperature superconducting wire program was development of the buffer layer architecture. The architecture designed at the Superconductivity Technology Center at Los Alamos National Laboratory consists of several oxide layers wherein each layer plays a specific role, namely: nucleation layer, diffusion barrier, biaxially textured template, and an intermediate layer with a good match to the lattice parameter of superconducting Y{sub 1}Ba{sub 2}Cu{sub 3}O{sub 7} (YBCO) compound. This report demonstrates how a wide range of ion beam analysis techniques (SIMS, RBS, channeling, PIXE, PIGE, NRA, ERD) was employed for analysis of each buffer layer and the YBCO films. These results assisted in understanding of a variety of physical processes occurring during the buffet layer fabrication and helped to optimize the buffer layer architecture as a whole.

  2. FFR guided PCI on long coronary lesions: 2-year clinical results with 2nd or newer generation DES

    PubMed Central

    Arvydas, Baranauskas; Vilhelmas, Bajoras; Povilas, Budrys; Aleksandras, Laucevičius; Giedrius, Davidavičius

    2016-01-01

    Background. Despite improvements in drug-eluting stent (DES) technology, treatment strategies for long coronary artery lesions remain a controversial issue. The aim of our study was to evaluate the long-term clinical results after FFR guided PCI on long coronary lesions. Materials and methods. A total of 74 consecutive patients with significant (mean FFR 0.61 ± 0.11) coronary artery lesions ≥30 mm in length were included in the prospective study. All patients were treated with FFR guided PCI implanting newer generation Biolimus, Everolimus or Zotarolimus eluting stents. Clinical endpoints – target vessel revascularization (TVR) and major adverse cardiac events (MACE) – were recorded at 1 and 2 years. Results. 100% angiographic procedure success was achieved, the mean post procedural FFR was 0.88 ± 0.06. At 2-year follow-up, 6 (8.1%) patients had ischemia driven TVR, all within the first 12 months. There were no target vessel related acute coronary syndromes and definite stent thromboses in the study group. At 2 years, the total MACE rate was 29.7%. There was a trend towards a higher TVR rate in patients with overlapping DES vs single DES implanted (9.6 vs 4.5%, p = 0.6). On regression analysis, the total stent length had no influence on the TVR rate. Conclusions. At 2 years after stenting long coronary lesions with newer generation DES the TVR rate was 8.1%, which is acceptable in the high cardiovascular risk population with diffuse coronary artery disease. The total stent length did not affect the long-term clinical outcomes. PMID:28356786

  3. New approaches for improving the production of the 1st and 2nd generation ethanol by yeast.

    PubMed

    Kurylenko, Olena; Semkiv, Marta; Ruchala, Justyna; Hryniv, Orest; Kshanovska, Barbara; Abbas, Charles; Dmytruk, Kostyantyn; Sibirny, Andriy

    2016-01-01

    Increase in the production of 1st generation ethanol from glucose is possible by the reduction in the production of ethanol co-products, especially biomass. We have developed a method to reduce biomass accumulation of Saccharomyces cerevisiae by the manipulation of the intracellular ATP level due to overexpression of genes of alkaline phosphatase, apyrase or enzymes involved in futile cycles. The strains constructed accumulated up to 10% more ethanol on a cornmeal hydrolysate medium. Similar increase in ethanol accumulation was observed in the mutants resistant to the toxic inhibitors of glycolysis like 3-bromopyruvate and others. Substantial increase in fuel ethanol production will be obtained by the development of new strains of yeasts that ferment sugars of the abundant lignocellulosic feedstocks, especially xylose, a pentose sugar. We have found that xylose can be fermented under elevated temperatures by the thermotolerant yeast, Hansenula polymorpha. We combined protein engineering of the gene coding for xylose reductase (XYL1) along with overexpression of the other two genes responsible for xylose metabolism in yeast (XYL2, XYL3) and the deletion of the global transcriptional activator CAT8, with the selection of mutants defective in utilizing ethanol as a carbon source using the anticancer drug, 3-bromopyruvate. Resulted strains accumulated 20-25 times more ethanol from xylose at the elevated temperature of 45°C with up to 12.5 g L(-1) produced. Increase in ethanol yield and productivity from xylose was also achieved by overexpression of genes coding for the peroxisomal enzymes: transketolase (DAS1) and transaldolase (TAL2), and deletion of the ATG13 gene.

  4. Direct and non-destructive proof of authenticity for the 2nd generation of Brazilian real banknotes via easy ambient sonic spray ionization mass spectrometry.

    PubMed

    Schmidt, Eduardo Morgado; Franco, Marcos Fernando; Regino, Karen Gomes; Lehmann, Eraldo Luiz; Arruda, Marco Aurélio Zezzi; de Carvalho Rocha, Werickson Fortunato; Borges, Rodrigo; de Souza, Wanderley; Eberlin, Marcos Nogueira; Correa, Deleon Nascimento

    2014-12-01

    Using a desorption/ionization technique, easy ambient sonic-spray ionization coupled to mass spectrometry (EASI-MS), documents related to the 2nd generation of Brazilian Real currency (R$) were screened in the positive ion mode for authenticity based on chemical profiles obtained directly from the banknote surface. Characteristic profiles were observed for authentic, seized suspect counterfeit and counterfeited homemade banknotes from inkjet and laserjet printers. The chemicals in the authentic banknotes' surface were detected via a few minor sets of ions, namely from the plasticizers bis(2-ethylhexyl)phthalate (DEHP) and dibutyl phthalate (DBP), most likely related to the official offset printing process, and other common quaternary ammonium cations, presenting a similar chemical profile to 1st-generation R$. The seized suspect counterfeit banknotes, however, displayed abundant diagnostic ions in the m/z 400-800 range due to the presence of oligomers. High-accuracy FT-ICR MS analysis enabled molecular formula assignment for each ion. The ions were separated by 44 m/z, which enabled their characterization as Surfynol® 4XX (S4XX, XX=40, 65, and 85), wherein increasing XX values indicate increasing amounts of ethoxylation on a backbone of 2,4,7,9-tetramethyl-5-decyne-4,7-diol (Surfynol® 104). Sodiated triethylene glycol monobutyl ether (TBG) of m/z 229 (C10H22O4Na) was also identified in the seized counterfeit banknotes via EASI(+) FT-ICR MS. Surfynol® and TBG are constituents of inks used for inkjet printing.

  5. Development of the 2nd generation z(Redshift) and early universe spectrometer & the study of far-IR fine structure emission in high-z galaxies

    NASA Astrophysics Data System (ADS)

    Ferkinhoff, Carl

    The 2nd generation z (Redshift) and Early Universe Spectrometer (ZEUS-2), is a long-slit echelle-grating spectrometer (R~1000) for observations at submillimeter wavelengths from 200 to 850 microm. Its design is optimized for the detection of redshifted far-infrared spectral lines from galaxies in the early universe. Combining exquisite sensitivity, broad wavelength coverage, and large (˜2.5%) instantaneous bandwidth, ZEUS-2 is uniquely suited for studying galaxies between z˜0.2 and 5---spanning the peaks in both the star formation rate and number of AGN in the universe. ZEUS-2 saw first light at the Caltech Submillimeter Observatory (CSO) in the Spring of 2012 and was commissioned on the Atacama Pathfinder Experiment (APEX) in November 2012. Here we detail the design and performance of ZEUS-2, first however we discuss important science results that are examples of the science enabled by ZEUS-2. Using the first generation z (Redshift) and Early Universe Spectrometer (ZEUS-1) we made the first high-z detections of the [NII] 122 microm and [OIII] 88 microm lines. We detect these lines from starburst galaxies between z ˜2.5 and 4 demonstrating the utility of these lines for characterizing the properties of early galaxies. Specifically we are able to determine the most massive star still on the main sequence, the number of those stars and a lower limit on the mass of ionized gas in the source. Next we present ZEUS-2's first science result. Using ZEUS-2 on APEX we have detected the [CII] 158 microm line from the z = 1.78 galaxy H-ATLAS J091043.1-000322 with a line flux of (6.44 +/- 0.42) ˜ 10-18 W m-2. Combined with its far-infrared luminosity and a new Herschel-PACS detection of the [OI] 63 microm line we are able to conclude that H-ATLAS J091043.1-000322 is a high redshift analogue of a local ultra-luminous infrared galaxy, i.e. it is likely the site of a compact starburst due to a major merger. This detection, combined with the ZEUS-1 observations of the [NII

  6. Gasification. 2nd. ed.

    SciTech Connect

    Christopher Higman; Maarten van der Burgt

    2008-02-15

    This book covers gasification as a comprehensive topic, covering its many uses, from refining, to natural gas, to coal. It provides an overview of commercial processes and covers applications relevant to today's demands. The new edition is expanded and provides more detail on the integration issues for current generation, state-of-the-art Integrated Gasification Combined Cycles (IGCC); CO{sub 2} capture in the IGCC context addressing the issues of pre-investment and retrofitting as well as defining what the term 'CO{sub 2} capture ready' might mean in practice; issues of plant reliability, availability and maintainability (RAM) including as evaluation of feedback from existing plants; implementation of fuel cell technology in IGCC concepts. Contents are: Introduction; The Thermodynamics of Gasification; The Kinetics of Gasification and Reactor Theory; Feedstocks and Feedstock Characteristics; Gasification Processes; Practical Issues; Applications; Auxiliary Technologies; Economics, environmental, and Safety Issues; Gasification and the Future. 5 apps.

  7. TrkA receptor ectodomain cleavage generates a tyrosine-phosphorylated cell-associated fragment

    PubMed Central

    1996-01-01

    The extracellular domain of several membrane-anchored proteins can be released as a soluble fragment by the action of a cell surface endoproteolytic system. This cleavage results in the generation of a soluble and a cell-bound fragment. In the case of proteins with signaling capability, such as tyrosine kinase receptors, the cleavage process may have an effect on the kinase activity of the cell-bound receptor fragment. By using several cell lines that express the TrkA neurotrophin receptor, we show that this receptor tyrosine kinase is cleaved by a proteolytic system that mimics the one that acts at the cell surface. TrkA cleavage is regulated by protein kinase C and several receptor agonists (including the TrkA ligand NGF), occurs at the ectodomain in a membrane-proximal region, and is independent of lysosomal function. TrkA cleavage results in the generation of a cell- associated fragment that is phosphorylated on tyrosine residues. Tyrosine phosphorylation of this fragment is not detected in TrkA mutants devoid of kinase activity, suggesting that phosphorylation requires an intact TrkA kinase domain, and is not due to activation of an intermediate intracellular tyrosine kinase. The increased phosphotyrosine content of the cell-bound fragment may thus reflect higher catalytic activity of the truncated fragment. We postulate that cleavage of receptor tyrosine kinases by this naturally occurring cellular mechanism may represent an additional mean for the regulation of receptor activity. PMID:8636219

  8. Control system for the 2nd generation Berkeley AutoMounters (BAM2) at GM/CA CAT macromolecular crystallography beamlines.

    PubMed

    Makarov, O; Hilgart, M; Ogata, C; Pothineni, S; Cork, C

    2011-09-01

    GM/CA CAT at Sector 23 of the Advanced Photon Source (APS) is an NIH funded facility for crystallographic structure determination of biological macromolecules by X-ray diffraction.A second generation Berkeley automounter is being integrated into the beamline control system at the 23-BM experimental station. This new device replaces the previous all-pneumatic gripper motions with a combination of pneumatics and XYZ motorized linear stages. The latter adds a higher degree of flexibility to the robot including auto-alignment capability, accommodation of a larger capacity sample Dewar of arbitrary shape, and support for advanced operations such as crystal washing, while preserving the overall simplicity and efficiency of the Berkeley automounter design.

  9. Population pharmacokinetics, brain distribution, and pharmacodynamics of 2nd generation dopamine transporter selective benztropine analogs developed as potential substitute therapeutics for treatment of cocaine abuse.

    PubMed

    Syed, Shariq A; Newman, Amy H; Othman, Ahmed A; Eddington, Natalie D

    2008-05-01

    A second generation of N-substituted 3alpha-[bis(4'-fluorophenyl)methoxy]-tropanes (GA 1-69, JHW 005 and JHW 013) binds with high affinity to the dopamine transporter (DAT) and are highly selective toward DAT compared to muscarinic receptor binding (M1). The objective of this study was to characterize brain distribution, pharmacokinetics, and pharmacodynamics [extracellular brain dopamine (DA) levels] of three novel N-substituted benztropine (BZT) analogs in male Sprague-Dawley rats. The BZT analogs displayed a higher distribution (Vd = 8.69-34.3 vs. 0.9 L/kg) along with longer elimination (t l/2: 4.1-5.4 vs. 0.5 h) than previously reported for cocaine. Brain-to-plasma partition coefficients were 1.3-2.5 vs. 2.1 for cocaine. The effect of the BZT analogs on extracellular brain (DA) levels ranged from minimal effects (GA 1-69) to several fold elevation (approximately 850% of basal DA for JHW 013) at the highest dose evaluated. PK/PD analysis of exposure-response data resulted in lower IC50 values for the BZT analogs compared to cocaine indicating their higher potency to inhibit DA reuptake (0.1-0.3 vs. 0.7 mg/L). These BZT analogs possess significantly different PK and PD profiles as compared to cocaine suggesting that further evaluation as cocaine abuse therapeutics is warranted.

  10. Techno-economic evaluation of 2nd generation bioethanol production from sugar cane bagasse and leaves integrated with the sugar-based ethanol process

    PubMed Central

    2012-01-01

    Background Bioethanol produced from the lignocellulosic fractions of sugar cane (bagasse and leaves), i.e. second generation (2G) bioethanol, has a promising market potential as an automotive fuel; however, the process is still under investigation on pilot/demonstration scale. From a process perspective, improvements in plant design can lower the production cost, providing better profitability and competitiveness if the conversion of the whole sugar cane is considered. Simulations have been performed with AspenPlus to investigate how process integration can affect the minimum ethanol selling price of this 2G process (MESP-2G), as well as improve the plant energy efficiency. This is achieved by integrating the well-established sucrose-to-bioethanol process with the enzymatic process for lignocellulosic materials. Bagasse and leaves were steam pretreated using H3PO4 as catalyst and separately hydrolysed and fermented. Results The addition of a steam dryer, doubling of the enzyme dosage in enzymatic hydrolysis, including leaves as raw material in the 2G process, heat integration and the use of more energy-efficient equipment led to a 37 % reduction in MESP-2G compared to the Base case. Modelling showed that the MESP for 2G ethanol was 0.97 US$/L, while in the future it could be reduced to 0.78 US$/L. In this case the overall production cost of 1G + 2G ethanol would be about 0.40 US$/L with an output of 102 L/ton dry sugar cane including 50 % leaves. Sensitivity analysis of the future scenario showed that a 50 % decrease in the cost of enzymes, electricity or leaves would lower the MESP-2G by about 20%, 10% and 4.5%, respectively. Conclusions According to the simulations, the production of 2G bioethanol from sugar cane bagasse and leaves in Brazil is already competitive (without subsidies) with 1G starch-based bioethanol production in Europe. Moreover 2G bioethanol could be produced at a lower cost if subsidies were used to compensate for the opportunity cost from the

  11. [Implications of TCGA Network Data on 2nd Generation Immunotherapy Concepts Based on PD-L1 and PD-1 Target Structures].

    PubMed

    Peters, I; Tezval, H; Kramer, M W; Wolters, M; Grünwald, V; Kuczyk, M A; Serth, J

    2015-11-01

    The era of cytokines, given to patients with metastatic renal cell carcinoma (mRCC) as part of an unspecific immunomodulatory treatment concept, seems to have ended with the introduction of targeted therapies. However, preliminary data from studies on treatment with checkpoint inhibitors (e. g. anti-PD-1 and anti-PD-L1) may point the way to second-generation immunotherapy. The rationale of such immunomodulatory treatment is to stop or interrupt the tumour from "escaping" the body's immune defence. Thompson et al. report that increased protein expression of PD-L1 (CD274/ B7-H1) in tumour cells and tumour-infiltrating immune cells (TILs; lymphocytes and histiocytes) is associated with unfavourable clinical pathological parameters as well as poor survival. In small pilot groups of mRCC patients it was found that increased PD-L1 protein expression in tumours and TILs may be correlated with the objective response to anti-PD-1 treatment. Sometimes, however, a very wide variety of response rates was observed, which raises the question if this can be explained by individual expression levels of PD-L1 (CD 274) or PD-1 (PDCD1).Recently published data from the Cancer Genome Atlas (TCGA) Kidney Renal Clear Cell Carcinoma (KIRC) Network now provide a genome-wide data base that allows us to review or validate the molecular results obtained in clear cell renal cell carcinomas (ccRCC) to date.In this study, we analysed the TCGA KIRC mRNA expression data for PD-L1 and PD-1 for a possible association with clinical pathological parameters and the survival of 417 ccRCC patients.The mRNA expression of PD-L1 in primary nephrectomy specimens revealed no significant association with unfavourable clinical parameters. Interestingly, though, a positive correlation with patient survival was found (HR=0,59, p=0,006).These results, which partly contradict the concept applied to date, point out the necessity to ascertain the characteristics of PD-L1 and PD-1 expression at mRNA and protein

  12. Free tyrosine and tyrosine-rich peptide-dependent superoxide generation catalyzed by a copper-binding, threonine-rich neurotoxic peptide derived from prion protein.

    PubMed

    Yokawa, Ken; Kagenishi, Tomoko; Goto, Kaishi; Kawano, Tomonori

    2009-01-01

    Previously, generation of superoxide anion (O(2)(*-)) catalyzed by Cu-binding peptides derived from human prion protein (model sequence for helical Cu-binding motif VNITKQHTVTTTT was most active) in the presence of catecholamines and related aromatic monoamines such as phenylethylamine and tyramine, has been reported [Kawano, T., Int J Biol Sci 2007; 3: 57-63]. The peptide sequence (corresponding to helix 2) tested here is known as threonine-rich neurotoxic peptide. In the present article, the redox behaviors of aromatic monoamines, 20 amino acids and prion-derived tyrosine-rich peptide sequences were compared as putative targets of the oxidative reactions mediated with the threonine-rich prion-peptide. For detection of O(2)(*-), an O(2)(*-)-specific chemiluminescence probe, Cypridina luciferin analog was used. We found that an aromatic amino acid, tyrosine (structurally similar to tyramine) behaves as one of the best substrates for the O(2)(*-) generating reaction (conversion from hydrogen peroxide) catalyzed by Cu-bound prion helical peptide. Data suggested that phenolic moiety is required to be an active substrate while the presence of neither carboxyl group nor amino group was necessarily required. In addition to the action of free tyrosine, effect of two tyrosine-rich peptide sequences YYR and DYEDRYYRENMHR found in human prion corresponding to the tyrosine-rich region was tested as putative substrates for the threonine-rich neurotoxic peptide. YYR motif (found twice in the Y-rich region) showed 2- to 3-fold higher activity compared to free tyrosine. Comparison of Y-rich sequence consisted of 13 amino acids and its Y-to-F substitution mutant sequence revealed that the tyrosine-residues on Y-rich peptide derived from prion may contribute to the higher production of O(2)(*-). These data suggest that the tyrosine residues on prion molecules could be additional targets of the prion-mediated reactions through intra- or inter-molecular interactions. Lastly, possible

  13. 2nd Generation QUATARA Flight Computer Project

    NASA Technical Reports Server (NTRS)

    Falker, Jay; Keys, Andrew; Fraticelli, Jose Molina; Capo-Iugo, Pedro; Peeples, Steven

    2015-01-01

    Single core flight computer boards have been designed, developed, and tested (DD&T) to be flown in small satellites for the last few years. In this project, a prototype flight computer will be designed as a distributed multi-core system containing four microprocessors running code in parallel. This flight computer will be capable of performing multiple computationally intensive tasks such as processing digital and/or analog data, controlling actuator systems, managing cameras, operating robotic manipulators and transmitting/receiving from/to a ground station. In addition, this flight computer will be designed to be fault tolerant by creating both a robust physical hardware connection and by using a software voting scheme to determine the processor's performance. This voting scheme will leverage on the work done for the Space Launch System (SLS) flight software. The prototype flight computer will be constructed with Commercial Off-The-Shelf (COTS) components which are estimated to survive for two years in a low-Earth orbit.

  14. Mechanisms of resistance to third-generation EGFR tyrosine kinase inhibitors.

    PubMed

    Wang, Shuhang; Song, Yongping; Yan, Feifei; Liu, Delong

    2016-12-01

    The tyrosine kinase inhibitors (TKI) of the epidermal growth factor receptor (EGFR) are becoming the first line of therapy for advanced non-small cell lung cancer (NSCLC). Acquired mutations in EGFR account for one of the major mechanisms of resistance to the TKIs. Three generations of EGFR TKIs have been used in clinical applications. AZD9291 (osimertinib; Tagrisso) is the first and only FDA approved third-generation EGFR TKI for T790M-positive advanced NSCLC patients. However, resistance to AZD9291 arises after 9-13 months of therapy. The mechanisms of resistance to third-generation inhibitors reported to date include the EGFR C797S mutation, EGFR L718Q mutation, and amplifications of HER-2, MET, or ERBB2. To overcome the acquired resistance to AZD9291, EAI045 was discovered and recently reported to be an allosteric EGFR inhibitor that overcomes T790M- and C797S-mediated resistance. This review summarizes recent investigations on the mechanisms of resistance to the EGFR TKIs, as well as the latest development of EAI045 as a fourth-generation EGFR inhibitor.

  15. PIRLS 2016 Assessment Framework. 2nd Edition

    ERIC Educational Resources Information Center

    Mullis, Ina V. S., Ed.; Martin, Michael O., Ed.

    2015-01-01

    The "PIRLS 2016 Assessment Framework, 2nd Edition" provides the foundation for the three international assessments planned as part of the International Association for the Evaluation of Educational Achievement's Progress in International Reading Literacy Study (PIRLS) 2016: PIRLS, PIRLS Literacy, and ePIRLS. PIRLS represents the…

  16. Medical museum, 2nd surgical hospital.

    PubMed

    Hawk, Alan J

    2013-12-01

    When his unit, the 2nd Surgical Hospital (MA), was established at An Khe in January 1966, MAJ Rich began collecting retrieved foreign bodies along with documentation of the wound. A museum displaying these objects was established at one end of the operating room Quonset hut. During Rich's tour of duty, there were 324 cases where the patient was wounded by a punji stick, representing 38% wounds because of hostile action.

  17. Third generation tyrosine kinase inhibitors and their development in advanced renal cell carcinoma.

    PubMed

    Bukowski, Ronald M

    2012-01-01

    Angiogenesis in general and the vascular endothelial growth factor (VEGF) signaling axis in particular is a validated target in renal cell carcinoma (RCC). Clear-cell carcinoma of the kidney is now recognized as a malignancy that is sensitive to inhibitors of the VEGF pathway. Treatment options for patients with metastatic renal cell carcinoma have evolved in dramatic fashion over the past 6 years, and a new paradigm has developed. The cytokines interferon-α and interleukin-2 were previously utilized for therapy, but since December 2005, six new agents have been approved in the United States for the treatment of advanced RCC. Two are tyrosine kinase inhibitors (TKI's) including sunitinib and recently pazopanib, and the multikinase inhibitor sorafenib. The current review examines the evolving data with the next generation of TKI's, axitinib and tivozanib being developed for the treatment of advanced RCC. These agents were synthesized to provide increased target specificity and enhanced target inhibition. The preclinical and clinical data are examined, an overview of the development of these TKI's is provided, and discussion plus speculation concerning their potential roles as RCC therapy is provided.

  18. EGF receptor-ligand interaction generates extracellular hydrogen peroxide that inhibits EGFR-associated protein tyrosine phosphatases.

    PubMed

    DeYulia, Garrett J; Cárcamo, Juan M

    2005-08-19

    Hydrogen peroxide (H(2)O(2)) has been shown to be an important modulator of intracellular phosphatase activity involved in cell signaling pathways, including signaling by members of the receptor tyrosine kinase family of receptors such as the epidermal growth factor receptor (EGFR). Intracellular H(2)O(2) can be generated by mitochondria-dependent pathways, whereas we recently showed that H(2)O(2) could be generated extracellularly by receptor-ligand interaction. Here, we show that H(2)O(2) produced by EGF-EGFR interaction can modulate the activity of intracellular protein tyrosine phosphatases (PTPs). Using purified proteins, we found that EGFR-ligand interaction generates H(2)O(2) that is capable of inhibiting the activity of PTP1B in vitro. Furthermore, the addition of catalase rescued phosphatase inhibition consequent to EGF-EGFR interaction. Using cells that overexpress EGFR, we found that the addition of extracellular catalase prevented EGF-induced inhibition of EGFR-associated phosphatase activity. Our findings suggest that extracellular H(2)O(2) generated by EGFR-ligand interaction permeates the plasma membrane and inhibits EGFR-associated tyrosine phosphatase activity, thereby modulating downstream signal transduction pathways.

  19. 2nd International Planetary Probe Workshop

    NASA Technical Reports Server (NTRS)

    Venkatapathy, Ethiraj; Martinez, Ed; Arcadi, Marla

    2005-01-01

    Included are presentations from the 2nd International Planetary Probe Workshop. The purpose of the second workshop was to continue to unite the community of planetary scientists, spacecraft engineers and mission designers and planners; whose expertise, experience and interests are in the areas of entry probe trajectory and attitude determination, and the aerodynamics/aerothermodynamics of planetary entry vehicles. Mars lander missions and the first probe mission to Titan made 2004 an exciting year for planetary exploration. The Workshop addressed entry probe science, engineering challenges, mission design and instruments, along with the challenges of reconstruction of the entry, descent and landing or the aerocapture phases. Topics addressed included methods, technologies, and algorithms currently employed; techniques and results from the rich history of entry probe science such as PAET, Venera/Vega, Pioneer Venus, Viking, Galileo, Mars Pathfinder and Mars MER; upcoming missions such as the imminent entry of Huygens and future Mars entry probes; and new and novel instrumentation and methodologies.

  20. Pathways for Intracellular Generation of Oxidants and Tyrosine Nitration by a Macrophage Cell Line†

    PubMed Central

    Palazzolo-Ballance, Amy M.; Suquet, Christine; Hurst, James K.

    2008-01-01

    -activation by using fluorescein-conjugated polyacrylamide beads, which efficiently trap MPO-generated HOCl in neutrophils to give stable chlorofluorescein products. However, chlorination of the dye was not detected under any conditions in RAW cells, virtually precluding MPO involvement in their intracellular reactions. This same probe was used to determine changes in intraphagosomal pH, which increased slowly from ∼6.5 to ∼8.2 over a 20 h post-phagocytosis period. The cumulative data suggest activation is followed by sequential induction of an endogenous peroxidase, iNOS, and COX-2, with NADPH oxidase-derived O2·- playing a minimal role in direct generation of intracellular oxidants. To account for reported observations of intracellular tyrosine nitration late in the life cycles of macrophages, we propose a novel mechanism wherein iNOS-generated NO2- is used by COX-2 to produce NO2· as a terminal microbicidal oxidant and nitrating agent. PMID:17530864

  1. Second-Generation Tyrosine Kinase Inhibitors (Tki) as Salvage Therapy for Resistant or Intolerant Patients to Prior TKIs.

    PubMed

    Breccia, Massimo; Alimena, Giuliana

    2014-01-02

    With the advent of target therapies, imatinib became the mainstay for treatment of chronic myeloid leukemia. However, despite the brilliant results obtained with this drug, more than 30% of patients discontinue therapy in long-term due to several reasons, including failure and/or intolerance. Second-generation tyrosine kinase inhibitors (TKIs) are more potent drugs and have expanded inhibition against a broad spectrum of mutations resistant to imatinib. Both nilotinib and dasatinib have demonstrated in vitro and in vivo clinical activity against different types of mutations and various forms of resistance. However, patients with T315I mutation do not obtain an advantage from these drugs and a third generation inhibitor ponatinib, a pan-BCR drug, was tested with significant results. In this review, we report the results of second-and third-generation TKIs tested as second or third line therapy in patients resistant and/or intolerant to previous inhibitors.

  2. Next-Generation EGFR Tyrosine Kinase Inhibitors for Treating EGFR-Mutant Lung Cancer beyond First Line

    PubMed Central

    Sullivan, Ivana; Planchard, David

    2017-01-01

    Tyrosine kinase inhibitors (TKIs) against the human epidermal growth factor receptor (EGFR) are now standard treatment in the clinic for patients with advanced EGFR mutant non-small-cell lung cancer (NSCLC). First-generation EGFR TKIs, binding competitively and reversibly to the ATP-binding site of the EGFR tyrosine kinase domain, have resulted in a significant improvement in outcome for NSCLC patients with activating EGFR mutations (L858R and Del19). However, after a median duration of response of ~12 months, all patients develop tumor resistance, and in over half of these patients this is due to the emergence of the EGFR T790M resistance mutation. The second-generation EGFR/HER TKIs were developed to treat resistant disease, targeting not only T790M but EGFR-activating mutations and wild-type EGFR. Although they exhibited promising anti-T790M activity in the laboratory, their clinical activity among T790M+ NSCLC was poor mainly because of dose-limiting toxicity due to simultaneous inhibition of wild-type EGFR. The third-generation EGFR TKIs selectively and irreversibly target EGFR T790M and activating EGFR mutations, showing promising efficacy in NSCLC resistant to the first- and second-generation EGFR TKIs. They also appear to have lower incidences of toxicity due to the limited inhibitory effect on wild-type EGFR. Currently, the first-generation gefitinib and erlotinib and second-generation afatinib have been approved for first-line treatment of metastatic NSCLC with activating EGFR mutations. Among the third-generation EGFR TKIs, osimertinib is today the only drug approved by the Food and Drug Administration and the European Medicines Agency to treat metastatic EGFR T790M NSCLC patients who have progressed on or after EGFR TKI therapy. In this review, we summarize the available post-progression therapies including third-generation EGFR inhibitors and combination treatment strategies for treating patients with NSCLC harboring EGFR mutations and address the

  3. Next-Generation EGFR Tyrosine Kinase Inhibitors for Treating EGFR-Mutant Lung Cancer beyond First Line.

    PubMed

    Sullivan, Ivana; Planchard, David

    2016-01-01

    Tyrosine kinase inhibitors (TKIs) against the human epidermal growth factor receptor (EGFR) are now standard treatment in the clinic for patients with advanced EGFR mutant non-small-cell lung cancer (NSCLC). First-generation EGFR TKIs, binding competitively and reversibly to the ATP-binding site of the EGFR tyrosine kinase domain, have resulted in a significant improvement in outcome for NSCLC patients with activating EGFR mutations (L858R and Del19). However, after a median duration of response of ~12 months, all patients develop tumor resistance, and in over half of these patients this is due to the emergence of the EGFR T790M resistance mutation. The second-generation EGFR/HER TKIs were developed to treat resistant disease, targeting not only T790M but EGFR-activating mutations and wild-type EGFR. Although they exhibited promising anti-T790M activity in the laboratory, their clinical activity among T790M+ NSCLC was poor mainly because of dose-limiting toxicity due to simultaneous inhibition of wild-type EGFR. The third-generation EGFR TKIs selectively and irreversibly target EGFR T790M and activating EGFR mutations, showing promising efficacy in NSCLC resistant to the first- and second-generation EGFR TKIs. They also appear to have lower incidences of toxicity due to the limited inhibitory effect on wild-type EGFR. Currently, the first-generation gefitinib and erlotinib and second-generation afatinib have been approved for first-line treatment of metastatic NSCLC with activating EGFR mutations. Among the third-generation EGFR TKIs, osimertinib is today the only drug approved by the Food and Drug Administration and the European Medicines Agency to treat metastatic EGFR T790M NSCLC patients who have progressed on or after EGFR TKI therapy. In this review, we summarize the available post-progression therapies including third-generation EGFR inhibitors and combination treatment strategies for treating patients with NSCLC harboring EGFR mutations and address the

  4. Elements of the Next Generation Science Standards' (NGSS) New Framework for K-12 Science Education aligned with STEM designed projects created by Kindergarten, 1st and 2nd grade students in a Reggio Emilio project approach setting

    NASA Astrophysics Data System (ADS)

    Facchini, Nicole

    This paper examines how elements of the Next Generation Science Standards' (NGSS) New Framework for K-12 Science Education standards (National Research Council 2011)---specifically the cross-cutting concept "cause and effect" are aligned with early childhood students' creation of projects of their choice. The study took place in a Reggio Emilio-inspired, K-12 school, in a multi-aged kindergarten, first and second grade classroom with 14 students. Students worked on their projects independently with the assistance of their peers and teachers. The students' projects and the alignment with the Next Generation Science Standards' New Framework were analyzed by using pre and post assessments, student interviews, and discourse analysis. Results indicate that elements of the New Framework for K-12 Science Education emerged through students' project presentation, particularly regarding the notion of "cause and effect". More specifically, results show that initially students perceived the relationship between "cause and effect" to be negative.

  5. Three generations of epidermal growth factor receptor tyrosine kinase inhibitors developed to revolutionize the therapy of lung cancer

    PubMed Central

    Zhang, Haijun

    2016-01-01

    Lung cancer, ~80%–85% of which is non-small-cell lung cancer (NSCLC), is the leading cause of cancer-related mortality worldwide. Sensitizing mutations in epidermal growth factor receptor (EGFR) gene (EGFRm+), such as exon 19 deletions and exon 21 L858R point mutations, are the most important drivers in NSCLC patients. In this respect, small-molecule EGFR tyrosine kinase inhibitors (TKIs) have been designed and developed, which launched the era of targeted, personalized and precise medicine for lung cancer. Patients with EGFRm+ could achieve good responses to the treatment with the first-generation EGFR TKIs, such as erlotinib and gefitinib. However, most patients develop acquired drug resistance mostly driven by the T790M mutation occurring within exon 20. Although the second-generation EGFR TKIs, such as afatinib, dacomitinib and neratinib, demonstrated promising activity against T790M in preclinical models, they have failed to overcome resistance in patients due to dose-limiting toxicity. Recently, the third-generation EGFR TKIs have shown to be effective against cell lines and murine models harboring T790M mutations while sparing wild-type EGFR, which represents a promising breakthrough approach in overcoming T790M-mediated resistance in NSCLC patients. This article provides a comprehensive review of the therapy revolution for NSCLC with three generations of EGFR TKIs. PMID:27920501

  6. 2ND FLOOR HALLWAY LOOKING EAST, NOTE PRESSED TIN CEILING ...

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

    2ND FLOOR HALLWAY LOOKING EAST, NOTE PRESSED TIN CEILING - New York State Soldiers & Sailors Home, Building No. 29, Department of Veterans Affairs Medical Center, 76 Veterans Avenue, Bath, Steuben County, NY

  7. Molecular motors and the 2nd law of thermodynamics

    NASA Astrophysics Data System (ADS)

    Wang, Zhisong

    2014-03-01

    Molecular motors from biology and nanotechnology often operate on chemical energy of fuel molecules in an isothermal environment, unlike macroscopic heat engines that draw energy from a heat flow between two temperatures. Nevertheless, isothermal molecular motors are still subject to the 2nd law of thermodynamics in a fundamental way: their directional motion must cost a finite amount of energy other than the environmental heat even though no work is done; otherwise the 2nd law would be violated. Hence the 2nd law requires a finite energy price for pure direction of molecular motors. But what is the lowest price of direction allowed by the 2nd law? And how does the 2nd law-decreed price of direction limit performance of molecular motors? In the talk, I shall present our theoretical study of the 2nd law-molecular motor link on basis of the accumulated biomotor phenomenology, and also introduce our experimental effort to develop biomimetic DNA bipedal nanomotors following the mechanistic guidelines out of the theoretical study. [Main contents of this talk are from references:] This work is partially supported by FRC grants R-144-000-259-112, R-144-000-290-112 and R-144-000-320-112.

  8. What's Up With Mercury's 2nd-Degree Shape?

    NASA Astrophysics Data System (ADS)

    Chen, E.; Phillips, R. J.; Zhong, S.

    2015-12-01

    The long-wavelength topography and geoid of a planet are basic observations fundamental to understanding the planet's thermal and dynamical history. Observations by the MESSENGER spacecraft have significantly reduced the uncertainty in the spherical harmonic 2nd-degree (l2) topography and gravity coefficients. Similar to those of the Moon, the long wavelength shape and geoid of Mercury are significantly out of hydrostatic equilibrium [Perry et al., 2015]. The diversion from equilibrium of the Moon has been attributed to orbital evolution and the "freezing-in" of a fossil bulge. With respect to Mercury, the disequilibrium of the l2 shape and geoid is unlikely to be due to its orbital history [Matsuyama and Nimmo, 2009]. Non-hydrostatic models can explain the gravity and shape of Mercury. Buoyancy from thermal anomalies isostatically supporting the surface falls short of reproducing the observed l2 admittance and topography. We explore three scenarios that can generate high admittances at degree-2: flexural/membrane loading on the surface, buoyant structures within the mantle, or topography on the core-mantle boundary. We discuss both isostatic and dynamic models of compensation, and include variations of viscosity structure and elastic properties. However, typical sources of these mechanisms (e.g. large volcanic provinces that collectively have symmetry about the equator or mantle convection with a strong l2 component) are not obviously present on Mercury.

  9. Safety profile of bilastine: 2nd generation H1-antihistamines.

    PubMed

    Scaglione, F

    2012-12-01

    Bilastine is a new H1 antagonist with no sedative side effects, no cardiotoxic effects, and no hepatic metabolism. In addition, bilastine has proved to be effective for the symptomatic treatment of allergic rhinoconjunctivitis and urticaria. Pharmacological studies have shown that bilastine is highly selective for the H1 receptor in both in vivo and in vitro studies, and with no apparent affinity for other receptors. The absorption of bilastine is fast, linear and dose-proportional; it appears to be safe and well tolerated at all doses levels in healthy population. Multiple administration of bilastine has confirmed the linearity of the kinetic parameters. The distribution in the brain is undetectable. The safety profile in terms of adverse effects is very similar to placebo in all Phase I, II and III clinical trials. Bilastine (20 mg), unlike cetirizine, does not increase alcohol effects on the CNS. Bilastine 20 mg does not increase the CNS depressant effect of lorazepam. Bilastine 20 mg is similar to placebo in the driving test. Therefore, it meets the current criteria for medication used in the treatment of allergic rhinitis and urticaria.

  10. 2nd Generation Airborne Precipitation Radar (APR-2)

    NASA Technical Reports Server (NTRS)

    Durden, S.; Tanelli, S.; Haddad, Z.; Im, E.

    2012-01-01

    Dual-frequency operation with Ku-band (13.4 GHz) and Ka-band (35.6 GHz). Geometry and frequencies chosen to simulate GPM radar. Measures reflectivity at co- and cross-polarizations, and Doppler. Range resolution is approx. 60 m. Horizontal resolution at surface is approx. 1 km. Reflectivity calibration is within 1.5 dB, based on 10 deg sigmaO at Ku-band and Mie scattering calculations in light rain at Ka-band. LDR measurements are OK to near -20 dB; LDR lower than this is likely contaminated by system cross-polarization isolation. Velocity is motion-corrected total Doppler, including particle fall speed. Aliasing can be seen in some places; can usually be dealiased with an algorithm. .

  11. 2nd Generation Reusable Launch Vehicle (2G RLV). Revised

    NASA Technical Reports Server (NTRS)

    Matlock, Steve; Sides, Steve; Kmiec, Tom; Arbogast, Tim; Mayers, Tom; Doehnert, Bill

    2001-01-01

    This is a revised final report and addresses all of the work performed on this program. Specifically, it covers vehicle architecture background, definition of six baseline engine cycles, reliability baseline (space shuttle main engine QRAS), and component level reliability/performance/cost for the six baseline cycles, and selection of 3 cycles for further study. This report further addresses technology improvement selection and component level reliability/performance/cost for the three cycles selected for further study, as well as risk reduction plans, and recommendation for future studies.

  12. Engine design considerations for 2nd generation supersonic transports

    NASA Technical Reports Server (NTRS)

    Howlett, R. A.

    1975-01-01

    The environmental and economic goals projected for advanced supersonic transports will require revolutionary improvements in propulsion systems. Variable cycle engine concepts that incorporate unique components and advanced technologies show promise in meeting these goals. Pratt & Whitney Aircraft is conducting conceptual design studies of variable cycle engine concepts under NASA sponsorship. This paper reviews some of the design considerations for these engine concepts. Emphasis is placed on jet noise abatement, reduction of emissions, performance improvements, installation considerations, hot-section characteristics and control system requirements. Two representative variable cycle engine concepts that incorporate these basic design considerations are described.

  13. The adenovirus type 2-simian virus 40 hybrid virus Ad2+ND4 requires deletion variants to grow in monkey cells.

    PubMed Central

    Lewis, A M; Westphal, H

    1983-01-01

    The Ad2+ND4 virus is an adenovirus type 2 (Ad2)-simian virus 40 (SV40) recombination. The Ad2 genome of this recombinant has a rearrangement within early region 3; Ad2 DNA sequences between map positions 81.3 and 85.5 have been deleted, and the SV40 DNA sequences between map positions 0.11 and 0.626 have been inserted into the deletion in an 81.3-0.626 orientation. Nonhybrid Ad2 is defective in monkey cells; however, the Ad2+ND4 virus can replicate in monkey cells due to the expression of the SV40-enhancing function encoded by the DNA insert. Stocks of the Ad2+ND4 hybrid were produced in primary monkey cells by using the progeny of a three-step plaque purification procedure and were considered to be homogeneous populations of Ad2+ND4 virions because they induced plaques in primary monkey cells by first-order kinetics. By studying the kinetics of plaque induction in continuous lines (BSC-1 and CV-1) of monkey cells, we have found that stocks (prepared with virions before and after plaque purification) of Ad2+ND4 are actually heterogeneous populations of Ad2+ND4 virions and Ad2+ND4 deletion variants that lack SV40 and frequently Ad2 DNA sequences at the left Ad2-SV40 junction. Due to the defectiveness of the Ad2+ND4 virus, the production of progeny in BSC-1 and CV-1 cells requires complementation between the Ad2+ND4 genome and the genome of an Ad2+ND4 deletion variant. Since the deletion variants that have been obtained from Ad2+ND4 stocks do not express the SV40-enhancing function in that they cannot produce progeny in monkey cells, we conclude that they are providing an Ad2 component that is essential for the production of Ad2+ND4 progeny. These data imply that the Ad2+ND4 virus is incapable of replicating in singly infected primary monkey cells without generating deletion variants that are missing various amounts of DNA around the left Ad2-SV40 junction in the hybrid genome. As the deletion variants that arise from the Ad2+ND4 virus are created by nonhomologous

  14. Overcoming the drug resistance problem with second-generation tyrosine kinase inhibitors: from enzymology to structural models.

    PubMed

    Crespan, E; Zucca, E; Maga, G

    2011-01-01

    Protein phosphorylation is one of the major pathways used by eukaryotic cells to propagate signals to the final effectors, regulating multiple aspects of the living cell, such as metabolism, growth, differentiation, adhesion, motility, genome stability and death. In this context, tyrosine kinases (TKs) play a central role in signal transduction and their overexpression or disregulated activity has been implicated in tumor onset and malignancy progression. To date, eight TKs inhibitors have been approved by FDA for the treatment of specific tumors. In spite of their efficacy, insurgence of resistance is a common feature after prolonged administration. The selective pressure by these drugs, in fact, induces clonal expansion of subsets of cancer cells harboring TKs mutations, leading to decreased inhibition potency. Alternatively, resistance to TK inhibitors can be acquired through the activation of others, often unrelated, TKs. For this reason, while stringent target selectivity of TKs inhibitors has been always considered a desirable feature in order to limit toxicity, molecules targeting different TKs have been recently shown to be promising anti-cancer agents as well. Understanding the molecular mechanisms that confer resistance to TK inhibitors, through a combination of enzymatic, structural and cellular studies, is essential in the development of second generation inhibitors active also towards drug resistant tumors.

  15. Mutational profiling of non-small-cell lung cancer patients resistant to first-generation EGFR tyrosine kinase inhibitors using next generation sequencing

    PubMed Central

    Jin, Ying; Shao, Yang; Shi, Xun; Lou, Guangyuan; Zhang, Yiping; Wu, Xue; Tong, Xiaoling; Yu, Xinmin

    2016-01-01

    Patients with advanced non-small-cell lung cancer (NSCLC) harboring sensitive epithelial growth factor receptor (EGFR) mutations invariably develop acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). Identification of actionable genetic alterations conferring drug-resistance can be helpful for guiding the subsequent treatment decision. One of the major resistant mechanisms is secondary EGFR-T790M mutation. Other mechanisms, such as HER2 and MET amplifications, and PIK3CA mutations, were also reported. However, the mechanisms in the remaining patients are still unknown. In this study, we performed mutational profiling in a cohort of 83 NSCLC patients with TKI-sensitizing EGFR mutations at diagnosis and acquired resistance to three different first-generation EGFR TKIs using targeted next generation sequencing (NGS) of 416 cancer-related genes. In total, we identified 322 genetic alterations with a median of 3 mutations per patient. 61% of patients still exhibit TKI-sensitizing EGFR mutations, and 36% of patients acquired EGFR-T790M. Besides other known resistance mechanisms, we identified TET2 mutations in 12% of patients. Interestingly, we also observed SOX2 amplification in EGFR-T790M negative patients, which are restricted to Icotinib treatment resistance, a drug widely used in Chinese NSCLC patients. Our study uncovered mutational profiles of NSCLC patients with first-generation EGFR TKIs resistance with potential therapeutic implications. PMID:27528220

  16. [Food intake regulation - 2nd part].

    PubMed

    Brunerová, Ludmila; Anděl, Michal

    2014-01-01

    The review article summarizes the principles of hedonic regulation of food intake which represents the food intake independent on the maintenance of homeostasis. The theory describing hedonic regulation, so called Incentive Salience Theory, comprises three major processes: liking (positive attribution to food stimulus), wanting (motivation to gain it) and learning (identification of these stimuli and distinguishing them from those connected with aversive reaction). Neuronal reward circuits are the anatomical and functional substrates of hedonic regulation. They react to gustatory and olfactory (or visual) stimuli associated with food intake. A food item is preferred in case its consumption is connected with a pleasant feeling thus promoting the behavioural reaction. The probability of this reaction after repetitive exposure to such a stimulus is increased (learned preference). On the contrary, learned aversion after repetitive exposure is connected with avoidance of a food item associated with a negative feeling. Main mediators of hedonic regulation are endocannabinoids, opioids and monoamines (dopamine, serotonin). Dopamine in dorsal striatum via D2 receptors generates food motivation as a key means of survival, however in ventral striatum (nucleus accumbens) is responsible for motivation to food bringing pleasure. Serotonin via its receptors 5-HT1A a T-HT2C decreases intake of palatable food. It plays a significant role in the pathogenesis of eating disorders, particularly mental anorexia. There, a food restriction represents a kind of automedication to constitutionally pathologically increased serotonin levels. Detailed understanding of processes regulating food intake is a key to new pharmacological interventions in eating disorders.

  17. 2nd Quarter Transportation Report FY 2014

    SciTech Connect

    Gregory, L.

    2014-07-01

    This report satisfies the U.S. Department of Energy (DOE), National Nuclear Security Administration Nevada Field Office (NNSA/NFO) commitment to prepare a quarterly summary report of radioactive waste shipments to the Nevada National Security Site (NNSS) Radioactive Waste Management Complex (RWMC) at Area 5. There were no shipments sent for offsite treatment and returned to the NNSS this quarter. This report summarizes the second quarter of fiscal year (FY) 2014 low-level radioactive waste (LLW) and mixed low-level radioactive waste (MLLW) shipments. This report also includes annual summaries for FY 2014 in Tables 4 and 5. Tabular summaries are provided which include the following: Sources of and carriers for LLW and MLLW shipments to and from the NNSS; Number and external volume of LLW and MLLW shipments; Highway routes used by carriers; and Incident/accident data applicable to LLW and MLLW shipments. In this report shipments are accounted for upon arrival at the NNSS, while disposal volumes are accounted for upon waste burial. The disposal volumes presented in this report do not include minor volumes of non-radioactive materials that were approved for disposal. Volume reports showing cubic feet (ft3) generated using the Low-Level Waste Information System may vary slightly due to differing rounding conventions.

  18. BOOK REVIEW: Experimental Stochatics (2nd edition)

    NASA Astrophysics Data System (ADS)

    Wiberg, P.

    2004-05-01

    Otto Moeschlin and his co-authors have written a book about simulation of stochastic systems. The book comes with a CD-ROM that contains the experiments discussed in the book, and the text from the book is repeated on the CD-ROM. According to the authors, the aim of the book is to give a quick introduction to stochastic simulation for `all persons interested in experimental stochastics'. To please this diverse audience, the authors offer a book that has four parts. Part 1, called `Artificial Randomness', is the longest of the four parts. It gives an overview of the generation, testing and basic usage of pseudo random numbers in simulation. Although algorithms for generating sequences of random numbers are fundamental to simulation, it is a slightly unusual choice to give it such weight in comparison to other algorithmic topics. The remaining three parts consist of simulation case studies. Part 2, `Stochastic Models', treats four problems---Buffon's needle, a queuing system, and two problems related to the kinetic theory of gases. Part 3 is called `Stochastic Processes' and discusses the simulation of discrete time Markov chains, birth--death processes, Brownian motion and diffusions. The last section of Part 3 is about simulation as a tool to understand the traffic flow in a system controlled by stoplights, an area of research for the authors. Part4 is called `Evaluation of Statistical Procedures'. This section contains examples where simulation is used to test the performance of statistical methods. It covers four examples: the Neymann--Pearson lemma, the Wald sequential test, Bayesian point estimation and Hartigan procedures. The CD-ROM contains an easy-to-install software package that runs under Microsoft Windows. The software contains the text and simulations from the book. What I found most enjoyable about this book is the number of topics covered in the case studies. The highly individual selection of applications, which may serve as a source of inspiration

  19. [Health and environment: the 2nd public health revolution.].

    PubMed

    Cicolella, André

    2010-01-01

    As of the mid-19th century, most infectious disease epidemics have been fought and slowed down by taking action on the environment (water, housing, waste) and education. This constitutes the 1st public health revolution paradigm. As we face the current epidemic of chronic diseases and the failure of the dominant biomedical model to stop them, a 2nd public health revolution is needed. The vision for this 2nd public health revolution requires a new paradigm built upon an eco-systemic definition of health and the recognition of the legitimacy for citizen participation based on the precautionary principle.

  20. Feedback inhibition of chorismate mutase/prephenate dehydrogenase (TyrA) of Escherichia coli: generation and characterization of tyrosine-insensitive mutants.

    PubMed

    Lütke-Eversloh, Tina; Stephanopoulos, Gregory

    2005-11-01

    In order to get insights into the feedback regulation by tyrosine of the Escherichia coli chorismate mutase/prephenate dehydrogenase (CM/PDH), which is encoded by the tyrA gene, feedback-inhibition-resistant (fbr) mutants were generated by error-prone PCR. The tyrA(fbr) mutants were selected by virtue of their resistance toward m-fluoro-D,L-tyrosine, and seven representatives were characterized on the biochemical as well as on the molecular level. The PDH activities of the purified His6-tagged TyrA proteins exhibited up to 35% of the enzyme activity of TyrA(WT), but tyrosine did not inhibit the mutant PDH activities. On the other hand, CM activities of the TyrA(fbr) mutants were similar to those of the TyrA(WT) protein. Analyses of the DNA sequences of the tyrA genes revealed that tyrA(fbr) contained amino acid substitutions either at Tyr263 or at residues 354 to 357, indicating that these two sites are involved in the feedback inhibition by tyrosine.

  1. Test Review: The Profile of Mood States 2nd Edition

    ERIC Educational Resources Information Center

    Lin, Shuqiong; Hsiao, Yu-Yu; Wang, Miao

    2014-01-01

    The "Profile of Mood States 2nd Edition" (POMS 2) was published in 2012 by Multi-Health Systems (MHS) to assess transient feelings and mood among individuals aged 13 years and above. Evolving from the original POMS (McNair, Lorr, & Droppleman, 1971, 1992), the POMS 2 was designed for youth (13-17 years old) and adults (18 years old…

  2. Book Review: Bioassays with Arthropods: 2nd Edition

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The technical book "Bioassays with Arthropods: 2nd Edition" (2007. Jacqueline L. Robertson, Robert M. Russell, Haiganoush K, Preisler and N. E. Nevin, Eds. CRC Press, Boca Raton, FL, 224 pp.) was reviewed for the scientific readership of the peer-reviewed publication Journal of Economic Entomology. ...

  3. SrF2:Nd3+ laser fluoride ceramics.

    PubMed

    Basiev, T T; Doroshenko, M E; Konyushkin, V A; Osiko, V V

    2010-12-01

    SrF(2):Nd(3+) fluoride ceramics of high optical quality was prepared and its spectroscopic and laser properties investigated. Oscillations of different optical centers depending on the excitation wavelength were obtained with a slope efficiency of up to 19%.

  4. A Handbook for Classroom Instruction That Works, 2nd Edition

    ERIC Educational Resources Information Center

    Association for Supervision and Curriculum Development, 2012

    2012-01-01

    Perfect for self-help and professional learning communities, this handbook makes it much easier to apply the teaching practices from the ASCD-McREL best-seller "Classroom Instruction That Works: Research-Based Strategies for Increasing Student Achievement, 2nd Edition." The authors take you through the refined Instructional Planning Guide, so you…

  5. Quality of life in chronic myeloid leukaemia patients after haematopoietic cell transplantation pretreated with second-generation tyrosine kinase inhibitors

    PubMed Central

    Gil, Lidia; Jakitowicz, Karolina; Prejzner, Witold; Komarnicki, Mieczysław; Hellmann, Andrzej

    2016-01-01

    Aim of the study The majority of patients with chronic myeloid leukaemia (CML) respond to tyrosine kinase inhibitors (TKI), while allogeneic haematopoietic cell transplantation (HCT) is indicated in selected clinical situations. HCT carries the risk of severe complications, while the toxicity profile of dasatinib and nilotinib may lead to adverse reactions affecting the quality of life (QoL). We present the results of observational analysis of CML patients who underwent HCT after exposure to second-generation TKI (TKI2), with respect to their quality of life assessed comparatively after transplantation. Material and methods Eligible subjects included 19 patients. The quality of life and global health assessment were performed with a questionnaire comparing the signs and symptoms present during the TKI2-therapy with those related to post-transplant complications, including psychosocial problems. Results and conclusions Most patients had no/few problems with exhausting activities, no/few difficulties during long-distance walks, and do not/rarely rest in the daytime. Seventeen (89.5%) patients reported at least one symptom related to TKI2-therapy and most of them disappeared after HCT. Thirteen (68.4%) patients noted no serious complication after HCT. Most patients claimed to have a very good QoL and general health compared to the period prior to HCT. We found statistically significant improvement in global health (p = 0.016) and QoL (p = 0.043) after HCT. From the survivors perspective, HCT influence positively general health and QoL comparing to TKI2-therapy period. Further studies on larger group of patients will more precisely define the QoL level and possible predictors of changes in QoL, to assess which group of patients needs psychological support.

  6. Second generation tyrosine kinase inhibitors prevent disease progression in high-risk (high CIP2A) chronic myeloid leukaemia patients.

    PubMed

    Lucas, C M; Harris, R J; Holcroft, A K; Scott, L J; Carmell, N; McDonald, E; Polydoros, F; Clark, R E

    2015-07-01

    High cancerous inhibitor of PP2A (CIP2A) protein levels at diagnosis of chronic myeloid leukaemia (CML) are predictive of disease progression in imatinib-treated patients. It is not known whether this is true in patients treated with second generation tyrosine kinase inhibitors (2G TKI) from diagnosis, and whether 2G TKIs modulate the CIP2A pathway. Here, we show that patients with high diagnostic CIP2A levels who receive a 2G TKI do not progress, unlike those treated with imatinib (P=<0.0001). 2G TKIs induce more potent suppression of CIP2A and c-Myc than imatinib. The transcription factor E2F1 is elevated in high CIP2A patients and following 1 month of in vivo treatment 2G TKIs suppress E2F1 and reduce CIP2A; these effects are not seen with imatinib. Silencing of CIP2A, c-Myc or E2F1 in K562 cells or CML CD34+ cells reactivates PP2A leading to BCR-ABL suppression. CIP2A increases proliferation and this is only reduced by 2G TKIs. Patients with high CIP2A levels should be offered 2G TKI treatment in preference to imatinib. 2G TKIs disrupt the CIP2A/c-Myc/E2F1 positive feedback loop, leading to lower disease progression risk. The data supports the view that CIP2A inhibits PP2Ac, stabilising E2F1, creating a CIP2A/c-Myc/E2F1 positive feedback loop, which imatinib cannot overcome.

  7. [Tyrosine kinase inhibitors].

    PubMed

    Robert, Jacques

    2011-11-01

    Membrane receptors with tyrosine kinase activity and cytoplasmic tyrosine kinases have emerged as important potential targets in oncology. Starting from basic structures such as anilino-quinazoline, numerous compounds have been synthesised, with the help of tyrosine kinase crystallography, which has allowed to optimise protein-ligand interactions. The catalytic domains of all kinases present similar three-dimensional structures, which explains that it may be difficult to identify molecules having a high specificity for a given tyrosine kinase. Some tyrosine kinase inhibitors are relatively specific for epidermal growth factor receptor (EGFR) such as géfitinib and erlotinib; other are mainly active against platelet-derived growth factor receptor (PDGFR) and the receptor KIT, such as imatinib or nilotinib, and other against vascular endothelial growth factor (VEGF) receptors involved in angiogenesis, such as sunitinib and sorafenib. The oral formulation of tyrosine kinase inhibitors is well accepted by the patients but may generate sometimes compliance problems requiring pharmacokinetic monitoring. This chemical family is in full expansion and several dozens of compounds have entered clinical trials.

  8. Monolithic Microwave Integrated Circuit (MMIC) Frequency Doublers - 2nd Pass Correction

    DTIC Science & Technology

    2013-09-01

    Monolithic Microwave Integrated Circuit (MMIC) Frequency Doublers—2nd Pass Correction by John E. Penn ARL-TN-0580 September 2013...September 2013 Monolithic Microwave Integrated Circuit (MMIC) Frequency Doublers—2nd Pass Correction John E. Penn Sensors and Electron...COVERED (From - To) 4. TITLE AND SUBTITLE Monolithic Microwave Integrated Circuit (MMIC) Frequency Doublers–2nd Pass Correction 5a. CONTRACT NUMBER

  9. Osimertinib, a third-generation tyrosine kinase inhibitor targeting non-small cell lung cancer with EGFR T790M mutations.

    PubMed

    McCoach, C E; Jimeno, A

    2016-10-01

    Oncogenic driver mutations in the epidermal growth factor receptor (EGFR) gene have provided a focus for effective targeted therapy. Unfortunately, all patients eventually develop resistance to frontline therapy with EGFR tyrosine kinase inhibitors (TKIs). The majority of patients develop a large subclonal population of tumor cells with a T790M mutation that renders these cells resistant to first-generation TKIs. Osimertinib is a third-generation EGFR TKI that was designed to overcome resistance from T790M mutations. This agent has demonstrated strong preclinical activity, and in the clinic it has demonstrated a high objective response rate and progression-free survival in patients with EGFR double mutations (L858R/T790M and exon 19 deletion/T790M). It is now approved by the FDA for patients who have a documented T790M mutation and who have progressed on a prior TKI. Osimertinib is also approved in the E.U. and Japan.

  10. Scoping analysis of the Advanced Test Reactor using SN2ND

    SciTech Connect

    Wolters, E.; Smith, M.

    2012-07-26

    A detailed set of calculations was carried out for the Advanced Test Reactor (ATR) using the SN2ND solver of the UNIC code which is part of the SHARP multi-physics code being developed under the Nuclear Energy Advanced Modeling and Simulation (NEAMS) program in DOE-NE. The primary motivation of this work is to assess whether high fidelity deterministic transport codes can tackle coupled dynamics simulations of the ATR. The successful use of such codes in a coupled dynamics simulation can impact what experiments are performed and what power levels are permitted during those experiments at the ATR. The advantages of the SN2ND solver over comparable neutronics tools are its superior parallel performance and demonstrated accuracy on large scale homogeneous and heterogeneous reactor geometries. However, it should be noted that virtually no effort from this project was spent constructing a proper cross section generation methodology for the ATR usable in the SN2ND solver. While attempts were made to use cross section data derived from SCALE, the minimal number of compositional cross section sets were generated to be consistent with the reference Monte Carlo input specification. The accuracy of any deterministic transport solver is impacted by such an approach and clearly it causes substantial errors in this work. The reasoning behind this decision is justified given the overall funding dedicated to the task (two months) and the real focus of the work: can modern deterministic tools actually treat complex facilities like the ATR with heterogeneous geometry modeling. SN2ND has been demonstrated to solve problems with upwards of one trillion degrees of freedom which translates to tens of millions of finite elements, hundreds of angles, and hundreds of energy groups, resulting in a very high-fidelity model of the system unachievable by most deterministic transport codes today. A space-angle convergence study was conducted to determine the meshing and angular cubature

  11. HER2-Mutated Breast Cancer Responds to Treatment With Single-Agent Neratinib, a Second-Generation HER2/EGFR Tyrosine Kinase Inhibitor.

    PubMed

    Ben-Baruch, Noa Efrat; Bose, Ron; Kavuri, Shyam M; Ma, Cynthia X; Ellis, Matthew J

    2015-09-01

    Activating mutations in the HER2 tyrosine kinase have been identified in human breast cancers that lack HER2 gene amplification. These patients are not candidates for HER2-targeted drugs under current standards of care, but preclinical data strongly suggest that these patients will benefit from anti-HER2 drugs. This case report describes a young woman with metastatic breast cancer whose tumor was found to carry a HER2 L755S mutation, which is in the kinase domain of HER2. Treatment with the second-generation HER2/EGFR tyrosine kinase inhibitor neratinib resulted in partial response and dramatic improvement in the patient's functional status. This partial response lasted 11 months, and when the patient's cancer progressed, she was treated with neratinib plus capecitabine and her cancer again responded. This second response parallels the benefit seen with continuing trastuzumab in HER2-amplified breast cancer after disease progression. This case represents the first report, to our knowledge, of successful single-agent treatment of HER2-mutated breast cancer. Two clinical trials of neratinib for HER2-mutated metastatic breast cancer are currently enrolling patients. Further, data from The Cancer Genome Atlas project have identified HER2 mutations in a wide range of solid tumors, including bladder, colorectal, and non-small cell lung cancers, suggesting that clinical trials of neratinib or neratinib-based combinations for HER2-mutated solid tumors is warranted.

  12. Transposon-mediated generation of BCR-ABL1-expressing transgenic cell lines for unbiased sensitivity testing of tyrosine kinase inhibitors

    PubMed Central

    Berkowitsch, Bettina; Koenig, Margit; Haas, Oskar A.; Hoermann, Gregor; Valent, Peter; Lion, Thomas

    2016-01-01

    Point mutations in the ABL1 kinase domain are an important mechanism of resistance to tyrosine kinase inhibitors (TKI) in BCR-ABL1-positive and, as recently shown, BCR-ABL1-like leukemias. The cell line Ba/F3 lentivirally transduced with mutant BCR-ABL1 constructs is widely used for in vitro sensitivity testing and response prediction to tyrosine kinase inhibitors. The transposon-based Sleeping Beauty system presented offers several advantages over lentiviral transduction including the absence of biosafety issues, faster generation of transgenic cell lines, and greater efficacy in introducing large gene constructs. Nevertheless, both methods can mediate multiple insertions in the genome. Here we show that multiple BCR-ABL1 insertions result in elevated IC50 levels for individual TKIs, thus overestimating the actual resistance of mutant subclones. We have therefore established flow-sorting-based fractionation of BCR-ABL1-transformed Ba/F3 cells facilitating efficient enrichment of cells carrying single-site insertions, as demonstrated by FISH-analysis. Fractions of unselected Ba/F3 cells not only showed a greater number of BCR-ABL1 hybridization signals, but also revealed higher IC50 values for the TKIs tested. The data presented highlight the need to carefully select transfected cells by flow-sorting, and to control the insertion numbers by FISH and real-time PCR to permit unbiased in vitro testing of drug resistance. PMID:27801667

  13. Involvement of protein kinase C, phospholipase C, and protein tyrosine kinase pathways in oxygen radical generation by asbestos-stimulated alveolar macrophage.

    PubMed

    Lim, Y; Kim, S H; Kim, K A; Oh, M W; Lee, K H

    1997-09-01

    Although asbestos stimulates oxygen radical generation in alveolar macrophages, the exact mechanism is still not clear. The purpose of this study was to compare the ability of three asbestos fibers (amosite, chrysotile, and crocidolite) to generate oxygen radicals in macrophages and examine the mechanism of this action. All asbestos fibers were able to induce chemiluminescence but chrysotile induced maximal chemiluminescence at higher concentrations than amosite and crocidolite. Protein kinase C (PKC) inhibitors (sphingosine and staurosporine) suppressed the ability of asbestos to induce oxygen radical generation. Phospholipase C (PLC) inhibitors (U73122 and neomycin) and protein tyrosine kinase (PTK) inhibitors (erbstatin and genistein) decreased oxygen radical generation of asbestos-stimulated alveolar macrophages. Oxygen radical generation was not suppressed by an adenylate cyclase activator (forskolin), a protein kinase A inhibitor (H-8), and a protein serine-threonine phosphatase inhibitor (okadaic acid). PLC and PTK inhibitors suppressed the increment of phosphoinositide turnover by amosite. These results suggest that asbestos fibers induce the generation of oxygen radicals through PTK, PLC, and PKC pathways in a dose-response pattern.

  14. Serum concentrations of nitrite and malondialdehyde as markers of oxidative stress in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors

    PubMed Central

    Petrola, Maria Juracy; de Castro, Alana Joselina Montenegro; Pitombeira, Maria Helena da Silva; Barbosa, Maritza Cavalcante; Quixadá, Acy Telles de Souza; Duarte, Fernando Barroso; Gonçalves, Romelia Pinheiro

    2012-01-01

    Background: Chronic myeloid leukemia is a neoplasm characterized by clonal expansion of hematopoietic progenitor cells resulting from the (9:22)(q34,11) translocation. The tyrosine kinase abl fusion protein,the initial leukemogenic event in chronic myeloid leukemia, is constitutively activated thus inducing the production of reactive oxygen species. Of particular relevance is the fact that an increase in reactive oxygen species can facilitate genomic instability and may contribute to disease progression. Objetive: To evaluate oxidative stress by determining the levels of malondialdehyde and nitrite in chronic myeloid leukemia patients under treatment with 1st and 2nd generation tyrosine kinase inhibitors monitored at a referral hospital in Fortaleza, Ceará. Methods: A cross-sectional study was performed of 64 male and female adults. Patients were stratified according to treatment. The levels of malondialdehyde and nitrite were determined by spectrophotometry. Statistical differences between groups were observed using the Student t-test and Fisher's exact test. The results are expressed as mean ± standard error of mean. The significance level was set for a p-value < 0.05 in all analyses. Results: The results show significantly higher mean concentrations of nitrite and malondialdehyde in chronic myeloid leukemia patients using second-generation tyrosine kinase inhibitors compared to patients on imatinib. Conclusion: It follows that chronic myeloid leukemia patients present higher oxidative activity and that the increases in oxidative damage markers can indicate resistance to 1st generation tyrosine kinase inhibitors. PMID:23125543

  15. Role of Tyrosine Isomers in Acute and Chronic Diseases Leading to Oxidative Stress - A Review

    PubMed Central

    Molnár, Gergő A.; Kun, Szilárd; Sélley, Eszter; Kertész, Melinda; Szélig, Lívia; Csontos, Csaba; Böddi, Katalin; Bogár, Lajos; Miseta, Attila; Wittmann, István

    2016-01-01

    Oxidative stress plays a major role in the pathogenesis of a variety of acute and chronic diseases. Measurement of the oxidative stress-related end products may be performed, e.g. that of structural isomers of the physiological para-tyrosine, namely meta- and ortho-tyrosine, that are oxidized derivatives of phenylalanine. Recent data suggest that in sepsis, serum level of meta-tyrosine increases, which peaks on the 2nd and 3rd days (p<0.05 vs. controls), and the kinetics follows the intensity of the systemic inflammation correlating with serum procalcitonin levels. In a similar study subset, urinary meta-tyrosine excretion correlated with both need of daily insulin dose and the insulin-glucose product in non-diabetic septic cases (p<0.01 for both). Using linear regression model, meta-tyrosine excretion, urinary meta-tyrosine/para-tyrosine, urinary ortho-tyrosine/para-tyrosine and urinary (meta- + ortho-tyrosine)/para-tyrosine proved to be markers of carbohydrate homeostasis. In a chronic rodent model, we tried to compensate the abnormal tyrosine isomers using para-tyrosine, the physiological amino acid. Rats were fed a standard high cholesterol-diet, and were given para-tyrosine or vehicle orally. High-cholesterol feeding lead to a significant increase in aortic wall meta-tyrosine content and a decreased vasorelaxation of the aorta to insulin and the glucagon-like peptide-1 analogue, liraglutide, that both could be prevented by administration of para-tyrosine. Concluding, these data suggest that meta- and ortho-tyrosine are potential markers of oxidative stress in acute diseases related to oxidative stress, and may also interfere with insulin action in septic humans. Competition of meta- and ortho-tyrosine by supplementation of para-tyrosine may exert a protective role in oxidative stress-related diseases. PMID:26785996

  16. Improvement of a plasma uniformity of the 2nd ion source of KSTAR neutral beam injector

    SciTech Connect

    Jeong, S. H. Kim, T. S.; Lee, K. W.; Chang, D. H.; In, S. R.; Bae, Y. S.

    2014-02-15

    The 2nd ion source of KSTAR (Korea Superconducting Tokamak Advanced Research) NBI (Neutral Beam Injector) had been developed and operated since last year. A calorimetric analysis revealed that the heat load of the back plate of the ion source is relatively higher than that of the 1st ion source of KSTAR NBI. The spatial plasma uniformity of the ion source is not good. Therefore, we intended to identify factors affecting the uniformity of a plasma density and improve it. We estimated the effects of a direction of filament current and a magnetic field configuration of the plasma generator on the plasma uniformity. We also verified that the operation conditions of an ion source could change a uniformity of the plasma density of an ion source.

  17. Synaptic generation of an intracellular retrograde signal requires activation of the tyrosine kinase and mitogen-activated protein kinase signaling cascades in Aplysia.

    PubMed

    Stough, Shara; Kopec, Ashley M; Carew, Thomas J

    2015-11-01

    Cellular changes underlying memory formation can be generated in an activity-dependent manner at specific synapses. Thus an important question concerns the mechanisms by which synaptic signals communicate with the cell body to mediate these cellular changes. A monosynaptic circuit that is enhanced by sensitization in Aplysia is well-suited to study this question because three different subcellular compartments: (i) the sensorimotor SN-MN synapses, (ii) the SN projections to MNs via axonal connections, (iii) the SN cell bodies, can all be manipulated and studied independently. Here, we report that activity-dependent (AD) training in either the entire SN-MN circuit or in only the synaptic compartment, activates MAPK in a temporally and spatially specific pattern. Specifically, we find (i) MAPK activation is first transiently generated at SN-MN synapses during training, (ii) immediately after training MAPK is transiently activated in SN-MN axonal connections and persistently activated in SN cell bodies, and finally, (iii) MAPK is activated in SN cell bodies and SN-MN synapses 1h after training. These data suggest that there is an intracellularly transported retrograde signal generated at the synapse which is later responsible for delayed MAPK activation at SN somata. Finally, we find that this retrograde signal requires activation of tyrosine kinase (TK) and MEK signaling cascades at the synapses.

  18. PREFACE: 2nd International Symposium "Optics and its Applications"

    NASA Astrophysics Data System (ADS)

    Calvo, Maria L.; Dolganova, Irina N.; Gevorgyan, Narine; Guzman, Angela; Papoyan, Aram; Sarkisyan, Hayk; Yurchenko, Stanislav

    2016-01-01

    The ICTP smr2633: 2nd International Symposium "Optics and its Applications" (OPTICS-2014) http://indico.ictp.it/event/a13253/ was held in Yerevan and Ashtarak, Armenia, on 1-5 September 2014. The Symposium was organized by the Abdus Salam International Center for Theoretical Physics (ICTP) with the collaboration of the SPIE Armenian Student Chapter, the Armenian TC of ICO, the Russian-Armenian University (RAU), the Institute for Physical Research of the National Academy of Sciences of Armenia (IPR of NAS), the Greek-Armenian industrial company LT-Pyrkal, and the Yerevan State University (YSU). The Symposium was co-organized by the BMSTU SPIE & OSA student chapters. The International Symposium OPTICS-2014 was dedicated to the 50th anniversary of the Abdus Salam International Center for Theoretical Physics. This symposium "Optics and its Applications" was the First Official ICTP Scientific Event in Armenia. The presentations at OPTICS-2014 were centered on these topics: optical properties of nanostructures; quantum optics & information; singular optics and its applications; laser spectroscopy; strong field optics; nonlinear & ultrafast optics; photonics & fiber optics; optics of liquid crystals; and mathematical methods in optics.

  19. [Microsurgical 2nd toe transfer for catastrophic hand reconstruction].

    PubMed

    Placer, A; Lozano, Ja

    2007-01-01

    The correct reconstruction of the catastrophic hand requires complex surgical techniques. The microsurgical transference of a toe is indicated when all other reconstructive options are shown to be useless for the reconstruction of the required clamp function. In this clinical note we set out the case of a 32 year old man, who came to our accident and emergency department after suffering a traffic accident. After exploration the diagnosis was that of catastrophic left hand, among other policontusions. Urgent surgery was carried out, saving the maximum possible viable structures. The immediate result of this surgery was a hand with 1st, 4th and 5th functional fingers. As the essential clamp function between the 1st and 4th or 5th fingers was not totally satisfactory, we decided to reconstruct the 3rd finger of his hand with his ipsilateral 2nd toe. All pertinent studies to determine vascularisation of the flap were carried out in planning the surgery, and the microsurgical transfer was then realized, which was successful. Today, after a suitable rehabilitation, the patient has recovered a satisfactory function of heavy and fine clamp in the operated hand. Toe to hand transfer is a good option for finger reconstruction and its function. Rehabilitation is the key to functional recovery.

  20. Next-generation epidermal growth factor receptor tyrosine kinase inhibitors in epidermal growth factor receptor -mutant non-small cell lung cancer.

    PubMed

    Tan, Chee-Seng; Cho, Byoung-Chul; Soo, Ross A

    2016-03-01

    Since the discovery of sensitizing EGFR mutations as a predictive marker of sensitivity to EGFR tyrosine kinase inhibitors (TKIs), the field of targeted therapy in non-small cell lung cancer (NSCLC) has been revolutionized. Patients harbouring these sensitizing mutations treated with EGFR TKI have derived significant clinical outcome when compared with standard platinum based chemotherapy doublets. However disease progression invariably occurs at a median of about 9-13 months from initiation treatment, if acquired resistance commonly due to the development of EGFR T790M mutation. A novel class of "third generation" EGFR TKIs have been developed that is sensitising and T790M mutant-specific whilst sparing WT EGFR, representing a significant breakthrough in the treatment in NSCLC patients with acquired resistance harboring these genotypes. Early phase clinical data suggest the third generation EGFR TKIs such as osimertinib, rociletinib, and HM61713 are highly efficacious and well tolerated. Another promising class of EGFR TKI such as AZD3759 has been designed to penetrate blood brain barrier to treat brain metastases and leptomeningeal disease and has showed promising responses in patients with brain metastases. Acquired resistance to third generation EGFR TKIs has been reported including EGFR C797S. Given its non-invasive nature, plasma ctDNA is being explored as a possible approach to detect T790M mutation and to also inform on novel molecular mechansims of tertiary resistance to third generation EGFR TKIs. An understanding of the mechanisms of acquired resistance to the third-generation EGFR TKIs will greatly aid in the development of the next generation of EGFR TKIs.

  1. The anti-apoptotic form of tyrosine kinase Lyn that is generated by proteolysis is degraded by the N-end rule pathway

    PubMed Central

    Eldeeb, Mohamed A.

    2014-01-01

    The activation of apoptotic pathways results in the caspase cleavage of the Lyn tyrosine kinase to generate the N-terminal truncated LynΔN. This LynΔN fragment has been demonstrated to exert negative feedback on imatinib induced apoptosis in chronic myelogenous leukemia (CML) K562 cells. Our investigations focus on LynΔN stability and how reduced stability reduces imatinib resistance. As the proteolytical generated LynΔN has a leucine as an N-terminal amino acid, we hypothesized that LynΔN would be degraded by the N-end rule pathway. We demonstrated that LynΔN is unstable and that its stability is dependent on the identity of its N-terminus. Additionally we established that LynΔN degradation could be inhibited by either inhibiting the proteasome or knocking down the UBR1 and UBR2 ubiquitin E3 ligases. Importantly, we also demonstrate that LynΔN degradation by the N-end rule counters the imatinib resistance of K562 cells provided by LynΔN expression. Together our data suggest a possible mechanism for the N-end rule pathway having a link to imatinib resistance in CML. With LynΔN being an N-end rule substrate, it provides the first example that this pathway can also provide a pro-apoptotic function as previous reports have currently only demonstrated anti-apoptotic roles for the N-end rule pathway. PMID:24798867

  2. PREFACE: 2nd National Conference on Nanotechnology 'NANO 2008'

    NASA Astrophysics Data System (ADS)

    Czuba, P.; Kolodziej, J. J.; Konior, J.; Szymonski, M.

    2009-03-01

    This issue of Journal of Physics: Conference Series contains selected papers presented at the 2nd National Conference on Nanotechnology 'NANO2008', that was held in Kraków, Poland, 25-28 June 2008. It was organized jointly by the Polish Chemical Society, Polish Physical Society, Polish Vacuum Society, and the Centre for Nanometer-scale Science and Advanced Materials (NANOSAM) of the Jagiellonian University. The meeting presentations were categorized into the following topics: 1. Nanomechanics and nanotribology 2. Characterization and manipulation in nanoscale 3. Quantum effects in nanostructures 4. Nanostructures on surfaces 5. Applications of nanotechnology in biology and medicine 6. Nanotechnology in education 7. Industrial applications of nanotechnology, presentations of the companies 8. Nanoengineering and nanomaterials (international sessions shared with the fellows of Maria-Curie Host Fellowships within the 6th FP of the European Community Project 'Nano-Engineering for Expertise and Development, NEED') 9. Nanopowders 10. Carbon nanostructures and nanosystems 11. Nanoelectronics and nanophotonics 12. Nanomaterials in catalysis 13. Nanospintronics 14. Ethical, social, and environmental aspects of nanotechnology The Conference was attended by 334 participants. The presentations were delivered as 7 invited plenary lectures, 25 invited topical lectures, 78 oral and 108 poster contributions. Only 1/6 of the contributions presented during the Conference were submitted for publication in this Proceedings volume. From the submitted material, this volume of Journal of Physics: Conference Series contains 37 articles that were positively evaluated by independent referees. The Organizing Committee gratefully acknowledges all these contributions. We also thank all the referees of the papers submitted for the Proceedings for their timely and thorough work. We would like to thank all members of the National Program Committee for their work in the selection process of

  3. Development of a Hydrologic Characterization Technology for Fault Zones Phase II 2nd Report

    SciTech Connect

    Karasaki, Kenzi; Doughty, Christine; Gasperikova, Erika; Peterson, John; Conrad, Mark; Cook, Paul; Tiemi, Onishi

    2011-03-31

    This is the 2nd report on the three-year program of the 2nd phase of the NUMO-LBNL collaborative project: Development of Hydrologic Characterization Technology for Fault Zones under NUMO-DOE/LBNL collaboration agreement. As such, this report is a compendium of the results by Kiho et al. (2011) and those by LBNL.

  4. Highlights of the 2 nd Bioinformatics Student Symposium by ISCB RSG-UK

    PubMed Central

    White, Benjamen; Fatima, Vayani; Fatima, Nazeefa; Das, Sayoni; Rahman, Farzana; Hassan, Mehedi

    2016-01-01

    Following the success of the 1 st Student Symposium by ISCB RSG-UK, a 2 nd Student Symposium took place on 7 th October 2015 at The Genome Analysis Centre, Norwich, UK. This short report summarizes the main highlights from the 2 nd Bioinformatics Student Symposium. PMID:27239284

  5. 2nd interface between ecology and land development in California

    USGS Publications Warehouse

    Keeley, Jon E.; Baer-Keeley, Melanie; Fortheringham, C.J.

    2000-01-01

    The 2nd Interface Between Ecology and Land Development Conference was held in association with Earth Day 1997, five years after the first Interface Conference. Rapid population growth in California has intensified the inevitable conflict between land development and preservation of natural ecosystems. Sustainable development requires wise use of diminishing natural resources and, where possible, restoration of damaged landscapes. These Earth Week Celebrations brought together resource managers, scientists, politicians, environmental consultants, and concerned citizens in an effort to improve the communication necessary to maintain our natural biodiversity, ecosystem processes and general quality of life. As discussed by our keynote speaker, Michael Soule, the best predictor of habitat loss is population growth and nowhere is this better illustrated than in California. As urban perimeters expand, the interface between wildlands and urban areas increases. Few problems are more vexing than how to manage the fire prone ecosystems indigenous to California at this urban interface. Today resource managers face increasing challenges of dealing with this problem and the lead-off section of the proceedings considers both the theoretical basis for making decisions related to prescribed burning and the practical application. Habitat fragmentation is an inevitable consequence of development patterns with significant impacts on animal and plant populations. Managers must be increasingly resourceful in dealing with problems of fragmentation and the often inevitable consequences, including susceptibility to invasive oganisms. One approach to dealing with fragmentation problems is through careful landplanning. California is the national leader in the integration of conservation and economics. On Earth Day 1991, Governor Pete Wilson presented an environmental agenda that promised to create between land owners and environmentalists, agreements that would guarantee the protection of

  6. How to treat CML patients in the tyrosine kinase inhibitors era? From imatinib standard dose to second generation drugs front-line: unmet needs, pitfalls and advantages.

    PubMed

    Breccia, Massimo; Alimena, Giuliana

    2012-09-28

    Imatinib has revolutionized treatment strategies for chronic myeloid leukemia patients: long-term overall survival was reported to be up to 80% at 8 years of follow-up in respondent patients. Despite the straightforward results obtained, it has been estimated a failure rate per year of 2-4%. Several attempts to improve response have been made with high-dose of imatinib and with combination of standard dose with interferon, but both failed to ameliorate cytogenetic and molecular responses and long-term event-free and overall survival and no advantages were reported in high-risk patients. The introduction of second generation tyrosine kinase inhibitors in clinical practice allowed to rescue more than 50% of patients resistant or intolerant to imatinib. Both dasatinib and nilotinib were tested as single agent in first-line and then tested against imatinib standard dose: the results of phases II and III trials showed early and maintained complete cytogenetic response, rapid reduction of molecular burden and significant reduction of progression rate. At the present time, after FDA approval of both agents in first-line, several points of discussion are still unresolved.

  7. Generation and characterization of polyclonal antibodies against mouse T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory domain by DNA-based immunization.

    PubMed

    Gao, Y; Cui, J; He, W; Yue, J; Yu, D; Cai, L; Xu, H; Yang, C; Chen, Z K; Zhou, H

    2014-01-01

    Mouse T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory domain (TIGIT) is a newly identified surface protein expressed in regulatory, memory, natural killer (NK), and activated T cells. Several studies indicate that mouse TIGIT is a vital immunomodulator that can control the activities of both NK and T cells and plays an important role in transplantation tolerance. In this study, we designed a vector, TIGIT-pcDNA3.1 (+), that encodes the complete coding sequence of mouse TIGIT. The vector was intramuscularly injected into rats, and then the specific antisera were harvested and purified using a protein A/G PLUS-agarose affinity column. Western blot and immunohistochemistry analyses revealed that the antibodies generated by DNA immunization can bind with the mouse TIGIT. Using these antibodies in immunoblots, TIGIT was detected in lysates of mouse organs, T cells from mouse lymph nodes, and recombinant mouse fusion protein of TIGIT and Fc fragment. Immunohistochemistry analysis of normal mouse kidney showed that immunoreactivity was located on endothelial cells of glomerular capillary loops and peritubular capillaries. Our results demonstrated that the DNA immunization of rats through intramuscular injection was a simple and easily available method of producing polyclonal antibodies that can be used to detect and analyze mouse TIGIT expression in mouse systems.

  8. 1st- and 2nd-order motion and texture resolution in central and peripheral vision

    NASA Technical Reports Server (NTRS)

    Solomon, J. A.; Sperling, G.

    1995-01-01

    STIMULI. The 1st-order stimuli are moving sine gratings. The 2nd-order stimuli are fields of static visual texture, whose contrasts are modulated by moving sine gratings. Neither the spatial slant (orientation) nor the direction of motion of these 2nd-order (microbalanced) stimuli can be detected by a Fourier analysis; they are invisible to Reichardt and motion-energy detectors. METHOD. For these dynamic stimuli, when presented both centrally and in an annular window extending from 8 to 10 deg in eccentricity, we measured the highest spatial frequency for which discrimination between +/- 45 deg texture slants and discrimination between opposite directions of motion were each possible. RESULTS. For sufficiently low spatial frequencies, slant and direction can be discriminated in both central and peripheral vision, for both 1st- and for 2nd-order stimuli. For both 1st- and 2nd-order stimuli, at both retinal locations, slant discrimination is possible at higher spatial frequencies than direction discrimination. For both 1st- and 2nd-order stimuli, motion resolution decreases 2-3 times more rapidly with eccentricity than does texture resolution. CONCLUSIONS. (1) 1st- and 2nd-order motion scale similarly with eccentricity. (2) 1st- and 2nd-order texture scale similarly with eccentricity. (3) The central/peripheral resolution fall-off is 2-3 times greater for motion than for texture.

  9. Fms-like tyrosine kinase 3 ligand is required for thymic dendritic cell generation from bone marrow-derived CD117⁺ hematopoietic progenitor cells.

    PubMed

    Xu, Yunyun; Jiang, Dong; Hu, Yizhou; Li, Yiping; Zhang, Xueguang; Wang, Jian; Wang, Yong

    2015-11-01

    Thymic dendritic cells (TDCs) are a type of dendritic cell (DC) in the thymus, which can enhance the proliferation of thymic T lymphocytes, regulate negative selection and induce central tolerance through autoantigen presentation. However, further investigations using TDCs has been restricted due to insufficient numbers. Therefore, an effective expansion method for TDCs in vitro is urgently required to further examine their biological characteristics. In the present study, a novel system was established using fetal thymus organ culture (FTOC) and a hanging drop culture system in the presence of fms‑like tyrosine kinase 3 ligand (Flt3L), termed the Flt3L/FTOC system. TDCs were successfully generated and expanded from CD117+ bone marrow hematopoietic progenitor cells. Conventional DCs (cDCs; CD11c+B220‑ DCs) and plasmacytoid DCs (pDCs; CD11c+B220+ DCs) were found in the TDCs generated using the Flt3L/FTOC system. These cells exhibited the specific morphological features of DCs, which were confirmed using Giemsa staining. Furthermore, the cytokine and surface marker profiles were also analyzed. Higher expression levels of interferon‑α and interleukin‑12 were observed in the pDCs, compared with the cDCs, and higher expression levels of toll‑like receptor (TLR)7 and TLR9 were found in the pDCs than in the cDCs. In addition, the Flt3L/FTOC‑derived TDCs also exhibited the ability to stimulate the allogenic T cell response. In conclusion, a novel in vitro culture system of thymic cDCs and pDCs using Flt3L was established, and this may provide a methodological basis for understanding the properties of TDCs.

  10. PREFACE: 2nd Workshop on Germanium Detectors and Technologies

    NASA Astrophysics Data System (ADS)

    Abt, I.; Majorovits, B.; Keller, C.; Mei, D.; Wang, G.; Wei, W.

    2015-05-01

    The 2nd workshop on Germanium (Ge) detectors and technology was held at the University of South Dakota on September 14-17th 2014, with more than 113 participants from 8 countries, 22 institutions, 15 national laboratories, and 8 companies. The participants represented the following big projects: (1) GERDA and Majorana for the search of neutrinoless double-beta decay (0νββ) (2) SuperCDMS, EDELWEISS, CDEX, and CoGeNT for search of dark matter; (3) TEXONO for sub-keV neutrino physics; (4) AGATA and GRETINA for gamma tracking; (5) AARM and others for low background radiation counting; (5) as well as PNNL and LBNL for applications of Ge detectors in homeland security. All participants have expressed a strong desire on having better understanding of Ge detector performance and advancing Ge technology for large-scale applications. The purpose of this workshop was to leverage the unique aspects of the underground laboratories in the world and the germanium (Ge) crystal growing infrastructure at the University of South Dakota (USD) by brining researchers from several institutions taking part in the Experimental Program to Stimulate Competitive Research (EPSCoR) together with key leaders from international laboratories and prestigious universities, working on the forefront of the intensity to advance underground physics focusing on the searches for dark matter, neutrinoless double-beta decay (0νββ), and neutrino properties. The goal of the workshop was to develop opportunities for EPSCoR institutions to play key roles in the planned world-class research experiments. The workshop was to integrate individual talents and existing research capabilities, from multiple disciplines and multiple institutions, to develop research collaborations, which includes EPSCor institutions from South Dakota, North Dakota, Alabama, Iowa, and South Carolina to support multi-ton scale experiments for future. The topic areas covered in the workshop were: 1) science related to Ge

  11. 4. VIEW WEST, WEST SIDE, SHOWING CHANNELS 1ST AND 2ND ...

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

    4. VIEW WEST, WEST SIDE, SHOWING CHANNELS 1ST AND 2ND VERTICAL BRACED DOUBLE ANGLES, DIAGONAL BRACING AND CROSS BRACED RAILING - Thirty-Sixth Street Bridge, Spanning Rabbit River, Hamilton, Allegan County, MI

  12. 37. MILL NO. 2, 2nd FLOOR, CLOSE SHOT OF 2 ...

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

    37. MILL NO. 2, 2nd FLOOR, CLOSE SHOT OF 2 CREEL MACHINES, WHICH FEED YARN INTO KNITTING MACHINES. - Prattville Manufacturing Company, Number One, 242 South Court Street, Prattville, Autauga County, AL

  13. 42. OVERALL OF 2nd FLOOR PICKER ROOM OFF MILL NO. ...

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

    42. OVERALL OF 2nd FLOOR PICKER ROOM OFF MILL NO. 2. NOTE TRUSSWORK. SPACE TO RIGHT OF COLUMNS IS PART OF 1915 CLOTH ROOM ADDITION. - Prattville Manufacturing Company, Number One, 242 South Court Street, Prattville, Autauga County, AL

  14. 22. MILL NO. 1, 2nd FLOOR, LIGHT TABLES AND KNITTING ...

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

    22. MILL NO. 1, 2nd FLOOR, LIGHT TABLES AND KNITTING MACHINE. LIGHT TABLE USED TO CHECK FOR CLOTH DEFECTS. - Prattville Manufacturing Company, Number One, 242 South Court Street, Prattville, Autauga County, AL

  15. VIEW SOUTH/SOUTHEAST LOOKING DOWN ON 2ND AQUEDUCT AND 1ST AQUEDUCT ...

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

    VIEW SOUTH/SOUTHEAST LOOKING DOWN ON 2ND AQUEDUCT AND 1ST AQUEDUCT CASCADES TOWARDS FILTRATION PLANT AND LOS ANGELES RESERVOIR - Los Angeles Aqueduct, Cascades Structures, Los Angeles, Los Angeles County, CA

  16. 27. INTERIOR, ADMINISTRATION BUILDING, 2ND FLOOR, SOUTHEAST CORNER SPACE, LOOKING ...

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

    27. INTERIOR, ADMINISTRATION BUILDING, 2ND FLOOR, SOUTHEAST CORNER SPACE, LOOKING UP AT CIRCULAR MOTIF AND BANDS IN THE CEILING ABOVE THE ACOUSTICAL TILES - Ford Motor Company Plant, 700 South Union Street, Alexandria, Independent City, VA

  17. Different pathways of tyrosine oxidation by ozone

    SciTech Connect

    Verweij, H.; Christianse, K.; van Steveninck, J.

    1982-01-01

    The influence of OH. scavengers on DOPA and 0,0'-dityrosine generation during ozone-treatment of tyrosine and phenylalanine was studied. The results of these studies are presented in this communication.

  18. Plasmodium falciparum malaria in 1(st)-2(nd) century CE southern Italy.

    PubMed

    Marciniak, Stephanie; Prowse, Tracy L; Herring, D Ann; Klunk, Jennifer; Kuch, Melanie; Duggan, Ana T; Bondioli, Luca; Holmes, Edward C; Poinar, Hendrik N

    2016-12-05

    The historical record attests to the devastation malaria exacted on ancient civilizations, particularly the Roman Empire [1]. However, evidence for the presence of malaria during the Imperial period in Italy (1st-5th century CE) is based on indirect sources, such as historical, epigraphic, or skeletal evidence. Although these sources are crucial for revealing the context of this disease, they cannot establish the causative species of Plasmodium. Importantly, definitive evidence for the presence of malaria is now possible through the implementation of ancient DNA technology. As malaria is presumed to have been at its zenith during the Imperial period [1], we selected first or second molars from 58 adults from three cemeteries from this time: Isola Sacra (associated with Portus Romae, 1st-3rd century CE), Velia (1st-2nd century CE), and Vagnari (1st-4th century CE). We performed hybridization capture using baits designed from the mitochondrial (mtDNA) genomes of Plasmodium spp. on a prioritized subset of 11 adults (informed by metagenomic sequencing). The mtDNA sequences generated provided compelling phylogenetic evidence for the presence of P. falciparum in two individuals. This is the first genomic data directly implicating P. falciparum in Imperial period southern Italy in adults.

  19. Polyclonal antibody to soman-tyrosine

    PubMed Central

    Li, Bin; Duysen, Ellen G.; Froment, Marie-Thérèse; Masson, Patrick; Nachon, Florian; Jiang, Wei; Schopfer, Lawrence M.; Thiele, Geoffrey M.; Klassen, Lynell W.; Cashman, John; Williams, Gareth R.; Lockridge, Oksana

    2013-01-01

    Soman forms a stable, covalent bond with tyrosine 411 of human albumin, with tyrosines 257 and 593 in human transferrin, and with tyrosine in many other proteins. The pinacolyl group of soman is retained, suggesting that pinacolyl methylphosphonate bound to tyrosine could generate specific antibodies. Tyrosine in the pentapeptide RYGRK was covalently modified with soman simply by adding soman to the peptide. The phosphonylated-peptide was linked to keyhole limpet hemocyanin, and the conjugate was injected into rabbits. The polyclonal antiserum recognized soman-labeled human albumin, soman-mouse albumin, and soman human transferrin, but not non-phosphonylated control proteins. The soman-labeled tyrosines in these proteins are surrounded by different amino acid sequences, suggesting that the polyclonal recognizes soman-tyrosine independent of the amino acid sequence. Antiserum obtained after 4 antigen injections over a period of 18 weeks was tested in a competition ELISA where it had an IC50 of 10−11 M. The limit of detection on Western blots was 0.01 μg (15 picomoles) of soman-labeled albumin. In conclusion, a high-affinity, polyclonal antibody that specifically recognizes soman adducts on tyrosine in a variety of proteins has been produced. Such an antibody could be useful for identifying secondary targets of soman toxicity. PMID:23469927

  20. Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors in T790M-positive non-small cell lung cancer: review on emerged mechanisms of resistance

    PubMed Central

    Minari, Roberta; Bordi, Paola

    2016-01-01

    Osimertinib, third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), has been approved in the US and EU for the treatment of EGFR mutant T790M-positive non-small cell lung cancer (NSCLC) patients resistant to first- or second-generation EGFR-TKIs, such as gefitinib, erlotinib and afatinib. Although exciting survival data and response rates have been registered in patients treated with this and other third-generation EGFR-TKIs, unfortunately acquired resistance still occurs after approximately 10 months. Mechanisms determining progression of disease are heterogeneous and not fully understood. EGFR-dependent resistance mechanisms (such as new EGFR mutations), bypass pathway activation [as erb-b2 receptor tyrosine kinase 2 (HER2) or MET amplification] and histological transformation [in small cell lung cancer (SCLC)] have been reported, similarly to previous generation TKIs. Here, we review principle mechanisms of innate and acquired resistance described in literature both in clinical and preclinical settings during NSCLC treatment with third-generation EGFR-TKIs. PMID:28149764

  1. Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors in T790M-positive non-small cell lung cancer: review on emerged mechanisms of resistance.

    PubMed

    Minari, Roberta; Bordi, Paola; Tiseo, Marcello

    2016-12-01

    Osimertinib, third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), has been approved in the US and EU for the treatment of EGFR mutant T790M-positive non-small cell lung cancer (NSCLC) patients resistant to first- or second-generation EGFR-TKIs, such as gefitinib, erlotinib and afatinib. Although exciting survival data and response rates have been registered in patients treated with this and other third-generation EGFR-TKIs, unfortunately acquired resistance still occurs after approximately 10 months. Mechanisms determining progression of disease are heterogeneous and not fully understood. EGFR-dependent resistance mechanisms (such as new EGFR mutations), bypass pathway activation [as erb-b2 receptor tyrosine kinase 2 (HER2) or MET amplification] and histological transformation [in small cell lung cancer (SCLC)] have been reported, similarly to previous generation TKIs. Here, we review principle mechanisms of innate and acquired resistance described in literature both in clinical and preclinical settings during NSCLC treatment with third-generation EGFR-TKIs.

  2. Handbook of industrial and hazardous wastes treatment. 2nd ed.

    SciTech Connect

    Lawrence Wang; Yung-Tse Hung; Howard Lo; Constantine Yapijakis

    2004-06-15

    This expanded Second Edition offers 32 chapters of industry- and waste-specific analyses and treatment methods for industrial and hazardous waste materials - from explosive wastes to landfill leachate to wastes produced by the pharmaceutical and food industries. Key additional chapters cover means of monitoring waste on site, pollution prevention, and site remediation. Including a timely evaluation of the role of biotechnology in contemporary industrial waste management, the Handbook reveals sound approaches and sophisticated technologies for treating: textile, rubber, and timber wastes; dairy, meat, and seafood industry wastes; bakery and soft drink wastes; palm and olive oil wastes; pesticide and livestock wastes; pulp and paper wastes; phosphate wastes; detergent wastes; photographic wastes; refinery and metal plating wastes; and power industry wastes. This final chapter, entitled 'Treatment of power industry wastes' by Lawrence K. Wang, analyses the stream electric power generation industry, where combustion of fossil fuels coal, oil, gas, supplies heat to produce stream, used then to generate mechanical energy in turbines, subsequently converted to electricity. Wastes include waste waters from cooling water systems, ash handling systems, wet-scrubber air pollution control systems, and boiler blowdown. Wastewaters are characterized and waste treatment by physical and chemical systems to remove pollutants is presented. Plant-specific examples are provided.

  3. LAR tyrosine phosphatase receptor: alternative splicing is preferential to the nervous system, coordinated with cell growth and generates novel isoforms containing extensive CAG repeats

    PubMed Central

    1995-01-01

    Receptor-linked tyrosine phosphatases regulate cell growth by dephosphorylating proteins involved in tyrosine kinase signal transduction. The leukocyte common antigen-related (LAR) tyrosine phosphatase receptor has sequence similarity to the neural cell adhesion molecule N-CAM and is located in a chromosomal region (1p32- 33) frequently altered in neuroectodermal tumors. To understand the function of receptor-linked tyrosine phosphatases in neural development, we sought to identify LAR isoforms preferentially expressed in the nervous system and cellular processes regulating LAR alternative splicing. We report here the isolation of a series of rat LAR cDNA clones arising from complex combinatorial alternative splicing, not previously demonstrated for the tyrosine phosphatase- receptor gene family in general. Isoforms included: (a) deletions of the fourth, sixth and seventh fibronectin type III-like domains; (b) an alternatively spliced novel cassette exon in the fifth fibronectin type III-like domain; (c) two alternatively spliced novel cassette exons in the juxtamembrane region; (d) a retained intron in the extracellular region with in-frame stop codons predicting a secreted LAR isoform; and (e) an LAR transcript including an alternative 3' untranslated region containing multiple stretches of tandem CAG repeats up to 21 repeats in length. This number of repeats was in the range found in normal alleles of genes in which expansions of repeats are associated with neurodegenerative disease and the genetic phenomenon of anticipation. RT-PCR and Northern analysis demonstrated that LAR alternative splicing occurred preferentially in neuromuscular tissue in vivo and in neurons compared to astrocytes in vitro and was developmentally regulated. Alternative splicing was also regulated in PC12 cells by NGF, in 3T3 fibroblasts by cell confluence and in sciatic nerve and muscle subsequent to nerve transection. Western blot analysis demonstrated that alternatively spliced

  4. Overview of the 2nd Gen 3.7m HIAD Static Load Test

    NASA Technical Reports Server (NTRS)

    Swanson, G. T.; Kazemba, C. D.; Johnson, R. K.; Hughes, S. J.; Calomino, A. M.; Cheatwood, F. M.; Cassell, A. M.; Anderson, P.; Lowery, A.

    2015-01-01

    To support NASAs long term goal of landing humans on Mars, technologies which enable the landing of heavy payloads are being developed. Current entry, decent, and landing technologies are not practical for human class payloads due to geometric constraints dictated by current launch vehicle fairing limitations. Therefore, past and present technologies are now being explored to provide a mass and volume efficient solution to atmospheric entry, including Hypersonic Inflatable Aerodynamic Decelerators (HIADs). In October of 2014, a 3.7m HIAD inflatable structure with an integrated flexible thermal protection sys-tem (F-TPS) was subjected to a static load test series to verify the designs structural performance. The 3.7m HIAD structure was constructed in a 70 deg sphere-cone stacked-toroid configuration using eight inflatable tori, which were joined together using adhesives and high strength textile webbing to help distribute the loads throughout the inflatable structure. The inflatable structure was fabricated using 2nd generation structural materials that permit an increase in use temperature to 400 C+ as compared to the 250 C limitation of the 1st generation materials. In addition to the temperature benefit, these materials also offer a 40 reduction in structure mass. The 3.7m F-TPS was fabricated using high performance materials to protect the inflatable structure from heat loads that would be seen during atmospheric entry. The F-TPS was constructed of 2nd generation TPS materials increasing its heating capability from 35W sq cm to over 100W sq cm. This test article is the first stacked-torus HIAD to be fabricated and tested with a 70 deg sphere-cone. All previous stacked-torus HIADs have employed a 60o sphere-cone. To perform the static load test series, a custom test fixture was constructed. The fixture consisted of a structural tub rim with enough height to allow for dis-placement of the inflatable structure as loads were applied. The tub rim was attached to the

  5. The Mechanism of the Tyrosine Transporter TyrP Supports a Proton Motive Tyrosine Decarboxylation Pathway in Lactobacillus brevis

    PubMed Central

    Wolken, Wout A. M.; Lucas, Patrick M.; Lonvaud-Funel, Aline; Lolkema, Juke S.

    2006-01-01

    The tyrosine decarboxylase operon of Lactobacillus brevis IOEB9809 contains, adjacent to the tyrosine decarboxylase gene, a gene for TyrP, a putative tyrosine transporter. The two genes potentially form a proton motive tyrosine decarboxylation pathway. The putative tyrosine transporter gene of L. brevis was expressed in Lactococcus lactis and functionally characterized using right-side-out membranes. The transporter very efficiently catalyzes homologous tyrosine-tyrosine exchange and heterologous exchange between tyrosine and its decarboxylation product tyramine. Tyrosine-tyramine exchange was shown to be electrogenic. In addition to the exchange mode, the transporter catalyzes tyrosine uniport but at a much lower rate. Analysis of the substrate specificity of the transporter by use of a set of 19 different tyrosine substrate analogues showed that the main interactions between the protein and the substrates involve the amino group and the phenyl ring with the para hydroxyl group. The carboxylate group that is removed in the decarboxylation reaction does not seem to contribute to the affinity of the protein for the substrates significantly. The properties of the TyrP protein are those typical for precursor-product exchangers that operate in proton motive decarboxylation pathways. It is proposed that tyrosine decarboxylation in L. brevis results in proton motive force generation by an indirect proton pumping mechanism. PMID:16513749

  6. DOE performance indicators for 2nd quarter CY 1993

    SciTech Connect

    Not Available

    1993-11-01

    The Department of Energy (DOE) has established a Department-wide Performance Indicator (PI) Program for trending and analysis of operational data as directed by DOE Order 5480.26. The PI Program was established to provide a means for monitoring the environment, safety, and health (ES&H) performance of the DOE at the Secretary and other management levels. This is the tenth in a series of quarterly reports generated for the Department of Energy Idaho Operations Office (DOE-ID) by EG&G Idaho, Inc. to meet the requirements of the PI Program as directed by the DOE Standard (DOE-STD-1048-92). The information in this tenth quarterly report, while contributing to a historical database for supporting future trending analysis, does not at this time provide a sound basis for developing trend-related conclusions. In the future, it is expected that trending and analysis of operational data will enhance the safety culture in both DOE and contractor organizations by providing an early warning of deteriorating environment, safety, and health conditions. DOE-STD-1048-92 identifies four general areas of PIs. They are: Personnel Safety, Operational Incidents, Environment, and Management. These four areas have been subdivided into 26 performance indicators. Approximately 115 performance indicator control and distribution charts comprise the body of this report. A brief summary of PIs contained in each of these general areas is provided. The four EG&G facilities whose performance is charted herein are as follows: (1) The Advanced Test Reactor (ATR), (2) The Radioactive Waste Management Complex (RWMC), (3) The Waste Experimental Reduction Facility (WERF), and (4) The Test Reactor Area (TRA) Hot Cells.

  7. XAFS of human tyrosine hydroxylase

    NASA Astrophysics Data System (ADS)

    Meyer, W.; Haavik, J.; Winkler, H.; Trautwein, A. X.; Nolting, H.-F.

    1995-02-01

    Tyrosine hydroxylase (TH) catalyses the rate-limiting step (hydroxylation of tyrosine to form dihydroxyphenylalanine) in the biosynthetic pathway leading to the catecholamines dopamine, noradrenaline and adrenaline. The human enzyme (hTH) is present in four isoforms, generated by splicing of pre-mRNA. The purified apoenzyme (metal free) binds stoichiometric amounts of iron. The incorporation of Fe(II) results in a rapid and up to 40-fold increase of activity [1]. Besides the coordination of the metal centers in native enzyme we studied the purported inhibition of TH by its immediate products. So we analysed Fe-hTH isoform 1 native as well as oxidized with dopamine and Co-hTH isoform 2.

  8. 2nd International Forum for Surveillance and Control of Mosquitoes and Mosquito-borne Diseases

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The Entomological Society of China (ESC) and Beijing Institute of Microbiology and Epidemiology (BIME) hosted the 2nd International Forum for Surveillance and Control of Mosquitoes and Mosquito-borne Diseases in Beijing, China, May 23-27, 2011. The theme of the Forum was “Impact of global climate ch...

  9. Methods for the Determination of Chemical Substances in Marine and Estuarine Environmental Matrices - 2nd Edition

    EPA Science Inventory

    This NERL-Cincinnati publication, “Methods for the Determination of Chemical Substances in Marine and Estuarine Environmental Matrices - 2nd Edition” was prepared as the continuation of an initiative to gather together under a single cover a compendium of standardized laborato...

  10. Stem cells and cancer immunotherapy: Arrowhead’s 2nd annual cancer immunotherapy conference

    PubMed Central

    2014-01-01

    Investigators from academia and industry gathered on April 4 and 5, 2013, in Washington DC at the Arrowhead’s 2nd Annual Cancer Immunotherapy Conference. Two complementary concepts were discussed: cancer “stem cells” as targets and therapeutic platforms based on stem cells.

  11. Proceedings of the 2nd symposium on valves for coal conversion and utilization

    SciTech Connect

    Maxfield, D.A.

    1981-01-01

    The 2nd symposium on valves for coal conversion and utilization was held October 15 to 17, 1980. It was sponsored by the US Department of Energy, Morgantown Energy Technology Center, in cooperation with the Valve Manufacturers Association. Seventeen papers have been entered individually into EDB and ERA. (LTN)

  12. Evaluation of a Hand Washing Program for 2nd-Graders

    ERIC Educational Resources Information Center

    Tousman, Stuart; Arnold, Dani; Helland, Wealtha; Roth, Ruth; Heshelman, Nannatte; Castaneda, Oralia; Fischer, Emily; O'Neil, Kristen; Bileto, Stephanie

    2007-01-01

    The purpose of this project was to determine if a multiple-week learner-centered hand washing program could improve hand hygiene behaviors of 2nd-graders in a northern Illinois public school system. Volunteers from the Rockford Hand Washing Coalition went into 19 different classrooms for 4 consecutive weeks and taught a learner-centered program.…

  13. Technical Adequacy of the Disruptive Behavior Rating Scale-2nd Edition--Self-Report

    ERIC Educational Resources Information Center

    Erford, Bradley T.; Miller, Emily M.; Isbister, Katherine

    2015-01-01

    This study provides preliminary analysis of the Disruptive Behavior Rating Scale-2nd Edition--Self-Report, which was designed to screen individuals aged 10 years and older for anxiety and behavior symptoms. Score reliability and internal and external facets of validity were good for a screening-level test.

  14. The Effect of Using Computer Edutainment on Developing 2nd Primary Graders' Writing Skills

    ERIC Educational Resources Information Center

    Mohammed Abdel Raheem, Azza Ashraf

    2011-01-01

    The present study attempted to examine the effect of using computer edutainment on developing 2nd graders' writing skills. The study comprised thirty-second year primary stage enrolled in Bani Hamad primary governmental school, Minia governorate. The study adopted the quasi-experimental design. Thirty participants were randomly assigned to one…

  15. The immunopharmacologic potential of Semaxanib and new generation directed therapeutic drugs: Receptor tyrosine kinase regulation with anti-tumorigenensis/angiogenesis properties

    PubMed Central

    Haddad, John J.

    2011-01-01

    Molecular signaling of messages emanating from cellular membranes through receptor tyrosine kinases (RTKs) is a major mechanism for intercellular communication and transduction during development and metabolism, as well as in disease-associated processes. The phosphorylation status and signaling activity of RTKs are determined by a dynamic equilibrium of the activity of both RTKs and protein tyrosine phosphatases (PTPs). RTKs are essentially a class of cell-surface receptors for growth factors and other extracellular ligands, the most conspicuous perhaps are members of the vascular endothelial growth factor (VEGF) gene family, which plays a fundamental role in the growth and differentiation of vascular, as well as lymphatic endothelial cells. In particular, VEGF is a major regulator of normal (physiologic) and abnormal (cancerous) angiogenesis, including that associated with tumors and cancer. Blockers/inhibitors and regulators of RTKs are indeed promising cancer interventions, their specific mechanisms are yet to be unraveled. In this cutting-edge synopsis, I elaborate on breakthroughs/advances and current concepts of RTK regulation, further shedding light on exploring the role of potential regulators, particularly the RTK inhibitor Semaxanib, and the mechanisms associated with tumorigenesis in an effort to understand a potentially alleviating pharmacologic therapeutic intervention. This survey also tackles the loopholes and shortcomings of the aforementioned inhibitory role of Semaxanib, especially its inefficacy and ultimate discontinuation of relevant clinical trials. PMID:23960782

  16. Utilisation of 2nd Generation Web Technologies in Master Level Vocational Teacher Training

    ERIC Educational Resources Information Center

    Tóth, Péter

    2009-01-01

    The Masters level Opportunities and Technological Innovation in Vocational Teacher Education project (project site: http://motivate.tmpk.bmf.hu/) aims to develop the use and management of virtual learning environments in the area of vocational teacher training, drawing on a well established international partnership of institutions providing both…

  17. Performance of 2nd Generation BaBar Resistive Plate Chambers

    SciTech Connect

    Anulli, F.; Baldini, R.; Calcaterra, A.; de Sangro, R.; Finocchiaro, G.; Patteri, P.; Piccolo, M.; Zallo, A.; Cheng, C.H.; Lange, D.J.; Wright, D.M.; Messner, R.; Wisniewski, William J.; Pappagallo, M.; Andreotti, M.; Bettoni, D.; Calabrese, R.; Cibinetto, G.; Luppi, E.; Negrini, M.; Capra, R.; /Genoa U. /INFN, Genoa /Naples U. /INFN, Naples /Perugia U. /INFN, Perugia /Pisa U. /INFN, Pisa /Rome U. /INFN, Rome /Oregon U. /UC, Riverside /Wisconsin U., Madison

    2005-07-12

    The BaBar detector has operated nearly 200 Resistive Plate Chambers (RPCs), constructed as part of an upgrade of the forward endcap muon detector, for the past two years. The RPCs experience widely different background and luminosity-driven singles rates (0.01-10 Hz/cm{sup 2}) depending on position within the endcap. Some regions have integrated over 0.3 C/cm{sup 2}. RPC efficiency measured with cosmic rays is high and stable. The average efficiency measured with beam is also high. However, a few of the highest rate RPCs have suffered efficiency losses of 5-15%. Although constructed with improved techniques and minimal use of linseed oil, many of the RPCs, which are operated in streamer mode, have shown increased dark currents and noise rates that are correlated with the direction of the gas flow and the integrated current. Studies of the above aging effects are presented and correlated with detector operating conditions.

  18. Reed canary grass as a feedstock for 2nd generation bioethanol production.

    PubMed

    Kallioinen, Anne; Uusitalo, Jaana; Pahkala, Katri; Kontturi, Markku; Viikari, Liisa; Weymarn, Niklas von; Siika-Aho, Matti

    2012-11-01

    The enzymatic hydrolysis and fermentation of reed canary grass, harvested in the spring or autumn, and barley straw were studied. Steam pretreated materials were efficiently hydrolysed by commercial enzymes with a dosage of 10-20FPU/g d.m. Reed canary grass harvested in the spring was hydrolysed more efficiently than the autumn-harvested reed canary grass. Additional β-glucosidase improved the release of glucose and xylose during the hydrolysis reaction. The hydrolysis rate and level of reed canary grass with a commercial Trichoderma reesei cellulase could be improved by supplementation of purified enzymes. The addition of CBH II improved the hydrolysis level by 10% in 48hours' hydrolysis. Efficient mixing was shown to be important for hydrolysis already at 10% dry matter consistency. The highest ethanol concentration (20g/l) and yield (82%) was obtained with reed canary grass at 10% d.m. consistency.

  19. Screening for an Allergic Response to 2nd Generation Biofuel Sources

    EPA Science Inventory

    Abstract for March 2014 Society of Toxicology Annual Meeting The use of cellulosic biofuels crops can potentially reduce our carbon footprint. However, they may have unintended ecological and health effects such as increased competitiveness and allergenicity...

  20. Main Engine Prototype Development for 2nd Generation RLV RS-83

    NASA Technical Reports Server (NTRS)

    Vilja, John; Fisher, Mark; Lyles, Garry M. (Technical Monitor)

    2002-01-01

    This presentation reports on the NASA project to develop a prototype for RS-83 engine designed for use on reusable launch vehicles (RLV). Topics covered include: program objectives, overview schedule, organizational chart, integrated systems engineering processes, requirement analysis, catastrophic engine loss, maintainability analysis tools, and prototype design analysis.

  1. Protein tyrosine phosphatases as potential therapeutic targets

    PubMed Central

    He, Rong-jun; Yu, Zhi-hong; Zhang, Ruo-yu; Zhang, Zhong-yin

    2014-01-01

    Protein tyrosine phosphorylation is a key regulatory process in virtually all aspects of cellular functions. Dysregulation of protein tyrosine phosphorylation is a major cause of human diseases, such as cancers, diabetes, autoimmune disorders, and neurological diseases. Indeed, protein tyrosine phosphorylation-mediated signaling events offer ample therapeutic targets, and drug discovery efforts to date have brought over two dozen kinase inhibitors to the clinic. Accordingly, protein tyrosine phosphatases (PTPs) are considered next-generation drug targets. For instance, PTP1B is a well-known targets of type 2 diabetes and obesity, and recent studies indicate that it is also a promising target for breast cancer. SHP2 is a bona-fide oncoprotein, mutations of which cause juvenile myelomonocytic leukemia, acute myeloid leukemia, and solid tumors. In addition, LYP is strongly associated with type 1 diabetes and many other autoimmune diseases. This review summarizes recent findings on several highly recognized PTP family drug targets, including PTP1B, Src homology phosphotyrosyl phosphatase 2(SHP2), lymphoid-specific tyrosine phosphatase (LYP), CD45, Fas associated phosphatase-1 (FAP-1), striatal enriched tyrosine phosphatases (STEP), mitogen-activated protein kinase/dual-specificity phosphatase 1 (MKP-1), phosphatases of regenerating liver-1 (PRL), low molecular weight PTPs (LMWPTP), and CDC25. Given that there are over 100 family members, we hope this review will serve as a road map for innovative drug discovery targeting PTPs. PMID:25220640

  2. The rotational spectrum of tyrosine.

    PubMed

    Pérez, Cristóbal; Mata, Santiago; Cabezas, Carlos; López, Juan C; Alonso, José L

    2015-04-23

    In this work neutral tyrosine has been generated in the gas phase by laser ablation of solid samples, and its most abundant conformers characterized through their rotational spectra. Their identification has been made by comparison between the experimental and ab initio values of the rotational and quadrupole coupling constants. Both conformers are stabilized by an O-H•••N hydrogen bond established within the amino acid skeleton chain and an additional weak N-H•••π hydrogen bond. The observed conformers differ in the orientation of the phenolic -OH group.

  3. 2nd-Order CESE Results For C1.4: Vortex Transport by Uniform Flow

    NASA Technical Reports Server (NTRS)

    Friedlander, David J.

    2015-01-01

    The Conservation Element and Solution Element (CESE) method was used as implemented in the NASA research code ez4d. The CESE method is a time accurate formulation with flux-conservation in both space and time. The method treats the discretized derivatives of space and time identically and while the 2nd-order accurate version was used, high-order versions exist, the 2nd-order accurate version was used. In regards to the ez4d code, it is an unstructured Navier-Stokes solver coded in C++ with serial and parallel versions available. As part of its architecture, ez4d has the capability to utilize multi-thread and Messaging Passage Interface (MPI) for parallel runs.

  4. A Communications Guide for Sustainable Development: How Interested Parties Become Partners, 2nd Edition

    SciTech Connect

    Fowler, Kimberly M.; Hund, Gretchen; Engel-Cox, Jill A.

    2016-03-06

    The 2nd edition is an updated version plus an e-book. This book was developed to assist organizations in designing and managing their communication and stakeholder involvement programs. The guidebook describes a step-by-step approach, provides case studies, and presents tools to consider. The book uses a scenario approach to outline changes an organization may confront, and provides a menu of communication and engagement activities that support organizational decision making.

  5. Summary and agreement statement of the 2nd International Conference on Concussion in Sport, Prague 2004

    PubMed Central

    McCrory, P; Johnston, K; Meeuwisse, W; Aubry, M; Cantu, R; Dvorak, J; Graf-Baumann, T; Kelly, J; Lovell, M; Schamasch, P

    2005-01-01

    In November 2001, the 1st International Symposium on Concussion in Sport was held in Vienna, Austria to provide recommendations for the improvement of safety and health of athletes who suffer concussive injuries in ice hockey, football (soccer), and other sports. The 2nd International Symposium on Concussion in Sport was organised by the same group and held in Prague, Czech Republic in November 2004. It resulted in a revision and update of the Vienna consensus recommendations, which are presented here.

  6. Summary and agreement statement of the 2nd International Conference on Concussion in Sport, Prague 2004

    PubMed Central

    McCrory, P; Johnston, K; Meeuwisse, W; Aubry, M; Cantu, R; Dvorak, J; Graf-Baumann, T; Kelly, J; Lovell, M; Schamasch, P

    2005-01-01

    In November 2001, the 1st International Symposium on Concussion in Sport was held in Vienna, Austria to provide recommendations for the improvement of safety and health of athletes who suffer concussive injuries in ice hockey, football (soccer), and other sports. The 2nd International Symposium on Concussion in Sport was organised by the same group and held in Prague, Czech Republic in November 2004. It resulted in a revision and update of the Vienna consensus recommendations, which are presented here. PMID:15793085

  7. Graphical shapes of the 2nd type singularities of a 3-RR̠R planar mechanism

    NASA Astrophysics Data System (ADS)

    Buium, F.; Duca, C.; Doroftei, I.; Leohchi, D.

    2016-08-01

    This paper intends to discuss about singularity curves of 2nd type inside the workspace of a 3R̠RR planar parallel mechanism used as robot structure. In order to attain this goal we will use certain variation of the links dimensional parameters. This characterization of the mechanism singularities located inside mechanism workspace depends on the dimensional parameters and can be useful in mechanism designing accorded to some functional particularities in the sense that it can help in avoiding singular configurations.

  8. Idaho National Laboratory Quarterly Performance Analysis for the 2nd Quarter FY 2015

    SciTech Connect

    Mitchell, Lisbeth A.

    2015-04-01

    This report is published quarterly by the Idaho National Laboratory (INL) Quality and Performance Management Organization. The Department of Energy (DOE) Occurrence Reporting and Processing System (ORPS), as prescribed in DOE Order 232.2, “Occurrence Reporting and Processing of Operations Information,” requires a quarterly analysis of events, both reportable and not reportable, for the previous 12 months. This report is the analysis of events for the 2nd Qtr FY-15.

  9. Application research on enhancing near-infrared micro-imaging quality by 2nd derivative

    NASA Astrophysics Data System (ADS)

    Wang, Dong; Ma, Zhi-hong; Zhao, Liu; Wang, Bei-hong; Han, Ping; Pan, Li-gang; Wang, Ji-hua

    2013-08-01

    Near-infrared micro-imaging will not only provide the sample's spatial distribution information, but also the spectroscopic information of each pixel. In this thesis, it took the artificial sample of wheat flour and formaldehyde sodium sulfoxylate distribution given for example to research the data processing method for enhancing the quality of near-infrared micro-imaging. Near-infrared spectroscopic feature of wheat flour and formaldehyde sodium sulfoxylate being studied on, compare correlation imaging and 2nd derivative imaging were applied in the imaging processing of the near-infrared micro-image of the artificial sample. Furthermore, the two methods were combined, i.e. 2nd derivative compare correlation imaging was acquired. The result indicated that the difference of the correlation coefficients between the two substances, i.e. wheat flour and formaldehyde sodium sulfoxylate, and the reference spectrum has been increased from 0.001 in compare correlation image to 0.796 in 2nd derivative compare correlation image respectively, which enhances the imaging quality efficiently. This study will, to some extent, be of important reference significance to near-infrared micro-imaging method research of agricultural products and foods.

  10. Development of fetal intestinal length during 2nd-trimester in normal and pathologic pregnancies.

    PubMed

    Marnerides, Andreas; Ghazi, Sam; Sundberg, Anders; Papadogiannakis, Nikos

    2012-01-01

    Linear growth of the human fetal gastrointestinal tract is not often discussed in the literature, and little is known about the effects of chromosomal abnormalities and intrauterine growth restriction (IUGR) on intestinal length, especially during the 2nd trimester. Accurate evaluation of intestinal length and knowledge of normal and reference values are of clinical importance. For example, intestinal resection may be necessary in preterm infants with necrotizing enterocolitis or mid-gut volvulus, and the surgeon should use data to be judicious in the amount removed. Linear measurements are essential in evaluating fetal development ultrasonographically and are an integral part of the postmortem examination. The intestinal lengths of 203 2nd-trimester fetuses and premature infants were measured. Small intestine length (SIL), colon length (CL), total bowel length (TBL; TBL  =  SIL + CL), and the length of the appendix (AL) increased with gestational age. No differences between the genders were observed. Colon length increased secondary to maceration, but no such effects were shown on SIL, TBL, or AL. No differences were shown in relation to IUGR. Small intestine length, CL, and TBL, but not AL, were shorter in fetuses with trisomy 21. Appendix length was not affected by any of the studied factors. We propose that the measurement of the length of the appendix may be used as an additional parameter for the postmortem evaluation of gestational age. Furthermore, its assessment may have potential as an ultrasonographic indicator of gestational age, particularly for the 2nd trimester.

  11. Healing of rat mouth mucosa after irradiation with CO2, Nd:YAG, and CO2-Nd:YAG combination lasers.

    PubMed

    Luomanen, M; Rauhamaa-Mäkinen, R; Meurman, J H; Kosloff, T; Tiitta, O

    1994-08-01

    The healing process of wounds made by a combination laser was studied in 90 rats. The laser system enabled both separate and combined use of CO2 and Nd:YAG laser irradiations. The laser wounds and the control excision wounds made by alligator forceps appeared on both sides of the tongue. Specimens from the wound sites were taken immediately, 6 h, and 1, 2, 4, 7, 11, 21, 28, and 42 days after surgery. The wound-healing process was studied by macroscopic evaluation before preparing the specimens for light microscopy. Some differences were noted in the wound-healing process among the three groups into which the experimental animals were divided. Tissue coagulation damage was most extensive in the Nd:YAG laser sites, where it was observed in its full extent 4 days after surgery. Epithelial cells were seen to begin to proliferate in all the wounds 6 h after surgery. Re-epithelialization was completed by between 7 (CO2) and 21 days (Nd:YAG) at all the wound sites. The inflammatory cell infiltration was more prominent in the Nd:YAG and the CO2-Nd:YAG combination laser wounds than in the CO2 and excision wounds during healing. Tissue regeneration occurred faster with less contraction in the combination CO2-Nd:YAG wounds than in Nd:YAG wounds. The best macroscopic healing result was seen in the CO2 wound sites. The combination laser was effective both at cutting and at coagulating tissue. Combining the CO2 and Nd:YAG laser irradiation into one beam resulted in a greater incision depth than what could have been expected from using the two lasers separately.

  12. Effects of first- and second-generation tyrosine kinase inhibitor therapy on glucose and lipid metabolism in chronic myeloid leukemia patients: a real clinical problem?

    PubMed Central

    Iurlo, Alessandra; Orsi, Emanuela; Cattaneo, Daniele; Resi, Veronica; Bucelli, Cristina; Orofino, Nicola; Sciumè, Mariarita; Elena, Chiara; Grancini, Valeria; Consonni, Dario; Orlandi, Ester Maria; Cortelezzi, Agostino

    2015-01-01

    Background Tyrosine kinase inhibitors (TKIs) have dramatically changed the prognosis of patients with chronic myeloid leukemia (CML). They have a distinct toxicity profile that includes glycometabolic alterations: i.e. diabetes mellitus (DM), impaired fasting glucose (IFG), and the metabolic syndrome (MS). The aim of this study was to evaluate the prevalence of these alterations in a cohort of CML-chronic phase patients treated with imatinib, dasatinib or nilotinib. Methods The study involved 168 consecutive CML-chronic phase patients with no history of DM/IFG or MS. Anthropometric and metabolic parameters were assessed, and DM/IFG and MS were diagnosed based on the criteria of the American Diabetes Association and the National Cholesterol Education Program-Adult Treatment Panel III, respectively. Results The nilotinib group had significantly higher levels of fasting plasma glucose, insulin, C-peptide, insulin resistance, and total and LDL cholesterol than the imatinib and dasatinib groups. DM/IFG were identified in 25% of the imatinib- and dasatinib-treated patients, and 33% of those in the nilotinib cohort (p = 0.39 vs imatinib and p = 0.69 vs dasatinib). A diagnosis of MS was made in 42.4% of the imatinib-treated patients, 37.5% of the dasatinib-treated patients, and 36.1% of the nilotinib-treated patients (p = 0.46 vs imatinib and p = 0.34 vs dasatinib). Conclusions Treatment with nilotinib does not seem to induce DM/IFG or the MS to a significantly higher extent than imatinib or dasatinib, though it causes a worse glycometabolic profile. These findings suggest the need for a close monitoring of glucose and lipid metabolism and a multidisciplinary approach in patients treated with nilotinib. PMID:26376678

  13. Patan hospital experience in treating philadelphia chromosome/BCR-ABL1 positive chronic myeloid leukemia patients with gleevec (imatinib mesylate); the first generation specific tyrosine kinase inhibitor

    PubMed Central

    2010-01-01

    Background Chronic Myeloid Leukemia (CML) is caused by the abnormal fusion protein BCR-ABL1, a constitutively active tyrosine kinase and product of the Philadelphia chromosome. Gleevec (Imatinib mesylate) is a selective inhibitor of this kinase. Treatment with this agent is known to result in hematologic, cytogenetic, and molecular responses. Patan hospital (Patan, Nepal) is one of the Gleevec International Patient Assistance Program (GIPAP) centers for patients with CML. Methods A total of 106 Philadelphia positive CML patients were enrolled in our center between Feb 2003 and Jun 2008, and 103 of them were eligible for cytogenetic and/or hematologic response analyses. Results Out of 103 patients, 27% patients underwent cytogenetic analysis. Imatinib induced major cytogenetic responses in 89% and complete hematologic responses in almost 100% of the patients with confirmed CML. After a mean follow up of 27 months, an estimated 90% of the patients on imatinib remained in hematologic remission and more than 90% of the patients are still alive. About 30% of patients developed some form of manageable myelosuppression. A few patients developed non-hematologic toxic side effects such as edema and hepatotoxicity. Conclusions Our study demonstrates that imatinib is safe to use in a developing country. Furthermore, we demonstrate that imatinib is very effective and induced long lasting responses in a high proportion of patients with Ph chromosome/BCR-ABL1 positive CML. Imatinib is well tolerated by our patients. The lack of cytogenetic analysis in the majority of our patients hindered our ability to detect inadequate responses to imatinib and adjust therapy appropriately. PMID:21138592

  14. Carbon dioxide emissions and the overshoot ratio change resulting from the implementation of 2nd Energy Master Plan in South Korea

    NASA Astrophysics Data System (ADS)

    Yeo, M. J.; Kim, Y. P.

    2015-12-01

    The direction of the energy policies of the country is important in the projection of environmental impacts of the country. The greenhouse gases (GHGs) emission of the energy sector in South Korea is very huge, about 600 MtCO2e in 2011. Also the carbon footprint due to the energy consumption contributes to the ecological footprint is also large, more than 60%. Based on the official plans (the national greenhouse gases emission reduction target for 2030 (GHG target for 2030) and the 2nd Energy Master Plan (2nd EMP)), several scenarios were proposed and the sensitivity of the GHG emission amount and 'overshoot ratio' which is the ratio of ecological footprint to biocapacity were estimated. It was found that to meet the GHG target for 2030 the ratio of non-emission energy for power generation should be over 71% which would be very difficult. We also found that the overshoot ratio would increase from 5.9 in 2009 to 7.6 in 2035. Thus, additional efforts are required to reduce the environmental burdens in addition to optimize the power mix configuration. One example is the conversion efficiency in power generation. If the conversion efficiency in power generation rises up 50% from the current level, 40%, the energy demand and resultant carbon dioxide emissions would decrease about 10%. Also the influence on the environment through changes in consumption behavior, for example, the diet choice is expected to be meaningful.

  15. Mars Curriculum for K-12 Science Education, 2nd Edition, Making Tracks on Mars Teacher Resource and Activity Guide

    NASA Astrophysics Data System (ADS)

    Aubele, J. C.; Stanley, J.; Grochowski, A.; Jones, K.; Aragon, J.

    2012-03-01

    A Mars K-12 curriculum, created by the New Mexico Museum of Natural History & Science, is now in 2nd edition DVD, approved by NASA educational review, 508 compliant to ensure accessibility for people with disabilities, and applicable to MSL.

  16. PREFACE: 2nd International Conference on Innovative Materials, Structures and Technologies

    NASA Astrophysics Data System (ADS)

    Ručevskis, Sandris

    2015-11-01

    The 2nd International Conference on Innovative Materials, Structures and Technologies (IMST 2015) took place in Riga, Latvia from 30th September - 2nd October, 2015. The first event of the conference series, dedicated to the 150th anniversary of the Faculty of Civil Engineering of Riga Technical University, was held in 2013. Following the established tradition, the aim of the conference was to promote and discuss the latest results of industrial and academic research carried out in the following engineering fields: analysis and design of advanced structures and buildings; innovative, ecological and energy efficient building materials; maintenance, inspection and monitoring methods; construction technologies; structural management; sustainable and safe transport infrastructure; and geomatics and geotechnics. The conference provided an excellent opportunity for leading researchers, representatives of the industrial community, engineers, managers and students to share the latest achievements, discuss recent advances and highlight the current challenges. IMST 2015 attracted over 120 scientists from 24 countries. After rigorous reviewing, over 80 technical papers were accepted for publication in the conference proceedings. On behalf of the organizing committee I would like to thank all the speakers, authors, session chairs and reviewers for their efficient and timely effort. The 2nd International Conference on Innovative Materials, Structures and Technologies was organized by the Faculty of Civil Engineering of Riga Technical University with the support of the Latvia State Research Programme under the grant agreement "INNOVATIVE MATERIALS AND SMART TECHNOLOGIES FOR ENVIRONMENTAL SAFETY, IMATEH". I would like to express sincere gratitude to Juris Smirnovs, Dean of the Faculty of Civil Engineering, and Andris Chate, manager of the Latvia State Research Programme. Finally, I would like to thank all those who helped to make this event happen. Special thanks go to Diana

  17. PREFACE: 2nd International Meeting for Researchers in Materials and Plasma Technology

    NASA Astrophysics Data System (ADS)

    Niño, Ely Dannier V.

    2013-11-01

    These proceedings present the written contributions of the participants of the 2nd International Meeting for Researchers in Materials and Plasma Technology, 2nd IMRMPT, which was held from February 27 to March 2, 2013 at the Pontificia Bolivariana Bucaramanga-UPB and Santander and Industrial - UIS Universities, Bucaramanga, Colombia, organized by research groups from GINTEP-UPB, FITEK-UIS. The IMRMPT, was the second version of biennial meetings that began in 2011. The three-day scientific program of the 2nd IMRMPT consisted in 14 Magisterial Conferences, 42 Oral Presentations and 48 Poster Presentations, with the participation of undergraduate and graduate students, professors, researchers and entrepreneurs from Colombia, Russia, France, Venezuela, Brazil, Uruguay, Argentina, Peru, Mexico, United States, among others. Moreover, the objective of IMRMPT was to bring together national and international researchers in order to establish scientific cooperation in the field of materials science and plasma technology; introduce new techniques of surface treatment of materials to improve properties of metals in terms of the deterioration due to corrosion, hydrogen embrittlement, abrasion, hardness, among others; and establish cooperation agreements between universities and industry. The topics covered in the 2nd IMRMPT include New Materials, Surface Physics, Laser and Hybrid Processes, Characterization of Materials, Thin Films and Nanomaterials, Surface Hardening Processes, Wear and Corrosion / Oxidation, Modeling, Simulation and Diagnostics, Plasma Applications and Technologies, Biomedical Coatings and Surface Treatments, Non Destructive Evaluation and Online Process Control, Surface Modification (Ion Implantation, Ion Nitriding, PVD, CVD). The editors hope that those interested in the are of materials science and plasma technology, enjoy the reading that reflect a wide range of topics. It is a pleasure to thank the sponsors and all the participants and contributors for

  18. 2ND EF Conference in Turbulent Heat Transfer, Manchester, UK 1998. Volume 1

    DTIC Science & Technology

    1998-06-01

    1WB.7C 1W1UC •v*ataj «vnlMlai i-V 1 iBriMHI MWBlaj fprriatfa ■ HSV Of»U» Ia»fUC T-4UC : BBIW OIJIHIIM 1 *>IMC T»«MC (g) (h) Figure 7 Local...t’ k THE UNIVERSITY y MANCHESTER UMIST 2nd EF Conference in TURBULENT HEAT TRANSFER Manchester, UK 1 998 Approved /or public vil...QXTALTTY INSPECTED 1 CONTENTS VOLUME I Session 1 : Heat Transfer Under Simple Shearing (Chairmen: B. E. Launder and T. J. Hanratty) Y. Na, D. V

  19. [Model and enlightenment from rescue of August 2nd Kunshan explosion casualty].

    PubMed

    Tan, Q; Qiu, H B; Sun, B W; Shen, Y M; Nie, L J; Zhang, H W

    2016-01-01

    On August 2nd, 2014, a massive dust explosion occurred in a factory of Kunshan, resulting in a mass casualty involving 185 burn patients. They were transported to 20 medical institutions in Jiangsu province and Shanghai. More than one thousand of medical personnel of our country participated in this emergency rescue, and satisfactory results were achieved. In this paper, the characteristics of this accident were analyzed, the positive effects of interdisciplinary cooperation were affirmed, and the contingency plan, rescue process and pattern, and reserve, organization and management of talents during this rescue process were reviewed retrospectively.

  20. Dynamic Recrystallization Behavior of a Coarse-Grained Mg-2Zn-2Nd Magnesium Alloy

    NASA Astrophysics Data System (ADS)

    Wang, Tong; Jonas, John J.; Yue, Stephen

    2017-02-01

    Compression tests were performed on samples of Mg-2Zn-2Nd at 673 K (400 °C) and at three different strain rates. At 0.1/s, three mechanisms of dynamic recrystallization (DRX) were observed to operate: discontinuous DRX (DDRX), twinning DRX (TDRX), and continuous DRX (CDRX). At 0.01/s, DDRX took place as a result of grain boundary bulging, followed by CDRX on further straining. At 0.001/s, only CDRX was observed. At a strain of 0.3, the activation of multiple DRX mechanisms in the 0.1/s samples produced the weakest deformation textures.

  1. Secular Motion in a 2nd Degree and Order-Gravity Field with no Rotation

    NASA Astrophysics Data System (ADS)

    Scheeres, D. J.; Hu, W.

    2001-03-01

    The motion of a particle about a non-rotating 2nd degree and order-gravity field is investigated. Averaging conditions are applied to the particle motion and a qualitative analysis which reveals the general character of motion in this system is given. It is shown that the orbit plane will either be stationary or precess about the body's axis of minimum or maximum moment of inertia. It is also shown that the secular equations for this system can be integrated in terms of trigonometric, hyperbolic or elliptic functions. The explicit solutions are derived in all cases of interest.

  2. The Cytosolic Domain of Protein-tyrosine Kinase 7 (PTK7), Generated from Sequential Cleavage by a Disintegrin and Metalloprotease 17 (ADAM17) and γ-Secretase, Enhances Cell Proliferation and Migration in Colon Cancer Cells*

    PubMed Central

    Na, Hye-Won; Shin, Won-Sik; Ludwig, Andreas; Lee, Seung-Taek

    2012-01-01

    Protein-tyrosine kinase 7 (PTK7) is a member of the defective receptor protein-tyrosine kinases and is known to function as a regulator of planar cell polarity during development. Its expression is up-regulated in some cancers including colon carcinomas. A 100-kDa fragment of PTK7 was detected in the culture media from colon cancer cells and HEK293 cells. The shed fragment was named sPTK7-Ig1–7 because its molecular mass was very similar to that of the entire extracellular domain of PTK7 that contains immunoglobulin-like loops 1 to 7 (Ig1–7). The shedding of sPTK7-Ig1–7 was enhanced by treatment with phorbol 12-myristate 13-acetate. In addition to the sPTK7-Ig1–7 found in the culture medium, two C-terminal fragments of PTK7 were detected in the cell lysates: PTK7-CTF1, which includes a transmembrane segment and a cytoplasmic domain, and PTK7-CTF2, which lacks most of the transmembrane segment from PTK7-CTF1. Analysis of PTK7 processing in the presence of various protease inhibitors or after knockdown of potential proteases suggests that shedding of PTK7 into sPTK7-Ig1–7 and PTK7-CTF1 is catalyzed by ADAM17, and further cleavage of PTK7-CTF1 into PTK7-CTF2 is mediated by the γ-secretase complex. PTK7-CTF2 localizes to the nucleus and enhances proliferation, migration, and anchorage-independent colony formation. Our findings demonstrate a novel role for PTK7 in the tumorigenesis via generation of PTK7-CTF2 by sequential cleavage of ADAM17 and γ-secretase. PMID:22665490

  3. Next-generation EGFR/HER tyrosine kinase inhibitors for the treatment of patients with non-small-cell lung cancer harboring EGFR mutations: a review of the evidence

    PubMed Central

    Wang, Xiaochun; Goldstein, David; Crowe, Philip J; Yang, Jia-Lin

    2016-01-01

    Tyrosine kinase inhibitors (TKIs) against human epidermal growth factor receptor (EGFR/HER) family have been introduced into the clinic to treat cancers, particularly non-small-cell lung cancer (NSCLC). There have been three generations of the EGFR/HER-TKIs. First-generation EGFR/HER-TKIs, binding competitively and reversibly to the ATP-binding site of the EGFR TK domain, show a significant breakthrough treatment in selected NSCLC patients with activating EGFR mutations (actEGFRm) EGFRL858R and EGFRDel19, in terms of safety, efficacy, and quality of life. However, all those responders inevitably develop acquired resistance within 12 months, because of the EGFRT790M mutation, which prevents TKI binding to ATP-pocket of EGFR by steric hindrance. The second-generation EGFR/HER-TKIs were developed to prolong and maintain more potent response as well as overcome the resistance to the first-generation EGFR/HER-TKIs. They are different from the first-generation EGFR/HER-TKIs by covalently binding to the ATP-binding site, irreversibly blocking enzymatic activation, and targeting EGFR/HER family members, including EGFR, HER2, and HER4. Preclinically, these compounds inhibit the enzymatic activation for actEGFRm, EGFRT790M, and wtEGFR. The second-generation EGFR/HER-TKIs improve overall survival in cancer patients with actEGFRm in a modest way. However, they are not clinically active in overcoming EGFRT790M resistance, mainly because of dose-limiting toxicity due to simultaneous inhibition against wtEGFR. The third-generation EGFR/HER-TKIs selectively and irreversibly target EGFRT790M and actEGFRm while sparing wtEGFR. They yield promising efficacy in NSCLC patients with actEGFRm as well as EGFRT790M resistant to the first- and second-generation EGFR-TKIs. They also appear to have a lower incidence of toxicity due to the reduced inhibitory effect on wtEGFR. Currently, the first-generation EGFR/HER-TKIs gefitinib and erlotinib and second-generation EGFR/HER-TKI afatinib have

  4. Protein tyrosine phosphorylation in streptomycetes.

    PubMed

    Waters, B; Vujaklija, D; Gold, M R; Davies, J

    1994-07-01

    Using phosphotyrosine-specific antibodies, we demonstrate that in several Streptomyces spp. a variety of proteins are phosphorylated on tyrosine residues. Tyrosine phosphorylation was found in a number of Streptomyces species including Streptomyces lividans, Streptomyces hygroscopicus and Streptomyces lavendulae. Each species exhibited a unique pattern of protein tyrosine phosphorylation. Moreover, the patterns of tyrosine phosphorylation varied during the growth phase and were also influenced by culture conditions. We suggest that metabolic shifts during the complex growth cycle of these filamentous bacteria, and possibly secondary metabolic pathways, may be controlled by the action of protein tyrosine kinases and phosphatases, as has been demonstrated in signal transduction pathways in eukaryotic organisms.

  5. Roles of doping ions in afterglow properties of blue CaAl2O4:Eu2+,Nd3+ phosphors

    NASA Astrophysics Data System (ADS)

    Wako, A. H.; Dejene, B. F.; Swart, H. C.

    2014-04-01

    Eu2+ doped and Nd3+ co-doped calcium aluminate (CaAl2O4:Eu2+,Nd3+) phosphor was prepared by a urea-nitrate solution combustion method at furnace temperatures as low as 500 °C. The produced CaAl2O4:Eu2+,Nd3+ powder was investigated in terms of phase composition, morphology and luminescence by X-Ray diffraction (XRD), Scanning Electron Microscope (SEM), Fourier Transform Infra Red spectroscopy (FTIR) and Photoluminescence (PL) techniques respectively. XRD analysis depicts a dominant monoclinic phase that indicates no change in the crystalline structure of the phosphor with varying concentration of Eu2+ and Nd3+. SEM results show agglomerates with non-uniform shapes and sizes with a number of irregular network structures having lots of voids and pores. The Energy Dispersive X-ray Spectroscopy (EDS) and (FTIR) spectra confirm the expected chemical components of the phosphor. PL measurements indicated one broadband excitation spectra from 200 to 300 nm centered around 240 nm corresponding to the crystal field splitting of the Eu2+ d-orbital and an emission spectrum in the blue region with a maximum on 440 nm. This is a strong indication that there was dominantly one luminescence center, Eu2+ which represents emission from transitions between the 4f7 ground state and the 4f6-5d1 excited state configuration. High concentrations of Eu2+ and Nd3+ generally reduce both intensity and lifetime of the phosphor powders. The optimized content of Eu2+ is 1 mol% and for Nd3+ is 1 mol% for the obtained phosphors with excellent optical properties. The phosphor also emits visible light at around 587 and 616 nm. Such emissions can be ascribed to the 5D0-7F1 and 5D0-7F2 intrinsic transition of Eu3+ respectively. The decay characteristics exhibit a significant rise in initial intensity with increasing Eu2+ doping concentration while the decay time increased with Nd3+ co-doping. The observed afterglow can be ascribed to the generation of suitable traps due to the presence of the Nd3

  6. [How to read and understand Registries for Evaluating Patient Outcomes: A User's Guide (2nd Edition)].

    PubMed

    Yang, Wei; Xie, Yan-Ming

    2013-09-01

    Registry studies (RS) get more and more attention in recent years because it can reflect the health care situations of the real world. There are a number of large scale RS for traditional Chinese medicine (TCM). RS are observational studies that can complement randomized controlled trials (RCT). RS have an irreplaceable position in real word study (RWS), especially for small probability events. There are some different characters and qualities in RS. Registries for Evaluating Patient Outcomes: A User's Guide (2nd Edition) was published by the agency for healthcare research and quality (AHRQ) in 2010. It described the details of how to establish, maintain, and evaluate RS, and using 38 RS samples to illustrate the possible problems in undertaking such research. The User's Guide (2nd Edition) provides a reliable reference document for RS. TCM injections post-marketing safety surveillance RS is a national program involving multiple centers in China. This program can further improve RS quality their application in China and is a good illustration of how to follow this guide accurately.

  7. The relation between 1st grade grey matter volume and 2nd grade math competence.

    PubMed

    Price, Gavin R; Wilkey, Eric D; Yeo, Darren J; Cutting, Laurie E

    2016-01-01

    Mathematical and numerical competence is a critical foundation for individual success in modern society yet the neurobiological sources of individual differences in math competence are poorly understood. Neuroimaging research over the last decade suggests that neural mechanisms in the parietal lobe, particularly the intraparietal sulcus (IPS) are structurally aberrant in individuals with mathematical learning disabilities. However, whether those same brain regions underlie individual differences in math performance across the full range of math abilities is unknown. Furthermore, previous studies have been exclusively cross-sectional, making it unclear whether variations in the structure of the IPS are caused by or consequences of the development of math skills. The present study investigates the relation between grey matter volume across the whole brain and math competence longitudinally in a representative sample of 50 elementary school children. Results show that grey matter volume in the left IPS at the end of 1st grade relates to math competence a year later at the end of 2nd grade. Grey matter volume in this region did not change over that year, and was still correlated with math competence at the end of 2nd grade. These findings support the hypothesis that the IPS and its associated functions represent a critical foundation for the acquisition of mathematical competence.

  8. A novel 2nd-order bandpass MFSS filter with miniaturized structure

    NASA Astrophysics Data System (ADS)

    Fang, C. Y.; Gao, J. S.; Feng, X. G.

    2015-08-01

    In order to effectively obtain a miniaturized structure and good filtering properties, we propose a novel 2nd-order bandpass metamaterial frequency selective surface (MFSS) filter which contains two capacitive layers and one inductive layer, where there are multi-loop metallic patches as shunt capacitor C and planar wire grids as series inductor L respectively. Unlike the traditional operation way—the tuned elements used in resonant surface approximately equal to one wavelength in circumference and the structure thickness with a spacing of a quarter wavelength apart, by changing the value of L and C and matching multilayer dielectric to adjust the LC coupling resonance and the resonance impedance respectively, the proposed MFSS filter can achieves a miniatured structure with ideal bandpass properties. Measurement results of the fabricated prototype of the bandpass filter (BPF) indicate that the dimension of the tuned element on resonant surface is approximately 0.025 wavelength, i.e., 0.025λ. At the same time, the filter has the stable center frequency of f0 = 1.53GHz and the transmittance of T ⩾ 96.3% and high Q-value for the TE/TM wave polarization at various incidence angles. The novel 2nd-order bandpass MFSS filter with miniaturized structure not only can decrease structure dimension, but also has a wide range of applications to microwave and infrared band.

  9. Editorial: 2nd Special Issue on behavior change, health, and health disparities

    PubMed Central

    Higgins, Stephen T.

    2016-01-01

    This Special Issue of Preventive Medicine (PM) is the 2nd that we have organized on behavior change, health, and health disparities. This is a topic of fundamental importance to improving population health in the U.S. and other industrialized countries that are trying to more effectively manage chronic health conditions. There is broad scientific consensus that personal behavior patterns such as cigarette smoking, other substance abuse, and physical inactivity/obesity are among the most important modifiable causes of chronic disease and its adverse impacts on population health. As such behavior change needs to be a key component of improving population health. There is also broad agreement that while these problems extend across socioeconomic strata, they are overrepresented among more economically disadvantaged populations and contribute directly to the growing problem of health disparities. Hence, behavior change represents an essential step in curtailing that unsettling problem as well. In this 2nd Special Issue, we devote considerable space to the current U.S. prescription opioid addiction epidemic, a crisis that was not addressed in the prior Special Issue. We also continue to devote attention to the two largest contributors to preventable disease and premature death, cigarette smoking and physical inactivity/obesity as well as risks of co-occurrence of these unhealthy behavior patterns. Across each of these topics we included contributions from highly accomplished policymakers and scientists to acquaint readers with recent accomplishments as well as remaining knowledge gaps and challenges to effectively managing these important chronic health problems. PMID:26257372

  10. Characterization of the 1st and 2nd EF-hands of NADPH oxidase 5 by fluorescence, isothermal titration calorimetry, and circular dichroism

    PubMed Central

    2012-01-01

    Background Superoxide generated by non-phagocytic NADPH oxidases (NOXs) is of growing importance for physiology and pathobiology. The calcium binding domain (CaBD) of NOX5 contains four EF-hands, each binding one calcium ion. To better understand the metal binding properties of the 1st and 2nd EF-hands, we characterized the N-terminal half of CaBD (NCaBD) and its calcium-binding knockout mutants. Results The isothermal titration calorimetry measurement for NCaBD reveals that the calcium binding of two EF-hands are loosely associated with each other and can be treated as independent binding events. However, the Ca2+ binding studies on NCaBD(E31Q) and NCaBD(E63Q) showed their binding constants to be 6.5 × 105 and 5.0 × 102 M-1 with ΔHs of -14 and -4 kJ/mol, respectively, suggesting that intrinsic calcium binding for the 1st non-canonical EF-hand is largely enhanced by the binding of Ca2+ to the 2nd canonical EF-hand. The fluorescence quenching and CD spectra support a conformational change upon Ca2+ binding, which changes Trp residues toward a more non-polar and exposed environment and also increases its α-helix secondary structure content. All measurements exclude Mg2+-binding in NCaBD. Conclusions We demonstrated that the 1st non-canonical EF-hand of NOX5 has very weak Ca2+ binding affinity compared with the 2nd canonical EF-hand. Both EF-hands interact with each other in a cooperative manner to enhance their Ca2+ binding affinity. Our characterization reveals that the two EF-hands in the N-terminal NOX5 are Ca2+ specific. Graphical abstract PMID:22490336

  11. In vitro modeling to determine mutation specificity of EGFR tyrosine kinase inhibitors against clinically relevant EGFR mutants in non-small-cell lung cancer.

    PubMed

    Hirano, Toshiyuki; Yasuda, Hiroyuki; Tani, Tetsuo; Hamamoto, Junko; Oashi, Ayano; Ishioka, Kota; Arai, Daisuke; Nukaga, Shigenari; Miyawaki, Masayoshi; Kawada, Ichiro; Naoki, Katsuhiko; Costa, Daniel B; Kobayashi, Susumu S; Betsuyaku, Tomoko; Soejima, Kenzo

    2015-11-17

    EGFR mutated lung cancer accounts for a significant subgroup of non-small-cell lung cancer (NSCLC). Over the last decade, multiple EGFR tyrosine kinase inhibitors (EGFR-TKIs) have been developed to target mutated EGFR. However, there is little information regarding mutation specific potency of EGFR-TKIs against various types of EGFR mutations. The purpose of this study is to establish an in vitro model to determine the "therapeutic window" of EGFR-TKIs against various types of EGFR mutations, including EGFR exon 20 insertion mutations. The potency of 1st (erlotinib), 2nd (afatinib) and 3rd (osimertinib and rociletinib) generation EGFR-TKIs was compared in vitro for human lung cancer cell lines and Ba/F3 cells, which exogenously express mutated or wild type EGFR. An in vitro model of mutation specificity was created by calculating the ratio of IC50 values between mutated and wild type EGFR. The in vitro model identified a wide therapeutic window of afatinib for exon 19 deletions and L858R and of osimertinib and rociletinib for T790M positive mutations. The results obtained with our models matched well with previously reported preclinical and clinical data. Interestingly, for EGFR exon 20 insertion mutations, most of which are known to be resistant to 1st and 2nd generation EGFR-TKIS, osimertinib was potent and presented a wide therapeutic window. To our knowledge, this is the first report that has identified the therapeutic window of osimertinib for EGFR exon 20 insertion mutations. In conclusion, this model will provide a preclinical rationale for proper selection of EGFR-TKIs against clinically-relevant EGFR mutations.

  12. Establishment of the World Health Organization 2(nd) International Standard for Factor XI, Plasma, Human.

    PubMed

    Wilmot, Helen; Hockley, Jason; Rigsby, Peter; Gray, Elaine

    2017-01-01

    The 1(st) International Standard (IS) for blood coagulation factor XI (FXI), plasma, has been successfully used for potency labeling of FXI therapeutics and for diagnosis of FXI deficiency in patients. With stocks of the 1(st) IS near depletion, a replacement is required. In addition to the functional activity value, assignment of an antigen value to the 2(nd) IS would allow harmonization of antigen assay methods and differentiation of patients who have low functional activity but normal antigen FXI levels from patients who have both low functional and antigen FXI levels. The aims of this study were, therefore, to assign FXI functional activity to the 2(nd) IS for FXI, plasma, and to additionally assign a new analyte, FXI antigen, to the same International Standard. The candidate material was prepared from double-spun, virology negative, normal plasma, which was pooled and filled into siliconized glass ampoules and subsequently freeze-dried. Assignment of the functional activity (FXI:C) value in International Units (IUs) was performed by one-stage clotting assay by 29 laboratories, relative to the 1(st) IS. The overall geometric mean (GM) was 0.71 IU/amp with extremely low inter-laboratory variability (expressed as geometric coefficient of variation) of 1.8%. The antigen value assignment was performed by 11 laboratories and was calculated relative to normal plasma pools, as is customary with new coagulation factor analytes. The amount of antigen present in 1 ml of normal plasma was taken to be 1 U. The overall GM for the antigen assays was 0.78 IU/amp with an inter-laboratory variation of 10%. The candidate (National Institute for Biological Standards and Control code, 15/180) was established by the World Health Organization (WHO) Expert Committee on Biological Standardization in 2016 as the WHO 2(nd) IS for blood coagulation FXI, plasma, with a functional activity value (FXI:C) of 0.71 IU/amp and an antigen value (FXI:Ag) of 0.78 IU/amp.

  13. Establishment of the World Health Organization 2nd International Standard for Factor XI, Plasma, Human

    PubMed Central

    Wilmot, Helen; Hockley, Jason; Rigsby, Peter; Gray, Elaine

    2017-01-01

    The 1st International Standard (IS) for blood coagulation factor XI (FXI), plasma, has been successfully used for potency labeling of FXI therapeutics and for diagnosis of FXI deficiency in patients. With stocks of the 1st IS near depletion, a replacement is required. In addition to the functional activity value, assignment of an antigen value to the 2nd IS would allow harmonization of antigen assay methods and differentiation of patients who have low functional activity but normal antigen FXI levels from patients who have both low functional and antigen FXI levels. The aims of this study were, therefore, to assign FXI functional activity to the 2nd IS for FXI, plasma, and to additionally assign a new analyte, FXI antigen, to the same International Standard. The candidate material was prepared from double-spun, virology negative, normal plasma, which was pooled and filled into siliconized glass ampoules and subsequently freeze-dried. Assignment of the functional activity (FXI:C) value in International Units (IUs) was performed by one-stage clotting assay by 29 laboratories, relative to the 1st IS. The overall geometric mean (GM) was 0.71 IU/amp with extremely low inter-laboratory variability (expressed as geometric coefficient of variation) of 1.8%. The antigen value assignment was performed by 11 laboratories and was calculated relative to normal plasma pools, as is customary with new coagulation factor analytes. The amount of antigen present in 1 ml of normal plasma was taken to be 1 U. The overall GM for the antigen assays was 0.78 IU/amp with an inter-laboratory variation of 10%. The candidate (National Institute for Biological Standards and Control code, 15/180) was established by the World Health Organization (WHO) Expert Committee on Biological Standardization in 2016 as the WHO 2nd IS for blood coagulation FXI, plasma, with a functional activity value (FXI:C) of 0.71 IU/amp and an antigen value (FXI:Ag) of 0.78 IU/amp. PMID:28373973

  14. Simultaneous Vibrant Soundbridge Implantation and 2nd Stage Auricular Reconstruction for Microtia with Aural Atresia

    PubMed Central

    Lim, Lynne Hsueh Yee; Xiang, Ling; del Prado, Jocelynne; Ee Chin, Ling; Beltrame, Millo Achille

    2011-01-01

    Aural atresia and severe microtia are associated malformations that result in problems with hearing and cosmesis, associated speech and language difficulties and diminished self-esteem. In cases where middle ear ossiculoplasty and aural atresia canalplasty are expected to give poor hearing outcomes that would eventually require the use of hearing aids, bone anchored hearing aids or active middle ear implants may be better options. This case report describes a simultaneous Vibrant Soundbridge implantation and 2nd stage auricular reconstruction with rib graft cartilage for an 11-year-old boy with grade III microtia and aural atresia 8 months after the 1st stage reconstruction. Audiometric results of the Vibrant Soundbridge aided ear were comparable to that of the contralateral hearing aid aided ear. PMID:26557321

  15. A Perpendicular Biased 2nd Harmonic Cavity for the Fermilab Booster

    SciTech Connect

    Tan, C. Y.; Dey, J.; Madrak, R. L.; Pellico, W.; Romanov, G.; Sun, D.; Terechkine, I.

    2015-07-13

    A perpendicular biased 2nd harmonic cavity is currently being designed for the Fermilab Booster. Its purpose cavity is to flatten the bucket at injection and thus change the longitudinal beam distribution so that space charge effects are decreased. It can also with transition crossing. The reason for the choice of perpendicular biasing over parallel biasing is that the Q of the cavity is much higher and thus allows the accelerating voltage to be a factor of two higher than a similar parallel biased cavity. This cavity will also provide a higher accelerating voltage per meter than the present folded transmission line cavity. However, this type of cavity presents technical challenges that need to be addressed. The two major issues are cooling of the garnet material from the effects of the RF and the cavity itself from eddy current heating because of the 15 Hz bias field ramp. This paper will address the technical challenge of preventing the garnet from overheating.

  16. Preliminary GPS orbit combination results of the IGS 2nd reprocessing campaign

    NASA Astrophysics Data System (ADS)

    Choi, Kevin

    2015-04-01

    International GNSS Service (IGS) has contributed to the International Terrestrial Reference Frame by reprocessing historic GPS network data and submitting Terrestrial Reference Frame solutions and Earth Rotation Parameters. For the 2nd reprocessing campaign, Analysis Centers (ACs) used up to 21 years of GPS observation data with daily integrations. IERS2010 conventions are applied to model the physical effects of the Earth. Total eight ACs have participated (7 Global solutions, and 2 Tide Gauge solutions) by reprocessing entire time series in a consistent way using the latest models and methodology. IGS combined daily SINEX TRF and EOP combinations have already been submitted to the IERS for ITRF2013. This presentation mainly focuses on the preliminary quality assessment of the reprocessed AC orbits. Quality of the orbit products are examined by examining the repeatability between daily AC satellite ephemeris. Power spectral analysis shows the background noise characteristics of each AC products, and its periodic behaviors.

  17. Computation of equivalent poles placement for class of 2nd order discrete bilinear systems

    NASA Astrophysics Data System (ADS)

    Gadek, Lukasz; Koszalka, Leszek; Burnham, Keith

    2015-11-01

    This paper introduces an adaptation of the classical linear control theory representation of zeros, poles and gain into a bilinear approach. The placement of poles at the complex plane is a complete description of plants dynamics; hence it is a convenient form from which calculation of various properties, e.g. rise time, settling time, is plausible. Such technique can be adjusted into the bilinear structure if poles of a quasi-linear representation (linear with respect to input) are concerned. The research outcomes with conclusion on the equivalent poles displacement and generalized rules for a 2nd order bilinear system equivalent poles input dependent loci. The proposed approach seems to be promising, as simplification of design and identification of a bilinear system increases transparency during modelling and control in practical applications and hence it may be followed by applicability of such structure in common industrial problems.

  18. Simultaneous Vibrant Soundbridge Implantation and 2nd Stage Auricular Reconstruction for Microtia with Aural Atresia.

    PubMed

    Lim, Lynne Hsueh Yee; Xiang, Ling; Del Prado, Jocelynne; Ee Chin, Ling; Beltrame, Millo Achille

    2011-07-01

    Aural atresia and severe microtia are associated malformations that result in problems with hearing and cosmesis, associated speech and language difficulties and diminished self-esteem. In cases where middle ear ossiculoplasty and aural atresia canalplasty are expected to give poor hearing outcomes that would eventually require the use of hearing aids, bone anchored hearing aids or active middle ear implants may be better options. This case report describes a simultaneous Vibrant Soundbridge implantation and 2(nd) stage auricular reconstruction with rib graft cartilage for an 11-year-old boy with grade III microtia and aural atresia 8 months after the 1(st) stage reconstruction. Audiometric results of the Vibrant Soundbridge aided ear were comparable to that of the contralateral hearing aid aided ear.

  19. Roles of the tyrosine isomers meta-tyrosine and ortho-tyrosine in oxidative stress.

    PubMed

    Ipson, Brett R; Fisher, Alfred L

    2016-05-01

    The damage to cellular components by reactive oxygen species, termed oxidative stress, both increases with age and likely contributes to age-related diseases including Alzheimer's disease, atherosclerosis, diabetes, and cataract formation. In the setting of oxidative stress, hydroxyl radicals can oxidize the benzyl ring of the amino acid phenylalanine, which then produces the abnormal tyrosine isomers meta-tyrosine or ortho-tyrosine. While elevations in m-tyrosine and o-tyrosine concentrations have been used as a biological marker of oxidative stress, there is emerging evidence from bacterial, plant, and mammalian studies demonstrating that these isomers, particularly m-tyrosine, directly produce adverse effects to cells and tissues. These new findings suggest that the abnormal tyrosine isomers could in fact represent mediators of the effects of oxidative stress. Consequently the accumulation of m- and o-tyrosine may disrupt cellular homeostasis and contribute to disease pathogenesis, and as result, effective defenses against oxidative stress can encompass not only the elimination of reactive oxygen species but also the metabolism and ultimately the removal of the abnormal tyrosine isomers from the cellular amino acid pool. Future research in this area is needed to clarify the biologic mechanisms by which the tyrosine isomers damage cells and disrupt the function of tissues and organs and to identify the metabolic pathways involved in removing the accumulated isomers after exposure to oxidative stress.

  20. RTKdb: database of receptor tyrosine kinase

    PubMed Central

    Grassot, Julien; Mouchiroud, Guy; Perrière, Guy

    2003-01-01

    Receptor Tyrosine Kinases (RTK) are transmembrane receptors specifically found in metazoans. They represent an excellent model for studying evolution of cellular processes in metazoans because they encompass large families of modular proteins and belong to a major family of contingency generating molecules in eukaryotic cells: the protein kinases. Because tyrosine kinases have been under close scrutiny for many years in various species, they are associated with a wealth of information, mainly in mammals. Presently, most categories of RTK were identified in mammals, but in a near future other model species will be sequenced, and will bring us RTKs from other metazoan clades. Thus, collecting RTK sequences would provide a good starting point as a new model for comparative and evolutionary studies applying to multigene families. In this context, we are developing the Receptor Tyrosine Kinase database (RTKdb), which is the only database on tyrosine kinase receptors presently available. In this database, protein sequences from eight model metazoan species are organized under the format previously used for the HOVERGEN, HOBACGEN and NUREBASE systems. RTKdb can be accessed through the PBIL (Pôle Bioinformatique Lyonnais) World Wide Web server at http://pbil.univ-lyon1.fr/RTKdb/, or through the FamFetch graphical user interface available at the same address. PMID:12520021

  1. Switching to second-generation tyrosine kinase inhibitor improves the response and outcome of frontline imatinib-treated patients with chronic myeloid leukemia with more than 10% of BCR-ABL/ABL ratio at 3 months

    PubMed Central

    Casado, Luis-Felipe; García-Gutiérrez, José-Valentín; Massagué, Isabel; Giraldo, Pilar; Pérez-Encinas, Manuel; de Paz, Raquel; Martínez-López, Joaquín; Bautista, Guiomar; Osorio, Santiago; Requena, María-José; Palomera, Luis; Peñarrubia, María-Jesús; Calle, Carmen; Hernández-Rivas, José-Ángel; Burgaleta, Carmen; Maestro, Begoña; García-Ormeña, Nuria; Steegmann, Juan-Luis

    2015-01-01

    Chronic myeloid leukemia patients display heterogeneous responses to imatinib. Survival depends on baseline clinical characteristics (including prognostic scoring systems) and on early response (such as >10% BCR-ABL/ABL ratio at 3 months of therapy). The results of switching to second-generation tyrosine kinase inhibitors (2GTKIs) may contain a bias since, in the majority of these studies, patients who switch treatment due to intolerance or failure are censored or excluded. We analyzed the Spanish Registry data on switching in an intention-to-treat analysis of patients in standard clinical practice. Switching to 2GTKIs improves responses from 45% to 75% of complete cytogenetic response (CCyR) and from 15% to 45% of major molecular response (MMR) in the group without molecular response 1 (MR1) at 3 months and from 70% to 87% in CCyR and from 52% to 87% in MMR in the group with MR1. The final response rate is poorer in the group with no MR1 at 3 months. Nevertheless, the differences in the rates of response were not translated into differences in major events (transformations or deaths), and the final progression-free survival and overall survival were similar. PMID:25756742

  2. Switching to second-generation tyrosine kinase inhibitor improves the response and outcome of frontline imatinib-treated patients with chronic myeloid leukemia with more than 10% of BCR-ABL/ABL ratio at 3 months.

    PubMed

    Casado, Luis-Felipe; García-Gutiérrez, José-Valentín; Massagué, Isabel; Giraldo, Pilar; Pérez-Encinas, Manuel; de Paz, Raquel; Martínez-López, Joaquín; Bautista, Guiomar; Osorio, Santiago; Requena, María-José; Palomera, Luis; Peñarrubia, María-Jesús; Calle, Carmen; Hernández-Rivas, José-Ángel; Burgaleta, Carmen; Maestro, Begoña; García-Ormeña, Nuria; Steegmann, Juan-Luis

    2015-07-01

    Chronic myeloid leukemia patients display heterogeneous responses to imatinib. Survival depends on baseline clinical characteristics (including prognostic scoring systems) and on early response (such as >10% BCR-ABL/ABL ratio at 3 months of therapy). The results of switching to second-generation tyrosine kinase inhibitors (2GTKIs) may contain a bias since, in the majority of these studies, patients who switch treatment due to intolerance or failure are censored or excluded. We analyzed the Spanish Registry data on switching in an intention-to-treat analysis of patients in standard clinical practice. Switching to 2GTKIs improves responses from 45% to 75% of complete cytogenetic response (CCyR) and from 15% to 45% of major molecular response (MMR) in the group without molecular response 1 (MR1) at 3 months and from 70% to 87% in CCyR and from 52% to 87% in MMR in the group with MR1. The final response rate is poorer in the group with no MR1 at 3 months. Nevertheless, the differences in the rates of response were not translated into differences in major events (transformations or deaths), and the final progression-free survival and overall survival were similar.

  3. Brain order disorder 2nd group report of f-EEG

    NASA Astrophysics Data System (ADS)

    Lalonde, Francois; Gogtay, Nitin; Giedd, Jay; Vydelingum, Nadarajen; Brown, David; Tran, Binh Q.; Hsu, Charles; Hsu, Ming-Kai; Cha, Jae; Jenkins, Jeffrey; Ma, Lien; Willey, Jefferson; Wu, Jerry; Oh, Kenneth; Landa, Joseph; Lin, C. T.; Jung, T. P.; Makeig, Scott; Morabito, Carlo Francesco; Moon, Qyu; Yamakawa, Takeshi; Lee, Soo-Young; Lee, Jong-Hwan; Szu, Harold H.; Kaur, Balvinder; Byrd, Kenneth; Dang, Karen; Krzywicki, Alan; Familoni, Babajide O.; Larson, Louis; Harkrider, Susan; Krapels, Keith A.; Dai, Liyi

    2014-05-01

    Since the Brain Order Disorder (BOD) group reported on a high density Electroencephalogram (EEG) to capture the neuronal information using EEG to wirelessly interface with a Smartphone [1,2], a larger BOD group has been assembled, including the Obama BRAIN program, CUA Brain Computer Interface Lab and the UCSD Swartz Computational Neuroscience Center. We can implement the pair-electrodes correlation functions in order to operate in a real time daily environment, which is of the computation complexity of O(N3) for N=102~3 known as functional f-EEG. The daily monitoring requires two areas of focus. Area #(1) to quantify the neuronal information flow under arbitrary daily stimuli-response sources. Approach to #1: (i) We have asserted that the sources contained in the EEG signals may be discovered by an unsupervised learning neural network called blind sources separation (BSS) of independent entropy components, based on the irreversible Boltzmann cellular thermodynamics(ΔS < 0), where the entropy is a degree of uniformity. What is the entropy? Loosely speaking, sand on the beach is more uniform at a higher entropy value than the rocks composing a mountain - the internal binding energy tells the paleontologists the existence of information. To a politician, landside voting results has only the winning information but more entropy, while a non-uniform voting distribution record has more information. For the human's effortless brain at constant temperature, we can solve the minimum of Helmholtz free energy (H = E - TS) by computing BSS, and then their pairwise-entropy source correlation function. (i) Although the entropy itself is not the information per se, but the concurrence of the entropy sources is the information flow as a functional-EEG, sketched in this 2nd BOD report. Area #(2) applying EEG bio-feedback will improve collective decision making (TBD). Approach to #2: We introduce a novel performance quality metrics, in terms of the throughput rate of faster (

  4. Conference Proceedings: 2nd European Conference of Rehabilitation International; Disability in the Family. (Brighton, England, September 18-21, 1978)

    ERIC Educational Resources Information Center

    Royal Association for Disability and Rehabilitation, London (England).

    The conference proceedings of the 2nd European Conference of Rehabilitation International (1978) on the theme disability in the family contains the agenda and approximately 80 papers. National presentations consider the theme in papers by representatives of Finland, Hungary, Belgium, The Netherlands, Portugal, Hong Kong, India, The German…

  5. Curriculum on the Edge of Survival: How Schools Fail to Prepare Students for Membership in a Democracy. 2nd Edition

    ERIC Educational Resources Information Center

    Heller, Daniel

    2012-01-01

    Typically, school curriculum has been viewed through the lens of preparation for the workplace or higher education, both worthy objectives. However, this is not the only lens, and perhaps not even the most powerful one to use, if the goal is to optimize the educational system. "Curriculum on the Edge of Survival, 2nd Edition," attempts to define…

  6. Comparative analysis of 1st, 2nd, and 4th year MD students' attitudes toward Complementary Alternative Medicine (CAM)

    PubMed Central

    Riccard, Christopher P; Skelton, Michele

    2008-01-01

    Background To identify and report the attitudes and beliefs of 1st, 2nd, and 4th year medical students toward complementary alternative medicine (CAM). Methods The previously validated and reliability tested CHBQ was administered to medical students attending the University of South Florida School of Medicine. Results Significant changes were found between both 1st (46.0 ± 7.7) and 4th (37.8 ± 15.7) year students and 2nd (48.3 ± 7.8) and 4th (37.8 ± 15.7) year students. No significant difference was found between 1st (46.0 ± 7.7) and 2nd (48.3 ± 7.8) year students. When comparing scores based on gender, a significant difference was present between males (41.2 ± 12.2) and females (46.1 ± 11.0). Conclusion CHBQ scores were significantly more positive in both 1st and 2nd year medical students in comparison with 4th year student's scores. These findings suggest that as student exposure to allopathic techniques and procedures increases during the last year of medical school, their attitudes toward CAM decrease. Females were also significantly more likely to have stronger positive attitudes toward CAM than males, though both genders represented an overall positive attitude toward CAM. PMID:18799010

  7. The Hyphen as a Syllabification Cue in Reading Bisyllabic and Multisyllabic Words among Finnish 1st and 2nd Graders

    ERIC Educational Resources Information Center

    Häikiö, Tuomo; Bertram, Raymond; Hyönä, Jukka

    2016-01-01

    Finnish ABC books present words with hyphens inserted at syllable boundaries. Syllabification by hyphens is abandoned in the 2nd grade for bisyllabic words, but continues for words with three or more syllables. The current eye movement study investigated how and to what extent syllable hyphens in bisyllabic ("kah-vi" "cof-fee")…

  8. Give It a Shot! Toolkit for Nurses and Other Immunization Champions Working with Secondary Schools. 2nd Edition

    ERIC Educational Resources Information Center

    Boyer-Chu, Lynda; Wooley, Susan F.

    2008-01-01

    Adolescent immunization saves lives--but promoting immunization takes time and thought, and today's nurses and other health advocates are faced with a host of ever-expanding responsibilities in a time of reduced budgets and staff. This toolkit is thus structured as an easy and reliable resource. This 2nd edition contains: (1) a 64-page manual;…

  9. International Conference on Hyperbolic Problems (2nd). Theory, Numerical Methods and Applications, 14-18 March 1988

    DTIC Science & Technology

    1988-01-01

    SOlution of’ th icai Ele quations. Proceedings of (lie 2nd European Conference on Multigrid 3. - --- AND B. KoRSN (1997). A Non-linear Afiultq,’rid...of Aerospace Engineering Indian Institute of Science Bangalore, India A new upwind scheme called Kinetic Flux Vector Splitting (KFVS) method has been

  10. Perspectives on Art Therapy: The Proceedings of the Pittsburgh Conference on Art Therapy (2nd, Pittsburgh, Pennsylvania, May 20, 1977).

    ERIC Educational Resources Information Center

    Roth, Ellen A., Ed.; Rubin, Judith A., Ed.

    The proceedings of the 2nd annual Pittsburgh Conference on Art Therapy (with handicapped persons) consists of 44 items including full length papers, summaries of previously published papers, descriptions of workshops, and a limited number of abstracts (submitted by those who chose not to present a paper or workshop description). The papers are…

  11. Observation in a School without Walls: Peer Observation of Teaching in a 2nd-12th Grade Independent School

    ERIC Educational Resources Information Center

    Salvador, Josephine

    2012-01-01

    What happens when teachers start to observe each other's classes? How do teachers make meaning of observing and being observed? What effects, if any, does requiring peer observation have on the teaching community? This research explores these questions in a qualitative study of peer observation of teaching (POT) in the 2nd-12th grades of an…

  12. Efficient Simulation of Wing Modal Response: Application of 2nd Order Shape Sensitivities and Neural Networks

    NASA Technical Reports Server (NTRS)

    Kapania, Rakesh K.; Liu, Youhua

    2000-01-01

    At the preliminary design stage of a wing structure, an efficient simulation, one needing little computation but yielding adequately accurate results for various response quantities, is essential in the search of optimal design in a vast design space. In the present paper, methods of using sensitivities up to 2nd order, and direct application of neural networks are explored. The example problem is how to decide the natural frequencies of a wing given the shape variables of the structure. It is shown that when sensitivities cannot be obtained analytically, the finite difference approach is usually more reliable than a semi-analytical approach provided an appropriate step size is used. The use of second order sensitivities is proved of being able to yield much better results than the case where only the first order sensitivities are used. When neural networks are trained to relate the wing natural frequencies to the shape variables, a negligible computation effort is needed to accurately determine the natural frequencies of a new design.

  13. Wind-US Results for the AIAA 2nd Propulsion Aerodynamics Workshop

    NASA Technical Reports Server (NTRS)

    Dippold, Vance III; Foster, Lancert; Mankbadi, Mina

    2014-01-01

    This presentation contains Wind-US results presented at the 2nd Propulsion Aerodynamics Workshop. The workshop was organized by the American Institute of Aeronautics and Astronautics, Air Breathing Propulsion Systems Integration Technical Committee with the purpose of assessing the accuracy of computational fluid dynamics for air breathing propulsion applications. Attendees included representatives from government, industry, academia, and commercial software companies. Participants were encouraged to explore and discuss all aspects of the simulation process including the effects of mesh type and refinement, solver numerical schemes, and turbulence modeling. The first set of challenge cases involved computing the thrust and discharge coefficients for a 25deg conical nozzle for a range of nozzle pressure ratios between 1.4 and 7.0. Participants were also asked to simulate two cases in which the 25deg conical nozzle was bifurcated by a solid plate, resulting in vortex shedding (NPR=1.6) and shifted plume shock (NPR=4.0). A second set of nozzle cases involved computing the discharge and thrust coefficients for a convergent dual stream nozzle for a range of subsonic nozzle pressure ratios. The workshop committee also compared the plume mixing of these cases across various codes and models. The final test case was a serpentine inlet diffuser with an outlet to inlet area ratio of 1.52 and an offset of 1.34 times the inlet diameter. Boundary layer profiles, wall static pressure, and total pressure at downstream rake locations were examined.

  14. Minimal Clinically Important Difference on Parkinson's Disease Sleep Scale 2nd Version

    PubMed Central

    Horváth, Krisztina; Aschermann, Zsuzsanna; Ács, Péter; Deli, Gabriella; Janszky, József; Komoly, Sámuel; Karádi, Kázmér; Kovács, Márton; Makkos, Attila; Faludi, Béla; Kovács, Norbert

    2015-01-01

    Background and Aims. The aim of the present study was to determine the estimates of minimal clinically important difference for Parkinson's Disease Sleep Scale 2nd version (PDSS-2) total score and dimensions. Methods. The subject population consisted of 413 PD patients. At baseline, MDS-UPDRS, Hoehn-Yahr Scale, Mattis Dementia Rating Scale, and PDSS-2 were assessed. Nine months later the PDSS-2 was reevaluated with the Patient-Reported Global Impression Improvement Scale. Both anchor-based techniques (within patients' score change method and sensitivity- and specificity-based method by receiver operating characteristic analysis) and distribution-based approaches (effect size calculations) were utilized to determine the magnitude of minimal clinically important difference. Results. According to our results, any improvements larger than −3.44 points or worsening larger than 2.07 points can represent clinically important changes for the patients. These thresholds have the effect size of 0.21 and −0.21, respectively. Conclusions. Minimal clinically important differences are the smallest change of scores that are subjectively meaningful to patients. Studies using the PDSS-2 as outcome measure should utilize the threshold of −3.44 points for detecting improvement or the threshold of 2.07 points for observing worsening. PMID:26539303

  15. Evaluation of a hand washing program for 2nd-graders.

    PubMed

    Tousman, Stuart; Arnold, Dani; Helland, Wealtha; Roth, Ruth; Heshelman, Nannatte; Castaneda, Oralia; Fischer, Emily; O'Neil, Kristen; Bileto, Stephanie

    2007-12-01

    The purpose of this project was to determine if a multiple-week learner-centered hand washing program could improve hand hygiene behaviors of 2nd-graders in a northern Illinois public school system. Volunteers from the Rockford Hand Washing Coalition went into 19 different classrooms for 4 consecutive weeks and taught a learner-centered program. The program consisted of interactive class discussions and activities using GlitterBug training devices and agar plate materials. A one-factor repeated measure analysis of variance indicated a statistically significant 34% decrease in the absenteeism rate for students in the intervention group. Chi-square analyses on agar plate data indicated that students had cleaner hands after washing. Qualitative data from parents and teachers indicated that a majority of the students were engaging in hand-washing behavior. These results indicate that integrating a learner-centered interactive program in a multiple-week structure can lead to improvement in hand hygiene behavior.

  16. Introduction of the 2nd Phase of the Integrated Hydrologic Model Intercomparison Project

    NASA Astrophysics Data System (ADS)

    Kollet, Stefan; Maxwell, Reed; Dages, Cecile; Mouche, Emmanuel; Mugler, Claude; Paniconi, Claudio; Park, Young-Jin; Putti, Mario; Shen, Chaopeng; Stisen, Simon; Sudicky, Edward; Sulis, Mauro; Ji, Xinye

    2015-04-01

    The 2nd Phase of the Integrated Hydrologic Model Intercomparison Project commenced in June 2013 with a workshop at Bonn University funded by the German Science Foundation and US National Science Foundation. Three test cases were defined and compared that are available online at www.hpsc-terrsys.de including a tilted v-catchment case; a case called superslab based on multiple slab-heterogeneities in the hydraulic conductivity along a hillslope; and the Borden site case, based on a published field experiment. The goal of this phase is to further interrogate the coupling of surface-subsurface flow implemented in various integrated hydrologic models; and to understand and quantify the impact of differences in the conceptual and technical implementations on the simulation results, which may constitute an additional source of uncertainty. The focus has been broadened considerably including e.g. saturated and unsaturated subsurface storages, saturated surface area, ponded surface storage in addition to discharge, and pressure/saturation profiles and cross-sections. Here, first results are presented and discussed demonstrating the conceptual and technical challenges in implementing essentially the same governing equations describing highly non-linear moisture redistribution processes and surface-groundwater interactions.

  17. Studies with Ferrous Sulfamate and Alternate Reductants for 2nd Uranium Cycle

    SciTech Connect

    Crowder, M.L.

    2003-01-15

    A wide range of miniature mixer-settler tests were conducted to determine the source of iron and sulfur contamination in the uranium product stream (''1EU'') of H Canyon's 2nd Uranium Cycle. The problem was reproduced on the laboratory scale mixer-settlers by changing the feed location of ferrous sulfamate from stage D4 to stage D1. Other process variables effected no change. It was later determined that ferrous sulfamate (FS) solids had plugged the FS line to stage D4, causing FS to backup a ventline and enter the Canyon process at stage D1. Pluggage was almost certainly due to precipitation of FS solids during extended process downtime. During the search for the root cause, tests showed that FS solids were quite small (1-10 mm), and a portion of them could bypass the current Canyon prefilter (3-mm). Also, additional tests were done to find an alternate means of reducing and thereby removing plutonium and neptunium from the uranium product. These tests showed that FS was a more effective reductant than either ascorbic acid or a hydroxylamine nitrate (HAN) / dilute FS combination.

  18. Madeira Extreme Floods: 2009/2010 Winter. Case study - 2nd and 20th of February

    NASA Astrophysics Data System (ADS)

    Pires, V.; Marques, J.; Silva, A.

    2010-09-01

    Floods are at world scale the natural disaster that affects a larger fraction of the population. It is a phenomenon that extends it's effects to the surrounding areas of the hydrographic network (basins, rivers, dams) and the coast line. Accordingly to USA FEMA (Federal Emergency Management Agency) flood can be defined as:"A general and temporary condition of partial or complete inundation of two or more acres of normally dry land area or of two or more properties from: Overflow of inland or tidal waters; Unusual and rapid accumulation or runoff of surface waters from any source; Mudflow; Collapse or subsidence of land along the shore of a lake or similar body of water as a result of erosion or undermining caused by waves or currents of water exceeding anticipated cyclical levels that result in a flood as defined above." A flash flood is the result of intense and long duration of continuous precipitation and can result in dead casualties (i.e. floods in mainland Portugal in 1967, 1983 and 1997). The speed and strength of the floods either localized or over large areas, results in enormous social impacts either by the loss of human lives and or the devastating damage to the landscape and human infrastructures. The winter of 2009/2010 in Madeira Island was characterized by several episodes of very intense precipitation (specially in December 2009 and February 2010) adding to a new record of accumulated precipitation since there are records in the island. In February two days are especially rainy with absolute records for the month of February (daily records since 1949): 111mm and 97mm on the 2nd and 20th respectively. The accumulated precipitation ended up with the terrible floods on the 20th of February causing the lost of dozens of human lives and hundreds of millions of Euros of losses The large precipitation occurrences either more intense precipitation in a short period or less intense precipitation during a larger period are sometimes the precursor of

  19. Key role of succinate dehydrogenase in insulin-induced inactivation of protein tyrosine phosphatases.

    PubMed

    Pomytkin, I A; Kolesova, O E

    2002-06-01

    We studied the role of mitochondria in insulin-induced inactivation of protein tyrosine phosphatases in the liver. The mitochondrial respiratory chain is an insulin-sensitive source of H(2)O(2)that acts as a physiological inhibitor of protein tyrosine phosphatases. Succinate dehydrogenase plays a key role in insulin-stimulated generation of H(2)O(2)and inactivation of liver protein tyrosine phosphatases.

  20. The Ratio of 2nd to 4th Digit Length in Korean Alcohol-dependent Patients

    PubMed Central

    Han, Changwoo; Bae, Hwallip; Lee, Yu-Sang; Won, Sung-Doo; Kim, Dai Jin

    2016-01-01

    Objective The ratio of 2nd to 4th digit length (2D:4D) is a sexually dimorphic trait. Men have a relatively shorter second digit than fourth digit. This ratio is thought to be influenced by higher prenatal testosterone level or greater sensitivity to androgen. The purpose of this study is to investigate the relationship between alcohol dependence and 2D:4D in a Korean sample and whether 2D:4D can be a biologic marker in alcohol dependence. Methods In this study, we recruited 87 male patients with alcohol dependence from the alcohol center of one psychiatric hospital and 52 healthy male volunteers who were all employees in the same hospital as controls. We captured images of the right and left hands of patients and controls using a scanner and extracted data with a graphics program. We measured the 2D:4D of each hand and compared the alcohol dependence group with the control group. We analyzed these ratios using an independent-samples t-test. Results The mean 2D:4D of patients was 0.934 (right hand) and 0.942 (left hand), while the mean 2D:4D of controls was 0.956 (right hand) and 0.958 (left hand). Values for both hands were significantly lower for patients than controls (p<0.001, right hand; p=0.004, left hand). Conclusion Patients who are alcohol dependent have a significantly lower 2D:4D than controls, similar to the results of previous studies, which suggest that a higher prenatal testosterone level in the gonadal period is related to alcoholism. Furthermore, 2D:4D is a possible predictive marker of alcohol dependence. PMID:27121425

  1. PREFACE: 2nd International Conference on Competitive Materials and Technological Processes (IC-CMTP2)

    NASA Astrophysics Data System (ADS)

    László, Gömze A.

    2013-12-01

    Competitiveness is one of the most important factors in our life and it plays a key role in the efficiency both of organizations and societies. The more scientifically supported and prepared organizations develop more competitive materials with better physical, chemical and biological properties and the leading companies apply more competitive equipment and technology processes. The aims of the 2nd International Conference on Competitive Materials and Technology Processes (ic-cmtp2) are the following: Promote new methods and results of scientific research in the fields of material, biological, environmental and technology sciences; Change information between the theoretical and applied sciences as well as technical and technological implantations. Promote the communication between the scientist of different nations, countries and continents. Among the major fields of interest are materials with extreme physical, chemical, biological, medical, thermal, mechanical properties and dynamic strength; including their crystalline and nano-structures, phase transformations as well as methods of their technological processes, tests and measurements. Multidisciplinary applications of materials science and technological problems encountered in sectors like ceramics, glasses, thin films, aerospace, automotive and marine industry, electronics, energy, construction materials, medicine, biosciences and environmental sciences are of particular interest. In accordance to the program of the conference ic-cmtp2, more than 250 inquiries and registrations from different organizations were received. Researchers from 36 countries in Asia, Europe, Africa, North and South America arrived at the venue of conference. Including co-authors, the research work of more than 500 scientists are presented in this volume. Professor Dr Gömze A László Chair, ic-cmtp2 The PDF also contains lists of the boards, session chairs and sponsors.

  2. Conference Report on the 2nd International Symposium on Lithium Applications for Fusion Devices

    NASA Astrophysics Data System (ADS)

    Ono, M.; Bell, M. G.; Hirooka, Y.; Kaita, R.; Kugel, H. W.; Mazzitelli, G.; Menard, J. E.; Mirnov, S. V.; Shimada, M.; Skinner, C. H.; Tabares, F. L.

    2012-03-01

    The 2nd International Symposium on Lithium Applications for Fusion Devices (ISLA-2011) was held on 27-29 April 2011 at the Princeton Plasma Physics Laboratory (PPPL) with broad participation from the community working on aspects of lithium research for fusion energy development. This community is expanding rapidly in many areas including experiments in magnetic confinement devices and a variety of lithium test stands, theory and modeling and developing innovative approaches. Overall, 53 presentations were given representing 26 institutions from 10 countries. The latest experimental results from nine magnetic fusion devices were given in 24 presentations, from NSTX (PPPL, USA), LTX (PPPL, USA), FT-U (ENEA, Italy), T-11M (TRINITY, RF), T-10 (Kurchatov Institute, RF), TJ-II (CIEMAT, Spain), EAST (ASIPP, China), HT-7 (ASIPP, China), and RFX (Padova, Italy). Sessions were devoted to: I. Lithium in magnetic confinement experiments (facility overviews), II. Lithium in magnetic confinement experiments (topical issues), III. Special session on liquid lithium technology, IV. Lithium laboratory test stands, V. Lithium theory/modeling/comments, VI. Innovative lithium applications and VII. Panel discussion on lithium PFC viability in magnetic fusion reactors. There was notable participation from the fusion technology communities, including the IFE, IFMIF and TBM communities providing productive exchanges with the physics oriented magnetic confinement lithium research groups. It was agreed to continue future exchanges of ideas and data to help develop attractive liquid lithium solutions for very challenging magnetic fusion issues, such as development of a high heat flux steady-state divertor concept and acceptable plasma disruption mitigation techniques while improving plasma performance with lithium. The next workshop will be held at ENEA, Frascati, Italy in 2013.

  3. A convective divertor utilizing a 2nd-order magnetic field null

    NASA Astrophysics Data System (ADS)

    Rognlien, Thomas

    2014-10-01

    New results motivate a detailed study of a magnetic divertor concept characterized by strong plasma convection near a poloidal magnetic field (Bp) null region. The configuration is that of a near-2nd-order Bp null (Bp ~ Δ r2) , as in a snowflake divertor. The concept has 2 key features: (A) Convection spreads the heat flux between multiple divertor legs and further broadens the heat-flux profile within each leg, thereby greatly reducing target-plate heat loads. (B) The heat flux is further reduced by line radiation in each leg in detachment-like ionization zones. Theory indicates that convective turbulence arises when the poloidal plasma beta, βp = 2μ0nT/B p 2 >> 1 . Measurements in TCV now more fully quantify earlier NSTX and TCV observations of plasma mixing, and related modeling of TCV indicates that strongly enhanced null-region transport is present. Convective mixing provides a stabilizing mechanism to prevent the ionization fronts (hydrogenic and impurity) from collapsing to a highly radiating core MARFE. Also, the radiating zone maps to a very small region at the midplane owing to the very weak Bp in the convective region, thus minimizing its impact on the core plasma. Detailed calculations are reported that combine features A and B noted above. The plasma mixing mechanisms are described together with the corresponding transport model implemented in the 2D UEDGE edge transport code. UEDGE calculations are presented that quantify the roles of mixing, impurity radiation, and detachment stability for a realistic snowflake configuration. Work in collaboration with D.D. Ryutov, S.I. Krasheninnikov, and M.V. Umansky. Performed for the U.S. DoE by LLNS, LLC, LLNL, under Contract DE-AC52-07NA27344.

  4. The Influence of Instructional Climates on Time Spent in Management Tasks and Physical Activity of 2nd-Grade Students during Physical Education

    ERIC Educational Resources Information Center

    Logan, Samuel W.; Robinson, Leah E.; Webster, E. Kipling; Rudisill, Mary E.

    2015-01-01

    The purpose of this study is to determine the effect of two physical education (PE) instructional climates (mastery, performance) on the percentage of time students spent in a) moderate-to-vigorous physical activity (MVPA) and b) management tasks during PE in 2nd-grade students. Forty-eight 2nd graders (mastery, n = 23; performance, n = 25)…

  5. Evaluation of the Battelle Developmental Inventory, 2nd Edition, Screening Test for Use in States' Child Outcomes Measurement Systems under the Individuals with Disabilities Education Act

    ERIC Educational Resources Information Center

    Elbaum, Batya; Gattamorta, Karina A.; Penfield, Randall D.

    2010-01-01

    This study evaluated the Battelle Developmental Inventory, 2nd Edition, Screening Test (BDI-2 ST) for use in states' child outcomes accountability systems under the Individuals with Disabilities Education Act. Complete Battelle Developmental Inventory, 2nd Edition (BDI-2), assessment data were obtained for 142 children, ages 2 to 62 months, who…

  6. Tyrosine phosphorylation of WW proteins

    PubMed Central

    Reuven, Nina; Shanzer, Matan

    2015-01-01

    A number of key regulatory proteins contain one or two copies of the WW domain known to mediate protein–protein interaction via proline-rich motifs, such as PPxY. The Hippo pathway components take advantage of this module to transduce tumor suppressor signaling. It is becoming evident that tyrosine phosphorylation is a critical regulator of the WW proteins. Here, we review the current knowledge on the involved tyrosine kinases and their roles in regulating the WW proteins. PMID:25627656

  7. Differential contribution of specific working memory components to mathematics achievement in 2nd and 3rd graders.

    PubMed

    Meyer, M L; Salimpoor, V N; Wu, S S; Geary, D C; Menon, V

    2010-04-01

    The contribution of the three core components of working memory (WM) to the development of mathematical skills in young children is poorly understood. The relation between specific WM components and Numerical Operations, which emphasize computation and fact retrieval, and Mathematical Reasoning, which emphasizes verbal problem solving abilities in 48 2nd and 50 3rd graders was assessed using standardized WM and mathematical achievement measures. For 2nd graders, the central executive and phonological components predicted Mathematical Reasoning skills; whereas the visuo-spatial component predicted both Mathematical Reasoning and Numerical Operations skills in 3rd graders. This pattern suggests that the central executive and phonological loop facilitate performance during early stages of mathematical learning whereas visuo-spatial representations play an increasingly important role during later stages. We propose that these changes reflect a shift from prefrontal to parietal cortical functions during mathematical skill acquisition. Implications for learning and individual differences are discussed.

  8. [Re-operations for 2nd primary lung cancer detected during follow-up after lung cancer surgery].

    PubMed

    Tsuchida, Masanori

    2013-07-01

    Re-operations for 2nd primary lung cancers are one of the most challenging modality for thoracic surgeons. Surgeons should have knowledge of indication of re-operations as well as surgical techniques and perioperative management of patients with 2nd primary lung cancers. When performing repeated pulmonary resection on the same side of the 1st surgery, following points are important for accomplishment of a safe re-operation:1.Wide thoracotomy with muscle dissections is recommended. 2.Throughout adhesion lysis between lung parenchyma and surrounding structures are required before manipulating pulmonary vessels. 3.The main pulmonary artery is encircled before dissection of the pulmonary artery. 4.Surgeons should be familiar with intrapericardial exposure of the main pulmonary artery. The techniques consist of division of the ligament of arteriosum, incision of the pericardium, and encircle of the origin of the mail pulmonary. Re-operations for metachronous lung cancers provided favorable survival in patients with adequate physiologic pulmonary reserve.

  9. Physical properties of double perovskite-type barium neodymium osmate Ba{sub 2}NdOsO{sub 6}

    SciTech Connect

    Wakeshima, Makoto; Hinatsu, Yukio; Ohoyama, Kenji

    2013-01-15

    The crystal, magnetic structures and physical properties of the double perovskite-type barium neodymium osmate Ba{sub 2}NdOsO{sub 6} are investigated through powder X-ray and neutron diffraction, electrical conductivity, magnetic susceptibility, and specific heat measurements. The Rietveld analysis reveals that the Nd and Os ions are arranged with regularity over the six-coordinate B sites in a distorted perovskite ABO{sub 3} framework. The monoclinic crystal structure described by space group P2{sub 1}/n (tilt system a{sup -}a{sup -}c{sup +}) becomes more distorted with decreasing temperature from 300 K down to 2.5 K. This compound shows a long-range antiferromagnetic ordering of Os{sup 5+} below 65 K. An antiferromagnetic ordering of Nd{sup 3+} also occurs at lower temperatures ({approx}20 K). The magnetic structure is of Type I and the magnetic moments of Nd{sup 3+} and Os{sup 5+} ions are in the same direction in the ab-plane. - Graphical Abstract: The Magnetic structure of Ba{sub 2}NdOsO{sub 6} is of Type I, and the magnetic moments of the Nd{sup 3+} and Os{sup 5+} ions are in the same direction in the ab-plane. Highlights: Black-Right-Pointing-Pointer Crystal structures of Ba{sub 2}NdOsO{sub 6} are determined to be monoclinic below 300 K. Black-Right-Pointing-Pointer Its electrical resistivity shows a Mott variable-range hopping behavior with localized carriers. Black-Right-Pointing-Pointer An antiferromagnetic ordering of the Os{sup 5+}moment occurs at 65 K. Black-Right-Pointing-Pointer The magnetic structure of Ba{sub 2}NdOsO{sub 6} is determined to be of Type I.

  10. Teachers' Spatial Anxiety Relates to 1st-and 2nd-Graders' Spatial Learning

    ERIC Educational Resources Information Center

    Gunderson, Elizabeth A.; Ramirez, Gerardo; Beilock, Sian L.; Levine, Susan C.

    2013-01-01

    Teachers' anxiety about an academic domain, such as math, can impact students' learning in that domain. We asked whether this relation held in the domain of spatial skill, given the importance of spatial skill for success in math and science and its malleability at a young age. We measured 1st-and 2nd-grade teachers' spatial anxiety…

  11. White Paper Summary of 2nd ASTM International Workshop on Hydrides in Zirconium Alloy Cladding

    SciTech Connect

    Sindelar, R.; Louthan, M.; PNNL, B.

    2015-05-29

    This white paper recommends that ASTM International develop standards to address the potential impact of hydrides on the long term performance of irradiated zirconium alloys. The need for such standards was apparent during the 2nd ASTM International Workshop on Hydrides in Zirconium Alloy Cladding and Assembly Components, sponsored by ASTM International Committee C26.13 and held on June 10-12, 2014, in Jackson, Wyoming. The potentially adverse impacts of hydrogen and hydrides on the long term performance of irradiated zirconium-alloy cladding on used fuel were shown to depend on multiple factors such as alloy chemistry and processing, irradiation and post irradiation history, residual and applied stresses and stress states, and the service environment. These factors determine the hydrogen content and hydride morphology in the alloy, which, in turn, influence the response of the alloy to the thermo-mechanical conditions imposed (and anticipated) during storage, transport and disposal of used nuclear fuel. Workshop presentations and discussions showed that although hydrogen/hydride induced degradation of zirconium alloys may be of concern, the potential for occurrence and the extent of anticipated degradation vary throughout the nuclear industry because of the variations in hydrogen content, hydride morphology, alloy chemistry and irradiation conditions. The tools and techniques used to characterize hydrides and hydride morphologies and their impacts on material performance also vary. Such variations make site-to-site comparisons of test results and observations difficult. There is no consensus that a single material or system characteristic (e.g., reactor type, burnup, hydrogen content, end-of life stress, alloy type, drying temperature, etc.) is an effective predictor of material response during long term storage or of performance after long term storage. Multi-variable correlations made for one alloy may not represent the behavior of another alloy exposed to

  12. PREFACE: 1st-2nd Young Researchers Meetings in Rome - Proceedings

    NASA Astrophysics Data System (ADS)

    YRMR Organizing Committee; Cannuccia, E.; Mazzaferro, L.; Migliaccio, M.; Pietrobon, D.; Stellato, F.; Veneziani, M.

    2011-03-01

    Students in science, particularly in physics, face a fascinating and challenging future. Scientists have proposed very interesting theories, which describe the microscopic and macroscopic world fairly well, trying to match the quantum regime with cosmological scales. Between the extremes of this scenario, biological phenomena in all their complexity take place, challenging the laws we observe in the atomic and sub-atomic world. More and more accurate and complex experiments have been devised and these are now going to test the paradigms of physics. Notable experiments include: the Large Hadronic Collider (LHC), which is going to shed light on the physics of the Standard Model of Particles and its extensions; the Planck-Herschel satellites, which target a very precise measurement of the properties of our Universe; and the Free Electron Lasers facilities, which produce high-brilliance, ultrafast X-ray pulses, allowing the investigation of the fundamental processes of solid state physics, chemistry, and biology. These projects are the result of huge collaborations spread across the world, involving scientists belonging to different and complementary research fields: physicists, chemists, biologists and others, keen to make the best of these extraordinary laboratories. Even though each branch of science is experiencing a process of growing specialization, it is very important to keep an eye on the global picture, remaining aware of the deep interconnections between inherent fields. This is even more crucial for students who are beginning their research careers. These considerations motivated PhD students and young post-docs connected to the Roman scientific research area to organize a conference, to establish the background and the network for interactions and collaborations. This resulted in the 1st and 2nd Young Researchers Meetings in Rome (http://ryrm.roma2.infn.it), one day conferences aimed primarily at graduate students and post-docs, working in physics in Italy

  13. A semisynthetic Eph receptor tyrosine kinase provides insight into ligand-induced kinase activation

    PubMed Central

    Singla, Nikhil; Erdjument-Bromage, Hediye; Himanen, Juha P.; Muir, Tom W.; Nikolov, Dimitar B.

    2011-01-01

    SUMMARY We have developed a methodology for generating milligram amounts of functional Eph tyrosine kinase receptor using the protein engineering approach of expressed protein ligation. Stimulation with ligand induces efficient autophosphorylation of the semisynthetic Eph construct. The in vitro phosphorylation of key Eph tyrosine residues upon ligand-induced activation was monitored via time-resolved, quantitative phosphoproteomics, suggesting a precise and unique order of phosphorylation of the Eph tyrosines in the kinase activation process. To our knowledge, this work represents the first reported semisynthesis of a receptor tyrosine kinase and provides a potentially general method for producing single-pass membrane proteins for structural and biochemical characterization. PMID:21439481

  14. A redox-regulated tyrosine phosphorylation cascade in rat spermatozoa.

    PubMed

    Lewis, B; Aitken, R J

    2001-01-01

    Rat spermatozoa from both the caput and cauda epididymidis were shown to generate superoxide anion (O2-.) both spontaneously and following stimulation with NAD(P)H. Caput spermatozoa gave a significantly greater O2- response to NADPH stimulation than caudal cells, whereas in both cell types the responses to exogenous NADPH and NADH were approximately equivalent. Analysis of H2O2 production revealed that this oxidant was generated only by caudal epididymal cells and only in these cells did the stimulation of reactive oxygen species (ROS) production with NADPH lead to an increase in tyrosine phosphorylation. Stimulation of ROS production with NADPH increased intracellular cyclic adenosine monophosphate (cAMP) levels in both caput and caudal epididymal cells, but only in caudal cells did cAMP stimulate tyrosine phosphorylation, in keeping with the NADPH results. On the basis of these findings we propose that tyrosine phosphorylation in rat spermatozoa is driven by ROS acting via 2 different but complementary mechanisms; O2-. stimulates tyrosine kinase activity indirectly through the elevation of intracellular cAMP while H2O2 acts directly on the kinase/phosphatase system, stimulating the former and inhibiting the latter. Zinc was examined as a potential regulator of this signal transduction cascade and was shown to suppress tyrosine phosphorylation in caput cells but to promote this activity in caudal spermatozoa, possibly through an inhibitory effect on tyrosine phosphatase activity. These results reveal the maturation of a redox-regulated, cAMP-mediated, signal transduction cascade during epididymal transit in the rat that is sensitive to zinc and plays a key role in the control of tyrosine phosphorylation events associated with capacitation.

  15. Tyrosine - Effects on catecholamine release

    NASA Technical Reports Server (NTRS)

    Acworth, Ian N.; During, Matthew J.; Wurtman, Richard J.

    1988-01-01

    Tyrosine administration elevates striatal levels of dopamine metabolites in animals given treatments that accelerate nigrostriatal firing, but not in untreated rats. We examined the possibility that the amino acid might actually enhance dopamine release in untreated animals, but that the technique of measuring striatal dopamine metabolism was too insensitive to demonstrate such an effect. Dopamine release was assessed directly, using brain microdialysis of striatal extracellular fluid. Tyrosine administration (50-200 mg/kg IP) did indeed cause a dose related increase in extracellular fluid dopamine levels with minor elevations in levels of DOPAC and HVA, its major metabolites, which were not dose-related. The rise in dopamine was short-lived, suggesting that receptor-mediated feedback mechanisms responded to the increased dopamine release by diminishing neuronal firing or sensitivity to tyrosine. These observations indicate that measurement of changes in striatal DOPAC and HVA, if negative, need not rule out increases in nigrostriatal dopamine release.

  16. Proceedings of the Biennial EO/EEO Research Symposium (2nd) Held in Cocoa Beach, Florida on December 2-4, 1997

    DTIC Science & Technology

    1998-04-01

    PROCEEDINGS 2ND BIENNIAL EO/EEO RESEARCH SYMPOSIUM December 2-4, 1997 Cocoa Beach, Florida Sponsored by the Directorate of Research Defense Equal...2-89) Prescribed by ANSI Std. Z39-18 298-102 USAPPC V1.00 PROCEEDINGS 2nd BIENNIAL EO/EEO RESEARCH SYMPOSIUM December 2-4, 1997 COCOA BEACH, FLORIDA...Proceedings Editor Published April 1998 Preface PROCEEDINGS 2nd BIENNIAL EO/EEO RESEARCH SYMPOSIUM December 2-4, 1997 COCOA BEACH, FLORIDA The EO/EEO

  17. Development of a 2nd Generation Decision Support Tool to Optimize Resource and Energy Recovery for Municipal Solid Waste

    EPA Science Inventory

    In 2012, EPA’s Office of Research and Development released the MSW decision support tool (MSW-DST) to help identify strategies for more sustainable MSW management. Depending upon local infrastructure, energy grid mix, population density, and waste composition and quantity, the m...

  18. Explaining the Success of High-Achieving 2nd-Generation Latino Students at Elite Colleges and Universities

    ERIC Educational Resources Information Center

    Kula, Stacy M.

    2013-01-01

    Latinos represent the largest minority population in the US, yet are one of the most underserved groups in the educational system. As such, they have been the focus of much attention by educational researchers. However, there is little work enabling researchers to understand how many factors might interactively support achievement. Moreover, the…

  19. 2nd Generation RLV Risk Reduction Definition Program: Pratt & Whitney Propulsion Risk Reduction Requirements Program (TA-3 & TA-4)

    NASA Technical Reports Server (NTRS)

    Matlock, Steve

    2001-01-01

    This is the final report and addresses all of the work performed on this program. Specifically, it covers vehicle architecture background, definition of six baseline engine cycles, reliability baseline (space shuttle main engine QRAS), and component level reliability/performance/cost for the six baseline cycles, and selection of 3 cycles for further study. This report further addresses technology improvement selection and component level reliability/performance/cost for the three cycles selected for further study, as well as risk reduction plans, and recommendation for future studies.

  20. Research at the CEA in the field of safety in 2nd and 3rd generation light water reactors

    NASA Astrophysics Data System (ADS)

    Billot, Philippe

    2012-05-01

    The research programs at the CEA in the field of safety in nuclear reactors are carried out in a framework of international partnerships. Their purpose is to develop studies on: The methods allowing for the determination of earthquake hazards and their consequences; The behaviour of fuel in an accident situation; The comprehension of deflagration and detonation phenomena of hydrogen and the search for effective prevention methods involving an explosion risk; The cooling of corium in order to stop its progression in and outside the vessel thereby reducing the risk of perforating the basemat; The behaviour of the different fission product families according to their volatility for the UO2 and MOX fuels.

  1. Evaluation of 2nd generation flue gas conditioning for hot-side and cold-side ESPs

    SciTech Connect

    Durham, M.D.; Bustard, C.J.; Baldrey, K.E.; Martin, C.E.; Jackson, D.W.; Lindsey, C.V.; Millar, T.J.

    1999-07-01

    New and emerging regulations such as PM2.5 and restrictions on emission of air toxics have created a demand for new technologies to reduce the emissions of fine particles from large industrial sources. ADA Environmental Solutions, LLC (ADA-ES) has commercialized a family of proprietary, flue gas conditioning agents to provide utilities and industries with a cost-effective means of complying with environmental regulations on particulate emissions and opacity. The phosphate-based flue gas conditioning additives decrease particle resistivity and improve the performance of ESPs with resistivity related performance problems. In addition, the new additives are effective on a wide range of coal-ash chemistries, which allows the utility flexibility to select the most economical coal. Finally, this technology is effective in applications where conventional SO{sub 3} flue gas conditioning does not work such as hot-side ESPs and cold-side ESPs that operate above 375 degrees F. Based upon performance and economic criteria, ADA-ES expects to fill the following niches for improving performance of ESPs: (1) All hot-side ESPs and warm-side ({gt}350 degrees F) ESPs; (2) Cold-side ESPs with difficult to collect ash, such as those collecting ash from PRB coal; (3) Older units with limited operating life remaining; (4) ESP's that annually only need conditioning on an intermittent basis; and (5) Units that burn several coals with only a few that cause problems. This paper provides a summary of the relevant experience gained from the use of the ADA-ES conditioning technology at several different sites. Laboratory tests are presented which help explain the performance observed at some sites. In addition, a description of the development and the latest results from full-scale trials with an improved version of the product, ADA-34, are presented.

  2. 2nd Radio and Antenna Days of the Indian Ocean (RADIO 2014)

    NASA Astrophysics Data System (ADS)

    2014-10-01

    It was an honor and a great pleasure for all those involved in its organization to welcome the participants to the ''Radio and Antenna Days of the Indian Ocean'' (RADIO 2014) international conference that was held from 7th to 10th April 2014 at the Sugar Beach Resort, Wolmar, Flic-en-Flac, Mauritius. RADIO 2014 is the second of a series of conferences organized in the Indian Ocean region. The aim of the conference is to discuss recent developments, theories and practical applications covering the whole scope of radio-frequency engineering, including radio waves, antennas, propagation, and electromagnetic compatibility. The RADIO international conference emerged following discussions with engineers and scientists from the countries of the Indian Ocean as well as from other parts of the world and a need was felt for the organization of such an event in this region. Following numerous requests, the Island of Mauritius, worldwide known for its white sandy beaches and pleasant tropical atmosphere, was again chosen for the organization of the 2nd RADIO international conference. The conference was organized by the Radio Society, Mauritius and the Local Organizing Committee consisted of scientists from SUPELEC, France, the University of Mauritius, and the University of Technology, Mauritius. We would like to take the opportunity to thank all people, institutions and companies that made the event such a success. We are grateful to our gold sponsors CST and FEKO as well as URSI for their generous support which enabled us to partially support one PhD student and two scientists to attend the conference. We would also like to thank IEEE-APS and URSI for providing technical co-sponsorship. More than hundred and thirty abstracts were submitted to the conference. They were peer-reviewed by an international scientific committee and, based on the reviews, either accepted, eventually after revision, or rejected. RADIO 2014 brought together participants from twenty countries spanning

  3. 2nd International Conference on Rheology and Modeling of Materials (IC-RMM2)

    NASA Astrophysics Data System (ADS)

    2017-01-01

    Understanding the rheological properties of materials and their rheological behaviors during their manufacturing processes and in their applications in many cases can help to increase the efficiency and competitiveness not only of the finished goods and products but the organizations and societies also. The more scientific supported and prepared organizations develop more competitive products with better thermal, mechanical, physical, chemical and biological properties and the leading companies apply more competitive equipment and technology processes. The aims of the 2nd International Conference on Rheology and Modeling of Materials (ic-rmm2) and the parallel organized symposiums of the 1st International Symposium on Powder Injection Molding (is-pim1) and the 1st International Symposium on Rheology and Fracture of Solids (is-rfs1) are the followings: Promote new methods and results of scientific research in the fields of modeling and measurements of rheological properties and behavior of materials under processing and applications; Change information between the theoretical and applied sciences as well as technical and technological implantations. Promote the communication and collaboration between the scientists, researchers and engineers of different disciplines, different nations, countries and continents. The international conference ic-rmm2 and symposiums of is-pim1 and is-rfs1 provide a platform among the leading international scientists, researchers, PhD students and engineers for discussing recent achievements in measurement, modeling and application of rheology in materials technology and materials science of liquids, melts, solids, crystals and amorphous structures. Among thr major fields of interest are the influence of materials structures, mechanical stresses, temperatures, deformation speeds and shear rates on rheological and physical properties, phase transformation of foams, foods, polymers, plastics and other competitive materials like ceramics

  4. Development of Hydrologic Characterization Technology of Fault Zones -- Phase I, 2nd Report

    SciTech Connect

    Karasaki, Kenzi; Onishi, Tiemi; Black, Bill; Biraud, Sebastien

    2009-03-31

    This is the year-end report of the 2nd year of the NUMO-LBNL collaborative project: Development of Hydrologic Characterization Technology of Fault Zones under NUMO-DOE/LBNL collaboration agreement, the task description of which can be found in the Appendix 3. Literature survey of published information on the relationship between geologic and hydrologic characteristics of faults was conducted. The survey concluded that it may be possible to classify faults by indicators based on various geometric and geologic attributes that may indirectly relate to the hydrologic property of faults. Analysis of existing information on the Wildcat Fault and its surrounding geology was performed. The Wildcat Fault is thought to be a strike-slip fault with a thrust component that runs along the eastern boundary of the Lawrence Berkeley National Laboratory. It is believed to be part of the Hayward Fault system but is considered inactive. Three trenches were excavated at carefully selected locations mainly based on the information from the past investigative work inside the LBNL property. At least one fault was encountered in all three trenches. Detailed trench mapping was conducted by CRIEPI (Central Research Institute for Electric Power Industries) and LBNL scientists. Some intriguing and puzzling discoveries were made that may contradict with the published work in the past. Predictions are made regarding the hydrologic property of the Wildcat Fault based on the analysis of fault structure. Preliminary conceptual models of the Wildcat Fault were proposed. The Wildcat Fault appears to have multiple splays and some low angled faults may be part of the flower structure. In parallel, surface geophysical investigations were conducted using electrical resistivity survey and seismic reflection profiling along three lines on the north and south of the LBNL site. Because of the steep terrain, it was difficult to find optimum locations for survey lines as it is desirable for them to be as

  5. Distinct tyrosine autophosphorylation sites negatively and positively modulate neu-mediated transformation.

    PubMed Central

    Dankort, D L; Wang, Z; Blackmore, V; Moran, M F; Muller, W J

    1997-01-01

    A number of cytoplasmic signaling molecules are thought to mediate mitogenic signaling from the activated Neu receptor tyrosine kinase through binding specific phosphotyrosine residues located within the intracellular portion of Neu/c-ErbB-2. An activated neu oncogene containing tyrosine-to-phenylalanine substitutions at each of the known autophosphorylation sites was generated and assessed for its specific transforming potential in Rat1 and NIH 3T3 fibroblasts. Mutation of these sites resulted in a dramatic impairment of the transforming potential of neu. To assess the role of these tyrosine phosphorylation sites in cellular transformation, the transforming potential of a series of mutants in which individual tyrosine residues were restored to this transformation-debilitated neu mutant was evaluated. Reversion of any one of four mutated sites to tyrosine residues restored wild-type transforming activity. While each of these transforming mutants displayed Ras-dependent signaling, the transforming activity of two of these mutants was correlated with their ability to bind either the GRB2 or SHC adapter molecules that couple receptor tyrosine kinases to the Ras signaling pathway. By contrast, restoration of a tyrosine residue located at position 1028 completely suppressed the basal transforming activity of this mutated neu molecule or other transforming neu molecules which possessed single tyrosine residues. These data argue that the transforming potential of activated neu is mediated both by positive and negative regulatory tyrosine phosphorylation sites. PMID:9271418

  6. Discovering the first tyrosine kinase.

    PubMed

    Hunter, Tony

    2015-06-30

    In the middle of the 20th century, animal tumor viruses were heralded as possible models for understanding human cancer. By the mid-1970s, the molecular basis by which tumor viruses transform cells into a malignant state was beginning to emerge as the first viral genomic sequences were reported and the proteins encoded by their transforming genes were identified and characterized. This was a time of great excitement and rapid progress. In 1978, prompted by the discovery from Ray Erikson's group that the Rous sarcoma virus (RSV) v-Src-transforming protein had an associated protein kinase activity specific for threonine, my group at the Salk Institute set out to determine whether the polyomavirus middle T-transforming protein had a similar kinase activity. Here, I describe the experiments that led to the identification of a kinase activity associated with middle T antigen and our serendipitous discovery that this activity was specific for tyrosine in vitro, and how this in turn led to the fortuitous observation that the v-Src-associated kinase activity was also specific for tyrosine. Our finding that v-Src increased the level of phosphotyrosine in cellular proteins in RSV-transformed cells confirmed that v-Src is a tyrosine kinase and transforms cells by phosphorylating proteins on tyrosine. My colleague Bart Sefton and I reported these findings in the March issue of PNAS in 1980. Remarkably, all of the experiments in this paper were accomplished in less than one month.

  7. Discovering the first tyrosine kinase

    PubMed Central

    Hunter, Tony

    2015-01-01

    In the middle of the 20th century, animal tumor viruses were heralded as possible models for understanding human cancer. By the mid-1970s, the molecular basis by which tumor viruses transform cells into a malignant state was beginning to emerge as the first viral genomic sequences were reported and the proteins encoded by their transforming genes were identified and characterized. This was a time of great excitement and rapid progress. In 1978, prompted by the discovery from Ray Erikson’s group that the Rous sarcoma virus (RSV) v-Src–transforming protein had an associated protein kinase activity specific for threonine, my group at the Salk Institute set out to determine whether the polyomavirus middle T-transforming protein had a similar kinase activity. Here, I describe the experiments that led to the identification of a kinase activity associated with middle T antigen and our serendipitous discovery that this activity was specific for tyrosine in vitro, and how this in turn led to the fortuitous observation that the v-Src–associated kinase activity was also specific for tyrosine. Our finding that v-Src increased the level of phosphotyrosine in cellular proteins in RSV-transformed cells confirmed that v-Src is a tyrosine kinase and transforms cells by phosphorylating proteins on tyrosine. My colleague Bart Sefton and I reported these findings in the March issue of PNAS in 1980. Remarkably, all of the experiments in this paper were accomplished in less than one month. PMID:26130799

  8. Electrical Properties and Superconductivity of MSr2Nd2-xCexCu2O10-δ (M=Ta, Nb)

    NASA Astrophysics Data System (ADS)

    Zhu, Yingjie; Qian, Yitai; Li, Rukang; Wang, Shiwei; Chen, Zuyao; Chen, Zhaojia; Wang, Nanling; Zhou, Guien

    1992-09-01

    A new series of layered cuprate compounds MSr2Nd2-xCexCu2O10-δ (M=Ta, Nb) have been synthesized. The structure of the compounds is similar to that of T1-1222. A peak in the R-T curve for the sample of TaSr2Nd1.3Ce0.7Cu2O10-δ has been observed at about 50 K. For the sample of NbSr2Nd1.45Ce0.55Cu2O10-δ, metal-like conductivity behaviour has been observed. We have found superconductivity at about 13.2 K in the samples of NbSr2Nd2-xCexCu2O10-δ (x=0.49, 0.50, 0.51, 0.52).

  9. [In search of the ideal surgical treatment for lymphedema. Report of 2nd European Conference on supermicrosurgery (Barcelona - March 2012)].

    PubMed

    Rausky, J; Robert, N; Binder, J-P; Revol, M

    2012-12-01

    Since more than 50 years, many surgeons all around the world try to find the perfect surgical technique to treat limb lymphedemas. Decongestive physiotherapy associated with the use of a compressive garment has been the primary choice for lymphedema treatment. Many different surgical techniques have been developed, however, to date, there is no consensus on surgical procedure. Most surgical experts of lymphedema met in the second European Conference on supermicrosurgery, organized on March 1st and 2nd 2012, in San Pau Hospital, Barcelona. Together they tried to clarify these different options and ideally a strategy for using these techniques.

  10. 2nd International Salzburg Conference on Neurorecovery (ISCN 2013) Salzburg/ Austria | November 28th - 29th, 2013

    PubMed Central

    Brainin, M; Muresanu, D; Slavoaca, D

    2014-01-01

    The 2nd International Salzburg Conference on Neurorecovery was held on the 28th and 29th of November, 2013, in Salzburg, one of the most beautiful cities in Austria, which is well known for its rich cultural heritage, world-famous music and beautiful surrounding landscapes. The aim of the conference was to discuss the progress in the field of neurorecovery. The conference brought together internationally renowned scientists and clinicians, who described the clinical and therapeutic relevance of translational research and its applications in neurorehabilitation. PMID:25713602

  11. Comparison of the large scale structure of the ISM in the 2nd and 3rd Galactic Quadrants

    NASA Astrophysics Data System (ADS)

    Könyves, V.; Kiss, Cs.

    2002-05-01

    In this paper we are questing the large scale structure of the interstellar medium (ISM) using IRAS/ISSA 60 and 100 mum maps in the 3rd Galactic Quadrant (GQ). Here we identified 41 loop-like intensity enhancements and analysed their far-infrared (FIR) properties. We found major differences in the distribution and characteristics of these features when comparing the results of the 2nd and the 3rd GQs. This discrepancy can be satisfactorily explained by basic differences of the structure of the ISM in these two Galactic Quadrants.

  12. THE 2nd SCHIZOPHRENIA INTERNATIONAL RESEARCH SOCIETY CONFERENCE, 10–14 APRIL 2010, FLORENCE, ITALY: SUMMARIES OF ORAL SESSIONS

    PubMed Central

    Baharnoori, Moogeh; Bartholomeusz, Cali; Boucher, Aurelie A.; Buchy, Lisa; Chaddock, Christopher; Chiliza, Bonga; Föcking, Melanie; Fornito, Alex; Gallego, Juan A.; Hori, Hiroaki; Huf, Gisele; Jabbar, Gul A.; Kang, Shi Hyun; El Kissi, Yousri; Merchán-Naranjo, Jessica; Modinos, Gemma; Abdel-Fadeel, Nashaat A.M.; Neubeck, Anna-Karin; Ng, Hsiao Piau; Novak, Gabriela; Owolabi, Olasunmbo.O.; Prata, Diana P.; Rao, Naren P.; Riecansky, Igor; Smith, Darryl C.; Souza, Renan P.; Thienel, Renate; Trotman, Hanan D.; Uchida, Hiroyuki; Woodberry, Kristen A.; O'Shea, Anne; DeLisi, Lynn E.

    2014-01-01

    The 2nd Schizophrenia International Research Society Conference, was held in Florence, Italy, April 10–15, 2010. Student travel awardees served as rapporteurs of each oral session and focused their summaries on the most significant findings that emerged from each session and the discussions that followed. The following report is a composite of these reviews. It is hoped that it will provide an overview for those who were present, but could not participate in all sessions, and those who did not have the opportunity to attend, but who would be interested in an update on current investigations ongoing in the field of schizophrenia research. PMID:20934307

  13. 2nd International Salzburg Conference on Neurorecovery (ISCN 2013) Salzburg/Austria|November 28th-29th, 2013.

    PubMed

    Brainin, M; Muresanu, D; Slavoaca, D

    2014-01-01

    The 2nd International Salzburg Conference on Neurorecovery was held on the 28th and 29th of November, 2013, in Salzburg, one of the most beautiful cities in Austria, which is well known for its rich cultural heritage, world-famous music and beautiful surrounding landscapes. The aim of the conference was to discuss the progress in the field of neurorecovery. The conference brought together internationally renowned scientists and clinicians, who described the clinical and therapeutic relevance of translational research and its applications in neurorehabilitation.

  14. Tyrosine supplementation in chronic experimental uremia.

    PubMed

    Abitbol, C L; Mandel, S; Mrozinska, K; Wapnir, R A

    1983-08-01

    The occurrence of low tyrosine tissue levels in uremic subjects, possibly due to impaired phenylalanine hydroxylation, suggests that tyrosine may be an essential amino acid in uremia. Additional dietary tyrosine may thus re-dress the deficiency. This study examined growth and tyrosine/phenylalanine metabolism in uremic rats during tyrosine supplementation. Rats made uremic (U) by 7/8 nephrectomy were compared to pair-fed (CP) and ad libitum-fed (CA), sham-operated controls. Two sets of each group of rats were studied after 21 days on the respective diets: I = Purina Lab Chow; II = same + 3.5% tyrosine. Plasma tyrosine was below normal in U and CP-fed diet I. With diet II, the tyrosine:phenylalanine ratio in U was lower than both CA and CP. In rats fed diet II, the tyrosine:phenylalanine ratio became indistinguishable among the three groups. Growth parameters in U and CP were similar, regardless of the diet. Body weight gain, tibial length, muscle mass, and tissue protein did not improve in uremic animals supplemented with tyrosine. The specific activity of liver phenylalanine hydroxylase in U was not different from CA or CP. However, loss of cortical renal mass appeared to be the major determinant of decreased kidney phenylalanine hydroxylation in experimental uremia. This alteration is likely to be the greatest contributory factor to the alteration of plasma levels of tyrosine and phenylalanine. The data presented do not support a proposed essentiality of tyrosine in uremia.

  15. FOREWORD: 2nd International Workshop on New Computational Methods for Inverse Problems (NCMIP 2012)

    NASA Astrophysics Data System (ADS)

    Blanc-Féraud, Laure; Joubert, Pierre-Yves

    2012-09-01

    Conference logo This volume of Journal of Physics: Conference Series is dedicated to the scientific contributions presented during the 2nd International Workshop on New Computational Methods for Inverse Problems, (NCMIP 2012). This workshop took place at Ecole Normale Supérieure de Cachan, in Cachan, France, on 15 May 2012, at the initiative of Institut Farman. The first edition of NCMIP also took place in Cachan, France, within the scope of the ValueTools Conference, in May 2011 (http://www.ncmip.org/2011/). The NCMIP Workshop focused on recent advances in the resolution of inverse problems. Indeed inverse problems appear in numerous scientific areas such as geophysics, biological and medical imaging, material and structure characterization, electrical, mechanical and civil engineering, and finance. The resolution of inverse problems consists of estimating the parameters of the observed system or structure from data collected by an instrumental sensing or imaging device. Its success firstly requires the collection of relevant observation data. It also requires accurate models describing the physical interactions between the instrumental device and the observed system, as well as the intrinsic properties of the solution itself. Finally, it requires the design of robust, accurate and efficient inversion algorithms. Advanced sensor arrays and imaging devices provide high rate and high volume data; in this context, the efficient resolution of the inverse problem requires the joint development of new models and inversion methods, taking computational and implementation aspects into account. During this one-day workshop, researchers had the opportunity to bring to light and share new techniques and results in the field of inverse problems. The topics of the workshop were: algorithms and computational aspects of inversion, Bayesian estimation, kernel methods, learning methods, convex optimization, free discontinuity problems, metamodels, proper orthogonal decomposition

  16. Structural basis of tubulin tyrosination by tubulin tyrosine ligase

    PubMed Central

    Prota, Andrea E.; Magiera, Maria M.; Kuijpers, Marijn; Bargsten, Katja; Frey, Daniel; Wieser, Mara; Jaussi, Rolf; Hoogenraad, Casper C.; Kammerer, Richard A.; Janke, Carsten

    2013-01-01

    Tubulin tyrosine ligase (TTL) catalyzes the post-translational retyrosination of detyrosinated α-tubulin. Despite the indispensable role of TTL in cell and organism development, its molecular mechanism of action is poorly understood. By solving crystal structures of TTL in complex with tubulin, we here demonstrate that TTL binds to the α and β subunits of tubulin and recognizes the curved conformation of the dimer. Biochemical and cellular assays revealed that specific tubulin dimer recognition controls the activity of the enzyme, and as a consequence, neuronal development. The TTL–tubulin structure further illustrates how the enzyme binds the functionally crucial C-terminal tail sequence of α-tubulin and how this interaction catalyzes the tyrosination reaction. It also reveals how TTL discriminates between α- and β-tubulin, and between different post-translationally modified forms of α-tubulin. Together, our data suggest that TTL has specifically evolved to recognize and modify tubulin, thus highlighting a fundamental role of the evolutionary conserved tubulin tyrosination cycle in regulating the microtubule cytoskeleton. PMID:23358242

  17. Tyrosine kinases in inflammatory dermatologic disease

    PubMed Central

    Paniagua, Ricardo T.; Fiorentino, David; Chung, Lorinda; Robinson, William H.

    2010-01-01

    Tyrosine kinases are enzymes that catalyze the phosphorylation of tyrosine residues on protein substrates. They are key components of signaling pathways that drive an array of cellular responses including proliferation, differentiation, migration, and survival. Specific tyrosine kinases have recently been identified as critical to the pathogenesis of several autoimmune and inflammatory diseases. Small-molecule inhibitors of tyrosine kinases are emerging as a novel class of therapy that may provide benefit in certain patient subsets. In this review, we highlight tyrosine kinase signaling implicated in inflammatory dermatologic diseases, evaluate strategies aimed at inhibiting these aberrant signaling pathways, and discuss prospects for future drug development. PMID:20584561

  18. [Medical support of the 65th Army during the East Prussian offensive operation performed by the 2nd Belorussian Front].

    PubMed

    Shelepov, A M; Leonik, S I; Lemeshkin, R N

    2015-02-01

    Prussian offensive operation performed by the 2nd Belorussian Front. An activity of the medical An activity of the medical service of the 65th Army during the East Prussian offensive operation performed by the 2nd Belorussian Front is a typical example of the medical support of troops during the final stages of World War II. Forms and methods of medical support management, which were developed during the war, haven't lost their importance in modern conditions. These methods include the establishment of specialized surgical and therapeutic field hospital, establishment of medical institutions in the Army, which worked on the evacuation directions and reserve of mobile hospitals and transport, timely extension of the first echelons of the hospital base front to change institutions hospital deployed the army base. A research of experience in organizing medical support of the offensive operations performed during the last year of World War II provides the material for the development of the theory of modern medical support operations and ability to provide on this basis, the continuity of the hospitals, the continuity of qualified and specialized medical care, improve the performance of diagnostic and treatment work.

  19. Influence of Nd dopant amount on microstructure and photoluminescence of TiO2:Nd thin films

    NASA Astrophysics Data System (ADS)

    Wojcieszak, Damian; Mazur, Michal; Kaczmarek, Danuta; Morgiel, Jerzy; Zatryb, Grzegorz; Domaradzki, Jaroslaw; Misiewicz, Jan

    2015-10-01

    TiO2 and TiO2:Nd thin films were deposited using reactive magnetron sputtering process from mosaic Ti-Nd targets with various Nd concentration. The thin films were characterized using X-ray diffraction (XRD), transmission electron microscopy (TEM) and spectroscopic techniques. Photoluminescence (PL) in the near infrared obtained upon 514.5 nm excitation was also examined. The relationship between the Nd concentration, structural, optical and photoluminescence properties of prepared thin films was investigated and discussed. XRD and TEM measurements showed that an increase in the Nd concentration in the thin films hinders the crystal growth in the deposited coatings. Depending on the Nd amount in the thin films, TiO2 with the rutile, mixed rutile-amorphous or amorphous phase was obtained. Transmittance measurements revealed that addition of Nd dopant to titania matrix did not deteriorate optical transparency of the coatings, however it influenced on the position of the fundamental absorption edge and therefore on the width of optical band gap energy. All TiO2:Nd thin films exhibited PL emission that occurred at ca. 0.91, 1.09 and 1.38 μm. Finally, results obtained for deposited coatings showed that titania with the rutile structure and 1.0 at.% of Nd was the most efficient in VIS to NIR photon conversion.

  20. Efficacy and Safety of rAAV2-ND4 Treatment for Leber’s Hereditary Optic Neuropathy

    PubMed Central

    Wan, Xing; Pei, Han; Zhao, Min-jian; Yang, Shuo; Hu, Wei-kun; He, Heng; Ma, Si-qi; Zhang, Ge; Dong, Xiao-yan; Chen, Chen; Wang, Dao-wen; Li, Bin

    2016-01-01

    Leber’s hereditary optic neuropathy (LHON) is a mitochondrially inherited disease leading to blindness. A mitochondrial DNA point mutation at the 11778 nucleotide site of the NADH dehydrogenase subunit 4 (ND4) gene is the most common cause. The aim of this study was to evaluate the efficacy and safety of a recombinant adeno-associated virus 2 (AAV2) carrying ND4 (rAAV2-ND4) in LHON patients carrying the G11778A mutation. Nine patients were administered rAAV2-ND4 by intravitreal injection to one eye and then followed for 9 months. Ophthalmologic examinations of visual acuity, visual field, and optical coherence tomography were performed. Physical examinations included routine blood and urine. The visual acuity of the injected eyes of six patients improved by at least 0.3 log MAR after 9 months of follow-up. In these six patients, the visual field was enlarged but the retinal nerve fibre layer remained relatively stable. No other outcome measure was significantly changed. None of the nine patients had local or systemic adverse events related to the vector during the 9-month follow-up period. These findings support the feasible use of gene therapy for LHON. PMID:26892229

  1. Density functional theory calculations on the active site of biotin synthase: mechanism of S transfer from the Fe(2)S(2) cluster and the role of 1st and 2nd sphere residues.

    PubMed

    Rana, Atanu; Dey, Subal; Agrawal, Amita; Dey, Abhishek

    2015-10-01

    Density functional theory (DFT) calculations are performed on the active site of biotin synthase (BS) to investigate the sulfur transfer from the Fe(2)S(2) cluster to dethiobiotin (DTB). The active site is modeled to include both the 1st and 2nd sphere residues. Molecular orbital theory considerations and calculation on smaller models indicate that only an S atom (not S²⁻) transfer from an oxidized Fe(2)S(2) cluster leads to the formation of biotin from the DTB using two adenosyl radicals generated from S-adenosyl-L-methionine. The calculations on larger protein active site model indicate that a 9-monothiobiotin bound reduced cluster should be an intermediate during the S atom insertion from the Fe(2)S(2) cluster consistent with experimental data. The Arg260 bound to Fe1, being a weaker donor than cysteine bound to Fe(2), determines the geometry and the electronic structure of this intermediate. The formation of this intermediate containing the C9-S bond is estimated to have a ΔG(≠) of 17.1 kcal/mol while its decay by the formation of the 2nd C6-S bond is calculated to have a ΔG(≠) of 29.8 kcal/mol, i.e. the 2nd C-S bond formation is calculated to be the rate determining step in the cycle and it leads to the decay of the Fe(2)S(2) cluster. Significant configuration interaction (CI), present in these transition states, helps lower the barrier of these reactions by ~30-25 kcal/mol relative to a hypothetical outer-sphere reaction. The conserved Phe285 residue near the Fe(2)S(2) active site determines the stereo selectivity at the C6 center of this radical coupling reaction. Reaction mechanism of BS investigated using DFT calculations. Strong CI and the Phe285 residue control the kinetic rate and stereochemistry of the product.

  2. XUV spectra of 2nd transition row elements: identification of 3d-4p and 3d-4f transition arrays

    NASA Astrophysics Data System (ADS)

    Lokasani, Ragava; Long, Elaine; Maguire, Oisin; Sheridan, Paul; Hayden, Patrick; O'Reilly, Fergal; Dunne, Padraig; Sokell, Emma; Endo, Akira; Limpouch, Jiri; O'Sullivan, Gerry

    2015-12-01

    The use of laser produced plasmas (LPPs) in extreme ultraviolet/soft x-ray lithography and metrology at 13.5 nm has been widely reported and recent research efforts have focused on developing next generation sources for lithography, surface morphology, patterning and microscopy at shorter wavelengths. In this paper, the spectra emitted from LPPs of the 2nd transition row elements from yttrium (Z = 39) to palladium (Z = 46), with the exception of zirconium (Z = 40) and technetium (Z = 43), produced by two Nd:YAG lasers which delivered up to 600 mJ in 7 ns and 230 mJ in 170 ps, respectively, are reported. Intense emission was observed in the 2-8 nm spectral region resulting from unresolved transition arrays (UTAs) due to 3d-4p, 3d-4f and 3p-3d transitions. These transitions in a number of ion stages of yttrium, niobium, ruthenium and rhodium were identified by comparison with results from Cowan code calculations and previous studies. The theoretical data were parameterized using the UTA formalism and the mean wavelength and widths were calculated and compared with experimental results.

  3. Receptor Tyrosine Kinases in Drosophila Development

    PubMed Central

    Sopko, Richelle; Perrimon, Norbert

    2013-01-01

    Tyrosine phosphorylation plays a significant role in a wide range of cellular processes. The Drosophila genome encodes more than 20 receptor tyrosine kinases and extensive studies in the past 20 years have illustrated their diverse roles and complex signaling mechanisms. Although some receptor tyrosine kinases have highly specific functions, others strikingly are used in rather ubiquitous manners. Receptor tyrosine kinases regulate a broad expanse of processes, ranging from cell survival and proliferation to differentiation and patterning. Remarkably, different receptor tyrosine kinases share many of the same effectors and their hierarchical organization is retained in disparate biological contexts. In this comprehensive review, we summarize what is known regarding each receptor tyrosine kinase during Drosophila development. Astonishingly, very little is known for approximately half of all Drosophila receptor tyrosine kinases. PMID:23732470

  4. Protein tyrosine phosphatase: enzymatic assays.

    PubMed

    Montalibet, Jacqueline; Skorey, Kathryn I; Kennedy, Brian P

    2005-01-01

    Activity assays for tyrosine phosphatases are based on the hydrolysis of a arylphosphate moiety from a synthetic substrate yielding a spectroscopically active product. Many different substrates can be used for these assays with p-nitrophenyl phosphate (pNPP), fluorescein diphosphate (FDP), and 6,8-difluoro-4-methylumbellyferyl phosphate (DiFMUP) being the most efficient and versatile. Equally, larger molecules such as phosphotyrosyl peptides can also be used to mimic more natural substrates. Activity assays include the determinations of the rate of dephosphorylation and calculations of kinetic constants such as k(cat) and K(M). These assays are useful to identify and characterize tyrosine phosphatases and are commonly used to evaluate the efficiency of inhibitors.

  5. "The Program Evaluation Standards": How to Assess Evaluations of Educational Programs, 2nd Edition [Book Review].

    ERIC Educational Resources Information Center

    Fournier, Deborah M.

    1994-01-01

    The "Program Evaluation Standards" supplies a useful framework for generating questions to raise about any evaluation plan or evaluation report to assess its pros and cons. It is a valuable "how-to" for graduate students and professionals. This second edition incorporates changes in the field in the last decade. (SLD)

  6. Tyrosine Recombinase Retrotransposons and Transposons.

    PubMed

    Poulter, Russell T M; Butler, Margi I

    2015-04-01

    Retrotransposons carrying tyrosine recombinases (YR) are widespread in eukaryotes. The first described tyrosine recombinase mobile element, DIRS1, is a retroelement from the slime mold Dictyostelium discoideum. The YR elements are bordered by terminal repeats related to their replication via free circular dsDNA intermediates. Site-specific recombination is believed to integrate the circle without creating duplications of the target sites. Recently a large number of YR retrotransposons have been described, including elements from fungi (mucorales and basidiomycetes), plants (green algae) and a wide range of animals including nematodes, insects, sea urchins, fish, amphibia and reptiles. YR retrotransposons can be divided into three major groups: the DIRS elements, PAT-like and the Ngaro elements. The three groups form distinct clades on phylogenetic trees based on alignments of reverse transcriptase/ribonuclease H (RT/RH) and YR sequences, and also having some structural distinctions. A group of eukaryote DNA transposons, cryptons, also carry tyrosine recombinases. These DNA transposons do not encode a reverse transcriptase. They have been detected in several pathogenic fungi and oomycetes. Sequence comparisons suggest that the crypton YRs are related to those of the YR retrotransposons. We suggest that the YR retrotransposons arose from the combination of a crypton-like YR DNA transposon and the RT/RH encoding sequence of a retrotransposon. This acquisition must have occurred at a very early point in the evolution of eukaryotes.

  7. Cre Recombinase and Other Tyrosine Recombinases.

    PubMed

    Meinke, Gretchen; Bohm, Andrew; Hauber, Joachim; Pisabarro, M Teresa; Buchholz, Frank

    2016-10-26

    Tyrosine-type site-specific recombinases (T-SSRs) have opened new avenues for the predictable modification of genomes as they enable precise genome editing in heterologous hosts. These enzymes are ubiquitous in eubacteria, prevalent in archaea and temperate phages, present in certain yeast strains, but barely found in higher eukaryotes. As tools they find increasing use for the generation and systematic modification of genomes in a plethora of organisms. If applied in host organisms, they enable precise DNA cleavage and ligation without the gain or loss of nucleotides. Criteria directing the choice of the most appropriate T-SSR system for genetic engineering include that, whenever possible, the recombinase should act independent of cofactors and that the target sequences should be long enough to be unique in a given genome. This review is focused on recent advancements in our mechanistic understanding of simple T-SSRs and their application in developmental and synthetic biology, as well as in biomedical research.

  8. Conceptual design and optimization of a 1-1/2 generation PFBC plant task 14. Topical report

    SciTech Connect

    Rubow, L.N.; Horazak, D.A.; White, J.S.

    1994-12-01

    The economics and performance of advanced pressurized fluidized bed (PFBC) cycles developed for utility applications during the last 10 years (especially the 2nd-Generation PFBC cycle) are projected to be favorable compared to conventional pulverized coal power plants. However, the improved economics of 2nd-Generation PFBC cycles are accompanied by the perception of increased technological risk related to the pressurized carbonizer and its associated gas cleanup systems. A PFBC cycle that removed the uncertainties of the carbonizer while retaining the high efficiency and low cost of a 2nd-Generation PFBC cycle could improve the prospects for early commercialization and pave the way for the introduction of the complete 2nd-Generation PFBC cycle at some later date. One such arrangement is a PFBC cycle with natural gas topping combustion, referred to as the 1.5-Generation PFBC cycle. This cycle combines the advantages of the 2nd-Generation PFBC plant with the reduced risk associated with a gas turbine burning natural gas, and can potentially be part of a phased approach leading to the commercialization of utility 2nd-Generation PFBC cycles. The 1.5-Generation PFBC may also introduce other advantages over the more complicated 2nd-Generation PFBC system. This report describes the technical and economic evaluation of 1.5-Generation PFBC cycles for utility or industrial power generation.

  9. Specimen Examinations for Merchant Marine Engineer Licenses (2nd and 3rd Assistant).

    DTIC Science & Technology

    1978-02-01

    valves being not fully seated. D. moisture entrained in the steam . 5. Double helically cut gears are used for main reduction and pinion gears to A...A faulty coil in the solenoid valve -21- EXAMINATION SPECIFICATIONS SECOND ASSISTANT ENGINEER SUBJECT STEAM MOTOR I. Boilers, Fuel Oil & Combustion...engine back pressure. C. increase engine cycle efficiency. D. increase turbocharger efficiency. 2. A common method of varying the steam generating rate

  10. Post-flight BET products for the 2nd discovery entry, STS-19 (51-A)

    NASA Technical Reports Server (NTRS)

    Kelly, G. M.; Mcconnell, J. G.; Heck, M. L.; Troutman, P. A.; Waters, L. A.; Findlay, J. T.

    1985-01-01

    The post-flight products for the second Discovery flight, STS-19 (51-A), are summarized. The inertial best estimate trajectory (BET), BT19D19/UN=169750N, was developed using spacecraft dynamic measurements from Inertial Measurement Unit 2 (IMU2) in conjunction with the best tracking coverage available for any of the earlier Shuttle entries. As a consequence of the latter, an anchor epoch was selected which conforms to an initial altitude of greater than a million feet. The Extended BET, ST19BET/UN=274885C, incorporated the previously mentioned inertial reconstructed state information and the Langley Atmospheric Information Retrieval System (LAIRS) atmosphere, ST19MET/UN=712662N, with some minor exceptions. Primary and back-up AEROBET reels are NK0165 and NK0201, respectively. This product was only developed over the lowermost 360 kft altitude range due to atmosphere problems but this relates to altitudes well above meaningful signal in the IMUs. Summary results generated from the AEROBET for this flight are presented with meaningful configuration and statistical comparisons from the previous thirteen flights. Modified maximum likelihood estimation (MMLE) files were generated based on IMU2 and the Rate Gyro Assembly/Accelerometer Assembly (RGA/AA), respectively. Appendices attached define spacecraft and physical constants utilized, show plots of the final tracking data residuals from the post-flight fit, list relevant parameters from the BET at a two second spacing, and retain for archival purpose all relevant input and output tapes and files generated.

  11. Tyrosine Metabolism in Patients with Liver Disease*

    PubMed Central

    Levine, Robert J.; Conn, Harold O.

    1967-01-01

    Plasma levels of tyrosine were assayed in the fasting state and after oral administration of either tyrosine (tyrosine tolerance test) or phenylalanine (phenlyalanine conversion test) in normal subjects and in patients with hepatitis, biliary obstruction, or cirrhosis. Fasting tyrosine levels tended to be slightly increased in patients with hepatitis and biliary obstruction and markedly increased in patients with cirrhosis. Tyrosine tolerance tests in patients with cirrhosis were characterized by larger than normal increments in tyrosine levels and by delayed returns toward fasting levels. The results of phenylalanine conversion tests were abnormal in approximately one-half of patients with either hepatitis or biliary obstruction and four-fifths of patients with cirrhosis. Abnormalities were characterized by elevated fasting plasma tyrosine levels, or small and delayed increments in tyrosine levels, or both. Abnormal phenylalanine conversion test results in patients with cirrhosis did not correlate closely with any clinical feature of cirrhosis or with the results of any standard liver function test; there was positive correlation only with abnormal ammonia tolerance, a test of portalsystemic shunting. Tests of tyrosine metabolism do not appear to be useful for routine clinical assessment of liver function. Tyrosine tolerance tests and phenylalanine conversion tests done for purposes of diagnosis of other diseases may yield misleading results in patients with liver disease. PMID:6074004

  12. Numerical Simulation of the Francis Turbine and CAD used to Optimized the Runner Design (2nd).

    NASA Astrophysics Data System (ADS)

    Sutikno, Priyono

    2010-06-01

    Hydro Power is the most important renewable energy source on earth. The water is free of charge and with the generation of electric energy in a Hydroelectric Power station the production of green house gases (mainly CO2) is negligible. Hydro Power Generation Stations are long term installations and can be used for 50 years and more, care must be taken to guarantee a smooth and safe operation over the years. Maintenance is necessary and critical parts of the machines have to be replaced if necessary. Within modern engineering the numerical flow simulation plays an important role in order to optimize the hydraulic turbine in conjunction with connected components of the plant. Especially for rehabilitation and upgrading existing Power Plants important point of concern are to predict the power output of turbine, to achieve maximum hydraulic efficiency, to avoid or to minimize cavitations, to avoid or to minimized vibrations in whole range operation. Flow simulation can help to solve operational problems and to optimize the turbo machinery for hydro electric generating stations or their component through, intuitive optimization, mathematical optimization, parametric design, the reduction of cavitations through design, prediction of draft tube vortex, trouble shooting by using the simulation. The classic design through graphic-analytical method is cumbersome and can't give in evidence the positive or negative aspects of the designing options. So it was obvious to have imposed as necessity the classical design methods to an adequate design method using the CAD software. There are many option chose during design calculus in a specific step of designing may be verified in ensemble and detail form a point of view. The final graphic post processing would be realized only for the optimal solution, through a 3 D representation of the runner as a whole for the final approval geometric shape. In this article it was investigated the redesign of the hydraulic turbine's runner

  13. Use of 2nd and 3rd Level Correlation Analysis for Studying Degradation in Polycrystalline Thin-Film Solar Cells

    SciTech Connect

    Albin, D. S.; del Cueto, J. A.; Demtsu, S. H.; Bansal, S.

    2011-03-01

    The correlation of stress-induced changes in the performance of laboratory-made CdTe solar cells with various 2nd and 3rd level metrics is discussed. The overall behavior of aggregated data showing how cell efficiency changes as a function of open-circuit voltage (Voc), short-circuit current density (Jsc), and fill factor (FF) is explained using a two-diode, PSpice model in which degradation is simulated by systematically changing model parameters. FF shows the highest correlation with performance during stress, and is subsequently shown to be most affected by shunt resistance, recombination and in some cases voltage-dependent collection. Large decreases in Jsc as well as increasing rates of Voc degradation are related to voltage-dependent collection effects and catastrophic shunting respectively. Large decreases in Voc in the absence of catastrophic shunting are attributed to increased recombination. The relevance of capacitance-derived data correlated with both Voc and FF is discussed.

  14. Effect of the nanocrystalline structure type on the optical properties of TiO2:Nd (1 at.%) thin films

    NASA Astrophysics Data System (ADS)

    Mazur, Michal; Wojcieszak, Damian; Kaczmarek, Danuta; Domaradzki, Jaroslaw; Zatryb, Grzegorz; Misiewicz, Jan; Morgiel, Jerzy

    2015-04-01

    Titanium dioxide thin films, each doped with the same amount of neodymium (1 at.%) were deposited by Low Pressure Hot Target Reactive Sputtering and High Energy Reactive Magnetron Sputtering processes in order to obtain anatase and rutile thin film structures respectively. The microstructure and phase composition were analyzed using the transmission electron microscopy method including high resolution electron microscopy imaging. The measurements of the optical properties showed, that both prepared thin films were transparent in the visible light range and had a low extinction coefficient of ca. 3 ṡ 10-3. The thin film with the anatase structure had a lower cut-off wavelength and refractive index and a higher value of optical energy band gap as-compared to the TiO2:Nd coating with the rutile structure. Simultaneously, more efficient photoluminescence emission was observed for the rutile thin films.

  15. 2nd ESMO Consensus Conference in Lung Cancer: locally advanced stage III non-small-cell lung cancer.

    PubMed

    Eberhardt, W E E; De Ruysscher, D; Weder, W; Le Péchoux, C; De Leyn, P; Hoffmann, H; Westeel, V; Stahel, R; Felip, E; Peters, S

    2015-08-01

    To complement the existing treatment guidelines for all tumour types, ESMO organises consensus conferences to focus on specific issues in each type of tumour. The 2nd ESMO Consensus Conference on Lung Cancer was held on 11-12 May 2013 in Lugano. A total of 35 experts met to address several questions on non-small-cell lung cancer (NSCLC) in each of four areas: pathology and molecular biomarkers, first-line/second and further lines of treatment in advanced disease, early-stage disease and locally advanced disease. For each question, recommendations were made including reference to the grade of recommendation and level of evidence. This consensus paper focuses on locally advanced disease.

  16. International collaborative study for establishment of the 2nd WHO International Standard for Haemophilus influenzae type b polysaccharide.

    PubMed

    Mawas, Fatme; Burkin, Karena; Dougall, Thomas; Saydam, Manolya; Rigsby, Peter; Bolgiano, Barbara

    2015-11-01

    In this report we present the results of a collaborative study for the preparation and calibration of a replacement International Standard (IS) for Haemophilus influenzae type b polysaccharide (polyribosyl ribitol phosphate; 5-d-ribitol-(1 → 1)-β-d-ribose-3-phosphate; PRP). Two candidate preparations were evaluated. Thirteen laboratories from 9 different countries participated in the collaborative study to assess the suitability and determine the PRP content of two candidate standards. On the basis of the results from this study, Candidate 2 (NIBSC code 12/306) has been established as the 2nd WHO IS for PRP by the Expert Committee of Biological Standards of the World Health Organisation with a content of 4.904 ± 0.185mg/ampoule, as determined by the ribose assays carried out by 11 of the participating laboratories.

  17. The 2nd Order Focusing by Energy for TOF Sector Field Mass Analyzer with an Orthogonal Acceleration: Theory, Modeling, Experiment

    NASA Astrophysics Data System (ADS)

    Poteshin, S. S.; Chernyshev, D. M.; Sysoev, Alexey A.; Sysoev, Alexander A.

    Currently axially symmetric type of analyzer with an electrostatic sector fields (AESF) is rarely used to construct time-of-flight mass spectrometers. The main drawback, hindering the wider use of the analyzers of this type, is the lack of chromatic second-order focusing by energy. However, the configuration of AESF in combination with orthogonal accelerator (OA) allows to achieved it through compensation of energy aberrations of the analyzer in the system of orthogonal input of the ion beam. In the presented work the results of theoretical calculation, simulation and experimentally obtained data are compared. Characteristics of the analyzer with OA in a large extent depend on the parameters of the incoming ion beam. Data of modeling the 2nd stage of gas-dynamic interface, which have the greatest influence on the parameters of the ion beam, is provided.

  18. Sleeping Beauty Transposition of Chimeric Antigen Receptors Targeting Receptor Tyrosine Kinase-Like Orphan Receptor-1 (ROR1) into Diverse Memory T-Cell Populations

    PubMed Central

    Deniger, Drew C.; Yu, Jianqiang; Huls, M. Helen; Figliola, Matthew J.; Mi, Tiejuan; Maiti, Sourindra N.; Widhopf, George F.; Hurton, Lenka V.; Thokala, Radhika; Singh, Harjeet; Olivares, Simon; Champlin, Richard E.; Wierda, William G.; Kipps, Thomas J.; Cooper, Laurence J. N.

    2015-01-01

    T cells modified with chimeric antigen receptors (CARs) targeting CD19 demonstrated clinical activity against some B-cell malignancies. However, this is often accompanied by a loss of normal CD19+ B cells and humoral immunity. Receptor tyrosine kinase-like orphan receptor-1 (ROR1) is expressed on sub-populations of B-cell malignancies and solid tumors, but not by healthy B cells or normal post-partum tissues. Thus, adoptive transfer of T cells specific for ROR1 has potential to eliminate tumor cells and spare healthy tissues. To test this hypothesis, we developed CARs targeting ROR1 in order to generate T cells specific for malignant cells. Two Sleeping Beauty transposons were constructed with 2nd generation ROR1-specific CARs signaling through CD3ζ and either CD28 (designated ROR1RCD28) or CD137 (designated ROR1RCD137) and were introduced into T cells. We selected for T cells expressing CAR through co-culture with γ-irradiated activating and propagating cells (AaPC), which co-expressed ROR1 and co-stimulatory molecules. Numeric expansion over one month of co-culture on AaPC in presence of soluble interleukin (IL)-2 and IL-21 occurred and resulted in a diverse memory phenotype of CAR+ T cells as measured by non-enzymatic digital array (NanoString) and multi-panel flow cytometry. Such T cells produced interferon-γ and had specific cytotoxic activity against ROR1+ tumors. Moreover, such cells could eliminate ROR1+ tumor xenografts, especially T cells expressing ROR1RCD137. Clinical trials will investigate the ability of ROR1-specific CAR+ T cells to specifically eliminate tumor cells while maintaining normal B-cell repertoire. PMID:26030772

  19. Laparoscopic hepatectomy is theoretically better than open hepatectomy: preparing for the 2nd International Consensus Conference on Laparoscopic Liver Resection.

    PubMed

    Wakabayashi, Go; Cherqui, Daniel; Geller, David A; Han, Ho-Seong; Kaneko, Hironori; Buell, Joseph F

    2014-10-01

    Six years have passed since the first International Consensus Conference on Laparoscopic Liver Resection was held. This comparatively new surgical technique has evolved since then and is rapidly being adopted worldwide. We compared the theoretical differences between open and laparoscopic liver resection, using right hepatectomy as an example. We also searched the Cochrane Library using the keyword "laparoscopic liver resection." The papers retrieved through the search were reviewed, categorized, and applied to the clinical questions that will be discussed at the 2nd Consensus Conference. The laparoscopic hepatectomy procedure is more difficult to master than the open hepatectomy procedure because of the movement restrictions imposed upon us when we operate from outside the body cavity. However, good visibility of the operative field around the liver, which is located beneath the costal arch, and the magnifying provide for neat transection of the hepatic parenchyma. Another theoretical advantage is that pneumoperitoneum pressure reduces hemorrhage from the hepatic vein. The literature search turned up 67 papers, 23 of which we excluded, leaving only 44. Two randomized controlled trials (RCTs) are underway, but their results are yet to be published. Most of the studies (n = 15) concerned short-term results, with some addressing long-term results (n = 7), cost (n = 6), energy devices (n = 4), and so on. Laparoscopic hepatectomy is theoretically superior to open hepatectomy in terms of good visibility of the operative field due to the magnifying effect and reduced hemorrhage from the hepatic vein due to pneumoperitoneum pressure. However, there is as yet no evidence from previous studies to back this up in terms of short-term and long-term results. The 2nd International Consensus Conference on Laparoscopic Liver Resection will arrive at a consensus on the basis of the best available evidence, with video presentations focusing on surgical techniques and the publication

  20. CO2 dynamics in nested catchments: a longitudinal perspective from soil to 1st and 2nd order streams

    NASA Astrophysics Data System (ADS)

    Johnson, M. S.; Lehmann, J.; Riha, S. J.; Couto, E. G.

    2005-12-01

    Fluxes of CO2 from terrestrial to aquatic environments were investigated in a nested catchment study in the seasonally-dry southern Amazon. Dissolved CO2 concentrations in groundwater springs, four 1st order streams and one 2nd order stream were determined via routine sampling and in-situ monitoring. CO2 concentrations were monitored in the soil atmosphere to 8m. Belowground, the seasonal trend in soil CO2 concentrations at depth lagged that of seasonal water table dynamics, with peak concentrations (8.7% CO2 vol/vol at 4m) occurring one month after maximum water table height, indicating a shift in root respiration and plant water uptake to deeper soil layers during the dry season. Peak dissolved CO2 concentrations in springs and streams lagged the soil CO2 maximum by an additional month. During storm events, streamflow CO2 concentrations were found to decrease initially, reflecting the initial contribution of low-CO2 direct precipitation and surface runoff. Streamwater CO2 then increased as the contribution of pre-event water to storm flow increased. Dissolved CO2 in springs was also found to increase during storm events. Diurnal fluctuations in dissolved CO2 of springs were also observed, indicating the connectivity of the biosphere, pedosphere and hydrosphere for headwater catchments. The dissolved CO2 concentration within 1st order streams decreases rapidly downstream from stream sources, with spring CO2 concentration 3.3 times that at headwater catchment outlets. This initial outgassing of CO2 within 1st order streams was found to be accompanied by a corresponding increase in the pH of stream water. However, dissolved CO2 concentrations were not found to be significantly different between 1st and 2nd order streams. This suggests a discontinuity between some processes at the terrestrial-aquatic interface in headwater catchments and those of larger-order watersheds.

  1. Tyrosine Kinase Inhibitors in Lung Cancer

    PubMed Central

    Thomas, Anish; Rajan, Arun; Giaccone, Giuseppe

    2012-01-01

    SYNOPSIS ‘Driver mutations’ are essential for carcinogenesis as well as tumor progression as they confer a selective growth advantage to cancer cells. Identification of driver mutations in growth related protein kinases, especially tyrosine kinases have led to clinical development of an array of tyrosine kinase inhibitors in various malignancies, including lung cancer. Inhibition of epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinases have proven to be of meaningful clinical benefit, while inhibition of several other tyrosine kinases have been of limited clinical benefit, thus far. An improved understanding of tyrosine kinase biology has also led to faster drug development, identification of resistance mechanisms and ways to overcome resistance. In this review, we discuss the clinical data supporting the use and practical aspects of management of patients on epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors. PMID:22520981

  2. An essential tyrosine residue of Aspergillus polygalacturonase.

    PubMed

    Stratilová, E; Dzúrová, M; Markovic, O; Jörnvall, H

    1996-03-11

    Based on strict conservation of a tyrosine residue in 24 polygalacturonases, tyrosine modification was assessed in two different forms of the Aspergillus enzyme. The second subform was unknown in structure but submitted to sequence analysis and was found also to have the conserved tyrosine residue. Results of chemical modifications are consistent in showing inactivation of the proteins with all tyrosine-reactive agents tested, acetic anhydride, N-acetyl imidazole, and tetranitromethane. Furthermore, after acetylation, regeneration of enzyme activity was possible with hydroxylamine. Spectrophotometric pH titration showed that one accessible tyrosine residue is ionized at pH 9.3-9.5, whereas the remaining, masked residues are all ionized at pH 10.5. It is concluded that one tyrosine residue is catalytically important, in agreement with the inactivation and reactivation data, that this residue is accessible, and that it is likely to correspond to the strictly conserved residue observed in all forms.

  3. Tyrosine Deprotonation Yields Abundant and Selective Backbone Cleavage in Peptide Anions upon Negative Electron transfer Dissociation and Ultraviolet Photodissociation

    PubMed Central

    Shaw, Jared B.; Ledvina, Aaron R.; Zhang, Xing; Julian, Ryan R.; Brodbelt, Jennifer S.

    2012-01-01

    Tyrosine deprotonation in peptides yields preferential electron detachment upon NETD or UVPD, resulting in prominent N – Cα bond cleavage N-terminal to the tyrosine residue. UVPD of iodo-tyrosine modified peptides was used to generate localized radicals on neutral tyrosine side chains by homolytic cleavage of the C – I bond. Subsequent collisional activation of the radical species yielded the same preferential cleavage of the adjacent N-terminal N – Cα bond. LC-MS/MS analysis of a tryptic digest of BSA demonstrated that these cleavages are regularly observed for peptides when using high pH mobile phases. PMID:22970927

  4. Tyrosine deprotonation yields abundant and selective backbone cleavage in peptide anions upon negative electron transfer dissociation and ultraviolet photodissociation.

    PubMed

    Shaw, Jared B; Ledvina, Aaron R; Zhang, Xing; Julian, Ryan R; Brodbelt, Jennifer S

    2012-09-26

    Tyrosine deprotonation in peptides yields preferential electron detachment upon NETD or UVPD, resulting in prominent N-Cα bond cleavage N-terminal to the tyrosine residue. UVPD of iodo-tyrosine-modified peptides was used to generate localized radicals on neutral tyrosine side chains by homolytic cleavage of the C-I bond. Subsequent collisional activation of the radical species yielded the same preferential cleavage of the adjacent N-terminal N-Cα bond. LC-MS/MS analysis of a tryptic digest of BSA demonstrated that these cleavages are regularly observed for peptides when using high-pH mobile phases.

  5. Zur Biosynthese von Phenylalanin und Tyrosin

    NASA Astrophysics Data System (ADS)

    Lingens, F.; Keller, E.

    1983-03-01

    With the discovery of arogenic acid two new pathways for the biosynthesis of phenylalanine and tyrosine have been revealed. The occurrence of two, three, or four pathways for the biosynthesis of phenylalanine and tyrosine in microorganisms and plants may be a useful tool for taxonomic classifications. Investigations on enterobacteriaceae, pseudomonads, flavobacteria, streptomycetes, archaebacteria, and on Sphaerotilus, Trichococcus and Leptothrix species from bulking sludge are described. The possible role of arogenate in the evolution of the pathways for tyrosine and phenylalanine biosynthesis is discussed.

  6. Directional fidelity of nanoscale motors and particles is limited by the 2nd law of thermodynamics--via a universal equality.

    PubMed

    Wang, Zhisong; Hou, Ruizheng; Efremov, Artem

    2013-07-21

    Directional motion of nanoscale motors and driven particles in an isothermal environment costs a finite amount of energy despite zero work as decreed by the 2nd law, but quantifying this general limit remains difficult. Here we derive a universal equality linking directional fidelity of an arbitrary nanoscale object to the least possible energy driving it. The fidelity-energy equality depends on the environmental temperature alone; any lower energy would violate the 2nd law in a thought experiment. Real experimental proof for the equality comes from force-induced motion of biological nanomotors by three independent groups - for translational as well as rotational motion. Interestingly, the natural self-propelled motion of a biological nanomotor (F1-ATPase) known to have nearly 100% energy efficiency evidently pays the 2nd law decreed least energy cost for direction production.

  7. Rocketdyne - J-2 Saturn V 2nd and 3rd Stage Engine. Chapter 2, Appendix D

    NASA Technical Reports Server (NTRS)

    Coffman, Paul

    2009-01-01

    The J-2 engine was unique in many respects. Technology was not nearly as well-developed in oxygen/hydrogen engines at the start of the J-2 project. As a result, it experienced a number of "teething" problems. It was used in two stages on the Saturn V vehicle in the Apollo Program, as well as on the later Skylab and Apollo/Soyuz programs. In the Apollo Program, it was used on the S-II stage, which was the second stage of the Saturn V vehicle. There were five J-2 engines at the back end of the S-II Stage. In the S-IV-B stage, it was a single engine, but that single engine had to restart. The Apollo mission called for the entire vehicle to reach orbital velocity in low Earth orbit after the first firing of the Saturn-IV-B stage and, subsequently, to fire a second time to go on to the moon. The engine had to be man-rated (worthy of transporting humans). It had to have a high thrust rate and performance associated with oxygen/hydrogen engines, although there were some compromises there. It had to gimbal for thrust vector control. It was an open-cycle gas generator engine delivering up to 230,000 pounds of thrust.

  8. Detection of 1st- and 2nd-order temporal-envelope cues in a patient with left superior cortical damage.

    PubMed

    Füllgrabe, Christian; Maillet, Didier; Moroni, Christine; Belin, Catherine; Lorenzi, Christian

    2004-06-01

    This psychophysical study explores the extent to which the auditory cortex is necessary for various aspects of temporal-envelope perception, that is, perception of the slow temporal modulations in amplitude known to be crucial for sound identification. The ability to detect 1st- and 2nd-order sinusoidal amplitude modulation (AM) is evaluated in a single patient showing left-hemisphere damage encroaching the primary and secondary auditory cortices. Here, 1st- and 2nd-order AM refer to (1) sinusoidal variation in the amplitude of a 2 kHz pure tone, and (2) sinusoidal variation in the depth of a 64 Hz AM applied to the 2 kHz pure tone, respectively. The results replicate previous findings by showing that damage to the left auditory cortex results in a selective deficit in auditory sensitivity to the lowest 1St-order AM (i.e., 1st-order AM frequencies < 16 Hz). Moreover, a dissociation is apparent between the ability to detect 1st- and 2nd-order temporal-envelope cues. The patient shows poorer than normal ability to detect 2nd-order AM at low frequencies ranging from 4-23 Hz, but normal ability to detect the high (64 Hz) 1st-order AM carrying these 2nd-order modulations. This result indicates that damage to the left primary and secondary auditory cortices affects the ability to detect temporal variations in the local properties of sounds(such as AM depth). It is also consistent with the idea that, as in vision, central nonlinear mechanisms are involved in the computation of such local (or 2nd-order) temporal properties.

  9. Tyrosine Ameliorates a Cold-Induced Delayed Matching-to-Sample Performance Decrement in Rats

    DTIC Science & Technology

    1993-01-01

    were controlled and creased firing rate of CNS neurons and the continued recorded by a computer system. release of catecholamines, tyrosine hydroxylase ... hydroxylase . In: Lipton MA, DiMascio ducing a working memory deficit under field conditions A, Killam KF (eds) Psychopharmacology: a generation of pro...of rats after acute oral doses of aspar- References tame, phenylalanine , and tyrosine. Fundam Appi Toxicol 16:495-505 Ahlers ST, Thomas JR, Berkey DL

  10. Highlights from AGU's 2nd virtual session: New magnetic field satellites

    NASA Astrophysics Data System (ADS)

    Convenors, S.; Olsen, N.; Luehr, H.

    2002-05-01

    Over the past 150 years, the axial dipole component of the Earth's magnetic field has decayed by nearly 10%. This is ten times faster than if the dynamo that generates the field were switched off completely. The current decay rate is characteristic of magnetic reversals, which paleomagnetic data sets have shown occur on average about once every half million years. Three new geomagnetic field satellites have recently been placed in low-earth orbits and are investigating questions such as this rapid decay. Geographically, this decay is largely due to changes in the field in the South Atlantic region, where the expanding and deepening South Atlantic anomaly has serious implications for low-Earth orbit satellite operations. The magnetic field measured at or near the surface of the Earth is the superposition of contributions from a variety of sources: the fluid core,the magnetization of rocks in the Earth's crust, electric currents flowing in the ionosphere and magnetosphere, currents induced in the Earth by the time variations of the field, and electric currents induced by the oceanic circulation. The scientific challenge is the sophisticated separation of these various sources and the accurate determination of the spatial and temporal structure of them all. Multi-point measurements from high-precision satellites are a pre-requisite for such characterizations. With the launch of Oersted (1999), CHAMP and the Oersted-2 experiment onboard SAC-C (2000), there are now three satellites in near-Earth orbit measuring the scalar and vector magnetic fields at the nT accuracy level. In order to improve the utilization of these unique data sets, representatives of these projects publicly released simultaneous observations of data from all three satellites at www.dsri.dk/multimagsatellites. The data selection spanned a variety of viewing geometries, local times, and magnetic disturbance levels. Descriptive models and indices were also included. Presentations described the utility

  11. Dacomitinib (PF-00299804), a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor, demonstrates remarkable activity against HER2-amplified uterine serous endometrial cancer in vitro.

    PubMed

    Zhu, Liancheng; Lopez, Salvatore; Bellone, Stefania; Black, Jonathan; Cocco, Emiliano; Zigras, Tiffany; Predolini, Federica; Bonazzoli, Elena; Bussi, Beatrice; Stuhmer, Zachary; Schwab, Carlton L; English, Diana P; Ratner, Elena; Silasi, Dan-Arin; Azodi, Masoud; Schwartz, Peter E; Rutherford, Thomas J; Santin, Alessandro D

    2015-07-01

    Uterine serous carcinoma (USC) is an aggressive subtype of endometrial cancer that carries an extremely poor prognosis. Up to 35 % of USC may overexpress the epidermal growth factor receptor-2 (HER2/neu) at strong (i.e., 3+) level by immunohistochemistry (IHC) or harbor HER2/neu gene amplification by fluorescence in situ hybridization (FISH). In this study, we assessed the sensitivity of a panel of USC cell lines with and without HER2/neu gene amplification to dacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor tyrosine kinase inhibitor. Eight primary cell lines (i.e., four harboring HER2/neu gene amplification by FISH and four FISH- cell lines), all demonstrating similar in vitro growth rates, were evaluated in viability/proliferation assays. The effect of dacomitinib on cell growth, cell cycle distribution, and signaling was determined using flow cytometry-based assays. Dacomitinib caused a significantly stronger growth inhibition in HER2/neu FISH+ USC cell lines when compared to FISH- USC (dacomitinib half maximal inhibitory concentration (IC50) mean ± SEM = 0.02803 ± 0.003355 μM in FISH+ versus 1.498 ± 0.2209 μM in FISH- tumors, P < 0.0001). Dacomitinib growth inhibition was associated with a significant and dose-dependent decline in phosphorylated HER2/neu and S6 transcription factor and a dose-dependent and time-dependent cell cycle arrest in G0/G1 in FISH+ USC. Dacomitinib is remarkably effective against chemotherapy-resistant HER2/neu gene-amplified USC. Clinical studies with dacomitinib in HER2/neu FISH+ USC patients resistant to standard salvage chemotherapy are warranted.

  12. Pre-Treatment with Tyrosine Reverses Hypothermia Induced Behavioral Depression

    DTIC Science & Technology

    1989-09-01

    accelerated firing activates the enzyme tyrosine- hydroxylase , making it more tyrosine sensitive. The reduction of brain NA is accompanied by a behavioral...regions of the brain. The accelerated firing activates the enzyme tyrosine- hydroxylase , making it more tyrosine sensitive. The reduction of brain NA...depletion. The accelerated firing activates the enzyme tyrosine- hydroxylase (7), making it more tyrosine sensitive. It has been reported that

  13. Receptor tyrosine kinases in carcinogenesis.

    PubMed

    Zhang, Xiao-Ying; Zhang, Pei-Ying

    2016-11-01

    Receptor tyrosine kinases (RTKs) are cell surface glycoproteins with enzymatic activity involved in the regulation of various important functions. In all-important physiological functions including differentiation, cell-cell interactions, survival, proliferation, metabolism, migration and signaling these receptors are the key players of regulation. Additionally, mutations of RTKs or their overexpression have been described in many human cancers and are being explored as a novel avenue for a new therapeutic approach. Some of the deregulated RTKs observed to be significantly affected in cancers included vascular endothelial growth factor receptor, epidermal growth factor receptor, fibroblast growth factor receptor, RTK-like orphan receptor 1 (ROR1) and the platelet-derived growth factor receptor. These deregulated RTKs offer attractive possibilities for the new anticancer therapeutic approach involving specific targeting by monoclonal antibodies as well as kinase. The present review aimed to highlight recent perspectives of RTK ROR1 in cancer.

  14. Dynamics of the properties of steppe paleosols of the Sarmatian time (2nd century BC-4th century AD) in relation to secular variations in climatic humidity

    NASA Astrophysics Data System (ADS)

    Demkin, V. A.; Zolotareva, B. N.; Demkina, T. S.; Khomutova, T. E.; Kashirskaya, N. N.; El'Tsov, M. V.; Udal'Tsov, S. N.

    2012-02-01

    Paleosols buried under kurgans of the Early (2nd-1st centuries BC), Middle (1st-2nd centuries AD) and Late (2nd-IV centuries AD) Sarmatian epochs were studied in dry steppes and desert steppes of the Lower Volga region (the Privolzhskaya and Ergeni Uplands and the Caspian Lowland). It was found that temporal variations in the morphological, chemical, microbiological, and magnetic properties of the paleosols in the interval of 2200-1600 BP were characterized by the cyclic pattern related to secular dynamics of climatic humidity with changes in the mean annual precipitation of ±30-50 mm. These climate changes did not transform chestnut paleosols and paleosolonetzes at the type or subtype taxonomic levels. However, they led to certain changes in the humus, carbonate, and salt profiles of the soils; in the character of solonetzic horizon B1; and in the state of microbial communities. According to these data, the Sarmatian time was characterized by alternation of micropluvial and microarid stages lasting fro about 100-200 years. In particular, the stages of humidization were observed in the 1st century BC-1st century AD and in the 4th century AD; the most arid conditions were observed in the second half of the 2nd and the first half of the 3rd century AD.

  15. Experimental observations on the response of 1(st) and 2(nd) order fibre optic long period grating coupling bands to the deposition of nanostructured coatings.

    PubMed

    James, Stephen W; Cheung, C S; Tatam, Ralph P

    2007-10-01

    The sensitivity of attenuation bands corresponding to the 2(nd) order coupling to cladding modes by a fibre optic long period grating (LPG) to the deposition of nanostructured coatings is investigated and compared with that of the 1(st) order coupling. The experimental observations support previously reported theoretical descriptions of LPGs with nanoscale coatings.

  16. Research and Prediction of the Application of Multimedia Teaching Aid in Teaching Technical Education on the 2nd Level of Primary Schools

    ERIC Educational Resources Information Center

    Stebila, Ján

    2011-01-01

    The purpose and the main aim of the pedagogic experiment were to practically verify the success of Multimedia Teaching Aid (MTA) in conditions of primary schools. We assumed that the use of our multimedia teaching aid in teaching technical education on the 2nd level of primary schools would significantly affect the level of knowledge of pupils…

  17. 2nd dimensional GC-MS analysis of sweat volatile organic compounds prepared by solid phase micro-extraction.

    PubMed

    Choi, Mi-Jung; Oh, Chang-Hwan

    2014-01-01

    The characteristics of an individual's odor from sweat, breath and skin provide important information for criminal tracking in field of forensic science. Solid phase micro-extraction gas chromatography/mass spectrometry (SPME-GC/MS) was used to determine human sweat volatile organic compounds (VOCs) profiles. The mass spectrometric analysis (with electron impact mode) followed by 2nd dimensional separation with two different GC columns (one polar and one relatively nonpolar) connected in parallel were used to identify the 574 compounds from sweat samples. The components included alcohols, aldehydes, aliphatics/aromatics, carboxylic acids, esters, ketones, and other organic compounds (amides/amines, thio/thioesters, oxide, sulfides, nitro compounds). Of these compounds, 1-tridecanol, 1,3-bis(1,1-dimethyl ethyl)-benzene, 4,4'-(1-methylethylidene) bis-phenol and 7-acetyl-6-ethyl-1,1,4,4,-tetramethyl-tetraline were common components in all donor's sweat volatile samples. Age-related specific compounds were also detected. The results suggest that characteristic volatile profiles of human sweat emanations could provide the valuable information to forensic scientists.

  18. Explicit formulas for 2nd-order driving terms due to sextupoles and chromatic effects of quadrupoles.

    SciTech Connect

    Wang, C-X. )

    2012-04-25

    Optimization of nonlinear driving terms have become a useful tool for designing storage rings, especially modern light sources where the strong nonlinearity is dominated by the large chromatic effects of quadrupoles and strong sextupoles for chromaticity control. The Lie algebraic method is well known for computing such driving terms. However, it appears that there was a lack of explicit formulas in the public domain for such computation, resulting in uncertainty and/or inconsistency in widely used codes. This note presents explicit formulas for driving terms due to sextupoles and chromatic effects of quadrupoles, which can be considered as thin elements. The computation is accurate to the 4th-order Hamiltonian and 2nd-order in terms of magnet parameters. The results given here are the same as the APS internal note AOP-TN-2009-020. This internal nte has been revised and published here as a Light Source Note in order to get this information into the public domain, since both ELEGANT and OPA are using these formulas.

  19. 1st and 2nd order Raman scattering from n-Graphene Layer (nGL) Films on Silicon Substrates.

    NASA Astrophysics Data System (ADS)

    Gupta, Awnish; Chen, Gugang; Eklund, Peter

    2007-03-01

    Results of room temperature Raman scattering experiments on graphene and n-graphene layer films (nGLs) will be presented [1]. We find that the G band at ˜ 1582 cm-1 exhibits an interesting upshift in frequency with 1/n which we tentatively assign to a surface strain phenomenon connected with surface roughness of the substrate and compensated by the increase in stiffness of the nGL with increasing n. Interesting n-specific bands are observed in the ˜1350 cm-1 (or D-band) region which may correlate with deviations from planarity of the nGL. The second order scattering is very interesting and for small n (n<4) the (2D' or G') band intensity at ˜ 2700 cm-1 is actually higher than the first-order G-band scattering. The shape of this band is sensitive to n and thus can be used to identify n without an AFM measurement. Whereas, the 2D' band is sensitive to n, the 2nd order 2G band ˜ 3248 cm-1 is independent of n. These observations will be discussed in terms of the phonon and electronic dispersion of nGLs. 1 A. Gupta, G. Chen, P. Joshi, S. Tadigadapa and P.C. Eklund, `` Raman Scattering from High-Frequency Phonons in Supported n-Graphene Layer Films'' NanoLett (in Press).

  20. Increasing the water temperature of a 2nd order stream reach: Hydraulic aspects of a whole-stream manipulative experiment

    NASA Astrophysics Data System (ADS)

    de Lima, João L. M. P.; Canhoto, Cristina

    2015-04-01

    What will happen when water temperatures of streams increases, due to climate changes or in connection with rapidly changing human systems? Trying to answer to this question a whole-stream manipulative experiment was undertaken, where an increase in water temperature was artificially induced on a 2nd order stream reach. The main objective of this poster is to describe this experiment focusing on the design of the hydraulic system. The system maintained a steady flow while allowing natural variation in abiotic factors and was successfully used to evaluate the effects of warming on a stream ecosystem at several levels of biological organization. A constant flow of stream water was controlled by a hydraulic setup (~22m long; ~1.5m width) subdivided into two independent channels. One channel of the study reach received heated water (~3°C above the other), while the other received water at stream ambient temperature. The warming system maintained a steady gravity controlled flow making use of weirs and valves.

  1. Fabrication of 30 mm long baseline single-layer 2nd-order high- Tc SQUID gradiometer

    NASA Astrophysics Data System (ADS)

    Lee, Soon-Gul; Oh, Soo-Ho; Kang, Chan Seok; Kim, In-Seon

    2007-09-01

    We have designed and fabricated a 30 mm long baseline 2nd-order SQUID gradiometer from a single-layer YBa 2Cu 3O 7 film. The design rule was the same as that of our previous study on short baseline gradiometers. Three linearly aligned 10.2 mm × 10.2 mm pickup loops were coupled directly to a dc SQUID to measure ∂ 2Bz/∂ x2. The device had an overall size of 70.2 mm × 10.6 mm and was patterned from a single layer of YBa 2Cu 3O 7 film on a sapphire substrate by argon ion milling with a photoresist mask. The Josephson element of the SQUID was YBa 2Cu 3O 7 nanobridges formed by focused ion beam writing technique. Balancing of the device was achieved by optimizing the inductance of the center loop. Estimated sensitivity of the gradiometer was ∼1.8 × 10 -10 T/m 2/Hz 1/2, which is equivalent to a field noise of 160 fT/Hz 1/2, for an intrinsic SQUID flux noise of 10 -5 ϕ0/Hz 1/2.

  2. Horizontal transmission of hepatitis B virus amongst British 2nd World War soldiers in South-East Asia.

    PubMed

    Gill, G V; Bell, D R; Vandervelde, E M

    1991-01-01

    Infection with hepatitis B virus (HBV) is much more common in tropical than in temperate countries. Visitors to the tropics are thus at risk from HBV, though the degree of risk, and the routes of infection involved are uncertain. We report serological markers of HBV in two groups of 2nd World War soldiers, who served in the Thai/Burma jungles. The groups comprised 100 ex-prisoners of the Japanese (POW), and 100 Burma Campaign Veterans (BCV). Surface antigen to HBV (HbsAg) was positive in 0% of POW and 2% of BCV (P = not significant). Surface antibody (anti-HBs) and core antibody (anti-HBc) were both positive in 40% POW and 13% BCV (P less than 0.001). Quoted UK prevalence rates for these markers are 0.1% for HBsAg, 1.5% for anti-HBs and 0.7% for anti-HBc. Both groups thus show very high rates of past HBV infection. For the POW there were many possible reasons, including contaminated surgical instruments and needles, blood transfusions, and multiple beatings with common weapons. None of these factors operated significantly for BCV. Malarial transmission was, however, intense in both groups, though more so in POW. The data thus again raise the possibility of horizontal transmission of HBV by biting insects in tropical countries.

  3. [JAN JĘDRZEJEWICZ AND EUROPEAN ASTRONOMY OF THE 2ND HALF OF THE 19TH CENTURY].

    PubMed

    Siuda-Bochenek, Magda

    2015-01-01

    Jan Jędrzejewicz was an amateur astronomer who in the 2nd half of the 19th century created an observation centre, which considering the level of research was comparable to the European ones. Jędrzejewicz settled down in Plonsk in 1862 and worked as a doctor ever since but his greatest passion was astronomy, to which he dedicated all his free time. In 1875 Jędrzejewicz finished the construction of his observatory. He equipped it with basic astronomical and meteorological instruments, then began his observations and with time he became quite skilled in it. Jędrzejewicz focused mainly on binary stars but he also pointed his telescopes at the planets of the solar system, the comets, the Sun, as well as all the phenomena appearing in the sky at that time. Thanks to the variety of the objects observed and the number of observations he stood out from other observers in Poland and took a very good position in the mainstream of the 19th-century astronomy in Europe. Micrometer observations of binary stars made in Płońsk gained recognition in the West and were included in the catalogues of binary stars. Interest in Jędrzejewicz and his observatory was confirmed by numerous references in the English "Nature" magazine.

  4. Universe (2nd edition)

    SciTech Connect

    Kaufmann, W.J. III

    1988-01-01

    A general text on astronomy is presented. The foundations of the science are reviewed, including descriptions of naked-eye observatons of eclipses and planetary motions and such basic tools as Kepler's laws, the fundamental properties of light, and the optics of telescopes. The formation of the solar system is addressed, and the planets and their satellites are discussed individually. Solar science is treated in detail. Stellar evolution is described chronologically from birth to death. Molecular clouds, star clusters, nebulae, neutron stars, black holes, and various other phenomena that occur in the life of a star are examined in the sequence in which they naturally occur. A survey of the Milky Way introduces galactic astronomy. Quasars and cosmology are addressed, including the most recent developments in research. 156 references.

  5. Administration of supplemental L-tyrosine with phenelzine: a clinical literature review

    PubMed Central

    Hinz, Marty; Stein, Alvin; Cole, Ted; Ryan, Patricia

    2014-01-01

    The subject of this literature review is the alleged relationship between L-tyrosine, phenelzine, and hypertensive crisis. Phenelzine (Nardil®) prescribing information notes: “The potentiation of sympathomimetic substances and related compounds by MAO inhibitors may result in hypertensive crises (see WARNINGS). Therefore, patients being treated with NARDIL should not take […] L-tyrosine […]”. Interest in the scientific foundation of this claim was generated during routine patient care. A comprehensive literature search of Google Scholar and PubMed revealed no reported cases of hypertensive crisis associated with concomitant administration of L-tyrosine and phenelzine. Review of current US Food and Drug Administration nutritional guidelines relating to ongoing phenelzine studies reveals no mention and requires no consideration of L-tyrosine ingestion in combination with phenelzine. This paper is intended to provide an objective review of the science to then allow the reader to formulate the final opinion. PMID:25092999

  6. Generations.

    PubMed

    Chambers, David W

    2005-01-01

    Groups naturally promote their strengths and prefer values and rules that give them an identity and an advantage. This shows up as generational tensions across cohorts who share common experiences, including common elders. Dramatic cultural events in America since 1925 can help create an understanding of the differing value structures of the Silents, the Boomers, Gen Xers, and the Millennials. Differences in how these generations see motivation and values, fundamental reality, relations with others, and work are presented, as are some applications of these differences to the dental profession.

  7. High levels of virological failure with major genotypic resistance mutations in HIV-1-infected children after 5 years of care according to WHO-recommended 1st-line and 2nd-line antiretroviral regimens in the Central African Republic: A cross-sectional study.

    PubMed

    Mossoro-Kpinde, Christian Diamant; Gody, Jean-Chrysostome; Mboumba Bouassa, Ralph-Sydney; Mbitikon, Olivia; Jenabian, Mohammad-Ali; Robin, Leman; Matta, Mathieu; Zeitouni, Kamal; Longo, Jean De Dieu; Costiniuk, Cecilia; Grésenguet, Gérard; Touré Kane, Ndèye Coumba; Bélec, Laurent

    2017-03-01

    A large cohort of 220 HIV-1-infected children (median [range] age: 12 [4-17] years) was cared and followed up in the Central African Republic, including 198 in 1st-line and 22 in 2nd-line antiretroviral regimens. Patients were monitored clinically and biologically for HIV-1 RNA load and drug resistance mutations (DRMs) genotyping. A total of 87 (40%) study children were virological responders and 133 (60%) nonresponders. In children with detectable viral load, the majority (129; 97%) represented a virological failure. In children receiving 1st-line regimens in virological failure for whom genotypic resistance test was available, 45% displayed viruses harboring at least 1 DRM to NNRTI or NRTI, and 26% showed at least 1 major DRM to NNRTI or NRTI; more than half of children in 1st-line regimens were resistant to 1st-generation NNRTI and 24% of the children in 1st-line regimens had a major DRMs to PI. Virological failure and selection of DRMs were both associated with poor adherence. These observations demonstrate high rate of virological failure after 3 to 5 years of 1st-line or 2nd-line antiretroviral treatment, which is generally associated with DRMs and therapeutic failure. Overall, more than half (55%) of children receiving 1st-line antiretroviral treatment for a median of 3.4 years showed virological failure and antiretroviral-resistance and thus eligible to 2nd-line treatment. Furthermore, two-third (64%) of children under 2nd-line therapy were eligible to 3rd-line regimen. Taken together, these observations point the necessity to monitor antiretroviral-treated children by plasma HIV-1 RNA load to diagnose as early as possible the therapeutic failure and operate switch to a new therapeutic line.

  8. High levels of virological failure with major genotypic resistance mutations in HIV-1-infected children after 5 years of care according to WHO-recommended 1st-line and 2nd-line antiretroviral regimens in the Central African Republic

    PubMed Central

    Mossoro-Kpinde, Christian Diamant; Gody, Jean-Chrysostome; Mboumba Bouassa, Ralph-Sydney; Mbitikon, Olivia; Jenabian, Mohammad-Ali; Robin, Leman; Matta, Mathieu; Zeitouni, Kamal; Longo, Jean De Dieu; Costiniuk, Cecilia; Grésenguet, Gérard; Touré Kane, Ndèye Coumba; Bélec, Laurent

    2017-01-01

    Abstract A large cohort of 220 HIV-1-infected children (median [range] age: 12 [4–17] years) was cared and followed up in the Central African Republic, including 198 in 1st-line and 22 in 2nd-line antiretroviral regimens. Patients were monitored clinically and biologically for HIV-1 RNA load and drug resistance mutations (DRMs) genotyping. A total of 87 (40%) study children were virological responders and 133 (60%) nonresponders. In children with detectable viral load, the majority (129; 97%) represented a virological failure. In children receiving 1st-line regimens in virological failure for whom genotypic resistance test was available, 45% displayed viruses harboring at least 1 DRM to NNRTI or NRTI, and 26% showed at least 1 major DRM to NNRTI or NRTI; more than half of children in 1st-line regimens were resistant to 1st-generation NNRTI and 24% of the children in 1st-line regimens had a major DRMs to PI. Virological failure and selection of DRMs were both associated with poor adherence. These observations demonstrate high rate of virological failure after 3 to 5 years of 1st-line or 2nd-line antiretroviral treatment, which is generally associated with DRMs and therapeutic failure. Overall, more than half (55%) of children receiving 1st-line antiretroviral treatment for a median of 3.4 years showed virological failure and antiretroviral-resistance and thus eligible to 2nd-line treatment. Furthermore, two-third (64%) of children under 2nd-line therapy were eligible to 3rd-line regimen. Taken together, these observations point the necessity to monitor antiretroviral-treated children by plasma HIV-1 RNA load to diagnose as early as possible the therapeutic failure and operate switch to a new therapeutic line. PMID:28272247

  9. Chronotypic induction of tyrosine aminotransferase by. cap alpha. -methyl-p-tyrosine. [Rat liver

    SciTech Connect

    Cahill, A.L.; Ferguson, S.M.; Ehret, C.F.

    1981-04-06

    ..cap alpha..Methyl-p-tyrosine induced hepatic tyrosine aminotransferase activity to different extents depending upon the time of day of administration of the drug. Maximal induction occurred when ..cap alpha..-methyl-p-tyrosine (100 mg/kg) was injected intraperitoneally during the first several hours of the light phase of the daily cycle, but the magnitude of the induction depended on the nutritional state of the animal. Induction was 4- to 5-fold greater in fasting rats. The effect of ..cap alpha..-methyl-ptyrosine on hepatic tyrosine aminotransferase is believed to be mediated by decreases in hypothalamic norepinephrine. This hypothesis was supported by the demonstration that decreasing levels of hypothalamic norepinephrine at times of day when hypothalamic turnover of norepinephrine was greatest resulted in the greatest induction of tyrosine aminotransferase, while lowering hypothalamic norepinephrine at times when turnover was minimal resulted in minimal induction of tyrosine aminotransferase.

  10. Syntheses of L-tyrosine-related amino acids by tyrosine phenol-lyase of Citrobacter intermedius.

    PubMed

    Nagasawa, T; Utagawa, T; Goto, J; Kim, C J; Tani, Y; Kumagai, H; Yamada, H

    1981-06-01

    Degradation of tyrosine to phenol, pyruvate and ammonia by tyrosine phenol-lyase from Citrobacter intermedius (formerly named Escherichia intermedia) is readily reversible at high concentrations of pyruvate and ammonia. Spectrophotometric studies indicate that ammonia is the first substrate which interacts with bound pyridoxal 5'-phosphate. Kinetic results show that pyruvate is the second substrate bound, hence phenol must be the third. When an appropriate phenol derivative is substituted for phenol, the corresponding tyrosine analogue can be synthesized. 3-Fluoro-, 2-fluoro-, 3-chloro-, 2-chloro-, 3-bromo-, 2-bromo-, 2-iodo-, 3-methyl-, 2-methyl- and 2-methoxy-L-tyrosines have been synthesized by this reaction. By using various phenol derivatives or tyrosine analogues as substrates, the substrate specificity of tyrosine phenol-lyase is investigated and the situation of its active site is discussed.

  11. Use of prelecture assignment to enhance learning in pharmacology lectures for the 2nd year medical students

    PubMed Central

    Ahsan, Marya; Mallick, Ayaz Khurram

    2016-01-01

    Objectives: Majority of teaching hours allotted by the Medical Council of India in pharmacology are utilized in the form of didactic lecture. Although these lectures are an excellent tool to deliver the information to a large group of students, it usually ends up as a one-sided teaching session with most students being the passive listeners. To make these lectures interesting and effective, we introduced the students to prelecture assignment (PLA) in the form of clinical case before the delivery of the lecture. Methods: This prospective educational trial was conducted in the Department of Pharmacology with undergraduate medical students in their 2nd year of their professional course. They were divided into two groups of 75 each. Group A was provided the PLA before the lecture. Group B students directly attended the lecture, sans the PLA. Multiple-choice questions-based test was conducted 2 days after the lecture. Students who failed to complete the assignment and were absent from the lecture and test were excluded from the study. Feedback from the students was obtained after the lecture. The scores in the test and responses were compiled and analyzed using Statistical Package for Social Sciences (SPSS) software version 21.0 (SPSS Inc., Chicago, IL, USA). Results were expressed in percentages and as mean ± standard deviation as applicable. P < 0.05 was considered statistically significant. Results: Fifty-six students from Group A and 42 from Group B appeared for the test. The students who were given PLA scored better. They felt more confident in answering and understood the topic better than the students of other group. Conclusion: PLA is a useful teaching-learning tool. The pharmacology lectures are interactive, interesting, and easy to understand with this tool. PMID:28031612

  12. Differences in risk factors for 2nd and 3rd degree hypospadias in the National Birth Defects Prevention Study

    PubMed Central

    in 't Woud, Sander Groen; van Rooij, Iris A.L.M.; van Gelder, Marleen M.H.J.; Olney, Richard S.; Carmichael, Suzan L.; Roeleveld, Nel; Reefhuis, Jennita

    2015-01-01

    Background Hypospadias is a frequent birth defect with three phenotypic subtypes. With data from the National Birth Defects Prevention Study, a large, multi-state, population-based, case-control study, we compared risk factors for second and third degree hypospadias. Methods A wide variety of data on maternal and pregnancy-related risk factors for isolated second and third degree hypospadias was collected via computer-assisted telephone interviews to identify potential etiological differences between the two phenotypes. Logistic regression was used to calculate odds ratios including a random effect by study center. Results In total, 1547 second degree cases, 389 third degree cases, and 5183 male controls were included in our study. Third degree cases were more likely to have a non-Hispanic black or Asian/Pacific Islander mother, be delivered preterm, have a low birth weight, be small for gestational age, and be conceived with fertility treatments than second degree cases and controls. Associations with both second and third degree hypospadias were observed for maternal age, family history, parity, plurality, and hypertension during pregnancy. Risk estimates were generally higher for third degree hypospadias except for family history. Conclusions Most risk factors were associated with both or neither phenotype. Therefore, it is likely that the underlying mechanism is at least partly similar for both phenotypes. However, some associations were different between 2nd and 3rd degree hypospadias, and went in opposite directions for second and third degree hypospadias for Asian/Pacific Islander mothers. Effect estimates for subtypes of hypospadias may be over- or underestimated in studies without stratification by phenotype. PMID:25181604

  13. ENABLE -- A systolic 2nd level trigger processor for track finding and e/[pi] discrimination for ATLAS/LHC

    SciTech Connect

    Klefenz, F.; Noffz, K.H.; Zoz, R. . Lehrstuhl fuer Informatik V); Maenner, R. . Interdisziplinaeres Zentrum fuer Wissenschaftliches Rechnen)

    1994-08-01

    The Enable Machine is a systolic 2nd level trigger processor for the transition radiation detector (TRD) of ATLAS/LHC. It is developed within the EAST/RD-11 collaboration at CERN. The task of the processor is to find electron tracks and to reject pion tracks according to the EAST benchmark algorithm in less than 10[mu]s. Track are identified by template matching in a ([psi],z) region of interest (RoI) selected by a 1st level trigger. In the ([psi],z) plane tracks of constant curvature are straight lines. The relevant lines form mask templates. Track identification is done by histogramming the coincidences of the templates and the RoI data for each possible track. The Enable Machine is an array processor that handles tracks of the same slope in parallel, and tracks of different slope in a pipeline. It is composed of two units, the Enable histogrammer unit and the Enable z/[psi]-board. The interface daughter board is equipped with a HIPPI-interface developed at JINR/-Dubna, and Xilinx 'corner turning' data converter chips. Enable uses programmable gate arrays (XILINX) for histogramming and synchronous SRAMs for pattern storage. With a clock rate of 40 MHz the trigger decision time is 6.5 [mu]s and the latency 7.0 [mu]s. The Enable machine is scalable in the RoI size as well as in the number of tracks processed. It can be adapted to different recognition tasks and detector setups. The prototype of the Enable Machine has been tested in a beam time of the RD6 collaboration at CERN in October 1993.

  14. Interaction between Short-Term Heat Pretreatment and Fipronil on 2nd Instar Larvae of Diamondback Moth, Plutella Xylostella (Linn)

    PubMed Central

    Gu, Xiaojun; Tian, Sufen; Wang, Dehui; Gao, Fei; Wei, Hui

    2010-01-01

    Based on the cooperative virulence index (c.f.) and LC50 of fipronil, the interaction effect between short-term heat pretreatment and fipronil on 2nd instar larvae of diamondback moth (DBM), Plutella xylostella (Linnaeus), was assessed. The results suggested that pretreatment of the tested insects at 30 °C for 2, 4 and 8h could somewhat decrease the toxicity of fipronil at all set concentrations. The LC50 values of fipronil increased after heat pretreatment and c.f. values in all these treatments were below zero. These results indicated that real mortalities were less than theoretical ones and antagonism was found in the treatments of fipronil at 0.39 and 0.78 mg/L after heat pretreatment at 30 °C at 2, 4 and 8 h. However, pretreatment at 30 °C for 12h could increase the toxicity of fipronil at all set concentrations, the LC50 of fipronil decreased after heat pretreatment and c.f. values in all these treatments were above zero, which indicated real mortalities were higher than theoretical ones. Pretreatment of the tested insects at 35 °C for 2, 4, 8 and 12h was found to increase the toxicity of fipronil at all set concentrations which resulted in the decrease of LC50 values of fipronil and c.f. above zero in all treatments with only one exception. Most interactions were assessed as synergism. The results indicated that cooperative virulence index (c.f.) may be adopted in hormetic effect assessment. PMID:20877489

  15. Ocular Toxicity of Tyrosine Kinase Inhibitors

    PubMed Central

    Davis, Mary Elizabeth

    2016-01-01

    Purpose/Objectives To review common tyrosine kinase inhibitors, as well as their ocular side effects and management. Data Sources A comprehensive literature search was conducted using cINahl®, Pubmed, and cochrane databases for articles published since 2004 with the following search terms: ocular toxicities, tyrosine kinase inhibitors, ophthalmology, adverse events, eye, and vision. Data Synthesis Tyrosine kinase inhibitors can cause significant eye toxicity. Conclusions Given the prevalence of new tyrosine kinase inhibitor therapies and the complexity of possible pathogenesis of ocular pathology, oncology nurses can appreciate the occurrence of ocular toxicities and the role of nursing in the management of these problems. Implications for Nursing Knowledge of the risk factors and etiology of ocular toxicity of targeted cancer therapies can guide nursing assessment, enhance patient education, and improve care management. Including a review of eye symptoms and vision issues in nursing assessment can enhance early detection and treatment of ocular toxicity. PMID:26906134

  16. The Tyrosine Aminomutase TAM1 Is Required for β-Tyrosine Biosynthesis in Rice

    PubMed Central

    Yan, Jian; Aboshi, Takako; Teraishi, Masayoshi; Strickler, Susan R.; Spindel, Jennifer E.; Tung, Chih-Wei; Takata, Ryo; Matsumoto, Fuka; Maesaka, Yoshihiro; McCouch, Susan R.; Okumoto, Yutaka; Mori, Naoki; Jander, Georg

    2015-01-01

    Non-protein amino acids, often isomers of the standard 20 protein amino acids, have defense-related functions in many plant species. A targeted search for jasmonate-induced metabolites in cultivated rice (Oryza sativa) identified (R)-β-tyrosine, an isomer of the common amino acid (S)-α-tyrosine in the seeds, leaves, roots, and root exudates of the Nipponbare cultivar. Assays with 119 diverse cultivars showed a distinct presence/absence polymorphism, with β-tyrosine being most prevalent in temperate japonica cultivars. Genetic mapping identified a candidate gene on chromosome 12, which was confirmed to encode a tyrosine aminomutase (TAM1) by transient expression in Nicotiana benthamiana and in vitro enzyme assays. A point mutation in TAM1 eliminated β-tyrosine production in Nipponbare. Rice cultivars that do not produce β-tyrosine have a chromosome 12 deletion that encompasses TAM1. Although β-tyrosine accumulation was induced by the plant defense signaling molecule jasmonic acid, bioassays with hemipteran and lepidopteran herbivores showed no negative effects at physiologically relevant β-tyrosine concentrations. In contrast, root growth of Arabidopsis thaliana and other tested dicot plants was inhibited by concentrations as low as 1 μM. As β-tyrosine is exuded into hydroponic medium at higher concentrations, it may contribute to the allelopathic potential of rice. PMID:25901084

  17. Insulin stimulates the tyrosine phosphorylation of caveolin

    PubMed Central

    1995-01-01

    The specialized plasma membrane structures termed caveolae and the caveolar-coat protein caveolin are highly expressed in insulin- sensitive cells such as adipocytes and muscle. Stimulation of 3T3-L1 adipocytes with insulin significantly increased the tyrosine phosphorylation of caveolin and a 29-kD caveolin-associated protein in caveolin-enriched Triton-insoluble complexes. Maximal phosphorylation occurred within 5 min, and the levels of phosphorylation remained elevated for at least 30 min. The insulin-dose responses for the tyrosine phosphorylation of caveolin and the 29-kD caveolin-associated protein paralleled those for the phosphorylation of the insulin receptor. The stimulation of caveolin tyrosine phosphorylation was specific for insulin and was not observed with PDGF or EGF, although PDGF stimulated the tyrosine phosphorylation of the 29-kD caveolin- associated protein. Increased tyrosine phosphorylation of caveolin, its associated 29-kD protein, and a 60-kD protein was observed in an in vitro kinase assay after incubation of the caveolin-enriched Triton- insoluble complexes with Mg-ATP, suggesting the presence of an intrinsic tyrosine kinase in these complexes. These fractions contain only trace amounts of the activated insulin receptor. In addition, these complexes contain a 60-kD kinase detected in an in situ gel kinase assay and an approximately 60 kD protein that cross-reacts with an antibody against the Src-family kinase p59Fyn. Thus, the insulin- dependent tyrosine phosphorylation of caveolin represents a novel, insulin-specific signal transduction pathway that may involve activation of a tyrosine kinase downstream of the insulin receptor. PMID:7540611

  18. Protein tyrosine nitration in the cell cycle

    SciTech Connect

    Jia, Min; Mateoiu, Claudia; Souchelnytskyi, Serhiy

    2011-09-23

    Highlights: {yields} Enrichment of 3-nitrotyrosine containing proteins from cells synchronized in different phases of the cell cycle. {yields} Identification of 76 tyrosine nitrated proteins that change expression during the cell cycle. {yields} Nineteen identified proteins were previously described as regulators of cell proliferation. -- Abstract: Nitration of tyrosine residues in proteins is associated with cell response to oxidative/nitrosative stress. Tyrosine nitration is relatively low abundant post-translational modification that may affect protein functions. Little is known about the extent of protein tyrosine nitration in cells during progression through the cell cycle. Here we report identification of proteins enriched for tyrosine nitration in cells synchronized in G0/G1, S or G2/M phases of the cell cycle. We identified 27 proteins in cells synchronized in G0/G1 phase, 37 proteins in S phase synchronized cells, and 12 proteins related to G2/M phase. Nineteen of the identified proteins were previously described as regulators of cell proliferation. Thus, our data indicate which tyrosine nitrated proteins may affect regulation of the cell cycle.

  19. Biological Damage Threshold Induced by Ultrashort Fundamental, 2nd, and 4th Harmonic Light Pulses from a Mode-Locked Nd: Glass Laser.

    DTIC Science & Technology

    1980-12-01

    BY ULTRASHORT FUNDAMENTAL, 2ND, AND 4TH HARMONIC LIGHT PULSES 00 , FROM A MODE-LOCKED Nd:GLASS LASER C Adam P. Bruckner, Ph.D. J. Michael Schurr, Ph.D...Medicine, Aerospace Medical Division, AFSC, Brooks Air Force Base, Texas. Dr. Taboada (USAFSAM/RZL) was the Laboratory Project Scientist-in-Charge. When... TABOADA , Ph.D. /AONN E. PICKERING, M.S. Project Scientist Chief, Radiation Sciences Division ROY L. DEHART Colonel, USAF, MC Commander UNCLASSIFIED S

  20. All-optical 1st- and 2nd-order differential equation solvers with large tuning ranges using Fabry-Pérot semiconductor optical amplifiers.

    PubMed

    Chen, Kaisheng; Hou, Jie; Huang, Zhuyang; Cao, Tong; Zhang, Jihua; Yu, Yuan; Zhang, Xinliang

    2015-02-09

    We experimentally demonstrate an all-optical temporal computation scheme for solving 1st- and 2nd-order linear ordinary differential equations (ODEs) with tunable constant coefficients by using Fabry-Pérot semiconductor optical amplifiers (FP-SOAs). By changing the injection currents of FP-SOAs, the constant coefficients of the differential equations are practically tuned. A quite large constant coefficient tunable range from 0.0026/ps to 0.085/ps is achieved for the 1st-order differential equation. Moreover, the constant coefficient p of the 2nd-order ODE solver can be continuously tuned from 0.0216/ps to 0.158/ps, correspondingly with the constant coefficient q varying from 0.0000494/ps(2) to 0.006205/ps(2). Additionally, a theoretical model that combining the carrier density rate equation of the semiconductor optical amplifier (SOA) with the transfer function of the Fabry-Pérot (FP) cavity is exploited to analyze the solving processes. For both 1st- and 2nd-order solvers, excellent agreements between the numerical simulations and the experimental results are obtained. The FP-SOAs based all-optical differential-equation solvers can be easily integrated with other optical components based on InP/InGaAsP materials, such as laser, modulator, photodetector and waveguide, which can motivate the realization of the complicated optical computing on a single integrated chip.

  1. Hybrid distributed Raman amplification combining random fiber laser based 2nd-order and low-noise LD based 1st-order pumping.

    PubMed

    Jia, Xin-Hong; Rao, Yun-Jiang; Yuan, Cheng-Xu; Li, Jin; Yan, Xiao-Dong; Wang, Zi-Nan; Zhang, Wei-Li; Wu, Han; Zhu, Ye-Yu; Peng, Fei

    2013-10-21

    A configuration of hybrid distributed Raman amplification (H-DRA), that is formed by incorporating a random fiber laser (RFL) based 2nd-order pump and a low-noise laser-diode (LD) based 1st-order pump, is proposed in this paper. In comparison to conventional bi-directional 1st-order DRA, the effective noise figure (ENF) is found to be lower by amount of 0 to 4 dB due to the RFL-based 2nd-order pump, depending on the on-off gain, while the low-noise 1st-order Raman pump is used for compensating the worsened signal-to-noise ratio (SNR) in the vicinity towards the far end of the fiber and avoiding the potential nonlinear impact induced by excess injection of pump power and suppressing the pump-signal relative intensity noise (RIN) transfer. As a result, the gain distribution can be optimized along ultra-long fiber link, due to combination of the 2nd-order RFL and low-noise 1st-order pumping, making the transmission distance be extended significantly. We utilized such a configuration to achieve ultra-long-distance distributed sensing based on Brillouin optical time-domain analysis (BOTDA). A repeater-less sensing distance record of up to 154.4 km with 5 m spatial resolution and ~ ± 1.4 °C temperature uncertainty is successfully demonstrated.

  2. Cloud Occurrence Measurements Over Sea during the 2nd 7 Southeast Asian Studies (7SEAS) Field Campaign in Palawan Archipelago

    NASA Astrophysics Data System (ADS)

    Antioquia, C. T.; Uy, S. N.; Caballa, K.; Lagrosas, N.

    2014-12-01

    Ground based sky imaging cameras have been used to measure cloud cover over an area to aid in radiation budget models. During daytime, certain clouds tend to help decrease atmospheric temperature by obstructing sunrays in the atmosphere. Thus, the detection of clouds plays an important role in the formulation of radiation budget in the atmosphere. In this study, a wide angled sky imager (GoPro Hero 2) was brought on board M/Y Vasco to detect and quantity cloud occurrence over sea during the 2nd 7SEAS field campaign. The camera is just a part of a number of scientific instruments used to measure weather, aerosol chemistry and solar radiation among others. The data collection started during the departure from Manila Bay on 05 September 2012 and went on until the end of the cruise (29 September 2012). The camera was placed in a weather-proof box that is then affixed on a steel mast where other instruments are also attached during the cruise. The data has a temporal resolution of 1 minute, and each image is 500x666 pixels in size. Fig. 1a shows the track of the ship during the cruise. The red, blue, hue, saturation, and value of the pixels are analysed for cloud occurrence. A pixel is considered to "contain" thick cloud if it passes all four threshold parameters (R-B, R/B, R-B/R+B, HSV; R is the red pixel color value, blue is the blue pixel color value, and HSV is the hue saturation value of the pixel) and considered thin cloud if it passes two or three parameters. Fig. 1b shows the daily analysis of cloud occurrence. Cloud occurrence here is quantified as the ratio of the pixels with cloud to the total number of pixels in the data image. The average cloud cover for the days included in this dataset is 87%. These measurements show a big contrast when compared to cloud cover over land (Manila Observatory) which is usually around 67%. During the duration of the cruise, only one day (September 6) has an average cloud occurrence below 50%; the rest of the days have

  3. PREFACE: The 2nd International Conference on Geological, Geographical, Aerospace and Earth Sciences 2014 (AeroEarth 2014)

    NASA Astrophysics Data System (ADS)

    Lumban Gaol, Ford; Soewito, Benfano

    2015-01-01

    The 2nd International Conference on Geological, Geographical, Aerospace and Earth Sciences 2014 (AeroEarth 2014), was held at Discovery Kartika Plaza Hotel, Kuta, Bali, Indonesia during 11 - 12 October 2014. The AeroEarth 2014 conference aims to bring together researchers and engineers from around the world. Through research and development, earth scientists have the power to preserve the planet's different resource domains by providing expert opinion and information about the forces which make life possible on Earth. Earth provides resources and the exact conditions to make life possible. However, with the advent of technology and industrialization, the Earth's resources are being pushed to the brink of depletion. Non-sustainable industrial practices are not only endangering the supply of the Earth's natural resources, but are also putting burden on life itself by bringing about pollution and climate change. A major role of earth science scholars is to examine the delicate balance between the Earth's resources and the growing demands of industrialization. Through research and development, earth scientists have the power to preserve the planet's different resource domains by providing expert opinion and information about the forces which make life possible on Earth. We would like to express our sincere gratitude to all in the Technical Program Committee who have reviewed the papers and developed a very interesting Conference Program as well as the invited and plenary speakers. This year, we received 98 papers and after rigorous review, 17 papers were accepted. The participants come from eight countries. There are four Parallel Sessions and two invited Speakers. It is an honour to present this volume of IOP Conference Series: Earth and Environmental Science (EES) and we deeply thank the authors for their enthusiastic and high-grade contributions. Finally, we would like to thank the conference chairmen, the members of the steering committee, the organizing committee

  4. Brain catecholamine depletion and motor impairment in a Th knock-in mouse with type B tyrosine hydroxylase deficiency.

    PubMed

    Korner, Germaine; Noain, Daniela; Ying, Ming; Hole, Magnus; Flydal, Marte I; Scherer, Tanja; Allegri, Gabriella; Rassi, Anahita; Fingerhut, Ralph; Becu-Villalobos, Damasia; Pillai, Samyuktha; Wueest, Stephan; Konrad, Daniel; Lauber-Biason, Anna; Baumann, Christian R; Bindoff, Laurence A; Martinez, Aurora; Thöny, Beat

    2015-10-01

    Tyrosine hydroxylase catalyses the hydroxylation of L-tyrosine to l-DOPA, the rate-limiting step in the synthesis of catecholamines. Mutations in the TH gene encoding tyrosine hydroxylase are associated with the autosomal recessive disorder tyrosine hydroxylase deficiency, which manifests phenotypes varying from infantile parkinsonism and DOPA-responsive dystonia, also termed type A, to complex encephalopathy with perinatal onset, termed type B. We generated homozygous Th knock-in mice with the mutation Th-p.R203H, equivalent to the most recurrent human mutation associated with type B tyrosine hydroxylase deficiency (TH-p.R233H), often unresponsive to l-DOPA treatment. The Th knock-in mice showed normal survival and food intake, but hypotension, hypokinesia, reduced motor coordination, wide-based gate and catalepsy. This phenotype was associated with a gradual loss of central catecholamines and the serious manifestations of motor impairment presented diurnal fluctuation but did not improve with standard l-DOPA treatment. The mutant tyrosine hydroxylase enzyme was unstable and exhibited deficient stabilization by catecholamines, leading to decline of brain tyrosine hydroxylase-immunoreactivity in the Th knock-in mice. In fact the substantia nigra presented an almost normal level of mutant tyrosine hydroxylase protein but distinct absence of the enzyme was observed in the striatum, indicating a mutation-associated mislocalization of tyrosine hydroxylase in the nigrostriatal pathway. This hypomorphic mouse model thus provides understanding on pathomechanisms in type B tyrosine hydroxylase deficiency and a platform for the evaluation of novel therapeutics for movement disorders with loss of dopaminergic input to the striatum.

  5. Horseradish-Peroxidase-Catalyzed Tyrosine Click Reaction.

    PubMed

    Sato, Shinichi; Nakamura, Kosuke; Nakamura, Hiroyuki

    2017-03-02

    The efficiency of protein chemical modification on tyrosine residues with N-methylluminol derivatives was drastically improved by using horseradish peroxidase (HRP). In the previous method, based on the use of hemin and H2 O2 , oxidative side reactions such as cysteine oxidation were problematic for functionalization of proteins selectively on tyrosine residues. Oxidative activation of N-methylluminol derivatives with a minimum amount of H2 O2 prevented the occurrence of oxidative side reactions under HRP-catalyzed conditions. As probes for HRP-catalyzed protein modification, N-methylluminol derivatives showed much higher efficiency than tyramide without inducing oligomerization of probe molecules. Tyrosine modification also proceeded in the presence of β-nicotinamide adenine dinucleotide (NADH, H2 O2 -free conditions).

  6. Tyrosine kinase inhibitors in preclinical development.

    PubMed

    Levitt, M L; Koty, P P

    1999-01-01

    Due to the limited efficacy of cytotoxic chemotherapy in the treatment of advanced malignancy and its excessive toxicity precluding its use in chemoprevention, new therapeutic and preventive strategies have been sought. One of the most interesting of these new approaches is the manipulation of signal transduction pathways. Among the approaches being considered to eventuate such a strategy is the inhibition of autophosphorylation, a critical first step in the signal transduction pathways of many cell surface receptor tyrosine kinases, as well as of non-receptor tyrosine kinases. This article is intended to review those tyrosine kinase inhibitors that are currently in preclinical development, for which there are data to support consideration for their use in chemoprevention or cancer treatment. We will focus upon those agents that have received attention in the past several years.

  7. Different structural alterations upregulate in vitro tyrosine kinase activity and transforming potency of the erbB-2 gene.

    PubMed Central

    Segatto, O; King, C R; Pierce, J H; Di Fiore, P P; Aaronson, S A

    1988-01-01

    Compared with normal erbB-2 gp185, mutant erbB-2 proteins generated by mutations either in the transmembrane domain or by NH2-terminal deletion are able to transform NIH 3T3 cells at a 10- to 100-fold greater efficiency. Mutant proteins of both classes show increased tyrosine kinase activity, suggesting that an abnormal level of receptor-associated tyrosine kinase activity is a major determinant of erbB-2 oncogenic potential. Images PMID:2907606

  8. Haemophilus ducreyi LspA proteins are tyrosine phosphorylated by macrophage-encoded protein tyrosine kinases.

    PubMed

    Deng, Kaiping; Mock, Jason R; Greenberg, Steven; van Oers, Nicolai S C; Hansen, Eric J

    2008-10-01

    The LspA proteins (LspA1 and LspA2) of Haemophilus ducreyi are necessary for this pathogen to inhibit the phagocytic activity of macrophage cell lines, an event that can be correlated with a reduction in the level of active Src family protein tyrosine kinases (PTKs) in these eukaryotic cells. During studies investigating this inhibitory mechanism, it was discovered that the LspA proteins themselves were tyrosine phosphorylated after wild-type H. ducreyi cells were incubated with macrophages. LspA proteins in cell-free concentrated H. ducreyi culture supernatant fluid could also be tyrosine phosphorylated by macrophages. This ability to tyrosine phosphorylate the LspA proteins was not limited to immune cell lineages but could be accomplished by both HeLa and COS-7 cells. Kinase inhibitor studies with macrophages demonstrated that the Src family PTKs were required for this tyrosine phosphorylation activity. In silico methods and site-directed mutagenesis were used to identify EPIYG and EPVYA motifs in LspA1 that contained tyrosines that were targets for phosphorylation. A total of four tyrosines could be phosphorylated in LspA1, with LspA2 containing eight predicted tyrosine phosphorylation motifs. Purified LspA1 fusion proteins containing either the EPIYG or EPVYA motifs were shown to be phosphorylated by purified Src PTK in vitro. Macrophage lysates could also tyrosine phosphorylate the LspA proteins and an LspA1 fusion protein via a mechanism that was dependent on the presence of both divalent cations and ATP. Several motifs known to interact with or otherwise affect eukaryotic kinases were identified in the LspA proteins.

  9. Haemophilus ducreyi LspA Proteins Are Tyrosine Phosphorylated by Macrophage-Encoded Protein Tyrosine Kinases▿

    PubMed Central

    Deng, Kaiping; Mock, Jason R.; Greenberg, Steven; van Oers, Nicolai S. C.; Hansen, Eric J.

    2008-01-01

    The LspA proteins (LspA1 and LspA2) of Haemophilus ducreyi are necessary for this pathogen to inhibit the phagocytic activity of macrophage cell lines, an event that can be correlated with a reduction in the level of active Src family protein tyrosine kinases (PTKs) in these eukaryotic cells. During studies investigating this inhibitory mechanism, it was discovered that the LspA proteins themselves were tyrosine phosphorylated after wild-type H. ducreyi cells were incubated with macrophages. LspA proteins in cell-free concentrated H. ducreyi culture supernatant fluid could also be tyrosine phosphorylated by macrophages. This ability to tyrosine phosphorylate the LspA proteins was not limited to immune cell lineages but could be accomplished by both HeLa and COS-7 cells. Kinase inhibitor studies with macrophages demonstrated that the Src family PTKs were required for this tyrosine phosphorylation activity. In silico methods and site-directed mutagenesis were used to identify EPIYG and EPVYA motifs in LspA1 that contained tyrosines that were targets for phosphorylation. A total of four tyrosines could be phosphorylated in LspA1, with LspA2 containing eight predicted tyrosine phosphorylation motifs. Purified LspA1 fusion proteins containing either the EPIYG or EPVYA motifs were shown to be phosphorylated by purified Src PTK in vitro. Macrophage lysates could also tyrosine phosphorylate the LspA proteins and an LspA1 fusion protein via a mechanism that was dependent on the presence of both divalent cations and ATP. Several motifs known to interact with or otherwise affect eukaryotic kinases were identified in the LspA proteins. PMID:18678665

  10. Hyaluronan and the hyaluronan receptor RHAMM promote focal adhesion turnover and transient tyrosine kinase activity

    PubMed Central

    1994-01-01

    The molecular mechanisms whereby hyaluronan (HA) stimulates cell motility was investigated in a C-H-ras transformed 10T 1/2 fibroblast cell line (C3). A significant (p < 0.001) stimulation of C3 cell motility with HA (10 ng/ml) was accompanied by an increase in protein tyrosine phosphorylation as detected by anti-phosphotyrosine antibodies using immunoblot analysis and immunofluorescence staining of cells. Tyrosine phosphorylation of several proteins was found to be both rapid and transient with phosphorylation occurring within 1 min of HA addition and dissipating below control levels 10-15 min later. These responses were also elicited by an antibody generated against a peptide sequence within the HA receptor RHAMM. Treatment of cells with tyrosine kinase inhibitors (genistein, 10 micrograms/ml or herbimycin A, 0.5 micrograms/ml) or microinjection of anti-phosphotyrosine antibodies inhibited the transient protein tyrosine phosphorylation in response to HA as well as prevented HA stimulation of cell motility. To determine a link between HA-stimulated tyrosine phosphorylation and the resulting cell locomotion, cytoskeletal reorganization was examined in C3 cells plated on fibronectin and treated with HA or anti-RHAMM antibody. These agents caused a rapid assembly and disassembly of focal adhesions as revealed by immunofluorescent localization of vinculin. The time course with which HA and antibody induced focal adhesion turnover exactly paralleled the induction of transient protein tyrosine phosphorylation. In addition, phosphotyrosine staining colocalized with vinculin within structures in the lamellapodia of these cells. Notably, the focal adhesion kinase, pp125FAK, was rapidly phosphorylated and dephosphorylated after HA stimulation. These results suggest that HA stimulates locomotion via a rapid and transient protein tyrosine kinase signaling event mediated by RHAMM. They also provide a possible molecular basis for focal adhesion turnover, a process that is

  11. Meta-tyrosine. A powerful anti-metastatic factor with undetectable toxic-side effects.

    PubMed

    Machuca, Damián; Chiarella, Paula; Montagna, Daniela; Dran, Graciela; Meiss, Roberto P; Ruggiero, Raúl A

    2015-01-01

    Concomitant tumor resistance (CR) is a phenomenon in which a tumor-bearing host is resistant to the growth of secondary tumor implants and metastasis. While former studies have indicated that T-cell dependent processes mediate CR in hosts bearing immunogenic small tumors, the most universal manifestation of CR induced by immunogenic and non-immunogenic large tumors had been associated with an antitumor serum factor that remained an enigma for many years. In a recent paper, we identified that elusive factor(s) as an equi-molar mixture of meta-tyrosine and ortho-tyrosine, two isomers of tyrosine that are not present in normal proteins and that proved to be responsible for 90% and 10%, respectively, of the total serum anti-tumor activity. In this work, we have extended our previous findings demonstrating that a periodic intravenous administration of meta-tyrosine induced a dramatic reduction of lung and hepatic metastases generated in mice bearing two different metastatic murine tumors and decreased the rate of death from 100% up to 25% in tumor-excised mice that already exhibited established metastases at the time of surgery. These anti-metastatic effects were achieved even at very low concentrations and without displaying any detectable toxic-side effects, suggesting that the use of meta-tyrosine may help to develop new and less harmful means of managing malignant diseases, especially those aimed to control the growth of metastases that is the most serious problem in cancer pathology.

  12. Reduction of electron deficient guanine radical species in plasmid DNA by tyrosine derivatives.

    PubMed

    Tsoi, Mandi; Do, Trinh T; Tang, Vicky J; Aguilera, Joseph A; Milligan, Jamie R

    2010-06-07

    Guanine bases are the most easily oxidized sites in DNA and therefore electron deficient guanine radical species are major intermediates in the direct effect of ionizing radiation (ionization of the DNA itself) on DNA as a consequence of hole migration to guanine. As a model for this process we have used gamma-irradiation in the presence of thiocyanate ions to generate single electron oxidized guanine radicals in a plasmid target in aqueous solution. The stable species formed from these radicals can be detected and quantified by the formation of strand breaks in the plasmid after a post-irradiation incubation using a suitable enzyme. If a tyrosine derivative is also present during irradiation, the production of guanine oxidation products is decreased by electron transfer from tyrosine to the intermediate guanyl radical species. By using cationic tyrosine containing ligands we are able to observe this process when the tyrosine is electrostatically bound to the plasmid. The driving force dependence of this reaction was determined by comparing the reactivity of tyrosine with its 3-nitro analog. The results imply that the electron transfer reaction is coupled to a proton transfer. The experimental conditions used in this model system provide a reasonable approximation to those involved in the radioprotection of DNA by tightly bound proteins in chromatin.

  13. Src drives the Warburg effect and therapy resistance by inactivating pyruvate dehydrogenase through tyrosine-289 phosphorylation

    PubMed Central

    Shenoy, Anitha K.; Lim, Sangbin; Zhang, Ying; Charles, Steve; Tarrash, Miriam; Fu, Xueqi; Kamarajugadda, Sushama; Trevino, Jose G.; Tan, Ming; Lu, Jianrong

    2016-01-01

    The Warburg effect, which reflects cancer cells' preference for aerobic glycolysis over glucose oxidation, contributes to tumor growth, progression and therapy resistance. The restraint on pyruvate flux into mitochondrial oxidative metabolism in cancer cells is in part attributed to the inhibition of pyruvate dehydrogenase (PDH) complex. Src is a prominent oncogenic non-receptor tyrosine kinase that promotes cancer cell proliferation, invasion, metastasis and resistance to conventional and targeted therapies. However, the potential role of Src in tumor metabolism remained unclear. Here we report that activation of Src attenuated PDH activity and generation of reactive oxygen species (ROS). Conversely, Src inhibitors activated PDH and increased cellular ROS levels. Src inactivated PDH through direct phosphorylation of tyrosine-289 of PDH E1α subunit (PDHA1). Indeed, Src was the main kinase responsible for PDHA1 tyrosine phosphorylation in cancer cells. Expression of a tyrosine-289 non-phosphorable PDHA1 mutant in Src-hyperactivated cancer cells restored PDH activity, increased mitochondrial respiration and oxidative stress, decreased experimental metastasis, and sensitized cancer cells to pro-oxidant treatment. The results suggest that Src contributes to the Warburg phenotype by inactivating PDH through tyrosine phosphorylation, and the metabolic effect of Src is essential for Src-driven malignancy and therapy resistance. Combination therapies consisting of both Src inhibitors and pro-oxidants may improve anticancer efficacy. PMID:26848621

  14. Effects of Protonation State on a Tyrosine-Histidine Bioinspired Redox Mediator

    SciTech Connect

    Moore, Gary F.; Hambourger, Michael; Kodis, Gerdenis; Michl, Weston; Gust, Devens; Moore, Thomas A.; Moore, Ana L.

    2010-11-18

    The conversion of tyrosine to the corresponding tyrosyl radical in photosytem II (PSII) is an example of proton-coupled electron transfer. Although the tyrosine moiety (TyrZ) is known to function as a redox mediator between the photo-oxidized primary donor (P680 •+) and the Mn-containing oxygen-evolving complex, the protonation states involved in the course of the reaction remain an active area of investigation. Herein, we report on the optical, structural, and electrochemical properties of tyrosine-histidine constructs, which model the function of their naturally occurring counterparts in PSII. Electrochemical studies show that the phenoxyl/phenol couple of the model is chemically reversible and thermodynamically capable of water oxidation. Studies under acidic and basic conditions provide clear evidence that an ionizable proton controls the electrochemical potential of the tyrosine-histidine mimic and that an exogenous base or acid can be used to generate a low-potential or high-potential mediator, respectively. The phenoxyl/phenoxide couple associated with the low-potential mediator is thermodynamically incapable of water oxidation, whereas the relay associated with the high-potential mediator is thermodynamically incapable of reducing an attached photoexcited porphyrin. These studies provide insight regarding the mechanistic role of the tyrosine-histidine complex in water oxidation and strategies for making use of hydrogen bonds to affect the coupling between proton and electron transfer in artificial photosynthetic systems.

  15. Lichen planopilaris-like eruption during treatment with tyrosine kinase inhibitor nilotinib*

    PubMed Central

    Leitão, Juliana Ribeiro; Valente, Neusa Yuriko Sakai; Kakizaki, Priscila; Veronez, Isis Suga; Pires, Mario Cezar

    2016-01-01

    Tyrosine kinase inhibitors are effective as a target therapy for malignant neoplasms. Imatinib was the first tyrosine kinase inhibitor used. After its introduction, several other drugs have appeared with a similar mechanism of action, but less prone to causing resistance. Even though these drugs are selective, their toxicity does not exclusively target cancer cells, and skin toxicity is the most common non-hematologic adverse effect. We report an eruption similar to lichen planopilaris that developed during therapy with nilotinib, a second generation tyrosine kinase inhibitor, in a patient with chronic myeloid leukemia resistant to imatinib. In a literature review, we found only one report of non-scarring alopecia due to the use of nilotinib.

  16. Antioxidant promotion of tyrosine nitration in the presence of copper(II).

    PubMed

    Qiao, Liang; Liu, Baohong; Girault, Hubert H

    2013-06-01

    Copper(II) is known to catalyze the generation of reactive nitrogen species in the presence of hydrogen peroxide, nitrite or nitric oxide, leading to tyrosine nitration, a biomarker for free radical species associated diseases. Here, we find that biological antioxidants such as ascorbic acid can promote tyrosine nitration in the presence of copper(II) and nitrite under aerobic and weak acidic conditions. Tyrosine nitration is demonstrated on both the β-amyloid peptide and angiotensin I. These studies show that (i) ascorbic acid works as a pro-oxidant in the presence of copper(II) to induce oxidation and nitration on peptides, (ii) both free and coordinated copper(II) can catalyze peptide oxidation and nitration, (iii) nitration occurs under mild acidic conditions (pH = 6.0-6.5).

  17. The current status of research into Attention Deficit Hyperactivity Disorder: Proceedings of the 2nd International Congress on ADHD: From Childhood to Adult Disease.

    PubMed

    Thome, Johannes; Reddy, Duvvoor Prathap

    2009-12-01

    Despite being a devastating psychiatric condition with high prevalence, ADHD has traditionally been widely under-researched, specifically in adult patients. Therefore, the recent surge in scientific projects focusing on ADHD is impressive. By reviewing selected research findings presented at the 2nd International Congress on ADHD, this paper gives an overview about current state-of-the art research in such different areas as diagnosis, classification, epidemiology, differential diagnosis and comorbidity, neurobiology (including molecular genetics, proteomics, neuroimaging and electrophysiology), environmental factors, modelling of ADHD, treatment (pharmacological and non-pharmacological), as well as forensic and social aspects.

  18. Multiple tyrosine metabolites are GPR35 agonists

    PubMed Central

    Deng, Huayun; Hu, Haibei; Fang, Ye

    2012-01-01

    Both kynurenic acid and 2-acyl lysophosphatidic acid have been postulated to be the endogenous agonists of GPR35. However, controversy remains whether alternative endogenous agonists exist. The molecular targets accounted for many nongenomic actions of thyroid hormones are mostly unknown. Here we report the agonist activity of multiple tyrosine metabolites at the GPR35. Tyrosine metabolism intermediates that contain carboxylic acid and/or catechol functional groups were first selected. Whole cell dynamic mass redistribution (DMR) assays enabled by label-free optical biosensor were then used to characterize their agonist activity in native HT-29. Molecular assays including β-arrestin translocation, ERK phosphorylation and receptor internalization confirmed that GPR35 functions as a receptor for 5,6-dihydroxyindole-2-carboxylic acid, 3,3′,5′-triiodothyronine, 3,3′,5-triiodothyronine, gentisate, rosmarinate, and 3-nitrotyrosine. These results suggest that multiple tyrosine metabolites are alternative endogenous ligands of GPR35, and GPR35 may represent a druggable target for treating certain diseases associated with abnormality of tyrosine metabolism. PMID:22523636

  19. Second-order adjoint sensitivity analysis methodology (2nd-ASAM) for computing exactly and efficiently first- and second-order sensitivities in large-scale linear systems: I. Computational methodology

    NASA Astrophysics Data System (ADS)

    Cacuci, Dan G.

    2015-03-01

    This work presents the second-order forward and adjoint sensitivity analysis methodologies (2nd-FSAM and 2nd-ASAM) for computing exactly and efficiently the second-order functional derivatives of physical (engineering, biological, etc.) system responses (i.e., "system performance parameters") to the system's model parameters. The definition of "system parameters" used in this work includes all computational input data, correlations, initial and/or boundary conditions, etc. For a physical system comprising Nα parameters and Nr responses, we note that the 2nd-FSAM requires a total of (Nα2/2 + 3Nα / 2) large-scale computations for obtaining all of the first- and second-order sensitivities, for all Nr system responses. On the other hand, for one functional-type system response, the 2nd-ASAM requires one large-scale computation using the first-level adjoint sensitivity system for obtaining all of the first-order sensitivities, followed by at most Nα large-scale computations using the second-level adjoint sensitivity systems for obtaining exactly all of the second-order sensitivities. Therefore, the 2nd-FSAM should be used when Nr ≫Nα, while the 2nd-ASAM should be used when Nα ≫Nr. The original 2nd-ASAM presented in this work should enable the hitherto very difficult, if not intractable, exact computation of all of the second-order response sensitivities (i.e., functional Gateaux-derivatives) for large-systems involving many parameters, as usually encountered in practice. Very importantly, the implementation of the 2nd-ASAM requires very little additional effort beyond the construction of the adjoint sensitivity system needed for computing the first-order sensitivities.

  20. Brain catechol synthesis - Control by brain tyrosine concentration

    NASA Technical Reports Server (NTRS)

    Wurtman, R. J.; Larin, F.; Mostafapour, S.; Fernstrom, J. D.

    1974-01-01

    Brain catechol synthesis was estimated by measuring the rate at which brain dopa levels rose following decarboxylase inhibition. Dopa accumulation was accelerated by tyrosine administration, and decreased by treatments that lowered brain tyrosine concentrations (for example, intraperitoneal tryptophan, leucine, or parachlorophenylalanine). A low dose of phenylalanine elevated brain tyrosine without accelerating dopa synthesis. Our findings raise the possibility that nutritional and endocrine factors might influence brain catecholamine synthesis by controlling the availability of tyrosine.

  1. Receptor tyrosine kinase amplification is predictive of distant metastasis in patients with oral squamous cell carcinoma.

    PubMed

    Oikawa, Yu; Morita, Kei-Ichi; Kayamori, Kou; Tanimoto, Kousuke; Sakamoto, Kei; Katoh, Hiroto; Ishikawa, Shumpei; Inazawa, Johji; Harada, Hiroyuki

    2017-02-01

    This study aimed to clarify the genomic factors associated with the diagnosis and prognosis of oral squamous cell carcinoma via next-generation sequencing. We evaluated data from 220 cases of oral squamous cell carcinoma. Genomic DNA was eluted using formalin-fixed, paraffin-embedded samples, and targeted resequencing of 50 cancer-related genes was performed. In total, 311 somatic mutations were detected in 220 patients, consisting of 68 synonymous mutations and 243 non-synonymous mutations. Genes carrying mutations included TP53, CDKN2A, and PIK3CA in 79 (35.9%), 35 (15.9%), and 19 patients (8.6%), respectively. Copy number analysis detected amplification of PIK3CA and AKT1 in 38 (17.3%) and 11 patients (5.0%), respectively. Amplification of receptor tyrosine kinases was found in 37 patients (16.8%). Distant metastasis was noted in nine of 37 patients (24%) with receptor tyrosine kinase amplification, accounting for 43% of the 21 cases of distant metastasis. The cumulative 5-year survival rate was 64.6% in the receptor tyrosine kinase amplification group vs 85.2% in the no receptor tyrosine kinase amplification group. Moreover, we identified significantly poorer prognosis in the TP53 mutation/receptor tyrosine kinase amplification group, for which the cumulative 5-year survival rate was 41.6%. In conclusion, the results of this study demonstrated that receptor tyrosine kinase amplification is a prognostic factor for distant metastasis of oral squamous cell carcinoma, indicating the necessity of using next-generation sequencing in clinical sequencing.

  2. A novel proteomic approach for specific identification of tyrosine kinase substrates using [13C]tyrosine.

    PubMed

    Ibarrola, Nieves; Molina, Henrik; Iwahori, Akiko; Pandey, Akhilesh

    2004-04-16

    Proteomic studies to find substrates of tyrosine kinases generally rely on identification of protein bands that are "pulled down" by antiphosphotyrosine antibodies from ligand-stimulated samples. One can obtain erroneous results from such experiments because of two major reasons. First, some proteins might be basally phosphorylated on tyrosine residues in the absence of ligand stimulation. Second, proteins can bind non-specifically to the antibodies or the affinity matrix. Induction of phosphorylation of proteins by ligand must therefore be confirmed by a different approach, which is not always feasible. We have developed a novel proteomic approach to identify substrates of tyrosine kinases in signaling pathways studies based on in vivo labeling of proteins with "light" (12C-labeled) or "heavy" (13C-labeled) tyrosine. This stable isotope labeling in cell culture method enables the unequivocal identification of tyrosine kinase substrates, as peptides derived from true substrates give rise to a unique signature in a mass spectrometry experiment. By using this approach, from a single experiment, we have successfully identified several known substrates of insulin signaling pathway and a novel substrate, polymerase I and transcript release factor, a protein that is implicated in the control of RNA metabolism and regulation of type I collagen promoters. This approach is amenable to high throughput global studies as it simplifies the specific identification of substrates of tyrosine kinases as well as serine/threonine kinases using mass spectrometry.

  3. Management of osteoporosis in central and eastern Europe (CEE): conclusions of the "2nd Summit on Osteoporosis-CEE", 21-22 November 2008, Warsaw, Poland.

    PubMed

    Lorenc, Roman S; Resch, Heinrich

    2009-12-01

    In November 2008, the "2nd Summit on Osteoporosis-Central and Eastern Europe (CEE)" was held in Warsaw, Poland. Discussions at this meeting focused on the identification and discussion of diagnostic, preventive, and therapeutic measures used in CEE. Evaluated information was used to identify issues regarding diagnosis and therapy of osteoporosis in these countries to facilitate the subsequent setup of appropriate support and development strategies. The main debate was structured according to the following five subjects: (1) present status and future perspectives for implementation of FRAX(R) into local (CEE) diagnostic algorithms, (2) principles of drug selection in osteoporosis treatment in CEE countries, (3) nonpharmacological interventions in osteoporosis treatment and prophylaxis in CEE countries, (4) treatment benefit evaluation, and (5) cost-effectiveness and evaluation of reimbursement policies in CEE countries. The most important and substantial comments of the delegates are summarized in the present article. The multinational panel of experts with representatives from many CEE countries as well as Austria and Switzerland made the "2nd Summit on Osteoporosis-CEE" a perfect platform to identify issues and needs regarding diagnosis and therapy of osteoporosis as well as the cost-effectiveness of osteoporosis management in CEE countries. The information gained will serve as a basis for the development of strategies to resolve the identified issues at the "3rd Summit on Osteoporosis-CEE" in November 2009.

  4. Design and manufacture of a D-shape coil-based toroid-type HTS DC reactor using 2nd generation HTS wire

    NASA Astrophysics Data System (ADS)

    Kim, Kwangmin; Go, Byeong-Soo; Sung, Hae-Jin; Park, Hea-chul; Kim, Seokho; Lee, Sangjin; Jin, Yoon-Su; Oh, Yunsang; Park, Minwon; Yu, In-Keun

    2014-09-01

    This paper describes the design specifications and performance of a real toroid-type high temperature superconducting (HTS) DC reactor. The HTS DC reactor was designed using 2G HTS wires. The HTS coils of the toroid-type DC reactor magnet were made in the form of a D-shape. The target inductance of the HTS DC reactor was 400 mH. The expected operating temperature was under 20 K. The electromagnetic performance of the toroid-type HTS DC reactor magnet was analyzed using the finite element method program. A conduction cooling method was adopted for reactor magnet cooling. Performances of the toroid-type HTS DC reactor were analyzed through experiments conducted under the steady-state and charge conditions. The fundamental design specifications and the data obtained from this research will be applied to the design of a commercial-type HTS DC reactor.

  5. PF-06463922, an ALK/ROS1 inhibitor, overcomes resistance to 1st and 2nd generation ALK inhibitors in pre-clinical models

    PubMed Central

    Zou, Helen Y.; Friboulet, Luc; Kodack, David P.; Engstrom, Lars D.; Li, Qiuhua; West, Melissa; Tang, Ruth W.; Wang, Hui; Tsaparikos, Konstantinos; Wang, Jinwei; Timofeevski, Sergei; Katayama, Ryohei; Dinh, Dac M.; Lam, Hieu; Lam, Justine L.; Yamazaki, Shinji; Hu, Wenyue; Patel, Bhushankumar; Bezwada, Divya; Frias, Rosa L.; Lifshits, Eugene; Mahmood, Sidra; Gainor, Justin F.; Affolter, Timothy; Lappin, Patrick B.; Gukasyan, Hovhannes; Lee, Nathan; Deng, Shibing; Jain, Rakesh K; Johnson, Ted W.; Shaw, Alice T.; Fantin, Valeria R.; Smeal, Tod

    2015-01-01

    SUMMARY We report the preclinical evaluation of PF-06463922, a potent and brain penetrant ALK/ROS1 inhibitor. Compared to other clinically available ALK inhibitors, PF-06463922 displayed superior potency against all known clinically acquired ALK mutations, including the highly resistant G1202R mutant. Furthermore, PF-06463922 treatment led to regression of EML4-ALK driven brain metastases, leading to prolonged mouse survival, in a superior manner. Finally, PF-06463922 demonstrated high selectivity and safety margins in a variety of preclinical studies. These results suggest that PF-06463922 will be highly effective for the treatment of patients with ALK-driven lung cancers, including those who relapsed on clinically available ALK inhibitors due to secondary ALK kinase domain mutations and/or due to the failed control of brain metastases. PMID:26144315

  6. 1st, 2nd and 3rd Generation Implementations of an eLearning Design: Re-Use from Postgraduate Law to Block/Online Engineering Course

    ERIC Educational Resources Information Center

    Lambert, Sarah; Brewer, Chris

    2007-01-01

    In order to meet the demands of postgraduate students who were time poor and unable to regularly attend face-to-face classes, one lecturer in the Faculty Law at the University of Wollongong (UOW) sought the assistance of a Learning Designer to redesign the Postgraduate Practical Legal Training (PLT) program into a flexible blended learning format,…

  7. SHARK (System for coronagraphy with High order Adaptive optics from R to K band): a proposal for the LBT 2nd generation instrumentation

    NASA Astrophysics Data System (ADS)

    Farinato, Jacopo; Pedichini, Fernando; Pinna, Enrico; Baciotti, Francesca; Baffa, Carlo; Baruffolo, Andrea; Bergomi, Maria; Bruno, Pietro; Cappellaro, Enrico; Carbonaro, Luca; Carlotti, Alexis; Centrone, Mauro; Close, Laird; Codona, Johanan; Desidera, Silvano; Dima, Marco; Esposito, Simone; Fantinel, Daniela; Farisato, Giancarlo; Fontana, Adriano; Gaessler, Wolfgang; Giallongo, Emanuele; Gratton, Raffaele; Greggio, Davide; Guerra, Juan Carlos; Guyon, Olivier; Hinz, Philip; Leone, Francesco; Lisi, Franco; Magrin, Demetrio; Marafatto, Luca; Munari, Matteo; Pagano, Isabella; Puglisi, Alfio; Ragazzoni, Roberto; Salasnich, Bernardo; Sani, Eleonora; Scuderi, Salvo; Stangalini, Marco; Testa, Vincenzo; Verinaud, Christophe; Viotto, Valentina

    2014-08-01

    This article presents a proposal aimed at investigating the technical feasibility and the scientific capabilities of high contrast cameras to be implemented at LBT. Such an instrument will fully exploit the unique LBT capabilities in Adaptive Optics (AO) as demonstrated by the First Light Adaptive Optics (FLAO) system, which is obtaining excellent results in terms of performance and reliability. The aim of this proposal is to show the scientific interest of such a project, together with a conceptual opto-mechanical study which shows its technical feasibility, taking advantage of the already existing AO systems, which are delivering the highest Strehl experienced in nowadays existing telescopes. Two channels are foreseen for SHARK, a near infrared channel (2.5-0.9 um) and a visible one (0.9 - 0.6 um), both providing imaging and coronagraphic modes. The visible channel is equipped with a very fast and low noise detector running at 1.0 kfps and an IFU spectroscopic port to provide low and medium resolution spectra of 1.5 x 1.5 arcsec fields. The search of extra solar giant planets is the main science case and the driver for the technical choices of SHARK, but leaving room for several other interesting scientific topics, which will be briefly depicted here.

  8. Structure-borne sound: Structural vibrations and sound radiation at audio frequencies /2nd revised and enlarged edition/

    NASA Astrophysics Data System (ADS)

    Cremer, Lothar; Heckl, Manfred

    The fundamental principles of sound production and propagation in and from structures are examined analytically in an introductory textbook, and their design implications are considered. Chapters are devoted to the definition, measurement, and generation of structure-borne sound; wave types and characteristics; damping; impedances; attenuation; and sound radiation from structures. Diagrams, drawings, graphs, and tables of numerical data are provided.

  9. Molten carbonate fuel cell product design & improvement - 2nd quarter, 1996. Quarterly report, April 1--June 30, 1996

    SciTech Connect

    1997-05-01

    The main objective of this project is to establish the commercial readiness of a molten carbonate fuel cell power plant for distributed power generation, cogeneration, and compressor station applications. This effort includes marketing, systems design and analysis, packaging and assembly, test facility development, and technology development, improvement, and verification.

  10. Ror receptor tyrosine kinases: orphans no more

    PubMed Central

    Green, Jennifer L.; Kuntz, Steven G.; Sternberg, Paul W.

    2015-01-01

    Ror proteins are a conserved family of tyrosine kinase receptors that function in developmental processes, including skeletal and neuronal development, cell movement, and cell polarity. While Ror (receptor tyrosine kinase-like orphan receptor) proteins were originally named because the associated ligand and signaling pathway were unknown, recent studies in multiple species now establish that Ror proteins are Wnt receptors. Depending on the cellular context, Ror proteins can either activate or repress transcription of Wnt target genes and can modulate Wnt signaling by sequestering Wnt ligands. New evidence implicates Ror proteins in planar cell polarity (PCP), an alternative Wnt pathway. Here, we review the progress made in understanding these mysterious proteins and in particular we focus on their function as Wnt receptors. PMID:18848778

  11. Tyrosine Kinase Display of Prostate Cancer Cells

    DTIC Science & Technology

    2001-10-01

    transdifferentiation . The fact that some prostate cancer cell lines, such as LNCaP, can undergo NE differentiation suggests that at least a subset of NE cells is...Katz, C. A. Olsson, and R. Buttyan. 1997. Transdifferentiation of cultured human prostate cells to a neuroendocrine cell phenotype in a hormone...in the above-mentioned cases 3), and some of these cells can be induced to transdifferentiate are tyrosine kinases, which are known initiators of

  12. Behavioral Effects of Tyrosine during Sustained Wakefulness,

    DTIC Science & Technology

    1993-12-01

    Hefti, & Melamed, 1981). Tryptophan , a sleep promoter (Braverman, 1987), is a precursor of serotonin, which in turn is a precursor of melatonin...Melatonin also has known sleep-inducing effects (see Kelly et al., 1989, for a review). Tyrosine ingestion may reduce the levels of available tryptophan ...catecholamines, its possible role in decreasing brain levels of tryptophan , and its relative safety make it worthy of further study as a countermeasure to

  13. Infarction-induced cytokines cause local depletion of tyrosine hydroxylase in cardiac sympathetic nerves

    PubMed Central

    Parrish, Diana C.; Alston, Eric N.; Rohrer, Hermann; Nkadi, Paul; Woodward, William R.; Schütz, Günther; Habecker, Beth A.

    2010-01-01

    Myocardial infarction causes heterogeneity of noradrenergic transmission that contributes to the development of ventricular arrhythmias and sudden cardiac death. Ischemia-induced alterations in sympathetic transmission include regional variations in cardiac norepinephrine (NE) and in tyrosine hydroxylase, the rate-limiting enzyme in NE synthesis. Inflammatory cytokines that act through gp130 are elevated in the heart after myocardial infarction. These cytokines decrease expression of tyrosine hydroxylase in sympathetic neurons, and indirect evidence suggests they contribute to the local depletion of tyrosine hydroxylase in the damaged left ventricle. However, gp130 cytokines are also important for the survival of cardiac myocytes following damage to the heart. To examine the effect of cytokines on tyrosine hydroxylase and NE content in cardiac nerves we used gp130DBH-Cre/lox mice, which have a deletion of the gp130 receptor in neurons expressing dopamine beta hydroxylase. The absence of neuronal gp130 prevented the loss of tyrosine hydroxylase in cardiac sympathetic nerves innervating the left ventricle one week after ischemia-reperfusion. Surprisingly, restoring tyrosine hydroxylase in the damaged ventricle did not return neuronal NE content to normal levels. NE uptake into cardiac nerves was significantly lower in gp130 KO mice, contributing to the lack of neuronal NE stores. There were no significant differences in left ventricular peak systolic pressure, dP/dtMAX, or dP/dtMIN between the two genotypes after myocardial infarction, but ganglionic blockade revealed differences in autonomic tone between the genotypes. Stimulating the heart with dobutamine or releasing endogenous NE with tyramine generated similar responses in both genotypes. Thus, the removal of gp130 from sympathetic neurons prevents the post-infarct depletion of TH in the left ventricle, but does not alter NE content or cardiac function. PMID:19880537

  14. Readministration of EGFR Tyrosine Kinase Inhibitor in Non-small Cell Lung Cancer Patients after Initial Failure, What Affects its Efficacy?

    PubMed Central

    Zhao, Ze-Rui; li, Wei; Long, Hao

    2014-01-01

    Few therapeutic options are available for non-small cell lung cancer (NSCLC) after failure to primary epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). Since TKI rechallenge is one of the most common salvage approaches in clinical practice, we sought to identify the independent factors that associated with 2nd progression progression-free survival (PFS) and overall survival (OS). Seventy-two consecutive EGFR-mutated NSCLC patients with TKI retreatment after initial failure were retrospectively analyzed in this study. Univariate survival analysis and Cox proportional hazards regression model was used to determine if EGFR-TKIs readministration is tolerable as well as efficacious for a certain group of patients. PMID:25104233

  15. PREFACE: 2nd Russia-Japan-USA Symposium on the Fundamental and Applied Problems of Terahertz Devices and Technologies (RJUS TeraTech - 2013)

    NASA Astrophysics Data System (ADS)

    Karasik, Valeriy; Ryzhii, Viktor; Yurchenko, Stanislav

    2014-03-01

    The 2nd Russia-Japan-USA Symposium 'The Fundamental & Applied Problems of Terahertz Devices & Technologies' (RJUS TeraTech - 2013) Bauman Moscow State Technical University Moscow, Russia, 3-6 June, 2013 The 2nd Russia-Japan-USA Symposium 'The Fundamental & Applied Problems of Terahertz Devices & Technologies' (RJUS TeraTech - 2013) was held in Bauman Moscow State Technical University on 3-6 June 2013 and was devoted to modern problems of terahertz optical technologies. RJUS TeraTech 2013 was organized by Bauman Moscow State Technical University in cooperation with Tohoku University (Sendai, Japan) and University of Buffalo (The State University of New York, USA). The Symposium was supported by Bauman Moscow State Technical University (Moscow, Russia) and Russian Foundation for Basic Research (grant number 13-08-06100-g). RJUS TeraTech - 2013 became a foundation for sharing and discussing modern and promising achievements in fundamental and applied problems of terahertz optical technologies, devices based on grapheme and grapheme strictures, condensed matter of different nature. Among participants of RJUS TeraTech - 2013, there were more than 100 researchers and students from different countries. This volume contains proceedings of the 2nd Russia-Japan-USA Symposium 'The Fundamental & Applied Problems of Terahertz Devices & Technologies'. Valeriy Karasik, Viktor Ryzhii and Stanislav Yurchenko Bauman Moscow State Technical University Symposium chair Anatoliy A Aleksandrov, Rector of BMSTU Symposium co-chair Valeriy E Karasik, Head of the Research and Educational Center 'PHOTONICS AND INFRARED TECHNOLOGY' (Russia) Invited Speakers Taiichi Otsuji, Research Institute of Electrical Communication, Tohoku University, Sendai, Japan Akira Satou, Research Institute of Electrical Communication, Tohoku University, Sendai, Japan Michael Shur, Electrical, Computer and System Engineering and Physics, Applied Physics, and Astronomy, Rensselaer Polytechnic Institute, NY, USA Natasha

  16. Getting Syk: Spleen Tyrosine Kinase as a Therapeutic Target

    PubMed Central

    Geahlen, Robert L.

    2014-01-01

    Syk is a cytoplasmic protein-tyrosine kinase well known for its ability to couple immune cell receptors to intracellular signaling pathways that regulate cellular responses to extracellular antigens and antigen-immunoglobulin complexes of particular importance to the initiation of inflammatory responses. Thus, Syk is an attractive target for therapeutic kinase inhibitors designed to ameliorate symptoms and consequences of acute and chronic inflammation. Its more recently recognized role as a promoter of cell survival in numerous cancer cell types ranging from leukemia to retinoblastoma has attracted considerable interest as a target for a new generation of anticancer drugs. This review discusses the biological processes in which Syk participates that have made this kinase such a compelling drug target. PMID:24975478

  17. Association of plasma ortho-tyrosine/para-tyrosine ratio with responsiveness of erythropoiesis-stimulating agent in dialyzed patients.

    PubMed

    Kun, Szilárd; Mikolás, Esztella; Molnár, Gergo A; Sélley, Eszter; Laczy, Boglárka; Csiky, Botond; Kovács, Tibor; Wittmann, István

    2014-09-01

    Objectives Patients with end-stage renal failure (ESRF) treated with erythropoiesis-stimulating agents (ESAs) are often ESA-hyporesponsive associated with free radical production. Hydroxyl free radical converts phenylalanine into ortho-tyrosine, while physiological isomer para-tyrosine is formed enzymatically, mainly in the kidney. Production of 'para-tyrosine' is decreased in ESRF and it can be replaced by ortho-tyrosine in proteins. Our aim was to study the role of tyrosines in ESA-responsiveness. Methods Four groups of volunteers were involved in our cross-sectional study: healthy volunteers (CONTR; n = 16), patients on hemodialysis without ESA-treatment (non-ESA-HD; n = 8), hemodialyzed patients with ESA-treatment (ESA-HD; n = 40), and patients on continuous peritoneal dialysis (CAPD; n = 21). Plasma ortho-, para-tyrosine, and phenylalanine levels were detected using a high performance liquid chromatography (HPLC)-method. ESA-demand was expressed by ESA-dose, ESA-dose/body weight, and erythropoietin resistance index1 (ERI1, weekly ESA-dose/body weight/hemoglobin). Results We found significantly lower para-tyrosine levels in all groups of dialyzed patients when compared with control subjects, while in contrast ortho-tyrosine levels and ortho-tyrosine/para-tyrosine ratio were comparatively significantly higher in dialyzed patients. Among groups of dialyzed patients the ortho-tyrosine level and ortho-tyrosine/para-tyrosine ratio were significantly higher in ESA-HD than in the non-ESA-HD and CAPD groups. There was a correlation between weekly ESA-dose/body weight, ERI1, and ortho-tyrosine/para-tyrosine ratio (r = 0.441, P = 0.001; r = 0.434, P = 0.001, respectively). Our most important finding was that the ortho-tyrosine/para-tyrosine ratio proved to be an independent predictor of ERI1 (β = 0.330, P = 0.016). In these multivariate regression models most of the known predictors of ESA-hyporesponsiveness were included. Discussion Our findings may

  18. Influence of sodium fluoride (NaF) on the crystallization and spectral properties of L-tyrosine

    NASA Astrophysics Data System (ADS)

    Thenmozhi, M.; Suguna, K.; Sekar, C.

    2011-12-01

    L-Tyrosine (C 9H 11NO 3) is an essential amino acid in living organisms. It is also a building unit in protein, takes part in bio-synthesis of hormones, neurotransmitters, pigments and one of the organic chemical constituents of urinary stones. L-Tyrosine has been crystallized in silica gel by double diffusion technique with and without the addition of NaF. The crystals had rosette-like shape. In case of fluoride addition, two types of crystals have formed: rosette like crystallites, at the gel-solution interface and reticulate type crystallites beneath the interface. XRD results confirmed that both the products are of L-tyrosine with identical crystal structures. Crystal structure, morphology, thermal and spectral properties are analyzed using powder X-ray diffraction (XRD), scanning electron microscopy (SEM), thermogravimetric and differential thermal analysis (TG-DTA), Fourier transform infrared spectroscopy (FTIR) and UV-vis transmittance studies. The TG-DTA results suggest that the thermal stability of L-tyrosine has markedly improved due to fluoride doping. Optical band gap energy of NaF grown L-tyrosine crystallite is estimated as 4.28 eV. Second harmonic generation efficiency test indicates that L-tyrosine crystals can be used for application in nonlinear optical devices.

  19. Protein tyrosine adduct in humans self-poisoned by chlorpyrifos

    PubMed Central

    Li, Bin; Eyer, Peter; Eddleston, Michael; Jiang, Wei; Schopfer, Lawrence M.; Lockridge, Oksana

    2013-01-01

    Studies of human cases of self-inflicted poisoning suggest that chlorpyrifos oxon reacts not only with acetylcholinesterase and butyrylcholinesterase but also with other blood proteins. A favored candidate is albumin because in vitro and animal studies have identified tyrosine 411 of albumin as a site covalently modified by organophosphorus poisons. Our goal was to test this proposal in humans by determining whether plasma from humans poisoned by chlorpyrifos has adducts on tyrosine. Plasma samples from 5 self-poisoned humans were drawn at various time intervals after ingestion of chlorpyrifos for a total of 34 samples. All 34 samples were analyzed for plasma levels of chlorpyrifos and chlorpyrifos oxon (CPO) as a function of time post-ingestion. Eleven samples were analyzed for the presence of diethoxyphosphorylated tyrosine by mass spectrometry. Six samples yielded diethoxyphosphorylated tyrosine in pronase digests. Blood collected as late as 5 days after chlorpyrifos ingestion was positive for CPO-tyrosine, consistent with the 20-day half-life of albumin. High plasma CPO levels did not predict detectable levels of CPO-tyrosine. CPO-tyrosine was identified in pralidoxime treated patients as well as in patients not treated with pralidoxime, indicating that pralidoxime does not reverse CPO binding to tyrosine in humans. Plasma butyrylcholinesterase was a more sensitive biomarker of exposure than adducts on tyrosine. In conclusion, chlorpyrifos oxon makes a stable covalent adduct on the tyrosine residue of blood proteins in humans who ingested chlorpyrifos. PMID:23566956

  20. Simulating a measurement of the 2nd knee in the cosmic ray spectrum with an atmospheric fluorescence telescope tower array.

    PubMed

    Liu, Jiali; Yang, Qunyu; Bai, Yunxiang; Cao, Zhen

    2014-01-01

    A fluorescence telescope tower array has been designed to measure cosmic rays in the energy range of 10(17)-10(18) eV. A full Monte Carlo simulation, including air shower production, light generation and propagation, detector response, electronics, and trigger system, has been developed for that purpose. Using such a simulation tool, the detector configuration, which includes one main tower array and two side-trigger arrays, 24 telescopes in total, has been optimized. The aperture and the event rate have been estimated. Furthermore, the performance of the X max technique in measuring composition has also been studied.

  1. Simulating a Measurement of the 2nd Knee in the Cosmic Ray Spectrum with an Atmospheric Fluorescence Telescope Tower Array

    PubMed Central

    Liu, Jiali; Yang, Qunyu; Bai, Yunxiang; Cao, Zhen

    2014-01-01

    A fluorescence telescope tower array has been designed to measure cosmic rays in the energy range of 1017–1018 eV. A full Monte Carlo simulation, including air shower production, light generation and propagation, detector response, electronics, and trigger system, has been developed for that purpose. Using such a simulation tool, the detector configuration, which includes one main tower array and two side-trigger arrays, 24 telescopes in total, has been optimized. The aperture and the event rate have been estimated. Furthermore, the performance of the Xmax⁡ technique in measuring composition has also been studied. PMID:24737964

  2. Second Annual Systems Engineering Lessons Learned Conference (2nd) Held in Seaside, California on September 20-21, 2011

    DTIC Science & Technology

    2011-09-01

    Hybrid Architecture: Series – Primary Power Source: Diesel Engine – Secondary Power Source: Flywheel – Traction Motors : Permanent Magnet Motors 27...Renewable Fraction (%) Generator Electricity Production (kW) Solar Electricity Production (kW) Wind Electricity Production (kW) Battery...0.21 0.02 0.55 -0.20 -0.18 -0.20 -0.18 Gen Production -0.82 -0.19 0.35 -0.27 -0.11 -0.82 0.97 -0.82 -0.36 0.47 1.00 0.97 0.99 0.97 Tot. Electrical

  3. Report from the 2nd Cardiovascular Outcome Trial (CVOT) Summit of the Diabetes and Cardiovascular Disease (D&CVD) EASD Study Group.

    PubMed

    Schnell, Oliver; Standl, Eberhard; Catrinoiu, Doina; Genovese, Stefano; Lalic, Nebojsa; Skra, Jan; Valensi, Paul; Rahelic, Dario; Ceriello, Antonio

    2017-03-11

    The 2nd Cardiovascular Outcome Trial (CVOT) Summit of the Diabetes and Cardiovascular Disease (D&CVD) EASD Study Group was held on the 20th-21st October 2016 in Munich. This second Summit was organized in light of recently published CVOTs on diabetes, with the aim of serving as a reference meeting for discussion on this topic. Along with presentations on the results of the most recently published CVOTs, panel discussions on trial implications for reimbursement and the perspective of cardiologists and/or nephrologists, as well as on CVOTs weaknesses and potentials constituted the heart of the program. Future activities of the D&CVD EASD Study Group in 2017 include an annual meeting in Milano and the 3rd CVOT Summit on Diabetes of the D&CVD EASD Study Group, in Munich ( http://www.dcvd.org ).

  4. Phase transition in tungsten-bronze Li2Pb2Nd2W2Ti4Nb4O30 ferroelectric

    NASA Astrophysics Data System (ADS)

    Parida, B. N.; Das, Piyush R.; Padhee, R.; Choudhary, R. N. P.

    2013-08-01

    The polycrystalline sample of Li2Pb2Nd2W2Ti4Nb4O30 was prepared by a solid-state reaction technique. Room temperature X-ray structural analysis confirms the formation of a single-phase compound. The morphology of the sintered sample recorded by scanning electron microscope exhibits a uniform grain distribution. Detailed studies of the nature of variation of dielectric constant, tangent loss, and polarization with temperature and frequency confirmed the existence of ferroelectricity in the material at room temperature. The temperature and frequency dependence of impedance parameters (impedance, modulus, etc.) of the material exhibits a strong correlation of its microstructure (i.e., bulk, grain boundary, etc.). Furthermore, the temperature dependence of DC conductivity shows a typical Arrhenius behavior of the material. The nature of variation of pyroelectric coefficient and current with temperature suggests that material has good pyroelectric properties useful for pyroelectric detector.

  5. Crystal structure of nonsuperconducting Pb 2(Sr 0.94Nd 0.06) 2(Nd 0.76Sr 0.24)Cu 3O 8

    NASA Astrophysics Data System (ADS)

    Hayri, Eric A.; Kvick, Åke

    1990-01-01

    The crystal structure of Pb 2(Sr 0.94Nd 0.06) 2(Nd 0.76Sr 0.24)Cu 3O 8 was determined by single crystal X-ray diffraction. The compound was found to be orthorhombic ( Cmmm) with a = 5.437(3), b = 5.472(2), c = 15.797(7)Å and Z = 2. In the structure double layers of CuO square pyramids are separated by (Nd, Sr) oxygen deficient layers which are stacked between (PbO)Cu(PbO) slabs. The oxygen in the Pb planes is shifted toward a pair of Pb atoms resulting in an orthorhombic distortion of the tetragonal unit cell. The possibilities for modulations and superlattices are discussed as is the role of the PbO planes in superconductivity.

  6. Wound healing and soft tissue effects of CO2, contact Nd: YAG and combined CO2-Nd: YAG laser beams on rabbit trachea.

    PubMed

    Laranne, J; Lagerstedt, A; Pukander, J; Rantala, I

    1997-11-01

    Rabbit trachea was used as an experimental model to study tissue effects and healing of full-thickness tracheal lesions produced by CO2, contact Nd: YAG and combined, coaxial CO2-Nd: YAG (Combo) laser beams. Two power settings (10 W and 16 W) were used with CO2 and contact Nd: YAG lasers. Three different CO2/Nd:YAG power ratios (1:1, 1:2 and 1:4) and power settings (12 W 15 W and 16 W) were used with the Combolaser. Histological specimens for light and transmission electron microscopy were prepared immediately and 1, 3, 5, 7, 14 and 21 days postoperatively. The wound with the most precise and fastest healing was produced by contact Nd: YAG laser. CO2 laser produced a moderate amount of charring and the largest amount of coagulated tissue with a slightly prolonged healing period. In the acute phase, tissue defects produced by the Combolaser with power ratios 1:1 and 1:2 resembled the CO2 laser lesions but with slightly less charring. The power ratio 1:4 diminished the cutting properties of the beam considerably. During the healing period the Combolaser produced the most intensive inflammation and granulation tissue formation resulting in delayed regeneration of the lesion. In transmission electron micrographs the most severe damage to chondrocytes was seen after using the Combolaser. These findings indicate that the Combolaser produces deeper tissue damage than CO2 or contact Nd:YAG laser. However, the Combolaser appears to be suitable for tracheobronchial operations, owing to its good simultaneous cutting and haemostatic properties.

  7. The influence of Nd3+ in CaAl2O4:Eu2+,Nd3+ phosphor fabricated by combustion synthesis

    NASA Astrophysics Data System (ADS)

    Yang, Zhiping; Yang, Yong; Li, Xingmin; Li, Xu; Liu, Chong; Feng, Jianwei

    2005-01-01

    Eu2+, Nd3+ co-doped calcium aluminate (CaAl2O4) phosphor with high brightness and long afterglow were fabricated by urea-nitrate solution combustion synthesis at 600°C. The phosphor powder of combustion synthesis were generally more homogeneous and had fewer impurity than phosphor fabricated by conventional solid-state methods, the character could conduce to obtain more exact data. The excitation and emission spectrum indicated that there waxs only one luminescence center Eu2+, both of the characteristic spectrums of Eu3+ and Nd3+ weren't discovered. As a secondary activator, Nd3+ could make remarkable influence on the afterglow of phosphor. From altering the moral ratio of Eu2+ and Nd3+, the lasting time of afterglow and thermoluminescence were studied respectively, when Nd3+ wasn't appended, the intensity of initial brightness could compared with other materials which had different ratio of Eu2+ and Nd3+, however the brightness of afterglow decayed rapidly, the lasting time and brightness of afterglow were improved with reduce the radio of Eu2+ and Nd3+, while the ratio achieved some value, the lasting time of afterglow become shorten with the reduce of ratio of Eu2+ and Nd3+. Moreover the depth of trap was calculated from the parameter of thermoluminescence. However, the emission spectrum and XRD patterns didn't change obviously with the altering ratio of Eu2+ and Nd3+. It showed that the little amount of doped rear earth ions (Eu2+ and Nd3+) had almost no effect on the CaAl2O4 phase composition. Based on these conclusions, the model of the luminescence process of CaAl2O4:Eu2+, Nd3+ was built.

  8. Computer-Generated Geometry Instruction: A Preliminary Study

    ERIC Educational Resources Information Center

    Kang, Helen W.; Zentall, Sydney S.

    2011-01-01

    This study hypothesized that increased intensity of graphic information, presented in computer-generated instruction, could be differentially beneficial for students with hyperactivity and inattention by improving their ability to sustain attention and hold information in-mind. To this purpose, 18 2nd-4th grade students, recruited from general…

  9. Effects of modification of the tyrosine residues of bacteriorhodopsin with tetranitromethane.

    PubMed Central

    Campos-Cavieres, M; Moore, T A; Perham, R N

    1979-01-01

    Treatment of the purple membrane of Halobacterium halobium with tetranitromethane led to modification of tyrosine residues. Modification of more than 3-4 tyrosine residues per bacteriorhodopsin monomer caused a decrease in the light-induced proton-pumping ability of purple membrane in synthetic lipid vesicles, loss of the sharp X-ray-diffraction patterns characteristic of the crystal lattice, loss of the absorbance maximum at 560 nm, and change in the buoyant density of the membrane. No modification of lipid was detected. These changes were interpreted as a gradual denaturation of the protein component such that when 8-9 tyrosine residues are modified, no proton pumping is observed. Modification of less than 3-4 tyrosine residues with tetranitromethane caused an increse in light-induced proton pumping. It was possible to generate partly modified purple membrane which had completely lost the property of diffracting X-rays into the sharp pattern observed with native purple membrane, but which still retained the ability to pump protons in a vectorial manner. Retention of crystal lattice is not essential for proton pumping. Images Fig. 3. PMID:475758

  10. Inhibition of formation of filopodia after axotomy by inhibitors of protein tyrosine kinases.

    PubMed

    Goldberg, D J; Wu, D Y

    1995-08-01

    The activity of motile protrusions of the growth cone--filopodia, veils, and lamellipodia--is essential for directed growth of a neuronal process. The regulation of the formation of these protrusions is not well understood. Numerous filopodia and veils or lamellipodia form within minutes of transection of an Aplysia axon in culture, as the initial components of growth cones of regenerating neurites. Axotomy, therefore, provides a robust and reliable protocol for analyzing the formation of these protrusions. We evaluated the involvement of protein phosphorylation in the regulation of protrusive activity. Of the inhibitors of protein kinases assayed, only the inhibitors of protein tyrosine kinases--genistein, lavendustin A, herbimycin A, and erbstatin analogue--suppressed the formation of protrusions, as assessed by high magnification video microscopy. These drugs did not work by preventing resealing of the axon, as evident from visual inspection and by the unimpaired effectiveness of genistein or lavendustin in preventing formation of filopodia when applied after resealing. Inhibition of protein tyrosine kinases not only prevented the formation of actin-based protrusions, but also caused deterioration of the actin network underlying the protrusive area of preexisting growth cones. Consistent with an involvement of protein tyrosine phosphorylation in the generation of protrusive structures, immunocytochemistry revealed that aggregates of phosphotyrosine appeared at the margins of the axon, from which protrusions emerge shortly after axotomy. These results suggest a role for protein tyrosine phosphorylation in the formation and maintenance of actin-based protrusive structures.

  11. Modulation of protein tyrosine nitration and inflammatory mediators by isoprenylhydroquinone glucoside.

    PubMed

    Olmos, Ana; Giner, Rosa-María; Recio, María-Carmen; Ríos, José-Luis; Máñez, Salvador

    2007-03-01

    The nitration of tyrosine caused by peroxynitrite and other reactive nitrogen species is clearly detrimental for some physiological processes; however, its signalling role is still open to controversy. Among the natural phenolics known for their ability to oppose free tyrosine nitration, isoprenylhydroquinone glucoside is investigated due to its unusual structure, which contains a simple hydroxybenzene alkylated by a hemiterpenoid moiety. This hydroquinone was shown to be an effective inhibitor of peroxynitrite-induced protein tyrosine nitration in 3T3 fibroblasts. When tested on bovine seroalbumin nitration, however, the potency was reduced by half and the effect was almost abolished in the presence of bicarbonate. In contrast, addition of this anion had no effect on the nitrite/hydrogen peroxide/hemin system. Isoprenylhydroquinone glucoside was also active in the microM range on intra- and extracellular protein-bound tyrosine nitration by phorbol 12-myristate 13-acetate-stimulated neutrophils. The effects on nitric oxide synthase expression, interleukin-1beta and tumor necrosis factor-alpha production by lipopolysaccharide-stimulated macrophages were quite moderate. Thus, isoprenylhydroquinone glucoside is an inhibitor of protein nitration in situ, but lacks effect on the generation of either nitric oxide or inflammatory cytokines.

  12. Protein tyrosine adduct in humans self-poisoned by chlorpyrifos

    SciTech Connect

    Li, Bin; Eyer, Peter; Eddleston, Michael; Jiang, Wei; Schopfer, Lawrence M.; Lockridge, Oksana

    2013-06-15

    Studies of human cases of self-inflicted poisoning suggest that chlorpyrifos oxon reacts not only with acetylcholinesterase and butyrylcholinesterase but also with other blood proteins. A favored candidate is albumin because in vitro and animal studies have identified tyrosine 411 of albumin as a site covalently modified by organophosphorus poisons. Our goal was to test this proposal in humans by determining whether plasma from humans poisoned by chlorpyrifos has adducts on tyrosine. Plasma samples from 5 self-poisoned humans were drawn at various time intervals after ingestion of chlorpyrifos for a total of 34 samples. All 34 samples were analyzed for plasma levels of chlorpyrifos and chlorpyrifos oxon (CPO) as a function of time post-ingestion. Eleven samples were analyzed for the presence of diethoxyphosphorylated tyrosine by mass spectrometry. Six samples yielded diethoxyphosphorylated tyrosine in pronase digests. Blood collected as late as 5 days after chlorpyrifos ingestion was positive for CPO-tyrosine, consistent with the 20-day half-life of albumin. High plasma CPO levels did not predict detectable levels of CPO-tyrosine. CPO-tyrosine was identified in pralidoxime treated patients as well as in patients not treated with pralidoxime, indicating that pralidoxime does not reverse CPO binding to tyrosine in humans. Plasma butyrylcholinesterase was a more sensitive biomarker of exposure than adducts on tyrosine. In conclusion, chlorpyrifos oxon makes a stable covalent adduct on the tyrosine residue of blood proteins in humans who ingested chlorpyrifos. - Highlights: • Chlorpyrifos-poisoned patients have adducts on protein tyrosine. • Diethoxyphosphate-tyrosine does not lose an alkyl group. • Proteins in addition to AChE and BChE are modified by organophosphates.

  13. Microgravimetric and magnetometric three-dimensional analysis in the 2nd section of the Bosque de Chapultepec

    NASA Astrophysics Data System (ADS)

    Escobedo-Zenil, D.; Sanchez-Gonzalez, J.; García-Serrano, A.

    2013-05-01

    The Bosque de Chapultepec is the most important recreational area in Mexico City. In the early 20th century construction material in this region was exploited illegally generating a clandestine system of mines without any registration or census. Later in the early 50's it was planned the creation of a park in the area, nonetheless many mines were blocked by debris or vegetation and only a few mines were filled to build the infrastructure of the park. In June 2006, the collapse of the foundation slab of the Lago Mayor emptied 5000 cubic meters of water, which made clear the need of near surface geophysics studies to locate instabilities due to underground cavities. This work describes the progress of microgravimetry and magnetometry studies located in a forest region where the collapse of a mine entrance occurred. This mine has 4 known branches, but the full extent or if these branches are connected to the entrance of another filled mine located approximately to 100 meters is unknown. The results of this work, in correlation with the geological model and preliminary results of seismic and electrical methods, show lateral variations that may be associated with cavities and possible structural faults, which represent hazards to the Bosque de Chapultepec.

  14. Spectroscopy of jet-cooled tyrosine derivatives

    NASA Astrophysics Data System (ADS)

    Teh, Chin Khuan; Sulkes, Mark

    1991-05-01

    Using fluorescence-based techniques (excitation and emission spectra lifetimes), we have studied the jet-cooled tyrosine derivatives tyramine and 3-(4-hydroxyphenyl) propionic acid (HPA). For solvent addition resulting in small, mainly one adduct complexes, there is a high degree of analogy with the results for the corresponding analogs of the amino acid tryptophan. In particular, for tyramine, as had been the case with its tryptophan analog tryptamine, addition of one -OH bearing solvent molecule at the α-amine apparently results in a complex in a single conformation.

  15. Tyrosine metabolic enzymes from insects and mammals: a comparative perspective.

    PubMed

    Vavricka, Christopher John; Han, Qian; Mehere, Prajwalini; Ding, Haizhen; Christensen, Bruce M; Li, Jianyong

    2014-02-01

    Differences in the metabolism of tyrosine between insects and mammals present an interesting example of molecular evolution. Both insects and mammals possess fine-tuned systems of enzymes to meet their specific demands for tyrosine metabolites; however, more homologous enzymes involved in tyrosine metabolism have emerged in many insect species. Without knowledge of modern genomics, one might suppose that mammals, which are generally more complex than insects and require tyrosine as a precursor for important catecholamine neurotransmitters and for melanin, should possess more enzymes to control tyrosine metabolism. Therefore, the question of why insects actually possess more tyrosine metabolic enzymes is quite interesting. It has long been known that insects rely heavily on tyrosine metabolism for cuticle hardening and for innate immune responses, and these evolutionary constraints are likely the key answers to this question. In terms of melanogenesis, mammals also possess a high level of regulation; yet mammalian systems possess more mechanisms for detoxification whereas insects accelerate pathways like melanogenesis and therefore must bear increased oxidative pressure. Our research group has had the opportunity to characterize the structure and function of many key proteins involved in tyrosine metabolism from both insects and mammals. In this mini review we will give a brief overview of our research on tyrosine metabolic enzymes in the scope of an evolutionary perspective of mammals in comparison to insects.

  16. Potential sites of CFTR activation by tyrosine kinases

    PubMed Central

    Billet, Arnaud; Jia, Yanlin; Jensen, Timothy J.; Hou, Yue-Xian; Chang, Xiu-Bao; Riordan, John R.; Hanrahan, John W.

    2016-01-01

    ABSTRACT The CFTR chloride channel is tightly regulated by phosphorylation at multiple serine residues. Recently it has been proposed that its activity is also regulated by tyrosine kinases, however the tyrosine phosphorylation sites remain to be identified. In this study we examined 2 candidate tyrosine residues near the boundary between the first nucleotide binding domain and the R domain, a region which is important for channel function but devoid of PKA consensus sequences. Mutating tyrosines at positions 625 and 627 dramatically reduced responses to Src or Pyk2 without altering the activation by PKA, suggesting they may contribute to CFTR regulation. PMID:26645934

  17. Euglena mitochondria and chloroplasts form tyrosine-O-sulfate

    SciTech Connect

    Saidha, T.; Hanfstingl, U.; Schiff, J.A. )

    1989-04-01

    Mitochondria from light-grown wild-type Euglena gracilis var. bacillaris Cori or dark-grown mutant W{sub 10}BSmL incubated with {sup 35}SO{sub 4}{sup 2{minus}} and ATP, or with {sup 14}C-tyrosine, non-radioactive sulfate and ATP accumulate a labeled compound in the medium. Since this compound shows exact coelectrophoresis with tyrosine-O-sulfate (TOS) at pH 2.0, 5.8 or 8.0., yields sulfate and tyrosine on acid hydrolysis, and treatment with aryl sulfatase from Aerobacter aerogenes yields sulfate and tyrosine but no tyrosine methyl ester, it is identified as TOS. No TOS is found outside purified developing chloroplasts incubated with {sup 35}SO{sub 4}{sup 2{minus}} and ATP, but both chloroplasts and mitochondria form to {sup 35}S externally when incubated with adenosine 3{prime} phosphate 5{prime}phospho({sup 35}S) sulfate (PAP{sup 35}S). Since no tyrosine need be added, tyrosine is provided from endogenous sources. Although TOS is found in the free pool of Euglena cells it cannot be detected in proteins of cells or mucus ruling our sulfation of tyrosine of protein or incorporation of TOS into proteins. The system forming TOS is membrane-bound and may be involved in tyrosine transport.

  18. Tyrosine Kinase Inhibition: An Approach to Drug Development

    NASA Astrophysics Data System (ADS)

    Levitzki, Alexander; Gazit, Aviv

    1995-03-01

    Protein tyrosine kinases (PTKs) regulate cell proliferation, cell differentiation, and signaling processes in the cells of the immune system. Uncontrolled signaling from receptor tyrosine kinases and intracellular tyrosine kinases can lead to inflammatory responses and to diseases such as cancer, atherosclerosis, and psoriasis. Thus, inhibitors that block the activity of tyrosine kinases and the signaling pathways they activate may provide a useful basis for drug development. This article summarizes recent progress in the development of PTK inhibitors and demonstrates their potential use in the treatment of disease.

  19. Extraction-Separation Performance and Dynamic Modeling of Orion Test Vehicles with Adams Simulation: 2nd Edition

    NASA Technical Reports Server (NTRS)

    Fraire, Usbaldo, Jr.; Anderson, Keith; Varela, Jose G.; Bernatovich, Michael A.

    2015-01-01

    NASA's Orion Capsule Parachute Assembly System (CPAS) project has advanced into the third generation of its parachute test campaign and requires technically comprehensive modeling capabilities to simulate multi-body dynamics (MBD) of test articles released from a C-17. Safely extracting a 30,000 lbm mated test article from a C-17 and performing stable mid-air separation maneuvers requires an understanding of the interaction between elements in the test configuration and how they are influenced by extraction parachute performance, aircraft dynamics, aerodynamics, separation dynamics, and kinetic energy experienced by the system. During the real-time extraction and deployment sequences, these influences can be highly unsteady and difficult to bound. An avionics logic window based on time, pitch, and pitch rate is used to account for these effects and target a favorable separation state in real time. The Adams simulation has been employed to fine-tune this window, as well as predict and reconstruct the coupled dynamics of the Parachute Test Vehicle (PTV) and Cradle Platform Separation System (CPSS) from aircraft extraction through the mid-air separation event. The test-technique for the extraction of CPAS test articles has evolved with increased complexity and requires new modeling concepts to ensure the test article is delivered to a stable test condition for the programmer phase. Prompted by unexpected dynamics and hardware malfunctions in drop tests, these modeling improvements provide a more accurate loads prediction by incorporating a spring-damper line-model derived from the material properties. The qualification phase of CPAS testing is on the horizon and modeling increasingly complex test-techniques with Adams is vital to successfully qualify the Orion parachute system for human spaceflight.

  20. Redox regulation of protein tyrosine phosphatase activity by hydroxyl radical.

    PubMed

    Meng, Fan-Guo; Zhang, Zhong-Yin

    2013-01-01

    Substantial evidence suggests that transient production of reactive oxygen species (ROS) such as hydrogen peroxide (H(2)O(2)) is an important signaling event triggered by the activation of various cell surface receptors. Major targets of H(2)O(2) include protein tyrosine phosphatases (PTPs). Oxidation of the active site Cys by H(2)O(2) abrogates PTP catalytic activity, thereby potentially furnishing a mechanism to ensure optimal tyrosine phosphorylation in response to a variety of physiological stimuli. Unfortunately, H(2)O(2) is poorly reactive in chemical terms and the second order rate constants for the H(2)O(2)-mediated PTP inactivation are ~10M(-1)s(-1), which is too slow to be compatible with the transient signaling events occurring at the physiological concentrations of H(2)O(2). We find that hydroxyl radical is produced from H(2)O(2) solutions in the absence of metal chelating agent by the Fenton reaction. We show that the hydroxyl radical is capable of inactivating the PTPs and the inactivation is active site directed, through oxidation of the catalytic Cys to sulfenic acid, which can be reduced by low molecular weight thiols. We also show that hydroxyl radical is a kinetically more efficient oxidant than H(2)O(2) for inactivating the PTPs. The second-order rate constants for the hydroxyl radical-mediated PTP inactivation are at least 2-3 orders of magnitude higher than those mediated by H(2)O(2) under the same conditions. Thus, hydroxyl radical generated in vivo may serve as a more physiologically relevant oxidizing agent for PTP inactivation. This article is part of a Special Issue entitled: Chemistry and mechanism of phosphatases, diesterases and triesterases.

  1. An overview of second generation biofuel technologies.

    PubMed

    Sims, Ralph E H; Mabee, Warren; Saddler, Jack N; Taylor, Michael

    2010-03-01

    The recently identified limitations of 1st-generation biofuels produced from food crops (with perhaps the exception of sugarcane ethanol) have caused greater emphasis to be placed on 2nd-generation biofuels produced from ligno-cellulosic feedstocks. Although significant progress continues to be made to overcome the technical and economic challenges, 2nd-generation biofuels production will continue to face major constraints to full commercial deployment. The logistics of providing a competitive, all-year-round, supply of biomass feedstock to a commercial-scale plant is challenging, as is improving the performance of the conversion process to reduce costs. The biochemical route, being less mature, probably has a greater cost reduction potential than the thermo-chemical route, but here a wider range of synthetic fuels can be produced to better suit heavy truck, aviation and marine applications. Continued investment in research and demonstration by both public and private sectors, coupled with appropriate policy support mechanisms, are essential if full commercialisation is to be achieved within the next decade. After that, the biofuel industry will grow only at a steady rate and encompass both 1st- and 2nd-generation technologies that meet agreed environmental, sustainability and economic policy goals.

  2. Role of Protein Tyrosine Phosphatases in Plants

    PubMed Central

    Shankar, Alka; Agrawal, Nisha; Sharma, Manisha; Pandey, Amita; Pandey, Girdhar K.

    2015-01-01

    Reversible protein phosphorylation is a crucial regulatory mechanism that controls many biological processes in eukaryotes. In plants, phosphorylation events primarily occur on serine (Ser) and threonine (Thr) residues, while in certain cases, it was also discovered on tyrosine (Tyr) residues. In contrary to plants, extensive reports on Tyr phosphorylation regulating a large numbers of biological processes exist in animals. Despite of such prodigious function in animals, Tyr phosphorylation is a least studied mechanism of protein regulation in plants. Recently, various chemical analytical procedures have strengthened the view that Tyr phosphorylation is equally prevalent in plants as in animals. However, regardless of Tyr phosphorylation events occuring in plants, no evidence could be found for the existence of gene encoding for Tyr phosphorylation i.e. the typical Tyr kinases. Various methodologies have suggested that plant responses to stress signals and developmental processes involved modifications in protein Tyr phosphorylation. Correspondingly, various reports have established the role of PTPs (Protein Tyrosine Phosphatases) in the dephosphorylation and inactivation of mitogen activated protein kinases (MAPKs) hence, in the regulation of MAPK signaling cascade. Besides this, many dual specificity protein phosphatases (DSPs) are also known to bind starch and regulate starch metabolism through reversible phosphorylation. Here, we are emphasizing the significant progress on protein Tyr phosphatases to understand the role of these enzymes in the regulation of post-translational modification in plant physiology and development. PMID:26962298

  3. Abnormal tyrosine metabolism in chronic cluster headache.

    PubMed

    D'Andrea, Giovanni; Leone, Massimo; Bussone, Gennaro; Fiore, Paola Di; Bolner, Andrea; Aguggia, Marco; Saracco, Maria Gabriella; Perini, Francesco; Giordano, Giuseppe; Gucciardi, Antonina; Leon, Alberta

    2017-02-01

    Objective Episodic cluster headache is characterized by abnormalities in tyrosine metabolism (i.e. elevated levels of dopamine, tyramine, octopamine and synephrine and low levels of noradrenalin in plasma and platelets.) It is unknown, however, if such biochemical anomalies are present and/or constitute a predisposing factor in chronic cluster headache. To test this hypothesis, we measured the levels of dopamine and noradrenaline together with those of elusive amines, such as tyramine, octopamine and synephrine, in plasma of chronic cluster patients and control individuals. Methods Plasma levels of dopamine, noradrenaline and trace amines, including tyramine, octopamine and synephrine, were measured in a group of 23 chronic cluster headache patients (10 chronic cluster ab initio and 13 transformed from episodic cluster), and 16 control participants. Results The plasma levels of dopamine, noradrenaline and tyramine were several times higher in chronic cluster headache patients compared with controls. The levels of octopamine and synephrine were significantly lower in plasma of these patients with respect to control individuals. Conclusions These results suggest that anomalies in tyrosine metabolism play a role in the pathogenesis of chronic cluster headache and constitute a predisposing factor for the transformation of the episodic into a chronic form of this primary headache.

  4. Activation of the EGF receptor tyrosine kinase by divalent metal ions: comparison of holoreceptor and isolated kinase domain properties.

    PubMed

    Koland, J G; Cerione, R A

    1990-05-22

    The activation of the epidermal growth factor (EGF) receptor tyrosine kinase activity is thought to represent a key initial step in EGF-mediated mitogenesis. The mechanisms underlying the regulation of the EGF receptor tyrosine kinase activity were examined through comparisons of the holoreceptor, purified from human placenta, and a soluble 42 kDa tyrosine kinase domain (TKD), generated by the limited trypsin proteolysis of the holoreceptor. The results of these studies highlight the importance of divalent metal ions (Me2+), i.e., Mn2+ and Mg2+, as activators of the tyrosine kinase activity. Manganese is an extremely effective activator of the holoreceptor tyrosine kinase, and under some conditions (low ionic strength) it completely alleviates the need for EGF to stimulate activity. In contrast, Mg2+ only weakly stimulates the holoreceptor tyrosine kinase activity in the absence of EGF, but promotes essentially full activity in the presence of the growth factor. Like the holoreceptor, the soluble TKD is highly active in the presence of Mn2+. However, the isolated TKD is completely inactive in the presence of Mg2+, and, in fact, Mg2+ inhibits the Mn2(+)-stimulated tyrosine kinase activity. The differences in the effects of Mn2+ and Mg2+ on the isolated TKD were further demonstrated by monitoring the effects of Me2+ on the modification of a reactive cysteine residue(s) on the TKD. While Mn2+ potentiates the inhibition by cysteine-directed reagents of the tyrosine kinase activity, Mg2+ has no effect on either the rate or the extent of the inhibition. Both the regulation by Mn2+ of the kinase activity of the TKD and the potentiation by Mn2+ of the cysteine reactivity of the TKD occur over a millimolar concentration range, which implicates a direct binding interaction by the metal ion. Overall, these results demonstrate that there are two key activator sites on the EGF receptor, i.e., the EGF binding site on the extracellular domain and a Me2+ binding site on the

  5. The Safety of Artemisinin Derivatives for the Treatment of Malaria in the 2nd or 3rd Trimester of Pregnancy: A Systematic Review and Meta-Analysis

    PubMed Central

    van Eijk, Anna Maria; Sevene, Esperanca; Dellicour, Stephanie; Weiss, Noel S.; Emerson, Scott; Steketee, Richard; ter Kuile, Feiko O.; Stergachis, Andy

    2016-01-01

    Given the high morbidity for mother and fetus associated with malaria in pregnancy, safe and efficacious drugs are needed for treatment. Artemisinin derivatives are the most effective antimalarials, but are associated with teratogenic and embryotoxic effects in animal models when used in early pregnancy. However, several organ systems are still under development later in pregnancy. We conducted a systematic review and meta-analysis of the occurrence of adverse pregnancy outcomes among women treated with artemisinins monotherapy or as artemisinin-based combination therapy during the 2nd or 3rd trimesters relative to pregnant women who received non-artemisinin antimalarials or none at all. Pooled odds ratio (POR) were calculated using Mantel-Haenszel fixed effects model with a 0.5 continuity correction for zero events. Eligible studies were identified through Medline, Embase, and the Malaria in Pregnancy Consortium Library. Twenty studies (11 cohort studies and 9 randomized controlled trials) contributed to the analysis, with 3,707 women receiving an artemisinin, 1,951 a non-artemisinin antimalarial, and 13,714 no antimalarial. The PORs (95% confidence interval (CI)) for stillbirth, fetal loss, and congenital anomalies when comparing artemisinin versus quinine were 0.49 (95% CI 0.24–0.97, I2 = 0%, 3 studies); 0.58 (95% CI 0.31–1.16, I2 = 0%, 6 studies); and 1.00 (95% CI 0.27–3.75, I2 = 0%, 3 studies), respectively. The PORs comparing artemisinin users to pregnant women who received no antimalarial were 1.13 (95% CI 0.77–1.66, I2 = 86.7%, 3 studies); 1.10 (95% CI 0.79–1.54, I2 = 0%, 4 studies); and 0.79 (95% CI 0.37–1.67, I2 = 0%, 3 studies) for miscarriage, stillbirth and congenital anomalies respectively. Treatment with artemisinin in 2nd and 3rd trimester was not associated with increased risks of congenital malformations or miscarriage and may be was associated with a reduced risk of stillbirths compared to quinine. This study updates the reviews

  6. Toxicological disruption of signaling homeostasis: Tyrosine phosphatses as targets

    EPA Science Inventory

    The protein tyrosine phosphatases (PTP) comprised a diverse group of enzymes whose activity opposes that of the tyrosine kinases. As such, the PTP have critical roles in maintaining signaling quiescence in resting cells and in restoring homeostasis by effecting signal termination...

  7. Asymmetrical phosphorylation and function of immunoreceptor tyrosine-based activation motif tyrosines in B cell antigen receptor signal transduction.

    PubMed

    Pao, L I; Famiglietti, S J; Cambier, J C

    1998-04-01

    CD79a and CD79b function as transducers of B cell antigen receptor signals via a cytoplasmic sequence, termed the immunoreceptor tyrosine-based activation motif (ITAM). ITAMs contain two conserved tyrosines that may become phosphorylated upon receptor aggregation and bind distinct effectors by virtue of the distinct preference of phosphotyrosyl-containing sequences for SH2 domains. To explore the function of CD79a and CD79b ITAM tyrosines, we created membrane molecules composed of MHC class II I-Ak extracellular and transmembrane domains, and CD79a or CD79b cytoplasmic domains in which one or both of the ITAM tyrosines were mutated to phenylalanine. Functional analysis revealed that both ITAM tyrosines are required for ligand-induced Syk phosphorylation. However CD79a-ITAM and CD79b-ITAM tyrosine phosphorylations were asymmetrical, with >80% of phosphorylation occurring on the N-terminal tyrosine (Y-E-G-L). Thus, these findings suggest that following receptor ligation, only a minor proportion of phosphorylated ITAMs are doubly phosphorylated and thus can engage Syk. Only the N-terminal ITAM tyrosine of CD79a was required for ligand-mediated phosphorylation of the receptor and a subset of downstream substrates, including p62, p110, and Shc, and for Ca2+ mobilization. However, responses mediated through CD79b exhibited a greater dependence on the presence of both tyrosines. Neither tyrosine in CD79a or CD79b appeared absolutely essential for Src family kinase phosphorylation. These results indicate that phosphorylations of the tyrosines in CD79a and CD79b occur with very different stoichiometry, and the respective tyrosyl residues have distinct functions.

  8. Real-time imaging elucidates the role of H2O2 in regulating kinetics of epidermal growth factor-induced and Src-mediated tyrosine phosphorylation signaling

    NASA Astrophysics Data System (ADS)

    Su, Ting; Li, Xiangyong; Liu, Nisha; Pan, Shaotao; Lu, Jinling; Yang, Jie; Zhang, Zhihong

    2012-07-01

    Reversible oxidation is emerging as an important regulatory mechanism in protein tyrosine phosphorylation. Generation of hydrogen peroxide (H2O2), upon growth factor stimulation, is hypothesized to inhibit activity of protein tyrosine phosphatases (PTPs). This ensures that protein tyrosine kinases can elevate the steady-state level of protein tyrosine phosphorylation, which then allows propagation of the tyrosine phosphorylation signal. However, the effects of H2O2 on the kinetics of tyrosine phosphorylation signaling remain poorly understood, especially in living cells. Therefore, we used a genetically encoded Src kinase-specific biosensor based on fluorescence resonance energy transfer (FRET) to image the kinetics of the Src-mediated tyrosine phosphorylation signaling (Src signaling) induced by epidermal growth factor (EGF). We examined the kinetics under increased and decreased H2O2 levels. Through a straightforward, quantitative analysis method which characterized the signaling kinetics, we demonstrated that H2O2 modulated the amplitude and duration of the signal by inhibiting PTPs' activity. Our evidence also suggested the effect of H2O2 on Src activation is mediated by H2O2-dependent inhibition of PTPs. Furthermore, we provide evidence showing global elevation of intracellular H2O2 level attenuates EGF-induced Src signaling.

  9. Tyrosine Kinase Inhibitors for Non-Small Cell Lung Cancer and Eye Metastasis: Disease Relapse or a New Entity?

    PubMed Central

    ZAROGOULIDIS, Paul; LAMPAKI, Sofia; CHINELIS, Panos; LAZARIDIS, George; BAKA, Sofia; RAPTI, Aggeliki

    2016-01-01

    Lung cancer is still diagnosed during the advanced stage of the disease and most patients do not have the opportunity for surgical treatment, despite the new diagnostic equipment that has been made available in recent years, such as the radial and linear endobronchial ultrasound (EBUS) and electromagnetic fiberoptic bronchoscopy. However, novel targeted therapies with second generation tyrosine kinase inhibitors and immunotherapy are available. In this commentary, we will focus on eye metastasis after initiation of tyrosine kinase inhibitors due to epidermal growth factor mutation of lung cancer adenocarcinoma.

  10. The Futures of Adult Educator(s): Agency, Identity and Ethos. Joint Conference Proceedings of the 2nd ESREA/ReNAdET Meeting and the 4th TQF Seminar (Tallinn, Estonia, November 9-11, 2011)

    ERIC Educational Resources Information Center

    Heikkinen, Anja, Ed.; Jogi, Larissa, Ed.; Jutte, Wolfgang, Ed.; Zarifis, Georgios K., Ed.

    2012-01-01

    This edited volume contains the papers presented in the 2nd ESREA|ReNAdet meeting that was jointly organised with the VET & CULTURE Network in the University of Tallinn (Estonia), 9-11 November 2011. The papers that appear in the volume discuss the future (or the futures) of adult educators in respect to issues of developing their identities…

  11. Importance of tyrosine phosphorylation in receptor kinase complexes.

    PubMed

    Macho, Alberto P; Lozano-Durán, Rosa; Zipfel, Cyril

    2015-05-01

    Tyrosine phosphorylation is an important post-translational modification that is known to regulate receptor kinase (RK)-mediated signaling in animals. Plant RKs are annotated as serine/threonine kinases, but recent work has revealed that tyrosine phosphorylation is also crucial for the activation of RK-mediated signaling in plants. These initial observations have paved the way for subsequent detailed studies on the mechanism of activation of plant RKs and the biological relevance of tyrosine phosphorylation for plant growth and immunity. In this Opinion article we review recent reports on the contribution of RK tyrosine phosphorylation in plant growth and immunity; we propose that tyrosine phosphorylation plays a major regulatory role in the initiation and transduction of RK-mediated signaling in plants.

  12. Stable isotope and trace element studies on gladiators and contemporary Romans from Ephesus (Turkey, 2nd and 3rd Ct. AD)--mplications for differences in diet.

    PubMed

    Lösch, Sandra; Moghaddam, Negahnaz; Grossschmidt, Karl; Risser, Daniele U; Kanz, Fabian

    2014-01-01

    The gladiator cemetery discovered in Ephesus (Turkey) in 1993 dates to the 2nd and 3rd century AD. The aim of this study is to reconstruct diverse diet, social stratification, and migration of the inhabitants of Roman Ephesus and the distinct group of gladiators. Stable carbon, nitrogen, and sulphur isotope analysis were applied, and inorganic bone elements (strontium, calcium) were determined. In total, 53 individuals, including 22 gladiators, were analysed. All individuals consumed C3 plants like wheat and barley as staple food. A few individuals show indication of consumption of C4 plants. The δ13C values of one female from the gladiator cemetery and one gladiator differ from all other individuals. Their δ34S values indicate that they probably migrated from another geographical region or consumed different foods. The δ15N values are relatively low in comparison to other sites from Roman times. A probable cause for the depletion of 15N in Ephesus could be the frequent consumption of legumes. The Sr/Ca-ratios of the gladiators were significantly higher than the values of the contemporary Roman inhabitants. Since the Sr/Ca-ratio reflects the main Ca-supplier in the diet, the elevated values of the gladiators might suggest a frequent use of a plant ash beverage, as mentioned in ancient texts.

  13. Stable Isotope and Trace Element Studies on Gladiators and Contemporary Romans from Ephesus (Turkey, 2nd and 3rd Ct. AD) - Implications for Differences in Diet

    PubMed Central

    Lösch, Sandra; Moghaddam, Negahnaz; Grossschmidt, Karl; Risser, Daniele U.; Kanz, Fabian

    2014-01-01

    The gladiator cemetery discovered in Ephesus (Turkey) in 1993 dates to the 2nd and 3rd century AD. The aim of this study is to reconstruct diverse diet, social stratification, and migration of the inhabitants of Roman Ephesus and the distinct group of gladiators. Stable carbon, nitrogen, and sulphur isotope analysis were applied, and inorganic bone elements (strontium, calcium) were determined. In total, 53 individuals, including 22 gladiators, were analysed. All individuals consumed C3 plants like wheat and barley as staple food. A few individuals show indication of consumption of C4 plants. The δ13C values of one female from the gladiator cemetery and one gladiator differ from all other individuals. Their δ34S values indicate that they probably migrated from another geographical region or consumed different foods. The δ15N values are relatively low in comparison to other sites from Roman times. A probable cause for the depletion of 15N in Ephesus could be the frequent consumption of legumes. The Sr/Ca-ratios of the gladiators were significantly higher than the values of the contemporary Roman inhabitants. Since the Sr/Ca-ratio reflects the main Ca-supplier in the diet, the elevated values of the gladiators might suggest a frequent use of a plant ash beverage, as mentioned in ancient texts. PMID:25333366

  14. Bone fractures as indicators of intentional violence in the eastern Adriatic from the antique to the late medieval period (2nd-16th century AD).

    PubMed

    Slaus, Mario; Novak, Mario; Bedić, Zeljka; Strinović, Davor

    2012-09-01

    To test the historically documented hypothesis of a general increase in deliberate violence in the eastern Adriatic from the antique (AN; 2nd-6th c.) through the early medieval (EM; 7th-11th c.) to the late-medieval period (LM; 12th-16th c.), an analysis of the frequency and patterning of bone trauma was conducted in three skeletal series from these time periods. A total of 1,125 adult skeletons-346 from the AN, 313 from the EM, and 466 from the LM series-were analyzed. To differentiate between intentional violence and accidental injuries, data for trauma frequencies were collected for the complete skeleton, individual long bones, and the craniofacial region as well as by type of injury (perimortem vs. antemortem). The results of our analyses show a significant temporal increase in total fracture frequencies when calculated by skeleton as well as of individuals exhibiting one skeletal indicator of deliberate violence (sharp force lesions, craniofacial injuries, "parry" fractures, or perimortem trauma). No significant temporal increases were, however, noted in the frequencies of craniofacial trauma, "parry" fractures, perimortem injuries, or of individuals exhibiting multiple skeletal indicators of intentional violence. Cumulatively, these data suggest that the temporal increase in total fracture frequencies recorded in the eastern Adriatic was caused by a combination of factors that included not only an increase of intentional violence but also a significant change in lifestyle that accompanied the transition from a relatively affluent AN urban lifestyle to a more primitive rural medieval way of life.

  15. Development and Validation of Big Four Personality Scales for the Schedule for Nonadaptive and Adaptive Personality-2nd Edition (SNAP-2)

    PubMed Central

    Calabrese, William R.; Rudick, Monica M.; Simms, Leonard J.; Clark, Lee Anna

    2012-01-01

    Recently, integrative, hierarchical models of personality and personality disorder (PD)—such as the Big Three, Big Four and Big Five trait models—have gained support as a unifying dimensional framework for describing PD. However, no measures to date can simultaneously represent each of these potentially interesting levels of the personality hierarchy. To unify these measurement models psychometrically, we sought to develop Big Five trait scales within the Schedule for Adaptive and Nonadaptive Personality–2nd Edition (SNAP-2). Through structural and content analyses, we examined relations between the SNAP-2, Big Five Inventory (BFI), and NEO-Five Factor Inventory (NEO-FFI) ratings in a large data set (N = 8,690), including clinical, military, college, and community participants. Results yielded scales consistent with the Big Four model of personality (i.e., Neuroticism, Conscientiousness, Introversion, and Antagonism) and not the Big Five as there were insufficient items related to Openness. Resulting scale scores demonstrated strong internal consistency and temporal stability. Structural and external validity was supported by strong convergent and discriminant validity patterns between Big Four scale scores and other personality trait scores and expectable patterns of self-peer agreement. Descriptive statistics and community-based norms are provided. The SNAP-2 Big Four Scales enable researchers and clinicians to assess personality at multiple levels of the trait hierarchy and facilitate comparisons among competing “Big Trait” models. PMID:22250598

  16. The photoluminescence and thermoluminescence properties of novel green long-lasting phosphorescence materials Ca8Mg(SiO4)4Cl2:Eu2+,Nd3+

    NASA Astrophysics Data System (ADS)

    Wang, J.; Zhang, M.; Zhang, Q.; Ding, W.; Su, Q.

    2007-04-01

    The novel green long-lasting phosphorescence (LLP) material Ca8Mg(SiO4)4Cl2:Eu2+,Nd3+ was systematically investigated by means of photoluminescence (PL) excitation and emission, a thermal quenching process, long-lasting phosphorescent emission, decay curves, chromaticity and thermoluminescence (TL) spectra. It is clearly observed that there exist two distinguishable Eu sites, EuI for 426-nm and EuII for 504-nm emissions, but only the green LLP appears at the EuII site. The emissions for both PL and LLP are due to the 5d→4f transitions. The green phosphorescence with the chromaticity coordination x=0.196, y=0.506 can still be observed in the dark for no less than 5 h by the naked eye. The results of TL show that Nd3+ ions induce the predominating band at 335 K, associated with the charge-trapping centers that are responsible for the appearance of intense green phosphorescence.

  17. A low-pass differentiation filter based on the 2nd-order B-spline wavelet for calculating augmentation index.

    PubMed

    He, Zijun; Zhang, Yongliang; Ma, Zuchang; Hu, Fusong; Sun, Yining

    2014-06-01

    The key point to calculate augmentation index (AIx) related to cardiovascular diseases is the precise identification of the shoulder point. The commonly used method for extracting the shoulder point is to calculate the fourth derivative of the pulse waveform by numerical differentiation. However, this method has a poor anti-noise capability and is computationally intensive. The aims of this study were to develop a new method based on the 2nd-order B-spline wavelet for calculating AIx, and to compare it with numerical differentiation and Savitzky-Golay digital differentiator (SGDD). All the three methods were applied to pulse waveforms derived from 60 healthy subjects. There was a significantly high correlation between the proposed method and numerical differentiation (r=0.998 for carotid pulses, and r=0.997 for radial pulses), as well as between the proposed method and the SGDD (r=0.995 for carotid pulses, and r=0.993 for radial pulses). In addition, the anti-noise capability of the proposed method was evaluated by adding simulated noise (>10Hz) on pulse waveforms. The results showed that the proposed method was advantageous in noise tolerance than the other two methods. These findings indicate that the proposed method can quickly and accurately calculate AIx with a good anti-noise capability.

  18. Report on 2nd Royan Institute International Summer School on developmental biology and stem cells Tehran, Iran, 17-22nd July 2011.

    PubMed

    Newgreen, Donald; Grounds, Miranda; Jesuthasan, Suresh; Rashidi, Hassan; Familari, Mary

    2012-03-01

    The 2nd Royan Institute International Summer School was built around the topic of stem cells and grounding in the discipline of developmental biology. The meeting provided not only direct transfer of technical and intellectual information, the normal process in scientific meetings, but was also a forum for the exchange of personal ideas of science as a creative pursuit. This summer school introduced aspiring young Iranian scientists to international researchers and exposed the latter to a rich culture that highly values learning and education, attested by the confident, intelligent young men and women who asked probing questions and who were eager to participate in the workshops. Hossein Baharvand's dedication and passion for science have led to an impressive record of national and international peer-reviewed publications and an increasing number of students who pursue science in Iran, and shows how the right people can create an environment where good science, good science education and motivation will flourish. This report summarizes some of the activities of the workshop in the Royan Institute and the impressions of the visiting scientists in the wider context of the scientific and cultural heritage of Iran.

  19. Report on the 2nd International Consortium on Hallucination Research: Evolving Directions and Top-10 “Hot Spots” in Hallucination Research

    PubMed Central

    Waters, Flavie

    2014-01-01

    This article presents a report on the 2nd meeting of the International Consortium on Hallucination Research, held on September 12th and 13th 2013 at Durham University, UK. Twelve working groups involving specialists in each area presented their findings and sought to summarize the available knowledge, inconsistencies in the field, and ways to progress. The 12 working groups reported on the following domains of investigation: cortical organisation of hallucinations, nonclinical hallucinations, interdisciplinary approaches to phenomenology, culture and hallucinations, subtypes of auditory verbal hallucinations, a Psychotic Symptoms Rating Scale multisite study, visual hallucinations in the psychosis spectrum, hallucinations in children and adolescents, Research Domain Criteria behavioral constructs and hallucinations, new methods of assessment, psychological therapies, and the Hearing Voices Movement approach to understanding and working with voices. This report presents a summary of this meeting and outlines 10 hot spots for hallucination research, which include the in-depth examination of (1) the social determinants of hallucinations, (2) translation of basic neuroscience into targeted therapies, (3) different modalities of hallucination, (4) domain convergence in cross-diagnostic studies, (5) improved methods for assessing hallucinations in nonclinical samples, (6) using humanities and social science methodologies to recontextualize hallucinatory experiences, (7) developmental approaches to better understand hallucinations, (8) changing the memory or meaning of past trauma to help recovery, (9) hallucinations in the context of sleep and sleep disorders, and (10) subtypes of hallucinations in a therapeutic context. PMID:24282321

  20. Results of on-line tests of the ENABLE prototype, a 2nd level trigger processor for the TRT of ATLAS/LHC

    SciTech Connect

    Noffz, K.H.; Kugel, A.; Klefenz, F.; Zoz, R.; Maenner, R.

    1994-12-31

    The Enable Machine is a systolic 2nd level trigger processor for the transition radiation tracker (TRT) of ATLAS/LHC. The task of the processor is to find the best candidate for a lepton track in a high background of pions according to the EAST benchmark algorithm in less than 10 {mu}s. As described earlier, this is done in three steps. First all interesting tracks are histogrammed by accumulating for each track the coincidences between the track mask and the region-of-interest (RoI). Next the best defined track is identified. Eventually this track is classified as e or {pi}. A prototype has been developed and tested within the EAST/RD-11 collaboration at CERN. It operates at 50 MHz and finds up to 400 tracks in less than 10 {mu}s. It is assembled of an interface board and one or more histogrammer boards. The modular design makes the Enable Machine easily scalable. The histogrammer units are systolic arrays consisting of a matrix of 36 field programmable gate arrays. Through this it is possible to optimize the trigger algorithm, to adapt it to a changed detector setup, and even to implement completely new algorithms. For the beam tests in autumn 1993 at CERN the overall functionality within the detector environment could be shown. The authors were able to link successfully the Enable prototype to the detector raw data stream as well as to the data acquisition.

  1. The effect of magnetic field annealing on the texture of 2nd recrystallization for a deformed Fe-3.2% Si steel sheet

    NASA Astrophysics Data System (ADS)

    Kim, Byung Geol; Part, Su Dong; Kim, Shang Shu

    2004-12-01

    The effects of deformation on 2nd recrystallization behavior with or without magnetic field for a 1st recrystallized electrical steel sheet have been investigated. Annealing temperatures (800, 1000 °C) and cold-rolling rates (50, 70 %) were experimental parameters. A magnetic field of 5 T using a superconducting magnet at a heating rate of 15 °C/min was applied in a direction parallel to the rolling direction. The intensity of α-fiber was increased due to the deformation and, in particular, the formation of {100}<110> component was tremendous. Considerable formation of {001}<100> component was also found. At 800 °C, α-fiber was developed rapidly due to deformation, and η-fiber was also formed in the components {100}<100> and {110}<100> The effect of magnetic field annealing was more significant at 800 °C, while the effect at 1000 °C was negligible. These results are discussed in a phenomenological context considering the atomic fluctuation and magnetic induction depending on annealing temperature and magnetic field.

  2. Stable isotopic evidence for diet at the Imperial Roman coastal site of Velia (1st and 2nd centuries AD) in Southern Italy.

    PubMed

    Craig, Oliver E; Biazzo, Marco; O'Connell, Tamsin C; Garnsey, Peter; Martinez-Labarga, Cristina; Lelli, Roberta; Salvadei, Loretana; Tartaglia, Gianna; Nava, Alessia; Renò, Lorena; Fiammenghi, Antonella; Rickards, Olga; Bondioli, Luca

    2009-08-01

    Here we report on a stable isotope palaeodietary study of a Imperial Roman population interred near the port of Velia in Southern Italy during the 1st and 2nd centuries AD. Carbon and nitrogen stable isotope analyses were performed on collagen extracted from 117 adult humans as well as a range of fauna to reconstruct individual dietary histories. For the majority of individuals, we found that stable isotope data were consistent with a diet high in cereals, with relatively modest contributions of meat and only minor contributions of marine fish. However, substantial isotopic variation was found within the population, indicating that diets were not uniform. We suggest that a number of individuals, mainly but not exclusively males, had greater access to marine resources, especially high trophic level fish. However, the observed dietary variation did not correlate with burial type, number of grave goods, nor age at death. Also, individuals buried at the necropolis at Velia ate much less fish overall compared with the contemporaneous population from the necropolis of Portus at Isola Sacra, located on the coast close to Rome. Marine and riverine transport and commerce dominated the economy of Portus, and its people were in a position to supplement their own stocks of fish with imported goods in transit to Rome, whereas at Velia marine exploitation existed side-by-side with land-based economic activities.

  3. Food for creativity: tyrosine promotes deep thinking.

    PubMed

    Colzato, Lorenza S; de Haan, Annelies M; Hommel, Bernhard

    2015-09-01

    Anecdotal evidence suggests that creative people sometimes use food to overcome mental blocks and lack of inspiration, but empirical support for this possibility is still lacking. In this study, we investigated whether creativity in convergent- and divergent-thinking tasks is promoted by the food supplement L-Tyrosine (TYR)-a biochemical precursor of dopamine, which is assumed to drive cognitive control and creativity. We found no evidence for an impact of TYR on divergent thinking ("brainstorming") but it did promote convergent ("deep") thinking. As convergent thinking arguably requires more cognitive top-down control, this finding suggests that TYR can facilitate control-hungry creative operations. Hence, the food we eat may affect the way we think.

  4. R3 receptor tyrosine phosphatases: conserved regulators of receptor tyrosine kinase signaling and tubular organ development.

    PubMed

    Jeon, Mili; Zinn, Kai

    2015-01-01

    R3 receptor tyrosine phosphatases (RPTPs) are characterized by extracellular domains composed solely of long chains of fibronectin type III repeats, and by the presence of a single phosphatase domain. There are five proteins in mammals with this structure, two in Drosophila and one in Caenorhabditis elegans. R3 RPTPs are selective regulators of receptor tyrosine kinase (RTK) signaling, and a number of different RTKs have been shown to be direct targets for their phosphatase activities. Genetic studies in both invertebrate model systems and in mammals have shown that R3 RPTPs are essential for tubular organ development. They also have important functions during nervous system development. R3 RPTPs are likely to be tumor suppressors in a number of types of cancer.

  5. R3 receptor tyrosine phosphatases: conserved regulators of receptor tyrosine kinase signaling and tubular organ development

    PubMed Central

    Jeon, Mili; Zinn, Kai

    2014-01-01

    Summary R3 receptor tyrosine phosphatases (RPTPs) are characterized by extracellular domains composed solely of long chains of fibronectin type III repeats, and by the presence of a single phosphatase domain. There are five proteins in mammals with this structure, two in Drosophila, and one in Caenorhabditis elegans. R3 RPTPs are selective regulators of receptor tyrosine kinase (RTK) signaling, and a number of different RTKs have been shown to be direct targets for their phosphatase activities. Genetic studies in both invertebrate model systems and in mammals have shown that R3 RPTPs are essential for tubular organ development. They also have important functions during nervous system development. R3 RPTPs are likely to be tumor suppressors in a number of types of cancer. PMID:25242281

  6. Analysis of immunoreceptor tyrosine-based activation motif (ITAM) binding to ZAP-70 by surface plasmon resonance.

    PubMed

    Vély, F; Nunès, J A; Malissen, B; Hedgecock, C J

    1997-11-01

    The signaling function of the T cell antigen receptor (TCR) is mediated via CD3 polypeptides, the cytoplasmic sequences of which bear conserved immunoreceptor tyrosine-based activation motifs (ITAM). ITAM are defined by two YxxL/I sequences separated by a six-eight amino acid long spacer. Upon antigen recognition, ITAM become phosphorylated on both tyrosine residues, creating a high affinity binding site for the tandem SH2 domains found in the protein tyrosine kinase ZAP-70. Using surface plasmon resonance, we further dissected the sequences required for the binding of ZAP-70 to each TCR-associated ITAM. First, we generated protein tyrosine phosphatase-resistant ITAM peptide analogs, in which difluorophosphonomethyl phenylalanyl (F2p) replaced both phosphotyrosines, and showed that those protein tyrosine phosphatase-resistant analogs bind ZAP-70 with high affinity, establishing a rational strategy for the design of novel pharmacological tools capable of interfering with TCR signaling function. Second, we substituted the five amino acids separating the two YxxL/I sequences of the CD3 zeta 1 ITAM with a non-peptidic linker made up of gamma-amino butyric acid units and demonstrated that the length of this intervening sequence rather than its chemical composition is essential for high affinity binding of phosphorylated ITAM to the ZAP-70 SH2 domains.

  7. Tyrosine Kinase Receptor Expression in Canine Liposarcoma.

    PubMed

    Avallone, G; Pellegrino, V; Roccabianca, P; Lepri, E; Crippa, L; Beha, G; De Tolla, L; Sarli, G

    2017-03-01

    The expression of tyrosine kinase receptors is attracting major interest in human and veterinary oncological pathology because of their role as targets for adjuvant therapies. Little is known about tyrosine kinase receptor (TKR) expression in canine liposarcoma (LP), a soft tissue sarcoma. The aim of this study was to evaluate the immunohistochemical expression of the TKRs fibroblast growth factor receptor 1 (FGFR1) and platelet-derived growth factor receptor-β (PDGFRβ); their ligands, fibroblast growth factor 2 (FGF2) and platelet-derived growth factor B (PDGFB); and c-kit in canine LP. Immunohistochemical labeling was categorized as high or low expression and compared with the mitotic count and MIB-1-based proliferation index. Fifty canine LPs were examined, classified, and graded. Fourteen cases were classified as well differentiated, 7 as myxoid, 25 as pleomorphic, and 4 as dedifferentiated. Seventeen cases were grade 1, 26 were grade 2, and 7 were grade 3. A high expression of FGF2, FGFR1, PDGFB, and PDGFRβ was identified in 62% (31/50), 68% (34/50), 81.6% (40/49), and 70.8% (34/48) of the cases, respectively. c-kit was expressed in 12.5% (6/48) of the cases. Mitotic count negatively correlated with FGF2 ( R = -0.41; P < .01), being lower in cases with high FGF2 expression, and positively correlated with PDGFRβ ( R = 0.33; P < .01), being higher in cases with high PDGFRβ expression. No other statistically significant correlations were identified. These results suggest that the PDGFRβ-mediated pathway may have a role in the progression of canine LP and may thus represent a promising target for adjuvant cancer therapies.

  8. OH cleavage from tyrosine: debunking a myth

    PubMed Central

    Bury, Charles S.; Carmichael, Ian; Garman, Elspeth F

    2017-01-01

    During macromolecular X-ray crystallography experiments, protein crystals held at 100 K have been widely reported to exhibit reproducible bond scission events at doses on the order of several MGy. With the objective to mitigate the impact of radiation damage events on valid structure determination, it is essential to correctly understand the radiation chemistry mechanisms at play. OH-cleavage from tyrosine residues is regularly cited as amongst the most available damage pathways in protein crystals at 100 K, despite a lack of widespread reports of this phenomenon in protein crystal radiation damage studies. Furthermore, no clear mechanism for phenolic C—O bond cleavage in tyrosine has been reported, with the tyrosyl radical known to be relatively robust and long-lived in both aqueous solutions and the solid state. Here, the initial findings of Tyr –OH group damage in a myrosinase protein crystal have been reviewed. Consistent with that study, at increasing doses, clear electron density loss was detectable local to Tyr –OH groups. A systematic investigation performed on a range of protein crystal damage series deposited in the Protein Data Bank has established that Tyr –OH electron density loss is not generally a dominant damage pathway in protein crystals at 100 K. Full Tyr aromatic ring displacement is here proposed to account for instances of observable Tyr –OH electron density loss, with the original myrosinase data shown to be consistent with such a damage model. Systematic analysis of the effects of other environmental factors, including solvent accessibility and proximity to di­sulfide bonds or hydrogen bond interactions, is also presented. Residues in known active sites showed enhanced sensitivity to radiation-induced disordering, as has previously been reported. PMID:28009542

  9. Tyrosine phosphorylation of glutamate receptors by non-receptor tyrosine kinases: roles in depression-like behavior

    PubMed Central

    Mao, Li-Min; Wang, John Q.

    2016-01-01

    Several key members of the non-receptor tyrosine kinase (nRTK) family are abundantly present within excitatory synapses in the mammalian brain. These neuron-enriched nRTKs interact with glutamate receptors and phosphorylate the receptors at tyrosine sites. The N-methyl-D-aspartate receptor is a direct substrate of nRTKs and has been extensively investigated in its phosphorylation responses to nRTKs. The α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor is the other glutamate receptor subtype that is subject to nRTK-mediated tyrosine phosphorylation. Recently, group I metabotropic glutamate receptors (mGluR1/5) were found to be sensitive to nRTKs. Robust tyrosine phosphorylation may occur in C-terminal tails of mGluR5. Tyrosine phosphorylation of glutamate receptors is either constitutive or induced activity-dependently by changing cellular and/or synaptic input. Through inducing tyrosine phosphorylation, nRTKs regulate trafficking, subcellular distribution, and function of modified receptors. Available data show that nRTK-glutamate receptor interactions and tyrosine phosphorylation of the receptors undergo drastic adaptations in mood disorders such as major depressive disorder. The remodeling of the nRTK-glutamate receptor interplay contributes to the long-lasting pathophysiology and symptomology of depression. This review summarizes the recent progress in tyrosine phosphorylation of glutamate receptors and analyzes the role of nRTKs in regulating glutamate receptors and depression-like behavior. PMID:26942227

  10. General Physics, 2nd Edition

    NASA Astrophysics Data System (ADS)

    Sternheim, Morton M.; Kane, Joseph W.

    1991-01-01

    Introduces physics to science students with a wide range of interests. Unlike many other physics texts, the coverage and emphasis here is influenced by the specific needs of science majors, including those in the life sciences, and thus treats topics such as geometric optics, mechanics of fluids and acoustics. The derivative is introduced in Chapter One and integrals are used sparingly until electricity and magnetism are covered. Entire chapters are devoted to applications of physics covering subjects such as nerve conduction, ionizing radiation and nuclear magnetic resonance, demonstrating the widespread utility of physics and the unity of science. To aid in comprehension, calculations involving calculus are carried out with a good deal of detail and discussion. Each chapter features a checklist of terms to define or explain as well as problems and exercises. Additional problems and exercises are located in the Supplementary Topics section.

  11. Contaminant Hydrogeology, 2nd Edition

    NASA Astrophysics Data System (ADS)

    Smith, James E.

    Groundwater is a valuable resource that has received much attention over the last couple of decades. Extremely large sums of money have been and will be spent on groundwater contamination problems and the public has become increasingly sensitive to groundwater issues. Groundwater contamination has even become the subject of a major Hollywood movie with the recent release of A Civil Action starring John Travolta. The high profile of groundwater contaminant problems, the associated relatively strong job market over the last 20 years, and the general shift toward an environmental emphasis in science and engineering have resulted in a sustained high demand for senior undergraduate courses and graduate programs in hydrogeology Many voice the opinion that we have seen the peak demand for hydrogeologists pass, but the placement of graduates from hydrogeology programs into career-oriented positions has remained very high.

  12. Sedimentary petrology. 2nd edition

    SciTech Connect

    Blatt, H.

    1992-01-01

    The second edition of Sedimentary Petrology is extensively revised and updated; much effort has been expended to strengthen the weaknesses of the earlier edition, and much of this effort has been successful. It consists of sixteen chapters. Following two introductory chapters (occurrence of sedimentary rocks; weathering and soils), eleven chapters cover the various sedimentary rock types. Coverage is allocated in proportion to their relative abundance and relative ease of study -- three chapters on conglomerates and sandstones (textures and structures, composition, and diagenesis); one on mud rocks; three on carbonates (limestone textures, structures, and environments; limestone mineralogy and diagenesis; and dolostones); and one each on evaporites, cherts, iron-rich rocks, and phosphorites. A novel and useful chapter on paleogeothermometry rounds out the discussion of rocks, followed by chapters on The Development of a Research Project'' and common laboratory methods.

  13. Aquatic pollution, 2nd ed

    SciTech Connect

    Laws, E.A.

    1993-01-01

    This book systematically covers all aspects of water pollution in marine and freshwater systems. Didactic style, frequent use of case studies and an extensive bibliography facilitate understanding of fundamental concepts. Offers basic, relevant ecological and toxicological information. Straightforward presentation of the scientific aspects of environmental issues. Information updated, particularly the discussion of toxicology and the case studies of water pollution. Three new chapters on acid rain, groundwater pollution and plastics are added.

  14. Longwall mining. 2nd ed.

    SciTech Connect

    Peng, S.S.

    2006-10-15

    The book covers US longwall mining technology that was developed and practiced in the US for the past 30 years. It covers all phases of longwall technology in 14 chapters. Each chapter is devoted to a subsystem of equipment or engineering technology. Each chapter begins with a brief introduction on the historical trends of development of the subsystem equipment or engineering technology, followed by a detailed description of the subsystem and engineering technology as they are practiced in the US today.

  15. Electromagnetic Fields, 2nd Edition

    NASA Astrophysics Data System (ADS)

    Wangsness, Roald K.

    1986-07-01

    This revised edition provides patient guidance in its clear and organized presentation of problems. It is rich in variety, large in number and provides very careful treatment of relativity. One outstanding feature is the inclusion of simple, standard examples demonstrated in different methods that will allow students to enhance and understand their calculating abilities. There are over 145 worked examples; virtually all of the standard problems are included.

  16. Modern Physics, 2nd Edition

    NASA Astrophysics Data System (ADS)

    Krane, Kenneth S.

    1995-08-01

    Bring Modern Physics to Life with a Realistic Software Simulation! Enhance the thorough coverage of Krane's Modern Physics 2e with hands-on, real-world experience! Modern Physics Simulations, developed by the Consortium for Upper-Level Physics Software (CUPS), offers complex, realistic calculations of models of various physical systems. Like all of the CUPS simulations, it is remarkably easy to use, yet sophisticated enough for explorations of new ideas. Important Features Include: * Powerful simulations covering Historic Experiments in Electron Diffraction, Laser Cavities & Dynamics, Classical Scattering, Nuclear Properties & Decays, Special Relativity, Quantum Mechanics, and the Hydrogen Atom & the H2+ Molecule. * Pascal source code for all programs and a number of exercises suggesting specific ways the programs can be modified. * Graphical (often animated) displays in most simulations. The entire CUPS simulation series consists of nine books/software simulations which cover Astrophysics, Electricity and Magnetism, Classical Mechanics, Modern Physics, Quantum Mechanics, Nuclear and Particle Physics, Solid State Physics, Thermal and Statistical Physics, and Waves and Optics.

  17. [Patient reported outcome of tyrosine kinase inhibitor related side effects and their impact on daily life in Chinese patients with chronic myeloid leukemia in the chronic phase].

    PubMed

    Yu, L; Wang, H B; Jiang, Q

    2016-11-14

    Objective: To explore the impact of patient reported outcome of tyrosine kinase inhibitor (TKI) related side effects on daily life in Chinese patients with chronic myeloid leukemia (CML) in the chronic phase (CP). Methods: From May to November in 2014, anonymous questionnaires were distributed to adult CML patients who were receiving TKI treatment in China. The impact of TKI-related side effects on daily life were assessed by the score of 1 (no impact) to 5 (high impact) from patient self-report. Results: Data from 731 respondents in the CP who reported the score of the impact of TKI-related side effects on daily life were collected. 407 (56%) were male. The median age was 41 years (range, 18 to 88 years). 560 (77%) started TKI treatment within 1 year after diagnosis. With a median treatment duration of 3 years (range, <1 to 13 years), 549 (75% ) respondents achieved a complete cytogenetic response (CCyR) and 301 (41%) achieved a complete molecular response (CMR). The most common TKI-related adverse effects were edema (n=323, 44% ), fatigue (n=277, 38% ), gastrointestinal disorders (n=235, 32% ), skin color changes (n=142, 19% ), muscle cramps (n=137, 19% ), rash (n=105, 14% ), hepatic function abnormalities (n=91, 12%), weight gain (n=86, 12%), and cytopenia (n=59, 8%). Multivariate analyses showed that TKI treatment duration <4 years was the factor associated with fatigue; Edema was more observed in female, ≥40 years old and use of 1st generation TKI; Gastrointestinal disorders in use of 1st generation TKI; Hepatic function abnormalities and rash in use of 2nd generation TKI; Weight gain in female; Muscle cramps in long-term interval from diagnosis to therapy and use of 1st generation TKI; Low blood counts in use of generic TKI. There was no impact of TKI-related side effects on daily life in 218 (30%)respondents (1 score). 375 (51%)respondents reported their daily life were slightly or moderately decreased (2 or 3 score), while 138 (19%) significantly

  18. NLRP3 tyrosine phosphorylation is controlled by protein tyrosine phosphatase PTPN22

    PubMed Central

    Spalinger, Marianne R.; Kasper, Stephanie; Gottier, Claudia; Lang, Silvia; Atrott, Kirstin; Vavricka, Stephan R.; Scharl, Sylvie; Gutte, Petrus M.; Grütter, Markus G.; Beer, Hans-Dietmar; Contassot, Emmanuel; Chan, Andrew C.; Dai, Xuezhi; Rawlings, David J.; Mair, Florian; Becher, Burkhard; Falk, Werner; Fried, Michael; Rogler, Gerhard

    2016-01-01

    Inflammasomes form as the result of the intracellular presence of danger-associated molecular patterns and mediate the release of active IL-1β, which influences a variety of inflammatory responses. Excessive inflammasome activation results in severe inflammatory conditions, but physiological IL-1β secretion is necessary for intestinal homeostasis. Here, we have described a mechanism of NLRP3 inflammasome regulation by tyrosine phosphorylation of NLRP3 at Tyr861. We demonstrated that protein tyrosine phosphatase non-receptor 22 (PTPN22), variants in which are associated with chronic inflammatory disorders, dephosphorylates NLRP3 upon inflammasome induction, allowing efficient NLRP3 activation and subsequent IL-1β release. In murine models, PTPN22 deficiency resulted in pronounced colitis, increased NLRP3 phosphorylation, but reduced levels of mature IL-1β. Conversely, patients with inflammatory bowel disease (IBD) that carried an autoimmunity-associated PTPN22 variant had increased IL-1β levels. Together, our results identify tyrosine phosphorylation as an important regulatory mechanism for NLRP3 that prevents aberrant inflammasome activation. PMID:27043286

  19. How tyrosine kinase inhibitors impair metabolism and endocrine system function: a systematic updated review.

    PubMed

    Breccia, Massimo; Molica, Matteo; Alimena, Giuliana

    2014-12-01

    Tyrosine kinase inhibitors (TKIs) advent has deeply changed the outcome of chronic myeloid leukemia (CML) patients, with improved rates of response and overall survival. However, for this success some patients paid the price of a number of peculiar side effects, the so-called off-target side effects, specific for each one TKI. These effects are due to non-selective inhibition of other tyrosine kinase receptors, such as PDGFR, c-KIT, Src, VEGF. Consequences of this inhibition, some metabolic changes during the treatment with TKIs are reported. Aim of present review is to report metabolic changes and potential mechanisms involved in the pathogenesis related to imatinib, second (nilotinib and dasatinib) and third generation (bosutinib and ponatinib) TKIs.

  20. Activation of Helicobacter pylori CagA by tyrosine phosphorylation is essential for dephosphorylation of host cell proteins in gastric epithelial cells.

    PubMed

    Püls, Jurgen; Fischer, Wolfgang; Haas, Rainer

    2002-02-01

    Helicobacter pylori type I strains harbour the cag pathogenicity island (cag-PAI), a 37 kb sequence,which encodes the components of a type IV secretion system. CagA, the first identified effector protein of the cag-PAI, is translocated into eukaryotic cells and tyrosine phosphorylated (CagAP-tyr) by a host cell tyrosine kinase. Translocation of CagA induces the dephosphorylation of a set of phosphorylated host cell proteins of unknown identity. CagA proteins of independent H. pylori strains vary in sequence and thus in the number and composition of putative tyrosine phosphorylation motifs (TPMs). The CagA protein of H. pylori strain J99 (CagAJ99) does not carry any of three putative tyrosine phosphorylation motifs (TPM-A, TPM-B or TPM-C) predicted by the MOTIF algorithm in CagA proteins. CagA,n is not tyrosine phosphorylated and is inactive in the dephosphorylation of host cell proteins. By site-specific mutagenesis,we introduced a TPM-C into CagA,. by replacing a single lysine with a tyrosine. This slight modification resulted in tyrosine phosphorylation of CagAJ99 and host cell protein dephosphorylation. In contrast, the removal of the indigenous TPM-C from CagAP12 did not abolish its tyrosine phosphorylation, suggesting that further phosphorylated sites are present in CagAP12. By generation of hybrid CagA proteins, a phosphorylation of the most N-terminal TPM-A could be excluded. Our data suggest that tyrosine phosphorylation at TPM-C is sufficient, but not exclusive,to activate translocated CagA. Activated CagAPtr might either convert into a phosphatase itself or activate a cellular phosphatase to dephosphorylate cellular phosphoproteins and modulate cellular signalling cascades of the host.

  1. Facile and Stabile Linkages through Tyrosine: Bioconjugation Strategies with the Tyrosine-Click Reaction

    PubMed Central

    Ban, Hitoshi; Nagano, Masanobu; Gavrilyuk, Julia; Hakamata, Wataru; Inokuma, Tsubasa; Barbas, Carlos F.

    2013-01-01

    The scope, chemoselectivity, and utility of the click-like tyrosine labeling reaction with 4-phenyl-3H-1,2,4-triazoline-3,5(4H)-diones (PTADs) is reported. To study the utility and chemoselectivity of PTAD derivatives in peptide and protein chemistry, we synthesized PTAD derivatives possessing azide, alkyne, and ketone groups and studied their reactions with amino acid derivatives and peptides of increasing complexity. With proteins we studied the compatibility of the tyrosine click reaction with cysteine and lysine-targeted labeling approaches and demonstrate that chemoselective tri-functionalization of proteins is readily achieved. In particular cases, we noted PTAD decomposition resulted in formation of a putative isocyanate by-product that was promiscuous in labeling. This side reaction product, however, was readily scavenged by the addition of a small amount of 2-amino-2-hydroxymethyl-propane-1,3-diol (Tris) to the reaction medium. To study the potential of the tyrosine click reaction to introduce poly(ethylene) glycol chains onto proteins (PEGylation), we demonstrate that this novel reagent provides for the selective PEGylation of chymotrypsinogen whereas traditional succinimide-based PEGylation targeting lysine residues provided a more diverse range of PEGylated products. Finally, we applied the tyrosine click reaction to create a novel antibody drug conjugate. For this purpose, we synthesized a PTAD derivative linked to the HIV entry inhibitor aplaviroc. Labeling of the antibody trastuzumab with this reagent provided a labeled antibody conjugate that demonstrated potent HIV-1 neutralization activity demonstrating the potential of this reaction in creating protein conjugates with small molecules. The tyrosine click linkage demonstrated stability to extremes of pH, temperature and exposure to human blood plasma indicating that this linkage is significantly more robust than maleimide-type linkages that are commonly employed in bioconjugations. These studies

  2. Facile and stabile linkages through tyrosine: bioconjugation strategies with the tyrosine-click reaction.

    PubMed

    Ban, Hitoshi; Nagano, Masanobu; Gavrilyuk, Julia; Hakamata, Wataru; Inokuma, Tsubasa; Barbas, Carlos F

    2013-04-17

    The scope, chemoselectivity, and utility of the click-like tyrosine labeling reaction with 4-phenyl-3H-1,2,4-triazoline-3,5(4H)-diones (PTADs) is reported. To study the utility and chemoselectivity of PTAD derivatives in peptide and protein chemistry, we synthesized PTAD derivatives possessing azide, alkyne, and ketone groups and studied their reactions with amino acid derivatives and peptides of increasing complexity. With proteins we studied the compatibility of the tyrosine click reaction with cysteine and lysine-targeted labeling approaches and demonstrate that chemoselective trifunctionalization of proteins is readily achieved. In particular cases, we noted that PTAD decomposition resulted in formation of a putative isocyanate byproduct that was promiscuous in labeling. This side reaction product, however, was readily scavenged by the addition of a small amount of 2-amino-2-hydroxymethyl-propane-1,3-diol (Tris) to the reaction medium. To study the potential of the tyrosine click reaction to introduce poly(ethylene glycol) chains onto proteins (PEGylation), we demonstrate that this novel reagent provides for the selective PEGylation of chymotrypsinogen, whereas traditional succinimide-based PEGylation targeting lysine residues provided a more diverse range of PEGylated products. Finally, we applied the tyrosine click reaction to create a novel antibody-drug conjugate. For this purpose, we synthesized a PTAD derivative linked to the HIV entry inhibitor aplaviroc. Labeling of the antibody trastuzumab with this reagent provided a labeled antibody conjugate that demonstrated potent HIV-1 neutralization activity demonstrating the potential of this reaction in creating protein conjugates with small molecules. The tyrosine click linkage demonstrated stability to extremes of pH, temperature, and exposure to human blood plasma indicating that this linkage is significantly more robust than maleimide-type linkages that are commonly employed in bioconjugations. These

  3. Dopamine release in rat striatum - Physiological coupling to tyrosine supply

    NASA Technical Reports Server (NTRS)

    During, Matthew J.; Acworth, Ian N.; Wurtman, Richard J.

    1989-01-01

    Intracerebral microdialysis was used to monitor dopamine release in rat striatal extracellular fluid following the intraperitoneal administration of dopamine's precursor amino acid, L-tyrosine. Dopamine concentrations in dialysates increased transiently after tyrosine (50-100 mg/kg) administration. Pretreatment with haloperidol or the partial lesioning of nigrostriatal neurons enhanced the effect of tyrosine on dopamine release, and haloperidol also prolonged this effect. These data suggest that nigrostriatal dopaminergic neurons are responsive to changes in precursor availability under basal conditions, but that receptor-mediated feedback mechanisms limit the magnitude and duration of this effect.

  4. The truncated Newton using 1st and 2nd order adjoint-state method: a new approach for traveltime tomography without rays

    NASA Astrophysics Data System (ADS)

    Bretaudeau, F.; Metivier, L.; Brossier, R.; Virieux, J.

    2013-12-01

    named as the truncated Newton (TCN) (Métivier et al. 2012) with a more accurate estimation of the impact of the Hessian. We propose an efficient implementation for first-arrival traveltime tomography. In TCN, the model update Δm is obtained through the iterative resolution of the Newton linear system H Δm = - g. Based on a matrix-free conjugate gradient resolution, the iterative solver requires only the computation of the gradient and of Hessian-vector products. We propose a generalization of the computation of the gradient using the adjoint-state method that allows to consider receivers located anywhere. Then the Hessian-vector products are computed using an original formulation based on a 2nd-order adjoint-state method, at the cost of an additional forward modeling. The TCN algorithm is composed of two nested loops: an internal loop to compute Δm, and an external loop where a line search is performed to update the subsurface parameters. TCN thus considers locally the inversion of the traveltime data using an estimation of the full Hessian (both 1st and 2nd order terms) at an acceptable cost. Tomography with TCN is an improvement over the simple gradient-based adjoint-state tomography due to its good convergence property, to the better consideration of illumination, and is a promising tool for multi-parameter inversion as rescaling is given by the Hessian.

  5. The 1st and the 2nd Italian Consensus Conferences on low-density lipoprotein-apheresis. A practical synopsis and update

    PubMed Central

    Stefanutti, Claudia

    2017-01-01

    The clinical indications and guidelines for low-density lipoprotein (LDL)-apheresis set by the 1st Italian Consensus Conference held in Ostuni in 1990 and completed in 1992, but never published, are reported schematically. In 1994, within the Project “Prevention and control of the factors of the disease (FATMA)” by the Italian National Research Council, subproject 8 “Control of cardiovascular disease”, a “Hearing on therapeutic apheresis: need for a target-oriented project” was organised. The meeting was the last scientific initiative on LDL-apheresis supported by public funds in Italy. After roughly two decades of use of LDL-apheresis, new guidelines were required based on the latest scientific evidence. In 2006, the Italian multicentre study on LDL-apheresis Working Group (IMSLDLa-WP), a scientific initiative at national level, was developed. It initially gathered together 19 Italian centres qualified for the application of lipid apheresis and LDL-apheresis (2007–2008), then 23 in 2010, located in the north, south, centre of Italy and in Sicily and Sardinia. The multicentre study aimed to validate the protocol for selecting patients and to create a network between the Italian centres. A secondary objective was the creation of a database of patients with familial hypercholesterolaemia and other severe forms of dyslipidaemia undergoing treatment with LDL-apheresis using the available techniques. Since LDL-apheresis has multidisciplinary treatment indications, the agreement on the new guidelines was reached through a panel of experts, of different medical and surgical specialties, with scientific and medical interest in the treatment indications, application and development of LDL-apheresis. The initiatives of the IMSLDLa-WP led to the 2nd Italian Consensus Conference on LDL-apheresis held in Rome in 2009. The previous and most recent guidelines are reported here synoptically. PMID:27416576

  6. 2nd International Symposium on Fundamental Aspects of Rare-earth Elements Mining and Separation and Modern Materials Engineering (REES-2015)

    NASA Astrophysics Data System (ADS)

    Tavadyan, Levon, Prof; Sachkov, Viktor, Prof; Godymchuk, Anna, Dr.; Bogdan, Anna

    2016-01-01

    The 2nd International Symposium «Fundamental Aspects of Rare-earth Elements Mining and Separation and Modern Materials Engineering» (REES2015) was jointly organized by Tomsk State University (Russia), National Academy of Science (Armenia), Shenyang Polytechnic University (China), Moscow Institute of Physics and Engineering (Russia), Siberian Physical-technical Institute (Russia), and Tomsk Polytechnic University (Russia) in September, 7-15, 2015, Belokuriha, Russia. The Symposium provided a high quality of presentations and gathered engineers, scientists, academicians, and young researchers working in the field of rare and rare earth elements mining, modification, separation, elaboration and application, in order to facilitate aggregation and sharing interests and results for a better collaboration and activity visibility. The goal of the REES2015 was to bring researchers and practitioners together to share the latest knowledge on rare and rare earth elements technologies. The Symposium was aimed at presenting new trends in rare and rare earth elements mining, research and separation and recent achievements in advanced materials elaboration and developments for different purposes, as well as strengthening the already existing contacts between manufactures, highly-qualified specialists and young scientists. The topics of the REES2015 were: (1) Problems of extraction and separation of rare and rare earth elements; (2) Methods and approaches to the separation and isolation of rare and rare earth elements with ultra-high purity; (3) Industrial technologies of production and separation of rare and rare earth elements; (4) Economic aspects in technology of rare and rare earth elements; and (5) Rare and rare earth based materials (application in metallurgy, catalysis, medicine, optoelectronics, etc.). We want to thank the Organizing Committee, the Universities and Sponsors supporting the Symposium, and everyone who contributed to the organization of the event and to

  7. PREFACE: 2nd International School and Conference Saint-Petersburg OPEN on Optoelectronics, Photonics, Engineering and Nanostructures (SPbOPEN2015)

    NASA Astrophysics Data System (ADS)

    2015-11-01

    The 2nd International School and Conference ''Saint Petersburg OPEN 2015'' on Optoelectronics, Photonics, Engineering and Nanostructures was held on April 6 - 8, 2015 at St. Petersburg Academic University. The School and Conference included a series of invited talks given by leading professors with the aim to introduce young scientists with actual problems and major advances in physics and technology. The keynote speakers were Mikhail V. Maximov (Ioffe Physico-Technical Institute RAS, Russia) Vladimir G. Dubrovskii (St. Petersburg Academic University and St. Petersburg State University, Russia) Anton Yu. Egorov (JSC Connector Optics, Russia) Victor V. Luchinin (St. Petersburg State Electrotechnical University, Russia) Vladislav E. Bugrov (St. Petersburg University of Internet Technologies, Mechanics and Optics, Russia) Vitali A. Schukin (VI Systems, Germany) Yuri P. Svirko (University of Eastern Finland, Finland) During the poster session all undergraduate and graduate students attending the conference presented their works. A sufficiently large number of participants, with more than 170 student attendees from all over the world, allowed the Conference to provide a fertile ground for fruitful discussions between the young scientists as well as to become a perfect platform for valuable discussions between student authors and highly experienced scientists. The best student papers, which were selected by the Program Committee and by the invited speakers basing on the theses and their poster presentation, were awarded with diplomas of the conference - see the photos. This year ''Saint Petersburg OPEN 2015'' is organized by St. Petersburg Academic University in cooperation with Peter the Great St. Petersburg Polytechnic University. The School and Conference is supported by Russian Science Foundation, SPIE (The International Society for Optics and Photonics), OSA (The Optical Society) and by Skolkovo Foundation. It is a continuation of the annual schools and seminars for

  8. Early and comprehensive management of atrial fibrillation: executive summary of the proceedings from the 2nd AFNET-EHRA consensus conference 'research perspectives in AF'.

    PubMed

    Kirchhof, Paulus; Bax, Jeroen; Blomstrom-Lundquist, Carina; Calkins, Hugh; Camm, A John; Cappato, Ricardo; Cosio, Francisco; Crijns, Harry; Diener, Hans-Christian; Goette, Andreas; Israel, Carsten W; Kuck, Karl-Heinz; Lip, Gregory Y H; Nattel, Stanley; Page, Richard L; Ravens, Ursula; Schotten, Ulrich; Steinbeck, Gerhard; Vardas, Panos; Waldo, Albert; Wegscheider, Karl; Willems, Stephan; Breithardt, Günter

    2009-12-01

    Atrial fibrillation (AF) causes important mortality and morbidity on a population-level. So far, we do not have the means to prevent AF or AF-related complications adequately. Therefore, over 70 experts on atrial fibrillation convened for the 2nd AFNET/EHRA consensus conference to suggest directions for research to improve management of AF patients (Appendix 1). The group defined three main areas in need for research in AF: 1. better understanding of the mechanisms of AF; 2. Improving rhythm control monitoring and management; and 3. comprehensive cardiovascular risk management in AF patients. The group put forward the hypothesis that successful therapy of AF and its associated complications will require comprehensive therapy. This applies e.g. to the "old" debate of "rate versus rhythm control", since rhythm control is generally added to underlying (continued) rate control therapy, but also to the emerging debate of "antiarrhythmic drugs versus catheter ablation", of which both may be needed in most patients to maintain sinus rhythm, but also to therapy of conditions that predispose to AF and contribute to cardiovascular complications such as stroke, cognitive decline, heart failure, and acute coronary syndromes. We call for research initiatives aiming at a better understanding of the different causes of AF and its complications, and at development and validation of mechanism-based therapies. The future of AF therapy may require a combination of management of underlying and concomitant conditions, early and comprehensive rhythm control therapy, adequate control of ventricular rate and cardiac function, and continuous therapy to prevent AF-associated complications (e.g. antithrombotic therapy). The reasons for these suggestions are detailed in this paper.

  9. Receptor Tyrosine Kinase Signaling – A Proteomic Perspective

    PubMed Central

    Biarc, Jordane; Chalkley, Robert J.; Burlingame, A. L.; Bradshaw, Ralph A.

    2011-01-01

    The stimulation of various cellular processes through extracellular signals is of paramount importance in biological systems and is a central focus in the diagnosis, treatment and prevention of disease. The information transfer is accomplished in a variety of ways by the interaction of soluble, matrix-associated and cell bound ligands that either bind specifically to plasma membrane-associated proteins that act as receptors, or penetrate to the cytoplasmic/nuclear compartments to bind and activate receptors located there. The former class of entities generates intracellular signals that are transmitted and amplified by chemical modifications that are manifested as protein post-translational modifications (PTMs). These are both reversible and irreversible and range from phosphorylation of tyrosine, threonine and serine residues to endoproteolytic cleavages. Although the PTMs alter the activity and functions of many of the proteins in these cascades, the major outcomes of most of the signaling pathways are the activation/deactivation of transcriptional regulators with the concomitant changes in gene expression that generally underlie biological responses. PMID:21056590

  10. Proteolytic cleavage, trafficking, and functions of nuclear receptor tyrosine kinases.

    PubMed

    Chen, Mei-Kuang; Hung, Mien-Chie

    2015-10-01

    Intracellular localization has been reported for over three-quarters of receptor tyrosine kinase (RTK) families in response to environmental stimuli. Internalized RTK may bind to non-canonical substrates and affect various cellular processes. Many of the intracellular RTKs exist as fragmented forms that are generated by γ-secretase cleavage of the full-length receptor, shedding, alternative splicing, or alternative translation initiation. Soluble RTK fragments are stabilized and intracellularly transported into subcellular compartments, such as the nucleus, by binding to chaperone or transcription factors, while membrane-bound RTKs (full-length or truncated) are transported from the plasma membrane to the ER through the well-established Rab- or clathrin adaptor protein-coated vesicle retrograde trafficking pathways. Subsequent nuclear transport of membrane-bound RTK may occur via two pathways, INFS or INTERNET, with the former characterized by release of receptors from the ER into the cytosol and the latter characterized by release of membrane-bound receptor from the ER into the nucleoplasm through the inner nuclear membrane. Although most non-canonical intracellular RTK signaling is related to transcriptional regulation, there may be other functions that have yet to be discovered. In this review, we summarize the proteolytic processing, intracellular trafficking and nuclear functions of RTKs, and discuss how they promote cancer progression, and their clinical implications.

  11. Therapeutic drug monitoring and tyrosine kinase inhibitors

    PubMed Central

    Herviou, Pauline; Thivat, Emilie; Richard, Damien; Roche, Lucie; Dohou, Joyce; Pouget, Mélanie; Eschalier, Alain; Durando, Xavier; Authier, Nicolas

    2016-01-01

    The therapeutic activity of drugs can be optimized by establishing an individualized dosage, based on the measurement of the drug concentration in the serum, particularly if the drugs are characterized by an inter-individual variation in pharmacokinetics that results in an under- or overexposure to treatment. In recent years, several tyrosine kinase inhibitors (TKIs) have been developed to block intracellular signaling pathways in tumor cells. These oral drugs are candidates for therapeutic drug monitoring (TDM) due to their high inter-individual variability for therapeutic and toxic effects. Following a literature search on PubMed, studies on TKIs and their pharmacokinetic characteristics, plasma quantification and inter-individual variability was studied. TDM is commonly used in various medical fields, including cardiology and psychiatry, but is not often applied in oncology. Plasma concentration monitoring has been thoroughly studied for imatinib, in order to evaluate the usefulness of TDM. The measurement of plasma concentration can be performed by various analytical techniques, with liquid chromatography-mass spectrometry being the reference method. This method is currently used to monitor the efficacy and tolerability of imatinib treatments. Although TDM is already being used for imatinib, additional studies are required in order to improve this practice with the inclusion of other TKIs. PMID:27446421

  12. Protein tyrosine phosphatases: structure-function relationships.

    PubMed

    Tabernero, Lydia; Aricescu, A Radu; Jones, E Yvonne; Szedlacsek, Stefan E

    2008-03-01

    Structural analysis of protein tyrosine phosphatases (PTPs) has expanded considerably in the last several years, producing more than 200 structures in this class of enzymes (from 35 different proteins and their complexes with ligands). The small-medium size of the catalytic domain of approximately 280 residues plus a very compact fold makes it amenable to cloning and overexpression in bacterial systems thus facilitating crystallographic analysis. The low molecular weight PTPs being even smaller, approximately 150 residues, are also perfect targets for NMR analysis. The availability of different structures and complexes of PTPs with substrates and inhibitors has provided a wealth of information with profound effects in the way we understand their biological functions. Developments in mammalian expression technology recently led to the first crystal structure of a receptor-like PTP extracellular region. Altogether, the PTP structural work significantly advanced our knowledge regarding the architecture, regulation and substrate specificity of these enzymes. In this review, we compile the most prominent structural traits that characterize PTPs and their complexes with ligands. We discuss how the data can be used to design further functional experiments and as a basis for drug design given that many PTPs are now considered strategic therapeutic targets for human diseases such as diabetes and cancer.

  13. Tetrahydrobiopterin shows chaperone activity for tyrosine hydroxylase.

    PubMed

    Thöny, Beat; Calvo, Ana C; Scherer, Tanja; Svebak, Randi M; Haavik, Jan; Blau, Nenad; Martinez, Aurora

    2008-07-01

    Tyrosine hydroxylase (TH) is the rate-limiting enzyme in the synthesis of catecholamine neurotransmitters. Primary inherited defects in TH have been associated with l-DOPA responsive and non-responsive dystonia and infantile parkinsonism. In this study, we show that both the cofactor (6R)-l-erythro-5,6,7,8-tetrahydrobiopterin (BH(4)) and the feedback inhibitor and catecholamine product dopamine increase the kinetic stability of human TH isoform 1 in vitro. Activity measurements and synthesis of the enzyme by in vitro transcription-translation revealed a complex regulation by the cofactor including both enzyme inactivation and conformational stabilization. Oral BH(4) supplementation to mice increased TH activity and protein levels in brain extracts, while the Th-mRNA level was not affected. All together our results indicate that the molecular mechanisms for the stabilization are a primary folding-aid effect of BH(4) and a secondary effect by increased synthesis and binding of catecholamine ligands. Our results also establish that orally administered BH(4) crosses the blood-brain barrier and therapeutic regimes based on BH(4) supplementation should thus consider the effect on TH. Furthermore, BH(4) supplementation arises as a putative therapeutic agent in the treatment of brain disorders associated with TH misfolding, such as for the human TH isoform 1 mutation L205P.

  14. Weak oligomerization of low-molecular-weight protein tyrosine phosphatase is conserved from mammals to bacteria.

    PubMed

    Blobel, Jascha; Bernadó, Pau; Xu, Huimin; Jin, Changwen; Pons, Miquel

    2009-08-01

    The well-characterized self-association of a mammalian low-molecular-weight protein tyrosine phosphatase (lmwPTP) produces inactive oligomers that are in equilibrium with active monomers. A role of the inactive oligomers as supramolecular proenzymes has been suggested. The oligomerization equilibrium of YwlE, a lmwPTP from Bacillus subtilis, was studied by NMR. Chemical shift data and NMR relaxation confirm that dimerization takes place through the enzyme's active site, and is fully equivalent to the dimerization previously characterized in a eukaryotic low-molecular-weight phosphatase, with similarly large dissociation constants. The similarity between the oligomerization of prokaryotic and eukaryotic phosphatases extends beyond the dimer and involves higher order oligomers detected by NMR relaxation analysis at high protein concentrations. The conservation across different kingdoms of life suggests a physiological role for lmwPTP oligomerization in spite of the weak association observed in vitro. Structural data suggest that substrate modulation of the oligomerization equilibrium could be a regulatory mechanism leading to the generation of signaling pulses. The presence of a phenylalanine residue in the dimerization site of YwlE, replacing a tyrosine residue conserved in all eukaryotic lmwPTPs, demonstrates that lmwPTP regulation by oligomerization can be independent from tyrosine phosphorylation.

  15. No Obvious Abnormality in Mice Deficient in Receptor Protein Tyrosine Phosphatase β

    PubMed Central

    Harroch, S.; Palmeri, M.; Rosenbluth, J.; Custer, A.; Okigaki, M.; Shrager, P.; Blum, M.; Buxbaum, J. D.; Schlessinger, J.

    2000-01-01

    The development of neurons and glia is governed by a multitude of extracellular signals that control protein tyrosine phosphorylation, a process regulated by the action of protein tyrosine kinases and protein tyrosine phosphatases (PTPs). Receptor PTPβ (RPTPβ; also known as PTPζ) is expressed predominantly in the nervous system and exhibits structural features common to cell adhesion proteins, suggesting that this phosphatase participates in cell-cell communication. It has been proposed that the three isoforms of RPTPβ play a role in regulation of neuronal migration, neurite outgrowth, and gliogenesis. To investigate the biological functions of this PTP, we have generated mice deficient in RPTPβ. RPTPβ-deficient mice are viable, are fertile, and showed no gross anatomical alterations in the nervous system or other organs. In contrast to results of in vitro experiments, our study demonstrates that RPTPβ is not essential for neurite outgrowth and node formation in mice. The ultrastructure of nerves of the central nervous system in RPTPβ-deficient mice suggests a fragility of myelin. However, conduction velocity was not altered in RPTPβ-deficient mice. The normal development of neurons and glia in RPTPβ-deficient mice demonstrates that RPTPβ function is not necessary for these processes in vivo or that loss of RPTPβ can be compensated for by other PTPs expressed in the nervous system. PMID:11003666

  16. MAP kinase activator from insulin-stimulated skeletal muscle is a protein threonine/tyrosine kinase.

    PubMed Central

    Nakielny, S; Cohen, P; Wu, J; Sturgill, T

    1992-01-01

    A 'MAP kinase activator' was purified several thousand-fold from insulin-stimulated rabbit skeletal muscle, which resembled the 'activator' from nerve growth factor-stimulated PC12 cells in that it could be inactivated by incubation with protein phosphatase 2A, but not by protein tyrosine phosphatases and its apparent molecular mass was 45-50 kDa. In the presence of MgATP, 'MAP kinase activator' converted the normal 'wild-type' 42 kDa MAP kinase from an inactive dephosphorylated form to the fully active diphosphorylated species. Phosphorylation occurred on the same threonine and tyrosine residues which are phosphorylated in vivo in response to growth factors or phorbol esters. A mutant MAP kinase produced by changing a lysine at the active centre to arginine was phosphorylated in an identical manner by the 'MAP kinase activator', but no activity was generated. The results demonstrate that 'MAP kinase activator' is a protein kinase (MAP kinase kinase) and not a protein that stimulates the autophosphorylation of MAP kinase. MAP kinase kinase is the first established example of a protein kinase that can phosphorylate an exogenous protein on threonine as well as tyrosine residues. Images PMID:1318193

  17. Detection of tyrosine phosphorylated peptides via skimmer collision-induced dissociation/ion trap mass spectrometry.

    PubMed

    Zolodz, Melissa D; Wood, Karl V

    2003-03-01

    Phosphorylation of proteins is an important post-translational protein modification in cellular response to environmental change and occurs in both prokaryotes and eukaryotes. Identification of the amino acid on individual proteins that become phosphorylated in response to extracellular stimulus is essential for understanding the mechanisms involved in the intracellular signals that these modifications facilitate. Most protein kinases catalyze the phosphorylation of proteins on serine, threonine or tyrosine. Although tyrosine phosphorylation is often the least abundant of the three major phosphorylation sites, it is important owing to its role in signal pathways. Currently available methods for the identification of phosphorylation sites can often miss low levels of tyrosine phosphorylations. This paper describes a method for the identification of phosphotyrosine-containing peptides using electrospray ionization on an ion trap mass spectrometer. Skimmer-activated collision-induced dissociation (CID) was used to generate the phosphotyrosine immonium ion at m/z 216. This method is gentle enough that the protonated molecule of the intact peptide is still observed. In-trap CID was employed for the verification of the phosphotyrosine immonium ion. Using this technique, low levels of phosphotyrosine-containing peptides can be identified from peptide mixtures separated by nanoflow micro liquid chromatography/mass spectrometry.

  18. Enantiomeric interactions between liquid crystals and organized monolayers of tyrosine-containing dipeptides.

    PubMed

    Bai, Yiqun; Abbott, Nicholas L

    2012-01-11

    We have examined the orientational ordering of nematic liquid crystals (LCs) supported on organized monolayers of dipeptides with the goal of understanding how peptide-based interfaces encode intermolecular interactions that are amplified into supramolecular ordering. By characterizing the orientations of nematic LCs (4-cyano-4'-pentylbiphenyl and TL205 (a mixture of mesogens containing cyclohexane-fluorinated biphenyls and fluorinated terphenyls)) on monolayers of l-cysteine-l-tyrosine, l-cysteine-l-phenylalanine, or l-cysteine-l-phosphotyrosine formed on crystallographically textured films of gold, we conclude that patterns of hydrogen bonds generated by the organized monolayers of dipeptides are transduced via macroscopic orientational ordering of the LCs. This conclusion is supported by the observation that the ordering exhibited by the achiral LCs is specific to the enantiomers used to form the dipeptide-based monolayers. The dominant role of the -OH group of tyrosine in dictating the patterns of hydrogen bonds that orient the LCs was also evidenced by the effects of phosphorylation of the tyrosine on the ordering of the LCs. Overall, these results reveal that crystallographic texturing of gold films can direct the formation of monolayers of dipeptides with long-range order, thus unmasking the influence of hydrogen bonding, chirality, and phosphorylation on the macroscopic orientational ordering of LCs supported on these surfaces. These results suggest new approaches based on supramolecular assembly for reporting the chemical functionality and stereochemistry of synthetic and biological peptide-based molecules displayed at surfaces.

  19. Protein-tyrosine phosphatase activity regulates osteoclast formation and function: inhibition by alendronate.

    PubMed Central

    Schmidt, A; Rutledge, S J; Endo, N; Opas, E E; Tanaka, H; Wesolowski, G; Leu, C T; Huang, Z; Ramachandaran, C; Rodan, S B; Rodan, G A

    1996-01-01

    Alendronate (ALN), an aminobisphosphonate used in the treatment of osteoporosis, is a potent inhibitor of bone resorption. Its molecular target is still unknown. This study examines the effects of ALN on the activity of osteoclast protein-tyrosine phosphatase (PTP; protein-tyrosine-phosphate phosphohydrolase, EC 3.1.3.48), called PTPepsilon. Using osteoclast-like cells generated by coculturing mouse bone marrow cells with mouse calvaria osteoblasts, we found by molecular cloning and RNA blot hybridization that PTPepsilon is highly expressed in osteoclastic cells. A purified fusion protein of PTPepsilon expressed in bacteria was inhibited by ALN with an IC50 of 2 microM. Other PTP inhibitors--orthovanadate and phenylarsine oxide (PAO)-inhibited PTPepsilon with IC50 values of 0.3 microM and 18 microM, respectively. ALN and another bisphosphonate, etidronate, also inhibited the activities of other bacterially expressed PTPs such as PTPsigma and CD45 (also called leukocyte common antigen). The PTP inhibitors ALN, orthovanadate, and PAO suppressed in vitro formation of multinucleated osteoclasts from osteoclast precursors and in vitro bone resorption by isolated rat osteoclasts (pit formation) with estimated IC50 values of 10 microM, 3 microM, and 0.05 microM, respectively. These findings suggest that tyrosine phosphatase activity plays an important role in osteoclast formation and function and is a putative molecular target of bisphosphonate action. Images Fig. 2 Fig. 3 PMID:8610169

  20. SH2 domain proteins as high-affinity receptor tyrosine kinase substrates.

    PubMed

    Sierke, S L; Koland, J G

    1993-09-28

    Activation of a growth factor receptor tyrosine kinase (RTK) is accompanied by a rapid autophosphorylation of the receptor on tyrosine residues. Receptor activation has been shown to promote the association of signal-transducing proteins containing SH2 domains (second domain of src homology). These receptor-associated proteins can, in turn, be phosphorylated by the RTK, an event which presumably regulates their activities. It has been suggested that SH2 domains in signal-transducing proteins target these proteins as substrates of the activated RTK. To test this hypothesis, recombinant proteins were generated that contained tyrosine phosphorylation sites of the erbB3 receptor and/or the SH2 domain of c-src. Incorporation of the SH2 domain led to a decrease in KM and an increase in Vmax for the substrate. The KM determined for one chimeric SH2/erbB3 substrate was among the lowest reported for epidermal growth factor RTK substrates. Experiments with a truncated kinase lacking C-terminal autophosphorylation sites indicated that the reduction in KM for these substrates was mediated by interactions between the substrate SH2 domain and phosphotyrosine residues of the RTK. These interactions could also inhibit RTK activity. These results demonstrate that the SH2 domain can effectively target substrates to a RTK and that SH2 domain proteins can regulate RTK activity.

  1. Comparative study of protein tyrosine phosphatase-epsilon isoforms: membrane localization confers specificity in cellular signalling.

    PubMed Central

    Andersen, J N; Elson, A; Lammers, R; Rømer, J; Clausen, J T; Møller, K B; Møller, N P

    2001-01-01

    To study the influence of subcellular localization as a determinant of signal transduction specificity, we assessed the effects of wild-type transmembrane and cytoplasmic protein tyrosine phosphatase (PTP) epsilon on tyrosine kinase signalling in baby hamster kidney (BHK) cells overexpressing the insulin receptor (BHK-IR). The efficiency by which differently localized PTPepsilon and PTPalpha variants attenuated insulin-induced cell rounding and detachment was determined in a functional clonal-selection assay and in stable cell lines. Compared with the corresponding receptor-type PTPs, the cytoplasmic PTPs (cytPTPs) were considerably less efficient in generating insulin-resistant clones, and exceptionally high compensatory expression levels were required to counteract phosphotyrosine-based signal transduction. Targeting of cytPTPepsilon to the plasma membrane via the Lck-tyrosine kinase dual acylation motif restored high rescue efficiency and abolished the need for high cytPTPepsilon levels. Consistent with these results, expression levels and subcellular localization of PTPepsilon were also found to determine the phosphorylation level of cellular proteins including focal adhesion kinase (FAK). Furthermore, PTPepsilon stabilized binding of phosphorylated FAK to Src, suggesting this complex as a possible mediator of the PTPepsilon inhibitory response to insulin-induced cell rounding and detachment in BHK-IR cells. Taken together, the present localization-function study indicates that transcriptional control of the subcellular localization of PTPepsilon may provide a molecular mechanism that determines PTPepsilon substrate selectivity and isoform-specific function. PMID:11237862

  2. Direct Identification of Tyrosine Sulfation by using Ultraviolet Photodissociation Mass Spectrometry

    NASA Astrophysics Data System (ADS)

    Robinson, Michelle R.; Moore, Kevin L.; Brodbelt, Jennifer S.

    2014-08-01

    Sulfation is a common post-translational modification of tyrosine residues in eukaryotes; however, detection using traditional liquid chromatography-mass spectrometry (LC-MS) methods is challenging based on poor ionization efficiency in the positive ion mode and facile neutral loss upon collisional activation. In the present study, 193 nm ultraviolet photodissociation (UVPD) is applied to sulfopeptide anions to generate diagnostic sequence ions, which do not undergo appreciable neutral loss of sulfate even using higher energy photoirradiation parameters. At the same time, neutral loss of SO3 is observed from the precursor and charge-reduced precursor ions, a spectral feature that is useful for differentiating tyrosine sulfation from the nominally isobaric tyrosine phosphorylation. LC-MS detection limits for UVPD analysis in the negative mode were determined to be around 100 fmol for three sulfated peptides, caerulein, cionin, and leu-enkephalin. The LC-UVPD-MS method was applied for analysis of bovine fibrinogen, and its key sulfated peptide was confidently identified.

  3. Rational, combinatorial, and genomic approaches for engineering L-tyrosine production in Escherichia coli.

    PubMed

    Santos, Christine Nicole S; Xiao, Wenhai; Stephanopoulos, Gregory

    2012-08-21

    Although microbial metabolic engineering has traditionally relied on rational and knowledge-driven techniques, significant improvements in strain performance can be further obtained through the use of combinatorial approaches exploiting phenotypic diversification and screening. Here, we demonstrate the combined use of global transcriptional machinery engineering and a high-throughput L-tyrosine screen towards improving L-tyrosine production in Escherichia coli. This methodology succeeded in generating three strains from two separate mutagenesis libraries (rpoA and rpoD) exhibiting up to a 114% increase in L-tyrosine titer over a rationally engineered parental strain with an already high capacity for production. Subsequent strain characterization through transcriptional analysis and whole genome sequencing allowed complete phenotype reconstruction from well-defined mutations and point to important roles for both the acid stress resistance pathway and the stringent response of E. coli in imparting this phenotype. As such, this study presents one of the first examples in which cell-wide measurements have helped to elucidate the genetic and biochemical underpinnings of an engineered cellular property, leading to the total restoration of metabolite overproduction from specific chromosomal mutations.

  4. Direct Identification of Tyrosine Sulfation by using Ultraviolet Photodissociation Mass Spectrometry

    PubMed Central

    Robinson, Michelle R.; Moore, Kevin L.; Brodbelt, Brodbelt

    2014-01-01

    Sulfation is a common post-translational modification of tyrosine residues in eukaryotes; however, detection using traditional liquid chromatography-mass spectrometry (LC-MS) methods is challenging based on poor ionization efficiency in the positive ion mode and facile neutral loss upon collisional activation. In the present study, 193 nm ultraviolet photodissociation (UVPD) is applied to sulfopeptide anions to generate diagnostic sequence ions which do not undergo appreciable neutral loss of sulfate even using higher energy photoirradiation parameters. At the same time, neutral loss of sulfate is observed from the precursor and charge reduced precursor ions, a spectral feature that is useful for differentiating tyrosine sulfation from the nominally isobaric tyrosine phosphorylation. LC-MS detection limits for UVPD analysis in the negative mode were determined to be around 100 fmol for three sulfated peptides, caerulein, cionin, and leu-enkephalin. The LC-UVPD-MS method was applied for analysis of bovine fibrinogen, and its key sulfated peptide was confidently identified. PMID:24845354

  5. The transcription factor RUNX2 regulates receptor tyrosine kinase expression in melanoma

    PubMed Central

    Boregowda, Rajeev K.; Medina, Daniel J.; Markert, Elke; Bryan, Michael A.; Chen, Wenjin; Chen, Suzie; Rabkin, Anna; Vido, Michael J.; Gunderson, Samuel I.; Chekmareva, Marina; Foran, David J.; Lasfar, Ahmed; Goydos, James S.; Cohen-Solal, Karine A.

    2016-01-01

    Receptor tyrosine kinases-based autocrine loops largely contribute to activate the MAPK and PI3K/AKT pathways in melanoma. However, the molecular mechanisms involved in generating these autocrine loops are still largely unknown. In the present study, we examine the role of the transcription factor RUNX2 in the regulation of receptor tyrosine kinase (RTK) expression in melanoma. We have demonstrated that RUNX2-deficient melanoma cells display a significant decrease in three receptor tyrosine kinases, EGFR, IGF-1R and PDGFRβ. In addition, we found co-expression of RUNX2 and another RTK, AXL, in both melanoma cells and melanoma patient samples. We observed a decrease in phosphoAKT2 (S474) and phosphoAKT (T308) levels when RUNX2 knock down resulted in significant RTK down regulation. Finally, we showed a dramatic up regulation of RUNX2 expression with concomitant up-regulation of EGFR, IGF-1R and AXL in melanoma cells resistant to the BRAF V600E inhibitor PLX4720. Taken together, our results strongly suggest that RUNX2 might be a key player in RTK-based autocrine loops and a mediator of resistance to BRAF V600E inhibitors involving RTK up regulation in melanoma. PMID:27102439

  6. Protein Tyrosine Phosphatase PRL2 Mediates Notch and Kit Signals in Early T Cell Progenitors.

    PubMed

    Kobayashi, Michihiro; Nabinger, Sarah C; Bai, Yunpeng; Yoshimoto, Momoko; Gao, Rui; Chen, Sisi; Yao, Chonghua; Dong, Yuanshu; Zhang, Lujuan; Rodriguez, Sonia; Yashiro-Ohtani, Yumi; Pear, Warren S; Carlesso, Nadia; Yoder, Mervin C; Kapur, Reuben; Kaplan, Mark H; Daniel Lacorazza, Hugo; Zhang, Zhong-Yin; Liu, Yan

    2017-04-01

    The molecular pathways regulating lymphoid priming, fate, and development of multipotent bone marrow hematopoietic stem and progenitor cells (HSPCs) that continuously feed thymic progenitors remain largely unknown. While Notch signal is indispensable for T cell specification and differentiation, the downstream effectors are not well understood. PRL2, a protein tyrosine phosphatase that regulates hematopoietic stem cell proliferation and self-renewal, is highly expressed in murine thymocyte progenitors. Here we demonstrate that protein tyrosine phosphatase PRL2 and receptor tyrosine kinase c-Kit are critical downstream targets and effectors of the canonical Notch/RBPJ pathway in early T cell progenitors. While PRL2 deficiency resulted in moderate defects of thymopoiesis in the steady state, de novo generation of T cells from Prl2 null hematopoietic stem cells was significantly reduced following transplantation. Prl2 null HSPCs also showed impaired T cell differentiation in vitro. We found that Notch/RBPJ signaling upregulated PRL2 as well as c-Kit expression in T cell progenitors. Further, PRL2 sustains Notch-mediated c-Kit expression and enhances stem cell factor/c-Kit signaling in T cell progenitors, promoting effective DN1-DN2 transition. Thus, we have identified a critical role for PRL2 phosphatase in mediating Notch and c-Kit signals in early T cell progenitors. Stem Cells 2017;35:1053-1064.

  7. Evaluation of a tyrosine kinase peptide microarray for tyrosine kinase inhibitor therapy selection in cancer

    PubMed Central

    Labots, Mariette; Gotink, Kristy J; Dekker, Henk; Azijli, Kaamar; van der Mijn, Johannes C; Huijts, Charlotte M; Piersma, Sander R; Jiménez, Connie R; Verheul, Henk M W

    2016-01-01

    Personalized cancer medicine aims to accurately predict the response of individual patients to targeted therapies, including tyrosine kinase inhibitors (TKIs). Clinical implementation of this concept requires a robust selection tool. Here, using both cancer cell lines and tumor tissue from patients, we evaluated a high-throughput tyrosine kinase peptide substrate array to determine its readiness as a selection tool for TKI therapy. We found linearly increasing phosphorylation signal intensities of peptides representing kinase activity along the kinetic curve of the assay with 7.5–10 μg of lysate protein and up to 400 μM adenosine triphosphate (ATP). Basal kinase activity profiles were reproducible with intra- and inter-experiment coefficients of variation of <15% and <20%, respectively. Evaluation of 14 tumor cell lines and tissues showed similar consistently high phosphorylated peptides in their basal profiles. Incubation of four patient-derived tumor lysates with the TKIs dasatinib, sunitinib, sorafenib and erlotinib primarily caused inhibition of substrates that were highly phosphorylated in the basal profile analyses. Using recombinant Src and Axl kinase, relative substrate specificity was demonstrated for a subset of peptides, as their phosphorylation was reverted by co-incubation with a specific inhibitor. In conclusion, we demonstrated robust technical specifications of this high-throughput tyrosine kinase peptide microarray. These features required as little as 5–7 μg of protein per sample, facilitating clinical implementation as a TKI selection tool. However, currently available peptide substrates can benefit from an enhancement of the differential potential for complex samples such as tumor lysates. We propose that mass spectrometry-based phosphoproteomics may provide such an enhancement by identifying more discriminative peptides. PMID:27980342

  8. Treatment of non-small cell lung cancer, advanced disease, with erlotinib in 2(nd) and 3(rd) lines. Two cases report.

    PubMed

    Teixeira, Encarnação; Sotto-Mayor, Renato; Macedo, Rita; Todo-Bom, Filipa; de Almeida, A Bugalho

    2008-10-01

    Agents that inhibit the activity of cell membrane receptor tyrosine kinases, such as the human epidermal growth factor receptor (EGFR) have been an attractive target because EGFR is expressed by 80% of NSCLC. Erlotinib as monotherapy in the treatment of NSCLC after failure of at least one prior chemotherapy regimen, prolonged survival and improved quality of life, although modest response rate. Women, Asiens, patients with Adenocarcinoma and never smokers, were more likely than other patients to have a response to erlotinib. This is the group of patients that most commonly have an EGFR mutation. The authors describe two cases, with important control of symptoms and increased time to progression, independently o response rate (stable disease or partial response). Rev Port Pneumol 2008; XIV (Supl 3): S53-S60.

  9. Cell entry of Lassa virus induces tyrosine phosphorylation of dystroglycan.

    PubMed

    Moraz, Marie-Laurence; Pythoud, Christelle; Turk, Rolf; Rothenberger, Sylvia; Pasquato, Antonella; Campbell, Kevin P; Kunz, Stefan

    2013-05-01

    The extracellular matrix (ECM) receptor dystroglycan (DG) serves as a cellular receptor for the highly pathogenic arenavirus Lassa virus (LASV) that causes a haemorrhagic fever with high mortality in human. In the host cell, DG provides a molecular link between the ECM and the actin cytoskeleton via the adapter proteins utrophin or dystrophin. Here we investigated post-translational modifications of DG in the context of LASV cell entry. Using the tyrosine kinase inhibitor genistein, we found that tyrosine kinases are required for efficient internalization of virus particles, but not virus-receptor binding. Engagement of cellular DG by LASV envelope glycoprotein (LASV GP) in human epithelial cells induced tyrosine phosphorylation of the cytoplasmic domain of DG. LASV GP binding to DG further resulted in dissociation of the adapter protein utrophin from virus-bound DG. This virus-induced dissociation of utrophin was affected by genistein treatment, suggesting a role of receptor tyrosine phosphorylation in the process.

  10. A bacterial tyrosine phosphatase inhibits plant pattern recognition receptor activation.

    PubMed

    Macho, Alberto P; Schwessinger, Benjamin; Ntoukakis, Vardis; Brutus, Alexandre; Segonzac, Cécile; Roy, Sonali; Kadota, Yasuhiro; Oh, Man-Ho; Sklenar, Jan; Derbyshire, Paul; Lozano-Durán, Rosa; Malinovsky, Frederikke Gro; Monaghan, Jacqueline; Menke, Frank L; Huber, Steven C; He, Sheng Yang; Zipfel, Cyril

    2014-03-28

    Innate immunity relies on the perception of pathogen-associated molecular patterns (PAMPs) by pattern-recognition receptors (PRRs) located on the host cell's surface. Many plant PRRs are kinases. Here, we report that the Arabidopsis receptor kinase EF-TU RECEPTOR (EFR), which perceives the elf18 peptide derived from bacterial elongation factor Tu, is activated upon ligand binding by phosphorylation on its tyrosine residues. Phosphorylation of a single tyrosine residue, Y836, is required for activation of EFR and downstream immunity to the phytopathogenic bacterium Pseudomonas syringae. A tyrosine phosphatase, HopAO1, secreted by P. syringae, reduces EFR phosphorylation and prevents subsequent immune responses. Thus, host and pathogen compete to take control of PRR tyrosine phosphorylation used to initiate antibacterial immunity.

  11. Chlamydia trachomatis tarp is phosphorylated by src family tyrosine kinases.

    PubMed

    Jewett, Travis J; Dooley, Cheryl A; Mead, David J; Hackstadt, Ted

    2008-06-27

    The translocated actin recruiting phosphoprotein (Tarp) is injected into the cytosol shortly after Chlamydia trachomatis attachment to a target cell and subsequently phosphorylated by an unidentified tyrosine kinase. A role for Tarp phosphorylation in bacterial entry is unknown. In this study, recombinant C. trachomatis Tarp was employed to identify the host cell kinase(s) required for phosphorylation. Each tyrosine rich repeat of L2 Tarp harbors a sequence similar to a Src and Abl kinase consensus target. Furthermore, purified p60-src, Yes, Fyn, and Abl kinases were able to phosphorylate Tarp. Mutagenesis of potential tyrosines within a single tyrosine rich repeat peptide indicated that both Src and Abl kinases phosphorylate the same residues suggesting that C. trachomatis Tarp may serve as a substrate for multiple host cell kinases. Surprisingly, chemical inhibition of Src and Abl kinases prevented Tarp phosphorylation in culture and had no measurable effect on bacterial entry into host cells.

  12. Skin problems and EGFR-tyrosine kinase inhibitor

    PubMed Central

    Kozuki, Toshiyuki

    2016-01-01

    Epidermal growth factor receptor inhibition is a good target for the treatment of lung, colon, pancreatic and head and neck cancers. Epidermal growth factor receptor-tyrosine kinase inhibitor was first approved for the treatment of advanced lung cancer in 2002. Epidermal growth factor receptor-tyrosine kinase inhibitor plays an essential role in the treatment of cancer, especially for patients harbouring epidermal growth factor receptor activating mutation. Hence, skin toxicity is the most concerning issue for the epidermal growth factor receptor-tyrosine kinase inhibitor treatment. Skin toxicity is bothersome and sometimes affects the quality of life and treatment compliance. Thus, it is important for physicians to understand the background and how to manage epidermal growth factor receptor-tyrosine kinase inhibitor-associated skin toxicity. Here, the author reviewed the mechanism and upfront preventive and reactive treatments for epidermal growth factor receptor inhibitor-associated skin toxicities. PMID:26826719

  13. Skin problems and EGFR-tyrosine kinase inhibitor.

    PubMed

    Kozuki, Toshiyuki

    2016-04-01

    Epidermal growth factor receptor inhibition is a good target for the treatment of lung, colon, pancreatic and head and neck cancers. Epidermal growth factor receptor-tyrosine kinase inhibitor was first approved for the treatment of advanced lung cancer in 2002. Epidermal growth factor receptor-tyrosine kinase inhibitor plays an essential role in the treatment of cancer, especially for patients harbouring epidermal growth factor receptor activating mutation. Hence, skin toxicity is the most concerning issue for the epidermal growth factor receptor-tyrosine kinase inhibitor treatment. Skin toxicity is bothersome and sometimes affects the quality of life and treatment compliance. Thus, it is important for physicians to understand the background and how to manage epidermal growth factor receptor-tyrosine kinase inhibitor-associated skin toxicity. Here, the author reviewed the mechanism and upfront preventive and reactive treatments for epidermal growth factor receptor inhibitor-associated skin toxicities.

  14. Tyrosine phosphorylation of Rab7 by Src kinase.

    PubMed

    Lin, Xiaosi; Zhang, Jiaming; Chen, Lingqiu; Chen, Yongjun; Xu, Xiaohui; Hong, Wanjin; Wang, Tuanlao

    2017-03-20

    The small molecular weight GTPase Rab7 is a key regulator for late endosomal/lysosomal membrane trafficking, it was known that Rab7 is phosphorylated, but the corresponding kinase and the functional regulation of Rab7 phosphorylation remain unclear. We provide evidence here that Rab7 is a substrate of Src kinase, and is tyrosine-phosphorylated by Src, withY183 residue of Rab7 being the optimal phosphorylation site for Src. Further investigations demonstrated that the tyrosine phosphorylation of Rab7 depends on the guanine nucleotide binding activity of Rab7 and the activity of Src kinase. The tyrosine phosphorylation of Rab7 is physiologically induced by EGF, and impairs the interaction of Rab7 with RILP, consequently inhibiting EGFR degradation and sustaining Akt signaling. These results suggest that the tyrosine phosphorylation of Rab7 may be involved in coordinating membrane trafficking and cell signaling.

  15. Cell entry of Lassa virus induces tyrosine phosphorylation of dystroglycan

    PubMed Central

    Moraz, Marie-Laurence; Pythoud, Christelle; Turk, Rolf; Rothenberger, Sylvia; Pasquato, Antonella; Campbell, Kevin P.; Kunz, Stefan

    2013-01-01

    The extracellular matrix (ECM) receptor dystroglycan (DG) serves as a cellular receptor for the highly pathogenic arenavirus Lassa virus (LASV) that causes a hemorrhagic fever with high mortality in man. In the host cell, DG provides a molecular link between the ECM and the actin cytoskeleton via the adapter proteins utrophin or dystrophin. Here we investigated post-translational modifications of DG in the context of LASV cell entry. Using the tyrosine kinase inhibitor genistein, we found that tyrosine kinases are required for efficient internalization of virus particles, but not virus-receptor binding. Engagement of cellular DG by LASV envelope glycoprotein (LASV GP) in human epithelial cells induced tyrosine phosphorylation of the cytoplasmic domain of DG. LASV GP binding to DG further resulted in dissociation of the adapter protein utrophin from virus-bound DG. This virus-induced dissociation of utrophin was affected by genistein treatment, suggesting a role of receptor tyrosine phosphorylation in the process. PMID:23279385

  16. Anticipating and blocking HIV-1 escape by second generation antiviral shRNAs

    PubMed Central

    2010-01-01

    Background RNA interference (RNAi) is an evolutionary conserved gene silencing mechanism that mediates the sequence-specific breakdown of target mRNAs. RNAi can be used to inhibit HIV-1 replication by targeting the viral RNA genome. However, the error-prone replication machinery of HIV-1 can generate RNAi-resistant variants with specific mutations in the target sequence. For durable inhibition of HIV-1 replication the emergence of such escape viruses must be controlled. Here we present a strategy that anticipates HIV-1 escape by designing 2nd generation short hairpin RNAs (shRNAs) that form a complete match with the viral escape sequences. Results To block the two favorite viral escape routes observed when the HIV-1 integrase gene sequence is targeted, the original shRNA inhibitor was combined with two 2nd generation shRNAs in a single lentiviral expression vector. We demonstrate in long-term viral challenge experiments that the two dominant viral escape routes were effectively blocked. Eventually, virus breakthrough did however occur, but HIV-1 evolution was skewed and forced to use new escape routes. Conclusion These results demonstrate the power of the 2nd generation RNAi concept. Popular viral escape routes are blocked by the 2nd generation RNAi strategy. As a consequence viral evolution was skewed leading to new escape routes. These results are of importance for a deeper understanding of HIV-1 evolution under RNAi pressure. PMID:20529316

  17. Posttranslational protein knockdown coupled to receptor tyrosine kinase activation with phosphoPROTACs

    PubMed Central

    Hines, John; Gough, Jonathan D.; Corson, Timothy W.; Crews, Craig M.

    2013-01-01

    Posttranslational knockdown of a specific protein is an attractive approach for examining its function within a system. Here we introduce phospho-dependent proteolysis targeting chimeras (phosphoPROTACs), a method to couple the conditional degradation of targeted proteins to the activation state of particular kinase-signaling pathways. We generated two phosphoPROTACs that couple the tyrosine phosphorylation sequences of either the nerve growth factor receptor, TrkA (tropomyosin receptor kinase A), or the neuregulin receptor, ErbB3 (erythroblastosis oncogene B3), with a peptide ligand for the E3 ubiquitin ligase von Hippel Lindau protein. These phosphoPROTACs recruit either the neurotrophic signaling effector fibroblast growth factor receptor substrate 2α or the survival-promoting phosphatidylinositol-3-kinase, respectively, to be ubiquitinated and degraded upon activation of specific receptor tyrosine kinases and phosphorylation of the phosphoPROTACs. We demonstrate the ability of these phosphoPROTACs to suppress the short- and long-term effects of their respective activating receptor tyrosine kinase pathways both in vitro and in vivo. In addition, we show that activation of phosphoPROTACs is entirely dependent on their kinase-mediated phosphorylation, as phenylalanine-containing null variants are inactive. Furthermore, stimulation of unrelated growth factor receptors does not induce target protein knockdown. Although comparable in efficiency to RNAi, this approach has the added advantage of providing a degree of temporal and dosing control as well as cell-type selectivity unavailable using nucleic acid-based strategies. By varying the autophosphorylation sequence of a phosphoPROTAC, it is conceivable that other receptor tyrosine kinase/effector pairings could be similarly exploited to achieve other biological effects. PMID:23674677

  18. Posttranslational protein knockdown coupled to receptor tyrosine kinase activation with phosphoPROTACs.

    PubMed

    Hines, John; Gough, Jonathan D; Corson, Timothy W; Crews, Craig M

    2013-05-28

    Posttranslational knockdown of a specific protein is an attractive approach for examining its function within a system. Here we introduce phospho-dependent proteolysis targeting chimeras (phosphoPROTACs), a method to couple the conditional degradation of targeted proteins to the activation state of particular kinase-signaling pathways. We generated two phosphoPROTACs that couple the tyrosine phosphorylation sequences of either the nerve growth factor receptor, TrkA (tropomyosin receptor kinase A), or the neuregulin receptor, ErbB3 (erythroblastosis oncogene B3), with a peptide ligand for the E3 ubiquitin ligase von Hippel Lindau protein. These phosphoPROTACs recruit either the neurotrophic signaling effector fibroblast growth factor receptor substrate 2α or the survival-promoting phosphatidylinositol-3-kinase, respectively, to be ubiquitinated and degraded upon activation of specific receptor tyrosine kinases and phosphorylation of the phosphoPROTACs. We demonstrate the ability of these phosphoPROTACs to suppress the short- and long-term effects of their respective activating receptor tyrosine kinase pathways both in vitro and in vivo. In addition, we show that activation of phosphoPROTACs is entirely dependent on their kinase-mediated phosphorylation, as phenylalanine-containing null variants are inactive. Furthermore, stimulation of unrelated growth factor receptors does not induce target protein knockdown. Although comparable in efficiency to RNAi, this approach has the added advantage of providing a degree of temporal and dosing control as well as cell-type selectivity unavailable using nucleic acid-based strategies. By varying the autophosphorylation sequence of a phosphoPROTAC, it is conceivable that other receptor tyrosine kinase/effector pairings could be similarly exploited to achieve other biological effects.

  19. Method of making L-dopa from L-tyrosine

    DOEpatents

    Xun, Luying; Lee, Jang Young

    1998-01-01

    The invention is a method of making a L-dopa from L-tyrosine in the presence of an enzyme catalyst and oxygen. By starting with L-tyrosine, no variant of the L-dopa is produced and the L-dopa is stable in the presence of the enzyme catalyst. In other words, the reaction favors the L-dopa and is not reversible.

  20. Use of Tyrosine or Foods to Amplify Catecholamine Release.

    DTIC Science & Technology

    1987-11-02

    valine; phenylalanine ; tryptophan) are unaffected (see Figure 2). These observations suggest a second mechanism for the precursor- dependence of...involves the activation by phosphorylation of tyrosine hydroxylase that occurs when the neurons fire frequently. This activation changes the enzyme’s... phenylalanine , as well as their plasma "ratios" no changes were noted in the plasma tryptophan nor tyrosine ratios. The metabolic alterations induced by marathon

  1. Method of making L-dopa from L-tyrosine

    DOEpatents

    Xun, L.; Lee, J.Y.

    1998-11-17

    The invention is a method of making a L-dopa from L-tyrosine in the presence of an enzyme catalyst and oxygen. By starting with L-tyrosine, no variant of the L-dopa is produced and the L-dopa is stable in the presence of the enzyme catalyst. In other words, the reaction favors the L-dopa and is not reversible. 3 figs.

  2. Tyrosine Pretreatment Reverses Hypothermia-Induced Behavioral Depression

    DTIC Science & Technology

    1990-01-01

    behavioral depression induced by forced swimming in 21- Tyrosine significantly decreased immobility in the swim test 25C water, in a restricted space...Figure 2 shows the effect of tyrosine on immobility in the swim observed that tle behavioral inactivity and the reduction of brain test . A post hoc...Gibson. C. J.; Wurtman, R. J. Physiological control of brain Immobility induced by forced swimming ,n rats: Effects of agents norepinephrine synthesis by

  3. Channel modulation by tyrosine phosphorylation in an identified leech neuron.

    PubMed Central

    Aniksztejn, L; Catarsi, S; Drapeau, P

    1997-01-01

    1. We have examined the effects of tyrosine phosphorylation on a spontaneously active cation channel that also participates in the modulation of pressure-sensitive (P) neurons in the leech. Cation channel activity in cell-attached or isolated, inside-out membrane patches from P cells in culture was monitored before and after treatments that altered the level of tyrosine phosphorylation. 2. In cell-attached recordings from intact P cells, bath application of genistein, an inhibitor of tyrosine kinases, resulted in a 6.6 +/- 2.6-fold increase in channel activity with no change in the mean open time or amplitude. Daidzein, an inactive form of genistein, was without effect. Addition of pervanadate, a membrane-permeant inhibitor of tyrosine phosphatases, had no effect on its own and blocked the effect of subsequent addition of genistein. 3. In inside-out P cell membrane patch recordings, exposure to a catalytically active fragment of a tyrosine phosphatase resulted in a 10.3 +/- 3.6-fold increase in channel activity with no change in the mean open time or amplitude. Orthovanadate had no effect on channel activity and, when added with the phosphatase, prevented the increase in activity. 4. Our results demonstrate that the basal activity of cation channels is increased by tyrosine dephosphorylation, suggesting a constitutive modulation of channel activity under resting conditions. PMID:9023773

  4. Intricate regulation of tyrosine hydroxylase activity and gene expression.

    PubMed

    Kumer, S C; Vrana, K E

    1996-08-01

    Tyrosine hydroxylase catalyzes the rate-limiting step in the biosynthesis of the catecholamines dopamine, norepinephrine, and epinephrine. Therefore, the regulation of tyrosine hydroxylase enzyme number and intrinsic enzyme activity represents the central means for controlling the synthesis of these important biogenic amines. An intricate scheme has evolved whereby tyrosine hydroxylase activity is modulated by nearly every documented form of regulation. Beginning with the genomic DNA, evidence exists for the transcriptional regulation of tyrosine hydroxylase mRNA levels, alternative RNA processing, and the regulation of RNA stability. There is also experimental support for the role of both translational control and enzyme stability in establishing steady-state levels of active tyrosine hydroxylase protein. Finally, mechanisms have been proposed for feedback inhibition of the enzyme by catecholamine products, allosteric modulation of enzyme activity, and phosphorylation-dependent activation of the enzyme by various different kinase systems. Given the growing literature suggesting that different tissues regulate tyrosine hydroxylase mRNA levels and activity in different ways, regulatory mechanisms provide not only redundancy but also diversity in the control of catecholamine biosynthesis.

  5. Second-trimester urine nephrin:creatinine ratio versus soluble fms-like tyrosine kinase-1:placental growth factor ratio for prediction of preeclampsia among asymptomatic women

    PubMed Central

    Zhai, Tianyue; Furuta, Itsuko; Nakagawa, Kinuko; Kojima, Takashi; Umazume, Takeshi; Ishikawa, Satoshi; Yamada, Takahiro; Morikawa, Mamoru; Minakami, Hisanori

    2016-01-01

    This prospective observational study compare urine nephrin:creatinine ratio (NCR, ng/mg) with serum soluble fms-like tyrosine kinase-1:placental growth factor ratio (FPR, pg/pg) for preeclampsia (PE) prediction among unselected asymptomatic pregnant women in 2nd trimester. NCR and FPR were determined in 254 paired urine/blood samples collected simultaneously from 254 women at median gestational week (GW) 24 (range, 22–27) without hypertension or significant proteinuria in pregnancy (SPIP). Fifteen (5.9%) developed SPIP and hypertension at GW 34.0 (26.0–38.6) and 35.3 (27.6–38.6), respectively, and were diagnosed with PE at GW 35.7 (27.6–38.6). The 90th percentile level determined in 239 women normotensive throughout pregnancy gave NCR (139) sensitivity and positive predictive values (PPV) of 60% (9/15) and 27% (9/33), while those for serum FPR (4.85) were 40% (6/15) and 20% (6/30), respectively. Relative risks (95%CI) of later PE were 10.0 (3.82–26.4; 27% [9/33] vs. 2.7% [6/221]) and 4.98 (1.91–13.0; 20% [6/30] vs. 4.0% [9/224]) for NCR-positive and FPR-positive women, respectively. Cut-offs suggested by ROC gave NCR (86.6) sensitivity and PPV of 87% (13/15) and 17% (13/79), and FPR (8.8) values of 40% (6/15) and 40% (6/15), respectively. Thus, 2nd trimester NCR was superior to FPR for PE prediction. PMID:27874074

  6. Effect of reactive oxygen species on capacitation and associated protein tyrosine phosphorylation in buffalo (Bubalus bubalis) spermatozoa.

    PubMed

    Roy, S C; Atreja, S K

    2008-08-01

    In the present study, the effect of two particular reactive oxygen species (ROS), superoxide anion (O(2)(-)) and hydrogen peroxide (H(2)O(2)) on buffalo (Bubalus bubalis) sperm capacitation and associated protein tyrosine phosphorylation was studied. Ejaculated buffalo spermatozoa were suspended in sp-TALP medium at 50 x 10(6)/mL and incubated at 38.5 degrees C for 6h with or without heparin (10(g/mL; a positive control), or xanthine (X; 0.5mM)-xanthine oxidase (XO; 0.05 U/mL)-catalase (C; 2100 U/mL) system that generates O(2)(-) or NADPH (5mM) that stimulates the endogenous O(2)(-) production or H(2)O(2) (50 microM). The specific effect of O(2)(-), H(2)O(2) and NADPH on buffalo sperm capacitation and protein tyrosine phosphorylation was assessed by the addition of superoxide dismutase (SOD), catalase and diphenylene iodonium (DPI), respectively, to the incubation medium. Each of X+XO+C system, NADPH and H(2)O(2) induced a significantly higher percentage (P<0.05) of capacitation in buffalo spermatozoa compared to control. However, DPI inhibited this NADPH-induced capacitation and protein tyrosine phosphorylation and suggested for existence of an oxidase in buffalo spermatozoa. Using immunoblotting technique, at least seven tyrosine-phosphorylated proteins (20, 32, 38, 45, 49, 78 and 95 kDa) were detected in capacitated buffalo spermatozoa. Out of these, the tyrosine phosphorylation of p95 was induced extensively by both O(2)(-) as well as exogenous source of H(2)O(2) and using specific activators and inhibitors of signaling pathways, it was found this induction was regulated through a cAMP-dependent PKA pathway. Further, immunofluorescent localization study revealed that these ROS-induced tyrosine-phosphorylated proteins are mostly distributed in the midpiece and principal piece regions of the flagellum of capacitated spermatozoa and suggested for increased molecular activity in flagellum during capacitation. Thus, the study revealed that both O(2)(-) and H(2)O(2

  7. Are striatal tyrosine hydroxylase interneurons dopaminergic?

    PubMed

    Xenias, Harry S; Ibáñez-Sandoval, Osvaldo; Koós, Tibor; Tepper, James M

    2015-04-22

    Striatal GABAergic interneurons that express the gene for tyrosine hydroxylase (TH) have been identified previously by several methods. Although generally assumed to be dopaminergic, possibly serving as a compensatory source of dopamine (DA) in Parkinson's disease, this assumption has never been tested directly. In TH-Cre mice whose nigrostriatal pathway had been eliminated unilaterally with 6-hydroxydopamine, we injected a Cre-dependent virus coding for channelrhodopsin-2 and enhanced yellow fluorescent protein unilaterally into the unlesioned midbrain or bilaterally into the striatum. Fast-scan cyclic voltammetry in striatal slices revealed that both optical and electrical stimulation readily elicited DA release in control striata but not from contralateral striata when nigrostriatal neurons were transduced. In contrast, neither optical nor electrical stimulation could elicit striatal DA release in either the control or lesioned striata when the virus was injected directly into the striatum transducing only striatal TH interneurons. This demonstrates that striatal TH interneurons do not release DA. Fluorescence immunocytochemistry in enhanced green fluorescent protein (EGFP)-TH mice revealed colocalization of DA, l-amino acid decarboxylase, the DA transporter, and vesicular monoamine transporter-2 with EGFP in midbrain dopaminergic neurons but not in any of the striatal EGFP-TH interneurons. Optogenetic activation of striatal EGFP-TH interneurons produced strong GABAergic inhibition in all spiny neurons tested. These results indicate that striatal TH interneurons are not dopaminergic but rather are a type of GABAergic interneuron that expresses TH but none of the other enzymes or transporters necessary to operate as dopaminergic neurons and exert widespread GABAergic inhibition onto direct and indirect spiny neurons.

  8. Cyclin B targets p34cdc2 for tyrosine phosphorylation.

    PubMed

    Meijer, L; Azzi, L; Wang, J Y

    1991-06-01

    A universal intracellular factor, the 'M phase-promoting factor' (MPF), triggers the G2/M transition of the cell cycle in all organisms. In late G2, it is present as an inactive complex of tyrosine-phosphorylated p34cdc2 and unphosphorylated cyclin Bcdc13. In M phase, its activation as an active MPF displaying histone H1 kinase (H1K) originates from the concomitant tyrosine dephosphorylation of the p34cdc2 subunit and the phosphorylation of the cylin Bcdc13 subunit. We have investigated the role of cyclin in the formation of this complex and the tyrosine phosphorylation of p34cdc2, using highly synchronous mitotic sea urchin eggs as a model. As cells leave the S phase and enter the G2 phase, a massive tyrosine phosphorylation of p34cdc2 occurs. This large p34cdc2 tyrosine phosphorylation burst does not arise from a massive increase in p34cdc2 concentration. It even appears to affect only a fraction (non-immunoprecipitable by anti-PSTAIR antibodies) of the total p34cdc2 present in the cell. Several observations point to an extremely close association between accumulation of unphosphorylated cyclin and p34cdc2 tyrosine phosphorylation: (i) both events coincide perfectly during the G2 phase; (ii) both tyrosine-phosphorylated p34cdc2 and cyclin are not immunoprecipitated by anti-PSTAIR antibodies; (iii) accumulation of unphosphorylated cyclin by aphidicolin treatment of the cells, triggers a dramatic accumulation of tyrosine-phosphorylated p34cdc2; and (iv) inhibition of cyclin synthesis by emetine inhibits p34cdc2 tyrosine phosphorylation without affecting the p34cdc2 concentration. These results show that, as it is synthesized, cyclin B binds and recruits p34cdc2 for tyrosine phosphorylation; this inactive complex then requires the completion of DNA replication before it can be turned into fully active MPF. These results fully confirm recent data obtained in vitro with exogenous cyclin added to cycloheximide-treated Xenopus egg extracts.

  9. Performance of the Roche second generation hemoglobin A1c immunoassay in the presence of HB-S or HB-C traits.

    PubMed

    Abadie, Jude M; Koelsch, Angela A

    2008-01-01

    Blood HbA1c determination is a powerful tool for the evaluation and management of patients with diabetes mellitus. Many HbA1c analytical methods demonstrate bias in samples from patients with hemoglobinopathies. This study evaluated the analytical performance of Roche Diagnostics' 1st and 2nd generation HbA1c assays in patients with or without hemoglobinopathies whose HbA1c levels were elevated or normal, respectively. Boronate-affinity high performance liquid chromatography (HPLC) served as the reference method. Whole blood samples were collected from 80 patients with HbS or HbC whose group mean HbA1c value was elevated and also from 80 patients without hemoglobinopathy whose HbA1c values were in the well-controlled range. Each sample was assayed for HbA1c by the Primus boronate-affinity HPLC technique and by Roche's 1st and 2nd generation immunoassays using a Cobas Integra 800 analytical system. Results by the HPLC technique were compared with the results of both Roche assays by linear regression and Bland-Altman analysis. The 1st and 2nd generation assays yielded regression lines and correlation values vs HPLC assay of y = 1.43x - 1.59; R(2) = 0.83, and y = 0.94x + 0.10; R(2) = 0.92, respectively, in the 80 patients with hemoglobinopathies. The mean difference and the +/-2SD range were greater in the 1st than in the 2nd generation assay (2.68, +/-2.07 vs -0.54, +/-0.86, respectively). The 2nd generation assay also showed better performance than the 1st generation assay in samples from the 80 patients without hemoglobinopathy. In conclusion, this study validates the accuracy of Roche's 2nd generation assay, which is substantially improved over Roche's 1st generation HbA1c assay.

  10. Implementing Task-Oriented Content-Based Instruction for First- and Second-Generation Immigrant Students

    ERIC Educational Resources Information Center

    Santana-Williamson, Eliana

    2013-01-01

    This article discusses how the ESL program at an ethnically/linguistically diverse community college (between San Diego and the Mexican border) moved from a general, grammar-based ESL curriculum to a content-based instruction (CBI) curriculum. The move was designed to better prepare 1st- and 2nd-generation immigrant students for freshman…

  11. Dietary tyrosine benefits cognitive and psychomotor performance during body cooling.

    PubMed

    O'Brien, Catherine; Mahoney, Caroline; Tharion, William J; Sils, Ingrid V; Castellani, John W

    2007-02-28

    Supplemental tyrosine is effective at limiting cold-induced decreases in working memory, presumably by augmenting brain catecholamine levels, since tyrosine is a precursor for catecholamine synthesis. The effectiveness of tyrosine for preventing cold-induced decreases in physical performance has not been examined. This study evaluated the effect of tyrosine supplementation on cognitive, psychomotor, and physical performance following a cold water immersion protocol that lowered body core temperature. Fifteen subjects completed a control trial (CON) in warm (35 degrees C) water and two cold water trials, each spaced a week apart. Subjects ingested an energy bar during each trial; on one cold trial (TYR) the bar contained tyrosine (300 mg/kg body weight), and on the other cold trial (PLB) and on CON the bar contained no tyrosine. Following each water immersion, subjects completed a battery of performance tasks in a cold air (10 degrees C) chamber. Core temperature was lower (p=0.0001) on PLB and TYR (both 35.5+/-0.6 degrees C) than CON (37.1+/-0.3 degrees C). On PLB, performance on a Match-to-Sample task decreased 18% (p=0.02) and marksmanship performance decreased 14% (p=0.002), compared to CON, but there was no difference between TYR and CON. Step test performance decreased by 11% (p=0.0001) on both cold trials, compared to CON. These data support previous findings that dietary tyrosine supplementation is effective for mitigating cold-induced cognitive performance such as working memory, even with reduced core temperature, and extends those findings to include the psychomotor task of marksmanship.

  12. Second-order adjoint sensitivity analysis methodology (2nd-ASAM) for computing exactly and efficiently first- and second-order sensitivities in large-scale linear systems: II. Illustrative application to a paradigm particle diffusion problem

    NASA Astrophysics Data System (ADS)

    Cacuci, Dan G.

    2015-03-01

    This work presents an illustrative application of the second-order adjoint sensitivity analysis methodology (2nd-ASAM) to a paradigm neutron diffusion problem, which is sufficiently simple to admit an exact solution, thereby making transparent the underlying mathematical derivations. The general theory underlying 2nd-ASAM indicates that, for a physical system comprising Nα parameters, the computation of all of the first- and second-order response sensitivities requires (per response) at most (2Nα + 1) "large-scale" computations using the first-level and, respectively, second-level adjoint sensitivity systems (1st-LASS and 2nd-LASS). Very importantly, however, the illustrative application presented in this work shows that the actual number of adjoint computations needed for computing all of the first- and second-order response sensitivities may be significantly less than (2Nα + 1) per response. For this illustrative problem, four "large-scale" adjoint computations sufficed for the complete and exact computations of all 4 first- and 10 distinct second-order derivatives. Furthermore, the construction and solution of the 2nd-LASS requires very little additional effort beyond the construction of the adjoint sensitivity system needed for computing the first-order sensitivities. Very significantly, only the sources on the right-sides of the diffusion (differential) operator needed to be modified; the left-side of the differential equations (and hence the "solver" in large-scale practical applications) remained unchanged. All of the first-order relative response sensitivities to the model parameters have significantly large values, of order unity. Also importantly, most of the second-order relative sensitivities are just as large, and some even up to twice as large as the first-order sensitivities. In the illustrative example presented in this work, the second-order sensitivities contribute little to the response variances and covariances. However, they have the

  13. Negative regulation of Jak2 by its auto-phosphorylation at tyrosine 913 via the Epo signaling pathway.

    PubMed

    Funakoshi-Tago, Megumi; Tago, Kenji; Kasahara, Tadashi; Parganas, Evan; Ihle, James N

    2008-11-01

    Janus kinase 2 (Jak2) has a pivotal role in erythropoietin (Epo) signaling pathway, including erythrocyte differentiation and Stat5 activation. In the course of screening for critical phosphorylation of tyrosine residues in Jak2, we identified tyrosine 913 (Y(913)) as a novel and functional phosphorylation site, which negatively regulates Jak2. Phosphorylation at Y(913) rapidly occurred and was sustained for at least 120 min after Epo stimulation, in contrast to the transient phosphorylation of Y(1007/1008) in the activation loop of Jak2. Interestingly, phosphorylation defective mutation of Y(913) (Y(913)F) results in a significant enhancement of Epo-induced Jak2 activation, whereas phosphorylation mimic mutation of Y(913) (Y(913)E) completely abrogated its activation. Furthermore, Jak2 deficient fetal liver cells expressing Y(913)F mutant generated many mature erythroid BFU-E and CFU-E colonies, while Y(913)E mutant failed to reconstitute Jak2 deficiency. We also demonstrate, in Jak1, phosphorylation of Y(939), a corresponding tyrosine residue with Y(913), negatively regulated Jak1 signaling pathway. Accordingly, our results suggest that this tyrosine phosphorylation in JH1 domain may be involved in common negative regulation mechanism for Jak family.

  14. Identification of a human src homology 2-containing protein-tyrosine-phosphatase: a putative homolog of Drosophila corkscrew.

    PubMed Central

    Freeman, R M; Plutzky, J; Neel, B G

    1992-01-01

    src homology 2 (SH2) domains direct binding to specific phosphotyrosyl proteins. Recently, SH2-containing protein-tyrosine-phosphatases (PTPs) were identified. Using degenerate oligonucleotides and the PCR, we have cloned a cDNA for an additional PTP, SH-PTP2, which contains two SH2 domains and is expressed ubiquitously. When expressed in Escherichia coli, SH-PTP2 displays tyrosine-specific phosphatase activity. Strong sequence similarity between SH-PTP2 and the Drosophila gene corkscrew (csw) and their similar patterns of expression suggest that SH-PTP2 is the human corkscrew homolog. Sequence comparisons between SH-PTP2, SH-PTP1, corkscrew, and other SH2-containing proteins suggest the existence of a subfamily of SH2 domains found specifically in PTPs, whereas comparison of the PTP domains of the SH2-containing PTPs with other tyrosine phosphatases suggests the existence of a subfamily of PTPs containing SH2 domains. Since corkscrew, a member of the terminal class signal transduction pathway, acts in concert with D-raf to positively transduce the signal generated by the receptor tyrosine kinase torso, these findings suggest several mechanisms by which SH-PTP2 may participate in mammalian signal transduction. Images PMID:1280823

  15. Biochemical characterization of the protein tyrosine kinase homology domain of the ErbB3 (HER3) receptor protein.

    PubMed

    Sierke, S L; Cheng, K; Kim, H H; Koland, J G

    1997-03-15

    The putative protein tyrosine kinase domain (TKD) of the ErbB3 (HER3) receptor protein was generated as a histidine-tagged recombinant protein (hisTKD-B3) and characterized enzymologically. CD spectroscopy indicated that the hisTKD-B3 protein assumed a native conformation with a secondary structure similar to that of the epidermal growth factor (EGF) receptor TKD. However, when compared with the EGF receptor-derived protein, hisTKD-B3 exhibited negligible intrinsic protein tyrosine kinase activity. Immune complex kinase assays of full-length ErbB3 proteins also yielded no evidence of catalytic activity. A fluorescence assay previously used to characterize the nucleotide-binding properties of the EGF receptor indicated that the ErbB3 protein was unable to bind nucleotide. The hisTKD-B3 protein was subsequently found to be an excellent substrate for the EGF receptor protein tyrosine kinase, which suggested that in vivo phosphorylation of ErbB3 in response to EGF could be attributed to a direct cross-phosphorylation by the EGF receptor protein tyrosine kinase.

  16. Biochemical characterization of the protein tyrosine kinase homology domain of the ErbB3 (HER3) receptor protein.

    PubMed Central

    Sierke, S L; Cheng, K; Kim, H H; Koland, J G

    1997-01-01

    The putative protein tyrosine kinase domain (TKD) of the ErbB3 (HER3) receptor protein was generated as a histidine-tagged recombinant protein (hisTKD-B3) and characterized enzymologically. CD spectroscopy indicated that the hisTKD-B3 protein assumed a native conformation with a secondary structure similar to that of the epidermal growth factor (EGF) receptor TKD. However, when compared with the EGF receptor-derived protein, hisTKD-B3 exhibited negligible intrinsic protein tyrosine kinase activity. Immune complex kinase assays of full-length ErbB3 proteins also yielded no evidence of catalytic activity. A fluorescence assay previously used to characterize the nucleotide-binding properties of the EGF receptor indicated that the ErbB3 protein was unable to bind nucleotide. The hisTKD-B3 protein was subsequently found to be an excellent substrate for the EGF receptor protein tyrosine kinase, which suggested that in vivo phosphorylation of ErbB3 in response to EGF could be attributed to a direct cross-phosphorylation by the EGF receptor protein tyrosine kinase. PMID:9148746

  17. Bmx Tyrosine Kinase Has a Redundant Function Downstream of Angiopoietin and Vascular Endothelial Growth Factor Receptors in Arterial Endothelium

    PubMed Central

    Rajantie, Iiro; Ekman, Niklas; Iljin, Kristiina; Arighi, Elena; Gunji, Yuji; Kaukonen, Jaakko; Palotie, Aarno; Dewerchin, Mieke; Carmeliet, Peter; Alitalo, Kari

    2001-01-01

    The Bmx gene, a member of the Tec tyrosine kinase gene family, is known to be expressed in subsets of hematopoietic and endothelial cells. In this study, mice were generated in which the first coding exon of the Bmx gene was replaced with the lacZ reporter gene by a knock-in strategy. The homozygous mice lacking Bmx activity were fertile and had a normal life span without an obvious phenotype. Staining of their tissues using β-galactosidase substrate to assess the sites of Bmx expression revealed strong signals in the endothelial cells of large arteries and in the endocardium starting between days 10.5 and 12.5 of embryogenesis and continuing in adult mice, while the venular endothelium showed a weak signal only in the superior and inferior venae cavae. Of the five known endothelial receptor tyrosine kinases tested, activated Tie-2 induced tyrosyl phosphorylation of the Bmx protein and both Tie-2 and vascular endothelial growth factor receptor 1 (VEGFR-1) stimulated Bmx tyrosine kinase activity. Thus, the Bmx tyrosine kinase has a redundant role in arterial endothelial signal transduction downstream of the Tie-2 and VEGFR-1 growth factor receptors. PMID:11416142

  18. Use of double-stranded RNA-mediated interference to determine the substrates of protein tyrosine kinases and phosphatases.

    PubMed Central

    Muda, Marco; Worby, Carolyn A; Simonson-Leff, Nancy; Clemens, James C; Dixon, Jack E

    2002-01-01

    Despite the wealth of information generated by genome-sequencing projects, the identification of in vivo substrates of specific protein kinases and phosphatases is hampered by the large number of candidate enzymes, overlapping enzyme specificity and sequence similarity. In the present study, we demonstrate the power of RNA interference (RNAi) to dissect signal transduction cascades involving specific kinases and phosphatases. RNAi is used to identify the cellular tyrosine kinases upstream of the phosphorylation of Down-Syndrome cell-adhesion molecule (Dscam), a novel cell-surface molecule of the immunoglobulin-fibronectin super family, which has been shown to be important for axonal path-finding in Drosophila. Tyrosine phosphorylation of Dscam recruits the Src homology 2 domain of the adaptor protein Dock to the receptor. Dock, the ortho- logue of mammalian Nck, is also essential for correct axonal path-finding in Drosophila. We further determined that Dock is tyrosine-phosphorylated in vivo and identified DPTP61F as the protein tyrosine phosphatase responsible for maintaining Dock in its non-phosphorylated state. The present study illustrates the versatility of RNAi in the identification of the physiological substrates for protein kinases and phosphatases. PMID:12014990

  19. l-Tyrosine-loaded nanoparticles increase the antitumoral activity of direct electric current in a metastatic melanoma cell model

    PubMed Central

    de Campos, Vânia Emerich Bucco; Teixeira, Cesar Augusto Antunes; da Veiga, Venicio Feo; Júnior, Eduardo Ricci; Holandino, Carla

    2010-01-01

    Inhibition of tumor growth induced by treatment with direct electric current (DC) has been reported in several models. One of the mechanisms responsible for the antitumoral activity of DC is the generation of oxidative species, known as chloramines. With the aim of increasing chloramine production in the electrolytic medium and optimizing the antitumoral effects of DC, poly(ɛ-caprolactone) (PCL) nanoparticles (NPs) loaded with the amino acid tyrosine were obtained. The physical–chemical characterization showed that the NPs presented size in nanometric range and monomodal distribution. A slightly negative electrokinetic potential was also found in both blank NPs and l-tyrosine-loaded PCL NPs. The yield of the loading process was approximately 50%. Within 3 h of dissolution assay, a burst release of about 80% l-tyrosine was obtained. The in vitro cytotoxicity of DC was significantly increased when associated with l-tyrosine-loaded NPs, using a murine multidrug-resistant melanoma cell line model. This study showed that the use of the combination of nanotechnology and DC has a promising antineoplastic potential and opens a new perspective in cancer therapy. PMID:21187948

  20. Tyrosine aminotransferase contributes to benzylisoquinoline alkaloid biosynthesis in opium poppy.

    PubMed

    Lee, Eun-Jeong; Facchini, Peter J

    2011-11-01

    Tyrosine aminotransferase (TyrAT) catalyzes the transamination of L-Tyr and α-ketoglutarate, yielding 4-hydroxyphenylpyruvic acid and L-glutamate. The decarboxylation product of 4-hydroxyphenylpyruvic acid, 4-hydroxyphenylacetaldehyde, is a precursor to a large and diverse group of natural products known collectively as benzylisoquinoline alkaloids (BIAs). We have isolated and characterized a TyrAT cDNA from opium poppy (Papaver somniferum), which remains the only commercial source for several pharmaceutical BIAs, including codeine, morphine, and noscapine. TyrAT belongs to group I pyridoxal 5'-phosphate (PLP)-dependent enzymes wherein Schiff base formation occurs between PLP and a specific Lys residue. The amino acid sequence of TyrAT showed considerable homology to other putative plant TyrATs, although few of these have been functionally characterized. Purified, recombinant TyrAT displayed a molecular mass of approximately 46 kD and a substrate preference for L-Tyr and α-ketoglutarate, with apparent K(m) values of 1.82 and 0.35 mm, respectively. No specific requirement for PLP was detected in vitro. Liquid chromatography-tandem mass spectrometry confirmed the conversion of L-Tyr to 4-hydroxyphenylpyruvate. TyrAT gene transcripts were most abundant in roots and stems of mature opium poppy plants. Virus-induced gene silencing was used to evaluate the contribution of TyrAT to BIA metabolism in opium poppy. TyrAT transcript levels were reduced by at least 80% in silenced plants compared with controls and showed a moderate reduction in total alkaloid content. The modest correlation between transcript levels and BIA accumulation in opium poppy supports a role for TyrAT in the generation of alkaloid precursors, but it also suggests the occurrence of other sources for 4-hydroxyphenylacetaldehyde.

  1. Knock-in Mutation of the Distal Four Tyrosines of Linker for Activation of T Cells Blocks Murine T Cell Development

    PubMed Central

    Sommers, Connie L.; Menon, Rashmi K.; Grinberg, Alexander; Zhang, Weiguo; Samelson, Lawrence E.; Love, Paul E.

    2001-01-01

    The integral membrane adapter protein linker for activation of T cells (LAT) performs a critical function in T cell antigen receptor (TCR) signal transduction by coupling the TCR to downstream signaling pathways. After TCR engagement, LAT is tyrosine phosphorylated by ZAP-70 creating docking sites for multiple src homology 2–containing effector proteins. In the Jurkat T cell line, the distal four tyrosines of LAT bind PLCγ-1, Grb2, and Gads. Mutation of these four tyrosine residues to phenylalanine (4YF) blocked TCR-mediated calcium mobilization, Erk activation, and nuclear factor (NF)-AT activation. In this study, we examined whether these four tyrosine residues were essential for T cell development by generating LAT “knock-in” mutant mice that express the 4YF mutant protein under the control of endogenous LAT regulatory sequences. Significantly, the phenotype of 4YF knock-in mice was identical to LAT−/− (null) mice; thymocyte development was arrested at the immature CD4−CD8− stage and no mature T cells were present. Knock-in mice expressing wild-type LAT protein, generated by a similar strategy, displayed a normal T cell developmental profile. These results demonstrate that the distal four tyrosine residues of LAT are essential for preTCR signaling and T cell development in vivo. PMID:11457888

  2. Tubulin tyrosine nitration regulates microtubule organization in plant cells

    PubMed Central

    Blume, Yaroslav B.; Krasylenko, Yuliya A.; Demchuk, Oleh M.; Yemets, Alla I.

    2013-01-01

    During last years, selective tyrosine nitration of plant proteins gains importance as well-recognized pathway of direct nitric oxide (NO) signal transduction. Plant microtubules are one of the intracellular signaling targets for NO, however, the molecular mechanisms of NO signal transduction with the involvement of cytoskeletal proteins remain to be elucidated. Since biochemical evidence of plant α-tubulin tyrosine nitration has been obtained recently, potential role of this posttranslational modification in regulation of microtubules organization in plant cell is estimated in current paper. It was shown that 3-nitrotyrosine (3-NO2-Tyr) induced partially reversible Arabidopsis primary root growth inhibition, alterations of root hairs morphology and organization of microtubules in root cells. It was also revealed that 3-NO2-Tyr intensively decorates such highly dynamic microtubular arrays as preprophase bands, mitotic spindles and phragmoplasts of Nicotiana tabacum Bright Yellow-2 (BY-2) cells under physiological conditions. Moreover, 3D models of the mitotic kinesin-8 complexes with the tail of detyrosinated, tyrosinated and tyrosine nitrated α-tubulin (on C-terminal Tyr 450 residue) from Arabidopsis were reconstructed in silico to investigate the potential influence of tubulin nitrotyrosination on the molecular dynamics of α-tubulin and kinesin-8 interaction. Generally, presented data suggest that plant α-tubulin tyrosine nitration can be considered as its common posttranslational modification, the direct mechanism of NO signal transduction with the participation of microtubules under physiological conditions and one of the hallmarks of the increased microtubule dynamics. PMID:24421781

  3. The structural role of receptor tyrosine sulfation in chemokine recognition

    PubMed Central

    Ludeman, Justin P; Stone, Martin J

    2014-01-01

    Tyrosine sulfation is a post-translational modification of secreted and transmembrane proteins, including many GPCRs such as chemokine receptors. Most chemokine receptors contain several potentially sulfated tyrosine residues in their extracellular N-terminal regions, the initial binding site for chemokine ligands. Sulfation of these receptors increases chemokine binding affinity and potency. Although receptor sulfation is heterogeneous, insights into the molecular basis of sulfotyrosine (sTyr) recognition have been obtained using purified, homogeneous sulfopeptides corresponding to the N-termini of chemokine receptors. Receptor sTyr residues bind to a shallow cleft defined by the N-loop and β3-strand elements of cognate chemokines. Tyrosine sulfation enhances the affinity of receptor peptides for cognate chemokines in a manner dependent on the position of sulfation. Moreover, tyrosine sulfation can alter the selectivity of receptor peptides among several cognate chemokines for the same receptor. Finally, binding to receptor sulfopeptides can modulate the oligomerization state of chemokines, thereby influencing the ability of a chemokine to activate its receptor. These results increase the motivation to investigate the structural basis by which tyrosine sulfation modulates chemokine receptor activity and the biological consequences of this functional modulation. Linked ArticlesThis article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-5 PMID:24116930

  4. Queuine mediated inhibition in phosphorylation of tyrosine phosphoproteins in cancer.

    PubMed

    Pathak, Chandramani; Jaiswal, Yogesh K; Vinayak, Manjula

    2008-09-01

    Protein phosphorylation or dephosphorylation is the most important regulatory switch of signal transduction contributing to control of cell proliferation. The reversibility of phosphorylation and dephosphorylation is due to the activities of kinases and phosphatase, which determine protein phosphorylation level of cell under different physiological and pathological conditions. Receptor tyrosine kinase (RTK) mediated cellular signaling is precisely coordinated and tightly controlled in normal cells which ensures regulated mitosis. Deregulation of RTK signaling resulting in aberrant activation in RTKs leads to malignant transformation. Queuine is one of the modified base of tRNA which participates in down regulation of tyrosine kinase activity. The guanine analogue queuine is a nutrient factor to eukaryotes and occurs as free base or modified nucleoside queuosine into the first anticodon position of specific tRNAs. The tRNAs are often queuine deficient in cancer and fast proliferating tissues. The present study is aimed to investigate queuine mediated inhibition in phosphorylation of tyrosine phosphorylated proteins in lymphoma bearing mouse. The result shows high level of cytosolic and membrane associated tyrosine phosphoprotein in DLAT cancerous mouse liver compared to normal. Queuine treatments down regulate the level of tyrosine phosphoproteins, which suggests that queuine is involved in regulation of mitotic signaling pathways.

  5. Biphasic Affinity Chromatographic Approach for Deep Tyrosine Phosphoproteome Analysis.

    PubMed

    Deng, Zhenzhen; Dong, Mingming; Wang, Yan; Dong, Jing; Li, Shawn S-C; Zou, Hanfa; Ye, Mingliang

    2017-02-21

    Tyrosine phosphorylation (pTyr) is important for normal physiology and implicated in many human diseases, particularly cancer. Identification of pTyr sites is critical to dissecting signaling pathways and understanding disease pathologies. However, compared with serine/threonine phosphorylation (pSer/pThr), the analysis of pTyr at the proteome level is more challenging due to its low abundance. Here, we developed a biphasic affinity chromatographic approach where Src SH2 superbinder was coupled with NeutrAvidin affinity chromatography, for tyrosine phosphoproteome analysis. With the use of competitive elution agent biotin-pYEEI, this strategy can distinguish high-affinity phosphotyrosyl peptides from low-affinity ones, while the excess competitive agent is readily removed by using NeutrAvidin agarose resin in an integrated tip system. The excellent performance of this system was demonstrated by analyzing tyrosine phosphoproteome of Jurkat cells from which 3,480 unique pTyr sites were identified. The biphasic affinity chromatography method for deep Tyr phosphoproteome analysis is rapid, sensitive, robust, and cost-effective. It is widely applicable to the global analysis of the tyrosine phosphoproteome associated with tyrosine kinase signal transduction.

  6. Heterologous production of caffeic acid from tyrosine in Escherichia coli.

    PubMed

    Rodrigues, J L; Araújo, R G; Prather, K L J; Kluskens, L D; Rodrigues, L R

    2015-04-01

    Caffeic acid is a plant secondary metabolite and its biological synthesis has attracted increased attention due to its beneficial effects on human health. In this study, Escherichia coli was engineered for the production of caffeic acid using tyrosine as the initial precursor of the pathway. The pathway design included tyrosine ammonia lyase (TAL) from Rhodotorula glutinis to convert tyrosine to p-coumaric acid and 4-coumarate 3-hydroxylase (C3H) from Saccharothrix espanaensis or cytochrome P450 CYP199A2 from Rhodopseudomonas palustris to convert p-coumaric acid to caffeic acid. The genes were codon-optimized and different combinations of plasmids were used to improve the titer of caffeic acid. TAL was able to efficiently convert 3mM of tyrosine to p-coumaric acid with the highest production obtained being 2.62mM (472mg/L). CYP199A2 exhibited higher catalytic activity towards p-coumaric acid than C3H. The highest caffeic acid production obtained using TAL and CYP199A2 and TAL and C3H was 1.56mM (280mg/L) and 1mM (180mg/L), respectively. This is the first study that shows caffeic acid production using CYP199A2 and tyrosine as the initial precursor. This study suggests the possibility of further producing more complex plant secondary metabolites like flavonoids and curcuminoids.

  7. Mechanisms of peroxynitrite-mediated nitration of tyrosine.

    PubMed

    Gunaydin, Hakan; Houk, K N

    2009-05-01

    The mechanisms of tyrosine nitration by peroxynitrous acid or nitrosoperoxycarbonate were investigated with the CBS-QB3 method. Either the protonation of peroxynitrite or a reaction with carbon dioxide gives a reactive peroxide intermediate. Peroxynitrous acid-mediated nitration of phenol occurs via unimolecular decomposition to give nitrogen dioxide and hydroxyl radicals. Nitrosoperoxycarbonate also undergoes unimolecular decomposition to give carbonate and nitrogen dioxide radicals. The reactions of tyrosine with the hydroxyl or carbonate radicals give a phenoxy radical intermediate. The reaction of the nitrogen dioxide with this radical intermediate followed by tautomerization gives nitrated tyrosine in both cases. According to CBS-QB3 calculations, the rate-limiting step for the nitration of phenol is the decomposition of peroxynitrous acid or nitrosoperoxycarbonate.

  8. Tyrosine phosphorylation of clathrin heavy chain under oxidative stress.

    PubMed

    Ihara, Yoshito; Yasuoka, Chie; Kageyama, Kan; Wada, Yoshinao; Kondo, Takahito

    2002-09-20

    In mouse pancreatic insulin-producing betaTC cells, oxidative stress due to H(2)O(2) causes tyrosine phosphorylation in various proteins. To identify proteins bearing phosphotyrosine under stress, the proteins were affinity purified using an anti-phosphotyrosine antibody-conjugated agarose column. A protein of 180kDa was identified as clathrin heavy chain (CHC) by electrophoresis and mass spectrometry. Immunoprecipitated CHC showed tyrosine phosphorylation upon H(2)O(2) treatment and the phosphorylation was suppressed by the Src kinase inhibitor, PP2. The phosphorylation status of CHC affected the intracellular localization of CHC and the clathrin-dependent endocytosis of transferrin under oxidative stress. In conclusion, CHC is a protein that is phosphorylated at tyrosine by H(2)O(2) and this phosphorylation status is implicated in the intracellular localization and functions of CHC under oxidative stress. The present study demonstrates that oxidative stress affects intracellular vesicular trafficking via the alteration of clathrin-dependent vesicular trafficking.

  9. Tyrosine Kinase Inhibitors and Diabetes: A Novel Treatment Paradigm?

    PubMed

    Fountas, Athanasios; Diamantopoulos, Leonidas-Nikolaos; Tsatsoulis, Agathocles

    2015-11-01

    Deregulation of protein tyrosine kinase (PTK) activity is implicated in various proliferative conditions. Multi-target tyrosine kinase inhibitors (TKIs) are increasingly used for the treatment of different malignancies. Recently, several clinical cases of the reversal of both type 1 and 2 diabetes mellitus (T1DM, T2DM) during TKI administration have been reported. Experimental in vivo and in vitro studies have elucidated some of the mechanisms behind this effect. For example, inhibition of Abelson tyrosine kinase (c-Abl) results in β cell survival and enhanced insulin secretion, while platelet-derived growth factor receptor (PDGFR) and epidermal growth factor receptor (EGFR) inhibition leads to improvement in insulin sensitivity. In addition, inhibition of vascular endothelial growth factor receptor 2 (VEGFR2) reduces the degree of islet cell inflammation (insulitis). Therefore, targeting several PTKs may provide a novel approach for correcting the pathophysiologic disturbances of diabetes.

  10. Spectroscopic analysis of tyrosine derivatives: on the role of the tyrosine-histidine covalent linkage in cytochrome c oxidase.

    PubMed

    Voicescu, Mariana; El Khoury, Youssef; Martel, David; Heinrich, Martine; Hellwig, Petra

    2009-10-08

    2'-(1-Imidazolyl)-4-methylphenol (C-N bonding in the ortho' position at the phenyl group), a model compound for a tyrosine-histidine covalent linkage, was studied with a combined electrochemical and UV-vis/IR spectroscopic approach. Electrochemical analysis of the 2'-(1-imidazolyl)-4-methylphenol model compound by the means of cyclic voltammetry yielded a potential of 0.48 vs ferrocene (1.15 V vs NHE) for the oxidation of the deprotonated form, the reaction being kinetically irreversible. A tentative assignment of the electrochemically induced Fourier transform infrared (FTIR) difference infrared spectra is presented that indicates the deprotonation of the tyrosine before oxidation and importantly the strong influence of the solvent on the spectral properties and on the mechanism of radical formation. Fluorescence lifetimes and pre-exponential factors of the tyrosine-histidine model compounds are presented and discussed in comparison to tyrosine. The tyrosine-histidine fluorescence lifetime is found to be solvent dependent. The influence of the solvent on the reaction mechanism is proposed with regard to the mechanism of electron coupled proton transfer in proteins that include covalently linked amino acid side chains, like the cytochrome c oxidase.

  11. Tryptophan prenyltransferases showing higher catalytic activities for Friedel-Crafts alkylation of o- and m-tyrosines than tyrosine prenyltransferases.

    PubMed

    Fan, Aili; Xie, Xiulan; Li, Shu-Ming

    2015-07-21

    Tryptophan prenyltransferases FgaPT2, 5-DMATS, 6-DMATSSv and 7-DMATS catalyse regiospecific C-prenylations on the indole ring, while tyrosine prenyltransferases SirD and TyrPT catalyse the O-prenylation of the phenolic hydroxyl group. In this study, we report the Friedel-Crafts alkylation of L-o-tyrosine by these enzymes. Surprisingly, no conversion was detected with SirD and three tryptophan prenyltransferases showed significantly higher activity than another tyrosine prenyltransferase TyrPT. C5-prenylated L-o-tyrosine was identified as a unique product of these enzymes. Using L-m-tyrosine as the prenylation substrate, product formation was only observed with the tryptophan prenyltransferases FgaPT2 and 7-DMATS. C4- and C6-prenylated derivatives were identified in the reaction mixture of FgaPT2. These results provided additional evidence for the similarities and differences between these two subgroups within the DMATS superfamily in their catalytic behaviours.

  12. Evaluation of Brachypodium distachyon L-Tyrosine Decarboxylase Using L-Tyrosine Over-Producing Saccharomyces cerevisiae.

    PubMed

    Noda, Shuhei; Shirai, Tomokazu; Mochida, Keiichi; Matsuda, Fumio; Oyama, Sachiko; Okamoto, Mami; Kondo, Akihiko

    2015-01-01

    To demonstrate that herbaceous biomass is a versatile gene resource, we focused on the model plant Brachypodium distachyon, and screened the B. distachyon for homologs of tyrosine decarboxylase (TDC), which is involved in the modification of aromatic compounds. A total of 5 candidate genes were identified in cDNA libraries of B. distachyon and were introduced into Saccharomyces cerevisiae to evaluate TDC expression and tyramine production. It is suggested that two TDCs encoded in the transcripts Bradi2g51120.1 and Bradi2g51170.1 have L-tyrosine decarboxylation activity. Bradi2g51170.1 was introduced into the L-tyrosine over-producing strain of S. cerevisiae that was constructed by the introduction of mutant genes that promote deregulated feedback inhibition. The amount of tyramine produced by the resulting transformant was 6.6-fold higher (approximately 200 mg/L) than the control strain, indicating that B. distachyon TDC effectively converts L-tyrosine to tyramine. Our results suggest that B. distachyon possesses enzymes that are capable of modifying aromatic residues, and that S. cerevisiae is a suitable host for the production of L-tyrosine derivatives.

  13. Characterization of the interactions between the active site of a protein tyrosine kinase and a divalent metal activator

    PubMed Central

    Lin, Xiaofeng; Ayrapetov, Marina K; Sun, Gongqin

    2005-01-01

    Background Protein tyrosine kinases are important enzymes for cell signalling and key targets for anticancer drug discovery. The catalytic mechanisms of protein tyrosine kinase-catalysed phosphorylation are not fully understood. Protein tyrosine kinase Csk requires two Mg2+ cations for activity: one (M1) binds to ATP, and the other (M2) acts as an essential activator. Results Experiments in this communication characterize the interaction between M2 and Csk. Csk activity is sensitive to pH in the range of 6 to 7. Kinetic characterization indicates that the sensitivity is not due to altered substrate binding, but caused by the sensitivity of M2 binding to pH. Several residues in the active site with potential of binding M2 are mutated and the effect on metal activation studied. An active mutant of Asn319 is generated, and this mutation does not alter the metal binding characteristics. Mutations of Glu236 or Asp332 abolish the kinase activity, precluding a positive or negative conclusion on their role in M2 coordination. Finally, the ability of divalent metal cations to activate Csk correlates to a combination of ionic radius and the coordination number. Conclusion These studies demonstrate that M2 binding to Csk is sensitive to pH, which is mainly responsible for Csk activity change in the acidic arm of the pH response curve. They also demonstrate critical differences in the metal activator coordination sphere in protein tyrosine kinase Csk and a protein Ser/Thr kinase, the cAMP-dependent protein kinase. They shed light on the physical interactions between a protein tyrosine kinase and a divalent metal activator. PMID:16305747

  14. Phosphorylated tyrosine in the flagellum filament protein of Pseudomonas aeruginosa

    SciTech Connect

    Kelly-Wintenberg, K.; Anderson, T.; Montie, T.C. )

    1990-09-01

    Purified flagella from two strains of {sup 32}P-labeled Pseudomonas aeruginosa were shown to be phosphorylated. This was confirmed by autoradiography of flagellin protein in polyacrylamide gels. Thin-layer electrophoresis and autoradiography of flagellin partial hydrolysates indicated that phosphotyrosine was the major phosphorylated amino acid. High-pressure liquid chromatographic analysis confirmed the presence of phosphotyrosine in flagellum filament protein. Preliminary data indicated that less than one tyrosine per subunit was phosphorylated. No evidence was found for phosphorylation of serine or threonine. A function related to tyrosine phosphorylation has not been determined.

  15. Proteasomal inhibition causes loss of nigral tyrosine hydroxylase neurons.

    PubMed

    Schapira, Anthony H V; Cleeter, Michael W J; Muddle, John R; Workman, Jane M; Cooper, J Mark; King, Rosalind H M

    2006-08-01

    Dysfunction of the ubiquitin-proteasomal system (UPS) has been implicated in the pathogenesis of Parkinson's disease. The systemic administration of UPS inhibitors has been reported to induce nigrostriatal cell death and model Parkinson's disease pathology in rodents. We administered a synthetic, specific UPS inhibitor (PSI) subcutaneously to rats and quantified substantia nigral tyrosine hydroxylase-positive dopaminergic neurons by stereology. PSI caused a 15% decrease in UPS activity at 2 weeks and a 42% reduction in substantia nigra pars compacta tyrosine hydroxylase-positive neurons at 8 weeks. Systemic inhibition of the UPS warrants further evaluation as a means to model Parkinson's disease.

  16. Targeting Protein Tyrosine Phosphatases for Anticancer Drug Discovery

    PubMed Central

    Scott, Latanya. M.; Lawrence, Harshani. R.; Sebti, Saïd. M.; Lawrence, Nicholas. J.; Wu, Jie.

    2010-01-01

    Protein tyrosine phosphatases (PTPs) are a diverse family of enzymes encoded by 107 genes in the human genome. Together with protein tyrosine kinases (PTKs), PTPs regulate various cellular activities essential for the initiation and maintenance of malignant phenotypes. While PTK inhibitors are now used routinely for cancer treatment, the PTP inhibitor development field is still in the discovery phase. In this article, the suitability of targeting PTPs for novel anticancer drug discovery is discussed. Examples are presented for PTPs that have been targeted for anticancer drug discovery as well as potential new PTP targets for novel anticancer drug discovery. PMID:20337577

  17. Inhibition of acid, alkaline, and tyrosine (PTP1B) phosphatases by novel vanadium complexes.

    PubMed

    McLauchlan, Craig C; Hooker, Jaqueline D; Jones, Marjorie A; Dymon, Zaneta; Backhus, Emily A; Greiner, Bradley A; Dorner, Nicole A; Youkhana, Mary A; Manus, Lisa M

    2010-03-01

    In the course of our investigations of vanadium-containing complexes for use as insulin-enhancing agents, we have generated a series of novel vanadium coordination complexes with bidentate ligands. Specifically we have focused on two ligands: anthranilate (anc(-)), a natural metabolite of tryptophan, and imidizole-4-carboxylate (imc(-)), meant to mimic naturally occurring N-donor ligands. For each ligand, we have generated a series of complexes containing the V(III), V(IV), and V(V) oxidation states. Each complex was investigated using phosphatase inhibition studies of three different phosphatases (acid, alkaline, and tyrosine (PTP1B) phosphatase) as prima facia evidence for potential use as an insulin-enhancing agent. Using p-nitrophenyl phosphate as an artificial phosphatase substrate, the levels of inhibition were determined by measuring the absorbance of the product at 405nm using UV/vis spectroscopy. Under our experimental conditions, for instance, V(imc)(3) appears to be as potent an inhibitor of alkaline phosphatase as sodium orthovanadate when comparing the K(cat)/K(m) term. VO(anc)(2) is as potent an inhibitor of acid phosphatase and tyrosine phosphatase as the Na(3)VO(4). Thus, use of these complexes can increase our mechanistic understanding of the effects of vanadium in vivo.

  18. Proton-Coupled Electron Transfer and a Tyrosine-Histidine Pair in a Photosystem II-Inspired β-Hairpin Maquette: Kinetics on the Picosecond Time Scale.

    PubMed

    Pagba, Cynthia V; McCaslin, Tyler G; Chi, San-Hui; Perry, Joseph W; Barry, Bridgette A

    2016-02-25

    Photosystem II (PSII) and ribonucleotide reductase employ oxidation and reduction of the tyrosine aromatic ring in radical transport pathways. Tyrosine-based reactions involve either proton-coupled electron transfer (PCET) or electron transfer (ET) alone, depending on the pH and the pKa of tyrosine's phenolic oxygen. In PSII, a subset of the PCET reactions are mediated by a tyrosine-histidine redox-driven proton relay, YD-His189. Peptide A is a PSII-inspired β-hairpin, which contains a single tyrosine (Y5) and histidine (H14). Previous electrochemical characterization indicated that Peptide A conducts a net PCET reaction between Y5 and H14, which have a cross-strand π-π interaction. The kinetic impact of H14 has not yet been explored. Here, we address this question through time-resolved absorption spectroscopy and 280-nm photolysis, which generates a neutral tyrosyl radical. The formation and decay of the neutral tyrosyl radical at 410 nm were monitored in Peptide A and its variant, Peptide C, in which H14 is replaced by cyclohexylalanine (Cha14). Significantly, both electron transfer (ET, pL 11, L = lyonium) and PCET (pL 9) were accelerated in Peptide A and C, compared to model tyrosinate or tyrosine at the same pL. Increased electronic coupling, mediated by the peptide backbone, can account for this rate acceleration. Deuterium exchange gave no significant solvent isotope effect in the peptides. At pL 9, but not at pL 11, the reaction rate decreased when H14 was mutated to Cha14. This decrease in rate is attributed to an increase in reorganization energy in the Cha14 mutant. The Y5-H14 mechanism in Peptide A is reminiscent of proton- and electron-transfer events involving YD-H189 in PSII. These results document a mechanism by which proton donors and acceptors can regulate the rate of PCET reactions.

  19. Palmitoylation of protease-activated receptor-1 regulates adaptor protein complex-2 and -3 interaction with tyrosine-based motifs and endocytic sorting.

    PubMed

    Canto, Isabel; Trejo, JoAnn

    2013-05-31

    Protease-activated receptor-1 (PAR1) is a G protein-coupled receptor for the coagulant protease thrombin. Thrombin binds to and cleaves the N terminus of PAR1, generating a new N terminus that functions as a tethered ligand that cannot diffuse away. In addition to rapid desensitization, PAR1 trafficking is critical for the regulation of cellular responses. PAR1 displays constitutive and agonist-induced internalization. Constitutive internalization of unactivated PAR1 is mediated by the clathrin adaptor protein complex-2 (AP-2), which binds to a distal tyrosine-based motif localized within the C-terminal tail (C-tail) domain. Once internalized, PAR1 is sorted from endosomes to lysosomes via AP-3 interaction with a second C-tail tyrosine motif proximal to the transmembrane domain. However, the regulatory processes that control adaptor protein recognition of PAR1 C-tail tyrosine-based motifs are not known. Here, we report that palmitoylation of PAR1 is critical for regulating proper utilization of tyrosine-based motifs and endocytic sorting. We show that PAR1 is basally palmitoylated at highly conserved C-tail cysteines. A palmitoylation-deficient PAR1 mutant is competent to signal and exhibits a marked increase in constitutive internalization and lysosomal degradation compared with wild type receptor. Intriguingly, enhanced constitutive internalization of PAR1 is mediated by AP-2 and requires the proximal tyrosine-based motif rather than the distal tyrosine motif used by wild type receptor. Moreover, palmitoylation-deficient PAR1 displays increased degradation that is mediated by AP-3. These findings suggest that palmitoylation of PAR1 regulates appropriate utilization of tyrosine-based motifs by adaptor proteins and endocytic trafficking, processes that are critical for maintaining appropriate expression of PAR1 at the cell surface.

  20. A Prospective Three Generational Study of Fathers' Constructive Parenting: Influences from Family of Origin, Adolescent Adjustment, and Offspring Temperament

    ERIC Educational Resources Information Center

    Kerr, David C. R.; Capaldi, Deborah M.; Pears, Katherine C.; Owen, Lee D.

    2009-01-01

    This prospective, intergenerational study considered multiple influences on 102 fathers' constructive parenting of 181 children. Fathers in the 2nd generation (G2) were recruited as boys on the basis of neighborhood risk for delinquency and assessed through early adulthood. The fathers' parents (G1) and the G2 mothers of G3 also participated. A…

  1. Coumarins from Angelica decursiva inhibit α-glucosidase activity and protein tyrosine phosphatase 1B.

    PubMed

    Ali, Md Yousof; Jannat, Susoma; Jung, Hyun Ah; Jeong, Hyong Oh; Chung, Hae Young; Choi, Jae Sue

    2016-05-25

    In the present study, we investigated the anti-diabetic potential of six natural coumarins, 4-hydroxy Pd-C-III (1), 4'-methoxy Pd-C-I (2), decursinol (3), decursidin (4), umbelliferone 6-carboxylic acid (5), and 2'-isopropyl psoralene (6) isolated from Angelica decursiva and evaluated their inhibitory activities against protein tyrosine phosphatase 1B (PTP1B), α-glucosidase, and ONOO(-)-mediated protein tyrosine nitration. Coumarins 1-6 showed potent PTP1B and α-glucosidase inhibitory activities with ranges of IC50 values of 5.39-58.90 μM and 65.29-172.10 μM, respectively. In the kinetic study for PTP1B enzyme inhibition, compounds 1, 5, and 6 were competitive, whereas 2 and 4 showed mixed type, and 3 displayed noncompetitive type inhibition. For α-glucosidase enzyme inhibition, compounds 1 and 3 exhibited good mixed-type, while 2, 5, and 6 showed noncompetitive and 4 displayed competitive type inhibition. Furthermore, these coumarins also effectively suppressed ONOO(-)-mediated tyrosine nitration in a dose-dependent manner. To further investigate PTP1B inhibition, we generated a 3D structure of PTP1B using Autodock 4.2 and simulated the binding of compounds 1-6. Docking simulations showed that different residues of PTP1B interacted with different functional groups of compounds 1-6 through hydrogen and hydrophobic interactions. In addition, the binding energies of compounds 1-6 were negative, suggesting that hydrogen bonding may stabilize the open form of the enzyme and potentiate tight binding of the active site of PTP1B, thereby resulting in more effective PTP1B inhibition. These results demonstrate that the whole plant of A. decursiva and its coumarins are useful as potential functional food ingredients for the prevention and treatment of type 2 diabetes.

  2. The tyrosine kinase p60c-src regulates the fast gate of the cystic fibrosis transmembrane conductance regulator chloride channel.

    PubMed

    Fischer, H; Machen, T E

    1996-12-01

    The role of the tyrosine kinase p60c-src on the gating of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel was investigated with the cell-attached and excised patch clamp technique in conjunction with current noise analysis of recordings containing multiple channels per patch. Spectra of CFTR-generated current noise contained a low-frequency and a high-frequency Lorentzian noise component. In the cell-attached mode, the high-frequency Lorentzian was significantly dependent on the membrane potential, while the low-frequency Lorentzian was unaffected. Excision of forskolin-stimulated patches into ATP-containing solution significantly reduced the amplitude of the voltage-dependent high-frequency Lorentzian. Addition of the tyrosine kinase p60c-src to excised, active, CFTR-containing membrane patches increased mean currents by 54%, increased the corner frequency of the low-frequency Lorentzian, and recovered the high-frequency Lorentzian and its characteristics. Treatment with lambda-phosphatase inactivated src-induced currents and changes in gating. When active patches were excised under conditions in which patch-associated tyrosine phosphatases were blocked with sodium vanadate, the high-frequency gating remained relatively unchanged. The results suggest that CFTR's open probability and its voltage-dependent fast gate are dependent on tyrosine phosphorylation, and that membrane-associated tyrosine phosphatases are responsible for inactivation of the fast gate after patch excision.

  3. 21 CFR 862.1730 - Free tyrosine test system.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Free tyrosine test system. 862.1730 Section 862.1730 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... phenylketonuria (a disease that can cause brain damage). (b) Classification. Class I....

  4. 21 CFR 862.1730 - Free tyrosine test system.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Free tyrosine test system. 862.1730 Section 862.1730 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... phenylketonuria (a disease that can cause brain damage). (b) Classification. Class I....

  5. 21 CFR 862.1730 - Free tyrosine test system.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Free tyrosine test system. 862.1730 Section 862.1730 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... phenylketonuria (a disease that can cause brain damage). (b) Classification. Class I....

  6. 21 CFR 862.1730 - Free tyrosine test system.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Free tyrosine test system. 862.1730 Section 862.1730 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... phenylketonuria (a disease that can cause brain damage). (b) Classification. Class I....

  7. Tyrosine decarboxylase from Lactobacillus brevis: soluble expression and characterization.

    PubMed

    Zhang, Kai; Ni, Ye

    2014-02-01

    Tyrosine decarboxylase (TDC, EC 4.1.1.25) is an enzyme that catalyzes the decarboxylation of l-tyrosine to produce tyramine and CO2. In this study, a 1881-bp tdc gene from Lactobacillus brevis was cloned and heterologously expressed in Escherichia coli BL21 (DE3). Glucose was discovered to play an important role in the soluble expression of rLbTDC. After optimization, recombinant TDC (rLbTDC) was achieved in excellent solubility and a yield of 224mg rLbTDC/L broth. The C-terminal His-Tagged rLbTDC was one-step purified with 90% recovery. Based on SDS-PAGE and gel filtration analysis, rLbTDC is a dimer composed of two identical subunits of approximately 70kDa. Using l-tyrosine as substrate, the specific activity of rLbTDC was determined to be 133.5U/mg in the presence of 0.2mM pyridoxal-5'-phosphate at 40°C and pH 5.0. The Km and Vmax values of rLbTDC were 0.59mM and 147.1μmolmin(-1)mg(-1), respectively. In addition to l-tyrosine, rLbTDC also exhibited decarboxylase activity towards l-DOPA. This study has demonstrated, for the first time, the soluble expression of tdc gene from L. brevis in heterologous host.

  8. Old Tyrosine Kinase Inhibitors and Newcomers in Gastrointestinal Cancer Treatment.

    PubMed

    Giordani, Erika; Zoratto, Federica; Strudel, Martina; Papa, Anselmo; Rossi, Luigi; Minozzi, Marina; Caruso, Davide; Zaccarelli, Eleonora; Verrico, Monica; Tomao, Silverio

    2016-01-01

    Gastrointestinal cancer treatment is based more on molecular biology that has provided increasing knowledge about cancer pathogenesis on which targeted therapy is being developed. Precisely, targeted therapy is defined as a "type of treatment that uses drugs, such as monoclonal antibodies or tyrosine kinase inhibitors, to identify and attack specific cancer cells". Nowadays, the United States Food and Drug Administration has approved many targeted therapies for gastrointestinal cancer treatment, as many are in various phases of development as well. In a previous review we discussed the main monoclonal antibodies used and studied in gastrointestinal cancer. In addition to monoclonal antibodies, tyrosine kinase inhibitors represent another class of targeted therapy and following the approval of imatinib for gastrointestinal stromal tumours, other tyrosine kinase inhibitors have been approved for gastrointestinal cancers treatment such as sunitinib, regoragenib, sorafenib and erlotinib. Moving forward, the purpose of this review is to focus on the efficacy data of main tyrosine kinase inhibitors commonly used in the personalized treatment of each gastrointestinal tumour and to provide a comprehensive overview about experimental targeted therapies ongoing in this setting.

  9. Levodopa-induced dyskinesias in tyrosine hydroxylase deficiency.

    PubMed

    Pons, Roser; Syrengelas, Dimitris; Youroukos, Sotiris; Orfanou, Irene; Dinopoulos, Arqirios; Cormand, Bru; Ormazabal, Aida; Garzía-Cazorla, Angels; Serrano, Mercedes; Artuch, Rafael

    2013-07-01

    The objective of this study was to characterize levodopa (l-dopa)-induced dyskinesias in patients with tyrosine hydroxylase deficiency. Clinical observation was carried out on 6 patients who were diagnosed with tyrosine hydroxylase deficiency and were treated with escalating doses of l-dopa. All 6 patients showed l-dopa-induced dyskinesias of variable intensity early in the course of treatment and regardless of the age of initiation. l-Dopa-induced dyskinesias were precipitated by increases in the dose of l-dopa and also by febrile illnesses and stress. They caused dysfunction and distress in 2 patients. The dyskinesias were improved by decreasing the l-dopa dose or by slowing its titration upward. Increasing the dose frequency was helpful in 2 patients, and introducing amantadine was helpful in another 2 patients. l-Dopa-induced dyskinesias are a common phenomenon in tyrosine hydroxylase deficiency. The current observations show that l-dopa-induced dyskinesias are frequent in a dopamine-deficient state in the absence of nigrostriatal degeneration. Although l-dopa-induced dyskinesias in tyrosine hydroxylase deficiency are phenomenologically similar to those that occur in Parkinson's disease, they are different in a number of other respects, suggesting intrinsic differences in the pathophysiologic basis of l-dopa-induced dyskinesias in the 2 conditions. © 2013 Movement Disorder Society.

  10. 21 CFR 862.1730 - Free tyrosine test system.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... measure free tyrosine (an amono acid) in serum and urine. Measurements obtained by this device are used in the diagnosis and treatment of diseases such as congenital tyrosinemia (a disease that can cause liver... phenylketonuria (a disease that can cause brain damage). (b) Classification. Class I....

  11. ZDHHC3 Tyrosine Phosphorylation Regulates Neural Cell Adhesion Molecule Palmitoylation

    PubMed Central

    Lievens, Patricia Marie-Jeanne; Kuznetsova, Tatiana; Kochlamazashvili, Gaga; Cesca, Fabrizia; Gorinski, Natalya; Galil, Dalia Abdel; Cherkas, Volodimir; Ronkina, Natalia; Lafera, Juri; Gaestel, Matthias

    2016-01-01

    The neural cell adhesion molecule (NCAM) mediates cell-cell and cell-matrix adhesion. It is broadly expressed in the nervous system and regulates neurite outgrowth, synaptogenesis, and synaptic plasticity. Previous in vitro studies revealed that palmitoylation of NCAM is required for fibroblast growth factor 2 (FGF2)-stimulated neurite outgrowth and identified the zinc finger DHHC (Asp-His-His-Cys)-containing proteins ZDHHC3 and ZDHHC7 as specific NCAM-palmitoylating enzymes. Here, we verified that FGF2 controlled NCAM palmitoylation in vivo and investigated molecular mechanisms regulating NCAM palmitoylation by ZDHHC3. Experiments with overexpression and pharmacological inhibition of FGF receptor (FGFR) and Src revealed that these kinases control tyrosine phosphorylation of ZDHHC3 and that ZDHHC3 is phosphorylated by endogenously expressed FGFR and Src proteins. By site-directed mutagenesis, we found that Tyr18 is an FGFR1-specific ZDHHC3 phosphorylation site, while Tyr295 and Tyr297 are specifically phosphorylated by Src kinase in cell-based and cell-free assays. Abrogation of tyrosine phosphorylation increased ZDHHC3 autopalmitoylation, enhanced interaction with NCAM, and upregulated NCAM palmitoylation. Expression of ZDHHC3 with tyrosine mutated in cultured hippocampal neurons promoted neurite outgrowth. Our findings for the first time highlight that FGFR- and Src-mediated tyrosine phosphorylation of ZDHHC3 modulates ZDHHC3 enzymatic activity and plays a role in neuronal morphogenesis. PMID:27247265

  12. In vitro enzymatic assays of protein tyrosine phosphatase 1B.

    PubMed

    Lubben, T; Clampit, J; Stashko, M; Trevillyan, J; Jirousek, M R

    2001-08-01

    Many hormone or growth factor receptors signal via the activation of protein-tyrosine kinases and phosphatases. Alteration of the phosphorylation state of tyrosine residues in certain proteins can directly regulate enzyme activity or cause formation of protein complexes necessary for transducing intracellular signals. Genetic and biochemical evidence also implicates protein-tyrosine phosphatases in several disease processes, including negative regulation of insulin receptor signaling at the level of the insulin receptor and perhaps in signaling at the IRS-1 level. The expression of protein tyrosine phosphatase-1B (PTP1B) is elevated in muscle and adipose tissue in insulin-resistant states both in man and rodents suggesting that PTP1B may play a role in the insulin-resistant state associated with diabetes and obesity. As described in this unit, PTP1B activity can be determined with the small molecule substrate, p-nitrophenyl phosphate (pNPP), in which the cleavage of the phosphate results in production of p-nitrophenol (pNP) and an increase in absorbance at 405 nm. Alternatively, PTP1B activity can be measured as described using model phosphotyrosyl-containing peptide substrates in which the release of free phosphate from the peptide is determined using a malachite green colorimetric assay.

  13. Protein tyrosine nitration in pea roots during development and senescence

    PubMed Central

    Corpas, Francisco J.

    2013-01-01

    Protein tyrosine nitration is a post-translational modification mediated by reactive nitrogen species (RNS) that is associated with nitro-oxidative damage. No information about this process is available in relation to higher plants during development and senescence. Using pea plants at different developmental stages (ranging from 8 to 71 days), tyrosine nitration in the main organs (roots, stems, leaves, flowers, and fruits) was analysed using immunological and proteomic approaches. In the roots of 71-day-old senescent plants, nitroproteome analysis enabled the identification a total of 16 nitrotyrosine-immunopositive proteins. Among the proteins identified, NADP-isocitrate dehydrogenase (ICDH), an enzyme involved in the carbon and nitrogen metabolism, redox regulation, and responses to oxidative stress, was selected to evaluate the effect of nitration. NADP-ICDH activity fell by 75% during senescence. Analysis showed that peroxynitrite inhibits recombinant cytosolic NADP-ICDH activity through a process of nitration. Of the 12 tyrosines present in this enzyme, mass spectrometric analysis of nitrated recombinant cytosolic NADP-ICDH enabled this study to identify the Tyr392 as exclusively nitrated by peroxynitrite. The data as a whole reveal that protein tyrosine nitration is a nitric oxide-derived PTM prevalent throughout root development and intensifies during senescence. PMID:23362300

  14. Receptor for bombesin with associated tyrosine kinase activity.

    PubMed Central

    Cirillo, D M; Gaudino, G; Naldini, L; Comoglio, P M

    1986-01-01

    The neuropeptide bombesin is known for its potent mitogenic activity on murine 3T3 fibroblasts and other cells. Recently it has been implicated in the pathogenesis of small cell lung carcinoma, in which it acts through an autocrine loop of growth stimulation. Phosphotyrosine (P-Tyr) antibodies have been successfully used to recognize the autophosphorylated receptors for known growth factors. In Swiss 3T3 fibroblasts, phosphotyrosine antibodies identified a 115,000-Mr cell surface protein (p115) that became phosphorylated on tyrosine as a specific response to bombesin stimulation of quiescent cells. The extent of phosphorylation was dose dependent and correlated with the mitogenic effect induced by bombesin, measured by [3H]thymidine incorporation. Tyrosine phosphorylation of p115 was detectable minutes after the addition of bombesin, and its time course paralleled that described for the binding of bombesin to its receptor. Immunocomplexes of phosphorylated p115 and phosphotyrosine antibodies bound 125I-labeled [Tyr4]bombesin in a specific and saturable manner and displayed an associated tyrosine kinase activity enhanced by bombesin. Furthermore, the 125I-labeled bombesin analog gastrin-releasing peptide, bound to intact live cells, was coprecipitated with p115. These data strongly suggest that p115 participates in the structure and function of the surface receptor for bombesin, a new member of the family of growth factor receptors with associated tyrosine kinase activity. Images PMID:2432404

  15. Teaching resources. Growth factor and receptor tyrosine kinases.

    PubMed

    Aaronson, Stuart

    2005-02-22

    This Teaching Resource provides lecture notes and slides for a graduate-level class on ligand regulation of signaling by receptor tyrosine kinases and receptors involved in the Wnt canonical pathway. It is part of a series of lectures that constitute the Cell Signaling Systems course. A description of the lecture, along with a set of slides used to present this information, is provided.

  16. Feasibility Study of Supercritical Light Water Cooled Reactors for Electric Power Production, Progress Report for Work Through September 2003, 2nd Annual/8th Quarterly Report

    SciTech Connect

    Philip E. MacDonald

    2003-09-01

    The supercritical water-cooled reactor (SCWR) is one of the six reactor technologies selected for research and development under the Generation-IV program. SCWRs are promising advanced nuclear systems because of their high thermal efficiency (i.e., about 45% vs. about 33% efficiency for current Light Water Reactors, LWRs) and considerable plant simplification. SCWRs are basically LWRs operating at higher pressure and temperatures with a direct once-through cycle. Operation above the critical pressure eliminates coolant boiling, so the coolant remains single-phase throughout the system. Thus the need for recirculation and jet pumps, a pressurizer, steam generators, steam separators and dryers is eliminated. The main mission of the SCWR is generation of low-cost electricity. It is built upon two proven technologies, LWRs, which are the most commonly deployed power generating reactors in the world, and supercritical fossil-fired boilers, a large number of which is also in use around the world.

  17. Generation, Language, Body Mass Index, and Activity Patterns in Hispanic Children

    PubMed Central

    Taverno, Sharon E.; Rollins, Brandi Y.; Francis, Lori A.

    2010-01-01

    Background The acculturation hypothesis proposes an overall disadvantage in health outcomes for Hispanic immigrants with more time spent living in the U.S., but little is known about how generational status and language may influence Hispanic children’s relative weight and activity patterns. Purpose The association between generation and language was investigated with relative weight (BMI z-scores), physical activity, screen time, and participation in extracurricular activities (e.g., sports, clubs) in a U.S.-based, nationally representative sample of Hispanic children. Methods Participants included 2,012 Hispanic children aged 6–11 years from the cross-sectional, 2003 National Survey of Children’s Health. Children were grouped according to generational status (1st, 2nd or 3rd), and the primary language spoken in the home (English vs non-English). Primary analyses included adjusted logistic and multinomial logistic regression to examine the relationships among variables; all analyses were conducted between 2008 and 2009. Results Compared to 3rd generation, English speakers, 1st and 2nd generation, non-English speakers were over two times more likely to be obese. Moreover, 1st generation, non-English speakers were half as likely to engage in regular physical activity and sports. Both 1st and 2nd generation, non-English speakers were less likely to participate in clubs compared to 2nd and 3rd generation, English speakers. Overall, all non–English speaking groups reported less screen time compared to 3rd generation, English speakers. Conclusions The hypothesis that Hispanics lose their health protection with more time spent in the U.S. was not supported in this sample of Hispanic children. PMID:20117570

  18. Motogenic and morphogenic activity of epithelial receptor tyrosine kinases

    PubMed Central

    1996-01-01

    Receptor tyrosine kinases play essential roles in morphogenesis and differentiation of epithelia. Here we examined various tyrosine kinase receptors, which are preferentially expressed in epithelia (c-met, c- ros, c-neu, and the keratin growth factor [KGF] receptor), for their capacity to induce cell motility and branching morphogenesis of epithelial cells. We exchanged the ligand-binding domain of these receptors by the ectodomain of trkA and could thus control signaling by the new ligand, NGF. We demonstrate here that the tyrosine kinases of c- met, c-ros, c-neu, the KGF receptor, and trkA, but not the insulin receptor, induced scattering and increased motility of kidney epithelial cells in tissue culture. Mutational analysis suggests that SHC binding is essential for scattering and increased cell motility induced by trkA. The induction of motility in epithelial cells is thus an important feature of various receptor tyrosine kinases, which in vivo play a role in embryogenesis and metastasis. In contrast, only the c-met receptor promoted branching morphogenesis of kidney epithelial cells in three-dimensional matrices, which resemble the formation of tubular epithelia in development. Interestingly, the ability of c-met to induce morphogenesis could be transferred to trkA, when in a novel receptor hybrid COOH-terminal sequences of c-met (including Y14 to Y16) were fused to the trkA kinase domain. These data demonstrate that tubulogenesis of epithelia is a restricted activity of tyrosine kinases, as yet only demonstrated for the c-met receptor. We predict the existence of specific substrates that mediate this morphogenesis signal. PMID:8655582

  19. Biochemistry of primary headaches: role of tyrosine and tryptophan metabolism.

    PubMed

    D'Andrea, G; Cevoli, S; Colavito, D; Leon, A

    2015-05-01

    The pathogenesis of migraine as well as cluster headache (CH) is yet a debated question. In this review, we discuss the possible role of the of tyrosine and tryptophan metabolism in the pathogenesis of these primary headaches. These include the abnormalities in the synthesis of neurotransmitters: high level of DA, low level of NE and very elevated levels of octopamine and synephrine (neuromodulators) in plasma of episodic migraine without aura and CH patients. We hypothesize that the imbalance between the levels of neurotransmitters and elusive amines synthesis is due to a metabolic shift directing tyrosine toward an increased decarboxylase and reduced hydroxylase enzyme activities. The metabolic shift of the tyrosine is favored by a state of neuronal hyperexcitability and a reduced mitochondrial activity present in migraine. In addition we present biochemical studies performed in chronic migraine and chronic tension-type headache patients to verify if the same anomalies of the tyrosine and tryptophan metabolism are present in these primary headaches and, if so, their possible role in the chronicity process of CM and CTTH. The results show that important abnormalities of tyrosine metabolism are present only in CM patients (very high plasma levels of DA, NE and tryptamine). Tryptamine plasma levels were found significantly lower in both CM and CTTH patients. In view of this, we propose that migraine and, possibly, CH attacks derive from neurotransmitter and neuromodulator metabolic abnormalities in a hyperexcitable and hypoenergetic brain that spread from the frontal lobe, downstream, resulting in abnormally activated nuclei of the pain matrix. The low tryptamine plasma levels found in CM and CTTH patients suggest that these two primary chronic headaches are characterized by a common insufficient serotoninergic control of the pain threshold.

  20. Interaction between cAMP-dependent and insulin-dependent signal pathways in tyrosine phosphorylation in primary cultures of rat hepatocytes.

    PubMed Central

    Ito, Y; Uchijima, Y; Ariga, M; Seki, T; Takenaka, A; Hakuno, F; Takahashi, S I; Ariga, T; Noguchi, T

    1997-01-01

    The present studies were undertaken to determine whether the interaction between cAMP-dependent and insulin-dependent pathways in primary cultures of rat hepatocytes affects biological functions and tyrosine phosphorylation. Quiescent hepatocytes were pretreated with dibutyryl cAMP or cAMP-generating agents such as glucagon, and then treated or not with insulin. Preincubation for 6 h with dibutyryl cAMP or glucagon enhanced the effect of insulin on DNA synthesis, but not the effect of insulin on amino acid transport or glycogen and protein synthesis. Tyrosine phosphorylation of intracellular proteins was determined by immunoblot analysis using an anti-phosphotyrosine antibody. Maximum tyrosine phosphorylation of a 195 kDa protein, which may be a substrate of insulin receptor kinase, of 175-180 kDa proteins, including insulin receptor substrate (IRS)-1, and of 90-95 kDa proteins, including the insulin receptor beta-subunit, was reached within 30 s of incubation with insulin. Pretreatment for about 3 h with dibutyryl cAMP or cAMP-generating agents clearly increased insulin-dependent tyrosine phosphorylation of the 195 kDa protein, but not IRS-1, IRS-2 or the insulin receptor beta-subunit. Because dibutyryl cAMP and cAMP-generating agents did not increase insulin receptor number or its kinase activity, the effect of cAMP on this potentiation of tyrosine phosphorylation is assumed to be exerted at a step distal to insulin receptor kinase activation. The potentiation by cAMP pretreatment of insulin-stimulated tyrosine phosphorylation may in part be secondary to inhibition of phosphotyrosine phosphatase activity, because cAMP pretreatment blunted the effect of Na3VO4 on the net tyrosine phosphorylation of the 195 kDa protein as compared with cells pretreated with no additive. In summary, the interactions between cAMP-dependent and insulin-dependent pathways that lead to augmentation of DNA synthesis appear to parallel the changes in tyrosine phosphorylation. Further