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Sample records for 2nd generation tyrosine

  1. Outcome of Treatment of CML with 2nd Generation Tyrosine Kinase Inhibitors After Imatinib Failure

    PubMed Central

    Cornelison, A. Megan; Kantarjian, Hagop; Cortes, Jorge; Jabbour, Elias

    2015-01-01

    Although imatinib revolutionized the management of chronic myeloid leukemia (CML), recent data indicate a transformation in the treatment approach likely in the near future. For patients who fail with standard-dose imatinib therapy, imatinib dose escalation is a second-line option. However, high-dose imatinib is not an appropriate approach for patients experiencing drug toxicity, and there remain questions over the durability of responses achieved with this strategy. Alternative second-line options include the newer tyrosine kinase inhibitors (TKIs) like dasatinib and nilotinib. A substantial amount of long-term data for these agents is available. Although both are potent and specific BCR-ABL TKIs, dasatinib and nilotinib exhibit unique pharmacological profiles and response patterns relative to different patient characteristics, such as disease stage and BCR-ABL mutational status. The superiority of second generation TKIs over imatinib in newly diagnosed disease has been recognized as well. They induce high and rapid rates of cytogenetic and molecular response, with less progression to advanced forms of disease in comparison with imatinib. Several investigational agents specific for those patients with the T315I mutation remain under evaluation. The future of CML therapy may include early use of these potent agents to help more patients achieve molecular remission and potentially be a path to a CML cure. PMID:22035738

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

    PubMed Central

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

    2014-01-01

    Despite a well-recognized clinical benefit of the 2nd-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. PMID:24658819

  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. 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.

  9. 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.

  10. 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.

  11. 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

  12. 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

  13. Coal-fired generation staging a comeback. 2nd ed.

    SciTech Connect

    2007-07-01

    The report is an overview of the renewed U.S. market interest in coal-fired power generation. It provides a concise look at what is driving interest in coal-fired generation, the challenges faced in implementing coal-fired generation projects, and the current and future state of coal-fired generation. Topics covered in the report include: An overview of coal-fired generation including its history, the current market environment, and its future prospects; An analysis of the key business factors that are driving renewed interest in coal-fired generation; An analysis of the challenges that are hindering the implementation of coal-fired generation projects; A description of coal-fired generation technologies; A review of the economic drivers of coal-fired generation project success; An evaluation of coal-fired generation versus other generation technologies; A discussion of the key government initiatives supporting new coal-fired generation; and A listing of planned coal-fired generation projects. 13 figs., 12 tabs., 1 app.

  14. 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.

  15. Coal gasification for power generation. 2nd ed.

    SciTech Connect

    2006-10-15

    The report gives an overview of the opportunities for coal gasification in the power generation industry. It provides a concise look at the challenges faced by coal-fired generation, the ability of coal gasification to address these challenges, and the current state of IGCC power generation. Topics covered in the report include: An overview of coal generation including its history, the current market environment, and the status of coal gasification; A description of gasification technology including processes and systems; An analysis of the key business factors that are driving increased interest in coal gasification; An analysis of the barriers that are hindering the implementation of coal gasification projects; A discussion of Integrated Gasification Combined Cycle (IGCC) technology; An evaluation of IGCC versus other generation technologies; A discussion of IGCC project development options; A discussion of the key government initiatives supporting IGCC development; Profiles of the key gasification technology companies participating in the IGCC market; and A description of existing and planned coal IGCC projects.

  16. 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.

  17. Operations Analysis of the 2nd Generation Reusable Launch Vehicle

    NASA Technical Reports Server (NTRS)

    Noneman, Steven R.; Smith, C. A. (Technical Monitor)

    2002-01-01

    The Space Launch Initiative (SLI) program is developing a second-generation reusable launch vehicle. The program goals include lowering the risk of loss of crew to 1 in 10,000 and reducing annual operations cost to one third of the cost of the Space Shuttle. The SLI missions include NASA, military and commercial satellite launches and crew and cargo launches to the space station. The SLI operations analyses provide an assessment of the operational support and infrastructure needed to operate candidate system architectures. Measures of the operability are estimated (i.e. system dependability, responsiveness, and efficiency). Operations analysis is used to determine the impact of specific technologies on operations. A conceptual path to reducing annual operations costs by two thirds is based on key design characteristics, such as reusability, and improved processes lowering labor costs. New operations risks can be expected to emerge. They can be mitigated with effective risk management with careful identification, assignment, tracking, and closure. SLI design characteristics such as nearly full reusability, high reliability, advanced automation, and lowered maintenance and servicing coupled with improved processes are contributors to operability and large operating cost reductions.

  18. 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.

  19. 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.

  20. 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.

  1. 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

  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. Advanced Electron Beam Ion Sources (EBIS) for 2-nd generation carbon radiotherapy facilities

    NASA Astrophysics Data System (ADS)

    Shornikov, A.; Wenander, F.

    2016-04-01

    In this work we analyze how advanced Electron Beam Ion Sources (EBIS) can facilitate the progress of carbon therapy facilities. We will demonstrate that advanced ion sources enable operation of 2-nd generation ion beam therapy (IBT) accelerators. These new accelerator concepts with designs dedicated to IBT provide beams better suited for therapy and, are more cost efficient than contemporary IBT facilities. We will give a sort overview of the existing new IBT concepts and focus on those where ion source technology is the limiting factor. We will analyse whether this limitation can be overcome in the near future thanks to ongoing EBIS development.

  4. 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.

  5. 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. PMID:26972324

  6. The planar optics phase sensor: a study for the VLTI 2nd generation fringe tracker

    NASA Astrophysics Data System (ADS)

    Blind, Nicolas; Le Bouquin, Jean-Baptiste; Absil, Olivier; Alamir, Mazen; Berger, Jean-Philippe; Defrère, Denis; Feautrier, Philippe; Hénault, François; Jocou, Laurent; Kern, Pierre; Laurent, Thomas; Malbet, Fabien; Mourard, Denis; Rousselet-Perraut, Karine; Sarlette, Alain; Surdej, Jean; Tarmoul, Nassima; Tatulli, Eric; Vincent, Lionel

    2010-07-01

    In a few years, the second generation instruments of the Very Large Telescope Interferometer (VLTI) will routinely provide observations with 4 to 6 telescopes simultaneously. To reach their ultimate performance, they will need a fringe sensor capable to measure in real time the randomly varying optical paths differences. A collaboration between LAOG (PI institute), IAGL, OCA and GIPSA-Lab has proposed the Planar Optics Phase Sensor concept to ESO for the 2nd Generation Fringe Tracker. This concept is based on the integrated optics technologies, enabling the conception of extremely compact interferometric instruments naturally providing single-mode spatial filtering. It allows operations with 4 and 6 telescopes by measuring the fringes position thanks to a spectrally dispersed ABCD method. We present here the main analysis which led to the current concept as well as the expected on-sky performance and the proposed design.

  7. 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.

  8. 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.

  9. Computer Generation of Subduction Frequencies for 2ND Order Phase Transitions in Two-Dimensions

    NASA Astrophysics Data System (ADS)

    Deonarine, Samaroo

    The Landau theory of 2nd order phase transitions and Group theory Criteria are used to predict which subgroups G (L-HOOK EQ) G(,0) can occur in transitions for 2-D systems (plane-group to plane-group and diperiodic to diperiodic). Previous work 1 on the 17 plane space groups has been based on the tables of Coxeter & Moser 2 and the International Tables of X-ray Crystallography (ITXRC, 1965) 3 . These tables do not exhaust all the possible subgroups of a space group 4 . Since such explicit tables are non-existent for other families of space groups we have developed algorithms that make a systematic search of the parent unit cell of G(,0) to locate the origin and orientation of all its subgroups G, G (L-HOOK EQ) G(,0). We have written a RATFOR/FORTRAN program for the VAX 11-780 which will generate the subduction frequencies. (DIAGRAM, TABLE OR GRAPHIC OMITTED...PLEASE SEE DAI). for allowed second order phase transitions in 2-dimensional systems that are describable by the 80 diperiodic Groups G(,0) and G 5 . Our program gives a complete tabulation (Origin, new Translation Sublattice, Subduction Frequency, Subgroup and its Generators) of the allowed continuous or second order phase transitions from a parent diperiodic group G(,0) to another diperiodic subgroup G.

  10. Improved beam spot measurements in the 2nd generation proton beam writing system

    NASA Astrophysics Data System (ADS)

    Yao, Yong; van Mourik, Martin W.; Santhana Raman, P.; van Kan, Jeroen A.

    2013-07-01

    Nanosized ion beams (especially proton and helium) play a pivotal role in the field of ion beam lithography and ion beam analysis. Proton beam writing has shown lithographic details down to the 20 nm level, limited by the proton beam spot size. Introducing a smaller spot size will allow smaller lithographic features. Smaller probe sizes, will also drastically improve the spatial resolution for ion beam analysis techniques. Among many other requirements, having an ideal resolution standard, used for beam focusing and a reliable focusing method, is an important pre-requisite for sub-10 nm beam spot focusing. In this paper we present the fabrication processes of a free-standing resolution standard with reduced side-wall projection and high side-wall verticality. The resulting grid is orthogonal (90.0° ± 0.1), has smooth edges with better than 6 nm side-wall projection. The new resolution standard has been used in focusing a 2 MeV H2+ beam in the 2nd generation PBW system at Center for Ion Beam Applications, NUS. The beam size has been characterized using on- and off-axis scanning transmission ion microscopy (STIM) and ion induced secondary electron detection, carried out with a newly installed micro channel plate electron detector. The latter has been shown to be a realistic alternative to STIM measurements, as the drawback of PIN diode detector damage is alleviated. With these improvements we show reproducible beam focusing down to 14 nm.

  11. BMI differences in 1st and 2nd generation immigrants of Asian and European origin to Australia.

    PubMed

    Hauck, Katharina; Hollingsworth, Bruce; Morgan, Lawrie

    2011-01-01

    We estimate assimilation of immigrants' body mass index (BMI) to the host population of Australia over one generation, conducting separate analyses for immigrants from 7 regions of Europe and Asia. We use quantile regressions to allow for differing impact of generational status across 19 quantiles of BMI from under-weight to morbidly obese individuals. We find that 1st generation South European immigrants have higher, and South and East Asian immigrants have lower BMI than Australians, but have assimilated to the BMI of their hosts in the 2nd generation. There are no or only small BMI differences between Australians and 1st and 2nd generation immigrants from East Europe, North-West Europe, Middle East and Pacific regions. We conclude that both upward and downward assimilation in some immigrant groups is most likely caused by factors which can change over one generation (such as acculturation), and not factors which would take longer to change (such as genetics). Our results suggest that public health policies targeting the lifestyles of well educated Asian immigrants may be effective in preventing BMI increase in this subgroup. PMID:20869292

  12. Time resolved 2nd harmonic generation at LaAlO3/SrTiO3 Interfaces

    NASA Astrophysics Data System (ADS)

    Adhikari, Sanjay; Eom, Chang-Beom; Ryu, Sangwoo; Cen, Cheng

    2014-03-01

    Ultrafast spectroscopy can produce information of carrier/lattice dynamics, which is especially valuable for understanding phase transitions at LaAlO3/SrTiO3 interfaces. LaAlO3 (LAO) and SrTiO3 (STO) are both associated with wide band gap, which allows deep penetration of commonly used laser wavelengths and therefore usually leads to overwhelming bulk signal background. Here we report a time resolved study of a 2nd harmonic generation (SHG) signal resulting from impulsive below-the-band-gap optical pumping. The nonlinear nature of the signal enables us to probe the interface directly. Output of a home built Ti:Sapphire laser and BBO crystal were used to generate 30fs pulses of two colors (405nm and 810nm). The 405nm pulse was used to pump the LAO/STO interfaces, while 2nd harmonics of the 810nm pulse generated at the interfaces was probed as a function of the time delay. Signals from samples with varying LAO thicknesses clearly correlates to the metal-insulator transition. Distinct time dependent signals were observed at LAO/STO interfaces grown on different substrates. Experiments performed at different optical polarization geometries, interface electric fields and temperatures allow us to paint a clearer picture of the novel oxide heterostructures under investigation.

  13. Impact of Insulin Resistance on Neointimal Tissue Proliferation after 2nd-Generation Drug-Eluting Stent Implantation

    PubMed Central

    Yaguchi, Isao; Komatsu, Sachiko; Nakahara, Shiro; Kobayashi, Sayuki; Sakai, Yoshihiko; Taguchi, Isao

    2015-01-01

    Percutaneous coronary intervention is established as an effective treatment for patients with ischemic heart disease; in particular, drug-eluting stent implantation is known to suppress in-stent restenosis. Diabetes mellitus is an independent risk factor for restenosis, so reducing insulin resistance is being studied as a new treatment approach. In this prospective study, we sought to clarify the factors associated with in-stent restenosis after percutaneous coronary intervention, and we evaluated the homeostasis model assessment of insulin resistance (HOMA-IR) index as a predictor of restenosis. We enrolled 136 consecutive patients who underwent elective percutaneous coronary intervention at our hospital from February 2010 through April 2013. All were implanted with a 2nd-generation drug-eluting stent. We distributed the patients in accordance with their HOMA-IR index values into insulin-resistant Group P (HOMA-IR, ≥2.5; n=77) and noninsulin-resistant Group N (HOMA-IR, <2.5; n=59). Before and immediately after stenting, we measured reference diameter, minimal lumen diameter, and percentage of stenosis, and after 8 months we measured the last 2 factors and late lumen loss, all by means of quantitative coronary angiography. After 8 months, the mean minimal lumen diameter was smaller in Group P than that in Group N (1.85 ± 1.02 vs 2.37 ± 0.66 mm; P=0.037), and the mean late lumen loss was larger (0.4 ± 0.48 vs 0.16 ± 0.21 mm; P=0.025). These results suggest that insulin resistance affects neointimal tissue proliferation after 2nd-generation drug-eluting stent implantation. PMID:26413014

  14. 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.

  15. 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.

  16. InAs/GaSb type II superlattices for advanced 2nd and 3rd generation detectors

    NASA Astrophysics Data System (ADS)

    Walther, Martin; Rehm, Robert; Schmitz, Johannes; Fleissner, Joachim; Rutz, Frank; Kirste, Lutz; Scheibner, Ralf; Wendler, Joachim; Ziegler, Johann

    2010-01-01

    InAs/GaSb short-period superlattices (SL) based on GaSb, InAs and AlSb have proven their great potential for high performance infrared detectors. Lots of interest is currently focused on the development of short-period InAs/GaSb SLs for advanced 2nd and 3rd generation infrared detectors between 3 - 30 μm. For the fabrication of mono- and bispectral thermal imaging systems in the mid-wavelength infrared region (MWIR) a manufacturable technology for high responsivity thermal imaging systems has been developed. InAs/GaSb short-period superlattices can be fabricated with up to 1000 periods in the intrinsic region without revealing diffusion limited behavior. This enables the fabrication of InAs/GaSb SL camera systems with high responsivity comparable to state of the art CdHgTe and InSb detectors. The material system is also ideally suited for the fabrication of dual-color MWIR/MWIR InAs/GaSb SL camera systems with high quantum efficiency for missile approach warning systems with simultaneous and spatially coincident detection in both spectral channels.

  17. 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.

  18. [Modalities of use of ceritinib (Zykadia™), a 2nd generation ALK inhibitor, in advanced stage non-small cell lung cancer].

    PubMed

    Giroux Leprieur, Etienne; Fallet, Vincent; Wislez, Marie

    2015-12-01

    Around 4% of advanced non-small cell lung cancers (NSCLC) harbor a ALK rearrangement, with high sensitivity to ALK inhibitor as crizotinib. However, the vast majority of these tumors end with a tumor progression after several months of treatment with crizotinib. Ceritinib is a 2nd generation ALK inhibitor, which showed high efficiency in NSCLC with ALK rearrangement. Results from phase I trial showed a response rate at 58% in these tumors, with a similar rate for previously crizotinib-treated patients or crizotinib-naïve patients. Moreover, cerebral responses were observed with ceritinib. Preliminary date from a phase 2 trial confirmed these results. These promising results allowed a European marketing authorization (autorisation de mise sur le marché [AMM]) since May 2015 for the treatment of advanced NSCLC with ALK rearrangement and resistance or intolerance to crizotinib. PMID:26597476

  19. Bosutinib: a novel second-generation tyrosine kinase inhibitor.

    PubMed

    Isfort, Susanne; Keller-v Amsberg, Gunhild; Schafhausen, Philippe; Koschmieder, Steffen; Brümmendorf, Tim H

    2014-01-01

    Bosutinib (SKI-606) is a 4-anilino-3-quinoline carbonitrile, which acts as a dual inhibitor of Src and ABL kinases. In addition, the BCR-ABL fusion gene product, a constitutively activated tyrosine kinase which is crucial for the development of chronic myeloid leukemia (CML), is highly sensitive to bosutinib. Interestingly, distinctly lower concentrations of bosutinib are required to ablate BCR-ABL phosphorylation when compared to the first-generation tyrosine kinase inhibitor imatinib (IM). Bosutinib is a potent inhibitor of CML cell proliferation in vitro and has demonstrated promising activity in CML patients resistant or intolerant to IM as well as in newly diagnosed patients with chronic phase CML (CML-CP). Remarkably, bosutinib has been found to be capable of overcoming the majority of IM-resistant BCR-ABL mutations. Bosutinib has the potency to induce deep and fast responses in second- and third-/fourth-line treatment, and as a consequence, the drug has recently been licensed for patients previously treated with one or more tyrosine kinase inhibitor(s) and for whom imatinib, nilotinib, and dasatinib are not considered appropriate treatment options. Due to its potency and differing toxicity profile, it promises to be a good therapeutic option for a defined cohort of patients. The most common side effects are gastrointestinal with most of the patients suffering from nausea, vomiting, or diarrhea. For the most part, these gastrointestinal symptoms occur early after treatment initiation, are manageable, and often self-limiting. Continuous monitoring of liver enzymes upon treatment initiation is necessary during bosutinib treatment. In addition to CML treatment, bosutinib has shown some efficacy in selected patients suffering from advanced-stage solid tumors. In conclusion, bosutinib is a promising novel small molecule inhibitor approved now for targeted therapy of CML and in clinical development for other malignancies. PMID:24756786

  20. 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

    2008-02-01

    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%. PMID:18542230

  1. 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.

  2. Advances with the new AIMS fab 193 2nd generation: a system for the 65 nm node including immersion

    NASA Astrophysics Data System (ADS)

    Zibold, Axel M.; Poortinga, E.; Doornmalen, H. v.; Schmid, R.; Scherubl, T.; Harnisch, W.

    2005-06-01

    The Aerial Image Measurement System, AIMS, for 193nm lithography emulation is established as a standard for the rapid prediction of wafer printability for critical structures including dense patterns and defects or repairs on masks. The main benefit of AIMS is to save expensive image qualification consisting of test wafer exposures followed by wafer CD-SEM resist or wafer analysis. By adjustment of numerical aperture (NA), illumination type and partial coherence (σ) to match any given stepper/ scanner, AIMS predicts the printability of 193nm reticles such as binary with, or without OPC and phase shifting. A new AIMS fab 193 second generation system with a maximum NA of 0.93 is now available. Improvements in field uniformity, stability over time, measurement automation and higher throughput meet the challenging requirements of the 65nm node. A new function, "Global CD Map" can be applied to automatically measure and analyse the global CD uniformity of repeating structures across a reticle. With the options of extended depth-of-focus (EDOF) software and the upcoming linear polarisation capability in the illumination the new AIMS fab 193 second generation system is able to cover both dry and immersion requirements for NA < 1. Rigorous simulations have been performed to study the effects of polarisation for imaging by comparing the aerial image of the AIMS to the resist image of the scanner.

  3. 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.

  4. 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.

  5. Study of recovery characteristics of 2nd generation HTS tapes with different stabilizers for resistive type superconducting fault current limiters

    NASA Astrophysics Data System (ADS)

    Sheng, Jie; Zeng, Weina; Ma, Jun; Yao, Zhihao; Li, Zhuyong; Jin, Zhijian; Hong, Zhiyong

    2016-02-01

    The resistive type superconducting fault current limiter (SFCL) is one of the most important superconducting power applications nowadays. As known, this type of SFCL is settled directly in the power transmission line. When a short fault happens, the temperature of the superconductors in the SFCL will increase sharply due to the huge generated heat. This means the superconductors need time to recover the superconducting properties and be ready for the next short fault. So the recovery characteristics become one of the most crucial features of the resistive type SFCL. In this paper, several different kinds of measuring methods are presented to calculate the recovery time of the HTS tapes, and comparison of these methods is also carried out by a standard test. On basis of this, samples with different kinds of stabilizers are used to explore the influence of stabilizer on their recovery characteristics. In addition, the influence of the encapsulation technology is also discussed in this paper.

  6. Comparison of Five 2nd-Generation Supraglottic Airway Devices for Airway Management Performed by Novice Military Operators

    PubMed Central

    Henlin, Tomas; Sotak, Michal; Kovaricek, Petr; Tyll, Tomas; Balcarek, Lukas; Michalek, Pavel

    2015-01-01

    Objectives. Five different second-generation supraglottic airway devices, ProSeal LMA, Supreme LMA, i-gel, SLIPA, and Laryngeal Tube Suction-D, were studied. Operators were inexperienced users with a military background, combat lifesavers, nurses, and physicians. Methods. This was a prospective, randomized, single-blinded study. Devices were inserted in the operating room in low light conditions after induction of general anesthesia. Primary outcome was successful insertion on the first attempt while secondary aims were insertion time, number of attempts, oropharyngeal seal pressure, ease of insertion, fibre optic position of device, efficacy of ventilation, and intraoperative trauma or regurgitation of gastric contents. Results. In total, 505 patients were studied. First-attempt insertion success rate was higher in the Supreme LMA (96%), i-gel (87.9%), and ProSeal LMA (85.9%) groups than in the Laryngeal Tube Suction-D (80.6%) and SLIPA (69.4%) groups. Insertion time was shortest in the Supreme LMA (70.4 ± 32.5 s) and i-gel (74.4 ± 41.1 s) groups (p < 0.001). Oropharyngeal seal pressures were higher in the Laryngeal Tube Suction-D and ProSeal LMA groups than in other three devices. Conclusions. Most study parameters for the Supreme LMA and i-gel were found to be superior to the other three tested supraglottic airway devices when inserted by novice military operators. PMID:26495289

  7. 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. PMID:26619255

  8. Optical coherence tomography analysis of the stent strut and prediction of resolved strut malapposition at 3 months after 2nd-generation drug-eluting stent implantation.

    PubMed

    Izumi, Daisuke; Miyahara, Masatoshi; Fujimoto, Naoki; Fukuoka, Shusuke; Sakai, Masataka; Dohi, Kaoru; Ito, Masaaki

    2016-08-01

    Our objective was to clarify whether thrombogenic problems with stent struts are resolved at 3 months after 2nd-generation drug-eluting stent implantation. Twenty-one patients with stable angina pectoris having 28 (22 zotarolimus-eluting, 6 everolimus-eluting) stents with optical coherence tomography (OCT)-guided percutaneous coronary intervention (PCI) were evaluated. Stent strut coverage and malapposition were evaluated by OCT immediately after PCI and at 3-month follow-up. Acute strut malapposition was observed in 26 out of 28 analyzed stents (92.9 %). At 3-month follow-up, 7 (26.9 %) of those 26 stents with strut malapposition were completely resolved, and the mean percentages of uncovered struts and malapposed struts were 8.3 and 2.0 % when analyzed by each individual stent. When analyzing a total of 30,060 struts, 807 struts (2.7 %) demonstrated acute strut malapposition. Among these, 219 struts (27.1 %) demonstrated persistent strut malapposition. On the basis of receiver-operating characteristic curve analysis, a strut-to-vessel (S-V) distance ≤160 µm on post-stenting OCT images was the corresponding cutoff point for resolved malapposed struts (sensitivity 78.1 %, specificity 62.8 %, area under the curve 0.758). The S-V distance of persistent malapposed struts on post-stenting OCT images was longer than that of resolved malapposed struts (235 ± 112 vs. 176 ± 93 µm, p < 0.01). At 3 months after PCI, the prevalence rates of uncovered and malapposed struts were relatively low in 2nd-generation drug-eluting stent. Our results suggest that OCT-guide PCI with an S-V distance ≤160 µm may be recommended especially in patients with planed short-term DAPT. PMID:26334709

  9. Space Ops 2002: Bringing Space Operations into the 21st Century. Track 3: Operations, Mission Planning and Control. 2nd Generation Reusable Launch Vehicle-Concepts for Flight Operations

    NASA Technical Reports Server (NTRS)

    Hagopian, Jeff

    2002-01-01

    With the successful implementation of the International Space Station (ISS), the National Aeronautics and Space Administration (NASA) enters a new era of opportunity for scientific research. The ISS provides a working laboratory in space, with tremendous capabilities for scientific research. Utilization of these capabilities requires a launch system capable of routinely transporting crew and logistics to/from the ISS, as well as supporting ISS assembly and maintenance tasks. The Space Shuttle serves as NASA's launch system for performing these functions. The Space Shuttle also serves as NASA's launch system for supporting other science and servicing missions that require a human presence in space. The Space Shuttle provides proof that reusable launch vehicles are technically and physically implementable. However, a couple of problems faced by NASA are the prohibitive cost of operating and maintaining the Space Shuttle and its relative inability to support high launch rates. The 2nd Generation Reusable Launch Vehicle (2nd Gen RLV) is NASA's solution to this problem. The 2nd Gen RLV will provide a robust launch system with increased safety, improved reliability and performance, and less cost. The improved performance and reduced costs of the 2nd Gen RLV will free up resources currently spent on launch services. These resource savings can then be applied to scientific research, which in turn can be supported by the higher launch rate capability of the 2nd Gen RLV. The result is a win - win situation for science and NASA. While meeting NASA's needs, the 2nd Gen RLV also provides the United States aerospace industry with a commercially viable launch capability. One of the keys to achieving the goals of the 2nd Gen RLV is to develop and implement new technologies and processes in the area of flight operations. NASA's experience in operating the Space Shuttle and the ISS has brought to light several areas where automation can be used to augment or eliminate functions

  10. New efficient artemisinin derived agents against human leukemia cells, human cytomegalovirus and Plasmodium falciparum: 2nd generation 1,2,4-trioxane-ferrocene hybrids.

    PubMed

    Reiter, Christoph; Fröhlich, Tony; Zeino, Maen; Marschall, Manfred; Bahsi, Hanife; Leidenberger, Maria; Friedrich, Oliver; Kappes, Barbara; Hampel, Frank; Efferth, Thomas; Tsogoeva, Svetlana B

    2015-06-01

    In our ongoing search for highly active hybrid molecules exceeding their parent compounds in anticancer, antimalaria as well as antiviral activity and being an alternative to the standard drugs, we present the synthesis and biological investigations of 2nd generation 1,2,4-trioxane-ferrocene hybrids. In vitro tests against the CCRF-CEM leukemia cell line revealed di-1,2,4-trioxane-ferrocene hybrid 7 as the most active compound (IC50 of 0.01 μM). Regarding the activity against the multidrug resistant subline CEM/ADR5000, 1,2,4-trioxane-ferrocene hybrid 5 showed a remarkable activity (IC50 of 0.53 μM). Contrary to the antimalaria activity of hybrids 4-8 against Plasmodium falciparum 3D7 strain with slightly higher IC50 values (between 7.2 and 30.2 nM) than that of their parent compound DHA, hybrids 5-7 possessed very promising activity (IC50 values lower than 0.5 μM) against human cytomegalovirus (HCMV). The application of 1,2,4-trioxane-ferrocene hybrids against HCMV is unprecedented and demonstrated here for the first time. PMID:25965779

  11. 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. PMID:25498934

  12. 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.

  13. Enhanced animal productivity and health with improved manure management in 2nd Generation Environmentally Superior Technology in North Carolina: II. Air quality

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The aim of this study was to evaluate the effects of improved manure management on air quality and the beneficial effect of a cleaner environment on animal productivity and health using a second generation of Environmentally Superior Technology. The second generation system combines solid-liquid sep...

  14. Enhanced animal productivity and health with improved manure management in 2nd Generation Environmentally Superior Technology in North Carolina: I. Water quality

    Technology Transfer Automated Retrieval System (TEKTRAN)

    New legislation in North Carolina promotes the replacement of old lagoon technology with new Environmentally Superior Technology. Scientists at ARS Florence Center and industry cooperators completed design and demonstration of a second generation treatment system for swine waste that can achieve hig...

  15. Integration of health management and support systems is key to achieving cost reduction and operational concept goals of the 2nd generation reusable launch vehicle

    NASA Astrophysics Data System (ADS)

    Koon, Phillip L.; Greene, Scott

    2002-07-01

    Our aerospace customers are demanding that we drastically reduce the cost of operating and supporting our products. Our space customer in particular is looking for the next generation of reusable launch vehicle systems to support more aircraft like operation. To achieve this goal requires more than an evolution in materials, processes and systems, what is required is a paradigm shift in the design of the launch vehicles and the processing systems that support the launch vehicles. This paper describes the Automated Informed Maintenance System (AIM) we are developing for NASA's Space Launch Initiative (SLI) Second Generation Reusable Launch Vehicle (RLV). Our system includes an Integrated Health Management (IHM) system for the launch vehicles and ground support systems, which features model based diagnostics and prognostics. Health Management data is used by our AIM decision support and process aids to automatically plan maintenance, generate work orders and schedule maintenance activities along with the resources required to execute these processes. Our system will automate the ground processing for a spaceport handling multiple RLVs executing multiple missions. To accomplish this task we are applying the latest web based distributed computing technologies and application development techniques.

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

    PubMed Central

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

    2011-01-01

    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. PMID:21822343

  17. 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

  18. [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

  19. Influence of the tyrosine environment on the second harmonic generation of iturinic antimicrobial lipopeptides at the air-water interface.

    PubMed

    Nasir, Mehmet Nail; Benichou, Emmanuel; Loison, Claire; Russier-Antoine, Isabelle; Besson, Françoise; Brevet, Pierre-François

    2013-12-01

    The second harmonic generation (SHG) response at the air-water interface from the tyrosine-containing natural iturinic cyclo-lipopeptides mycosubtilin, iturin A and bacillomycin D is reported. It is shown that this response is dominated by the single tyrosine residue present in these molecules owing to the large first hyperpolarizability arising from the non-centrosymmetric aromatic ring structure of this amino acid. The SHG response of these iturinic antibiotics is also compared to the response of surfactin, a cyclo-lipopeptide with a similar l,d-amino acid sequence but lacking a tyrosine residue, and PalmATA, a synthetic linear lipopeptide possessing a single tyrosine residue but lacking the amino acid sequence structuring the cycle of the iturinic antibiotics. From the light polarization analysis of the SHG response, it is shown that the tyrosine local environment is critical in defining the SHG response of these peptides at the air-water interface. Our results demonstrate that tyrosine, similar to tryptophan, can be used as an endogenous molecular probe of peptides and proteins for SHG at the air-water interface, paving the way for SHG studies of other tyrosine-containing bioactive molecules. PMID:24149982

  20. 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.

  1. Second-generation tyrosine kinase inhibitors in first-line treatment of chronic myeloid leukaemia (CML).

    PubMed

    Abruzzese, Elisabetta; Breccia, Massimo; Latagliata, Roberto

    2014-02-01

    Tyrosine kinase inhibitors (TKIs) have contributed to marked improvements in survival in patients with chronic myeloid leukaemia (CML). This article discusses the place of the second-generation TKIs dasatinib and nilotinib in the first-line treatment of CML and is based on published literature. The new agents are more potent and effective than imatinib. Data from pivotal clinical trials indicate that response to dasatinib and nilotinib is greater and more rapid than that to imatinib, resulting in a higher probability of patients achieving an optimal response to treatment. Differences between the newer agents with respect to patient groups for whom caution is advised, drug interaction potential, haematological toxicity, pulmonary toxicity, changes in the immune system and effects on laboratory parameters are discussed. With similar levels of efficacy, the choice of second-generation agents should be guided by the characteristics of the individual patient and the most suitable dosing regimen. PMID:24043361

  2. Computational Identification of Phospho-Tyrosine Sub-Networks Related to Acanthocyte Generation in Neuroacanthocytosis

    PubMed Central

    De Franceschi, Lucia; Danek, Adrian; Walker, Ruth H.; Jung, Hans H.; Bader, Benedikt; Mazzucco, Sara; Dotti, Maria Teresa; Siciliano, Angela; Pantaleo, Antonella; Laudanna, Carlo

    2012-01-01

    Acanthocytes, abnormal thorny red blood cells (RBC), are one of the biological hallmarks of neuroacanthocytosis syndromes (NA), a group of rare hereditary neurodegenerative disorders. Since RBCs are easily accessible, the study of acanthocytes in NA may provide insights into potential mechanisms of neurodegeneration. Previous studies have shown that changes in RBC membrane protein phosphorylation state affect RBC membrane mechanical stability and morphology. Here, we coupled tyrosine-phosphoproteomic analysis to topological network analysis. We aimed to predict signaling sub-networks possibly involved in the generation of acanthocytes in patients affected by the two core NA disorders, namely McLeod syndrome (MLS, XK-related, Xk protein) and chorea-acanthocytosis (ChAc, VPS13A-related, chorein protein). The experimentally determined phosphoproteomic data-sets allowed us to relate the subsequent network analysis to the pathogenetic background. To reduce the network complexity, we combined several algorithms of topological network analysis including cluster determination by shortest path analysis, protein categorization based on centrality indexes, along with annotation-based node filtering. We first identified XK- and VPS13A-related protein-protein interaction networks by identifying all the interactomic shortest paths linking Xk and chorein to the corresponding set of proteins whose tyrosine phosphorylation was altered in patients. These networks include the most likely paths of functional influence of Xk and chorein on phosphorylated proteins. We further refined the analysis by extracting restricted sets of highly interacting signaling proteins representing a common molecular background bridging the generation of acanthocytes in MLS and ChAc. The final analysis pointed to a novel, very restricted, signaling module of 14 highly interconnected kinases, whose alteration is possibly involved in generation of acanthocytes in MLS and ChAc. PMID:22355334

  3. Structural basis of improved second-generation 3-nitro-tyrosine tRNA synthetases.

    PubMed

    Cooley, Richard B; Feldman, Jessica L; Driggers, Camden M; Bundy, Taylor A; Stokes, Audrey L; Karplus, P Andrew; Mehl, Ryan A

    2014-04-01

    Genetic code expansion has provided the ability to site-specifically incorporate a multitude of noncanonical amino acids (ncAAs) into proteins for a wide variety of applications, but low ncAA incorporation efficiency can hamper the utility of this powerful technology. When investigating proteins containing the post-translational modification 3-nitro-tyrosine (nitroTyr), we developed second-generation amino-acyl tRNA synthetases (RS) that incorporate nitroTyr at efficiencies roughly an order of magnitude greater than those previously reported and that advanced our ability to elucidate the role of elevated cellular nitroTyr levels in human disease (e.g., Franco, M. et al. Proc. Natl. Acad. Sci. U.S.A 2013 , 110 , E1102 ). Here, we explore the origins of the improvement achieved in these second-generation RSs. Crystal structures of the most efficient of these synthetases reveal the molecular basis for the enhanced efficiencies observed in the second-generation nitroTyr-RSs. Although Tyr is not detectably incorporated into proteins when expression media is supplemented with 1 mM nitroTyr, a major difference between the first- and second-generation RSs is that the second-generation RSs have an active site more compatible with Tyr binding. This feature of the second-generation nitroTyr-RSs appears to be the result of using less stringent criteria when selecting from a library of mutants. The observation that a different selection strategy performed on the same library of mutants produced nitroTyr-RSs with dramatically improved efficiencies suggests the optimization of established selection protocols could lead to notable improvements in ncAA-RS efficiencies and thus the overall utility of this technology. PMID:24611875

  4. 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…

  5. Singlet oxygen generation during the oxidation of L-tyrosine and L-dopa with mushroom tyrosinase.

    PubMed

    Miyaji, Akimitsu; Kohno, Masahiro; Inoue, Yoshihiro; Baba, Toshihide

    2016-03-18

    The generation of singlet oxygen during the oxidation of tyrosine and L-dopa using mushroom tyrosinase in a phosphate buffer (pH 7.4), the model of melanin synthesis in melanocytes, was examined. The reaction was performed in the presence of 2,2,6,6-tetramethyl-4-piperidone (4-oxo-TEMP), an acceptor of singlet oxygen and the electron spin resonance (ESR) of the spin adduct, 4-oxo-2,2,6,6-tetramethyl-1-piperidinyloxy (4-oxo-TEMPO), was measured. An increase in the ESR signal attributable to 4-oxo-TEMPO was observed during the oxidation of tyrosine and L-dopa with tyrosinase, indicating the generation of singlet oxygen. The results suggest that (1)O2 generation via tyrosinase-catalyzed melanin synthesis occurs in melanocyte. PMID:26898801

  6. Eradication of T315I mutation in chronic myeloid leukemia without third-generation tyrosine kinase inhibitor: a case report.

    PubMed

    Venton, Geoffroy; Colle, Julien; Mercier, Cedric; Fanciullino, Raphaelle; Ciccolini, Joseph; Ivanov, Vadim; Suchon, Pierre; Sebahoun, Gerard; Beaufils, Nathalie; Gabert, Jean; Hadjaj, Djamal; Costello, Regis

    2015-01-01

    We report the case of a patient bearing a T315I-mutant chronic myeloid leukemia resistant to nilotinib, successfully treated with omacetaxine and then with dasatinib. After 9 months of nilotinib, the patient achieved a major molecular response but relapsed 3 months later due to the T315I mutation. Because third-generation tyrosine kinase inhibitor was not available and the patient refused bone marrow transplantation, he received two cycles of omacetaxine. This treatment had been stopped after two cycles because of clinical intolerance, but a major molecular response and total disappearance of the T315I clone was obtained. Treatment with dasatinib was then started and after 34-month follow-up the patient is still in major molecular response, thus suggesting that eradication of the T315I mutation could be achieved without third-generation tyrosine kinase inhibitors. PMID:25950190

  7. Dual role for the tyrosine decarboxylation pathway in Enterococcus faecium E17: response to an acid challenge and generation of a proton motive force.

    PubMed

    Pereira, C I; Matos, D; San Romão, M V; Crespo, M T Barreto

    2009-01-01

    In this work we investigated the role of the tyrosine decarboxylation pathway in the response of Enterococcus faecium E17 cells to an acid challenge. It was found that 91% of the cells were able to remain viable in the presence of tyrosine when they were incubated for 3 h in a complex medium at pH 2.5. This effect was shown to be related to the tyrosine decarboxylation pathway. Therefore, the role of tyrosine decarboxylation in pH homeostasis was studied. The membrane potential and pH gradient, the parameters that compose the proton motive force (PMF), were measured at different pHs (pH 4.5 to 7). We obtained evidence showing that the tyrosine decarboxylation pathway generates a PMF composed of a pH gradient formed due to proton consumption in the decarboxylation reaction and by a membrane potential which results from electrogenic transport of tyrosine in exchange for the corresponding biogenic amine tyramine. The properties of the tyrosine transporter were also studied in this work by using whole cells and right-side-out vesicles. The results showed that the transporter catalyzes homologous tyrosine/tyrosine antiport, as well as electrogenic heterologous tyrosine-tyramine exchange. The tyrosine transporter had properties of a typical precursor-product exchanger operating in a proton motive decarboxylation pathway. Therefore, the tyrosine decarboxylation pathway contributes to an acid response mechanism in E. faecium E17. This decarboxylation pathway gives the strain a competitive advantage in nutrient-depleted conditions, as well as in harsh acidic environments, and a better chance of survival, which contributes to higher cell counts in food fermentation products. PMID:19011061

  8. Efficacy and Pharmacologic Data of Second-Generation Tyrosine Kinase Inhibitor Nilotinib in BCR-ABL-Positive Leukemia Patients with Central Nervous System Relapse after Allogeneic Stem Cell Transplantation

    PubMed Central

    Reinwald, Mark; Schleyer, Eberhard; Kiewe, Philipp; Blau, Igor Wolfgang; Burmeister, Thomas; Pursche, Stefan; Neumann, Martin; Notter, Michael; Thiel, Eckhard; Hofmann, Wolf-Karsten; Kolb, Hans-Jochem; Burdach, Stefan; Bender, Hans-Ulrich

    2014-01-01

    Central nervous system (CNS) involvement is a severe complication of BCR-ABL-positive leukemia after allogenic stem cell transplantation (alloSCT) associated with fatal outcome. Although second-generation tyrosine-kinase inhibitors (TKI) such as nilotinib have shown activity in systemic BCR-ABL+ disease, little data exists on their penetration and efficacy within the CNS. Four patients (3 male, 1 female; age 15–49) with meningeal relapse after alloSCT and subsequent treatment with nilotinib were identified. A total of 17 cerebrospinal fluid (csf) and serum samples were assessed for nilotinib concentration and patient outcome was recorded. Nilotinib concentrations showed a low median csf/plasma ratio of 0.53% (range 0.23–1.5%), yet pronounced clinical efficacy was observed with long-lasting responses (>1 year) in three patients. Comparison with historical data showed a trend towards superior efficacy of nilotinib versus imatinib. Despite poor csf penetration, nilotinib showed significant clinical activity in CNS relapse of BCR-ABL+ leukemias. As nilotinib has a high protein-binding affinity, the low-protein concentration in csf could translate into a relatively higher amount of free and therefore active nilotinib in csf as compared to blood, possibly explaining the observed efficacy. Thus, treatment with a 2nd generation TKI warrants further investigation and should be considered in cases of CNS relapse of BCR-ABL-positive leukemia after alloSCT. PMID:25025064

  9. 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.

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

    PubMed

    Breccia, Massimo; Alimena, Giuliana

    2014-01-01

    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. PMID:24455112

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

    PubMed Central

    Breccia, Massimo; Alimena, Giuliana

    2014-01-01

    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. PMID:24455112

  12. Neural stem cells from protein tyrosine phosphatase sigma knockout mice generate an altered neuronal phenotype in culture

    PubMed Central

    Kirkham, David L; Pacey, Laura KK; Axford, Michelle M; Siu, Roberta; Rotin, Daniela; Doering, Laurie C

    2006-01-01

    Background The LAR family Protein Tyrosine Phosphatase sigma (PTPσ) has been implicated in neuroendocrine and neuronal development, and shows strong expression in specific regions within the CNS, including the subventricular zone (SVZ). We established neural stem cell cultures, grown as neurospheres, from the SVZ of PTPσ knockout mice and sibling controls to determine if PTPσ influences the generation and the phenotype of the neuronal, astrocyte and oligodendrocyte cell lineages. Results The neurospheres from the knockout mice acquired heterogeneous developmental characteristics and they showed similar morphological characteristics to the age matched siblings. Although Ptprs expression decreases as a function of developmental age in vivo, it remains high with the continual renewal and passage of the neurospheres. Stem cells, progenitors and differentiated neurons, astrocytes and oligodendrocytes all express the gene. While no apparent differences were observed in developing neurospheres or in the astrocytes and oligodendrocytes from the PTPσ knockout mice, the neuronal migration patterns and neurites were altered when studied in culture. In particular, neurons migrated farther from the neurosphere centers and the neurite outgrowth exceeded the length of the neuronal processes from age matched sibling controls. Conclusion Our results imply a specific role for PTPσ in the neuronal lineage, particularly in the form of inhibitory influences on neurite outgrowth, and demonstrate a role for tyrosine phosphatases in neuronal stem cell differentiation. PMID:16784531

  13. Exogenous attention enhances 2nd-order contrast sensitivity.

    PubMed

    Barbot, Antoine; Landy, Michael S; Carrasco, Marisa

    2011-05-11

    Natural scenes contain a rich variety of contours that the visual system extracts to segregate the retinal image into perceptually coherent regions. Covert spatial attention helps extract contours by enhancing contrast sensitivity for 1st-order, luminance-defined patterns at attended locations, while reducing sensitivity at unattended locations, relative to neutral attention allocation. However, humans are also sensitive to 2nd-order patterns such as spatial variations of texture, which are predominant in natural scenes and cannot be detected by linear mechanisms. We assess whether and how exogenous attention--the involuntary and transient capture of spatial attention--affects the contrast sensitivity of channels sensitive to 2nd-order, texture-defined patterns. Using 2nd-order, texture-defined stimuli, we demonstrate that exogenous attention increases 2nd-order contrast sensitivity at the attended location, while decreasing it at unattended locations, relative to a neutral condition. By manipulating both 1st- and 2nd-order spatial frequency, we find that the effects of attention depend both on 2nd-order spatial frequency of the stimulus and the observer's 2nd-order spatial resolution at the target location. At parafoveal locations, attention enhances 2nd-order contrast sensitivity to high, but not to low 2nd-order spatial frequencies; at peripheral locations attention also enhances sensitivity to low 2nd-order spatial frequencies. Control experiments rule out the possibility that these effects might be due to an increase in contrast sensitivity at the 1st-order stage of visual processing. Thus, exogenous attention affects 2nd-order contrast sensitivity at both attended and unattended locations. PMID:21356228

  14. Exogenous attention enhances 2nd-order contrast sensitivity

    PubMed Central

    Barbot, Antoine; Landy, Michael S.; Carrasco, Marisa

    2011-01-01

    Natural scenes contain a rich variety of contours that the visual system extracts to segregrate the retinal image into perceptually coherent regions. Covert spatial attention helps extract contours by enhancing contrast sensitivity for 1st-order, luminance-defined patterns at attended locations, while reducing sensitivity at unattended locations, relative to neutral attention allocation. However, humans are also sensitive to 2nd-order patterns such as spatial variations of texture, which are predominant in natural scenes and cannot be detected by linear mechanisms. We assess whether and how exogenous attention—the involuntary and transient capture of spatial attention—affects the contrast sensitivity of channels sensitive to 2nd-order, texture-defined patterns. Using 2nd-order, texture-defined stimuli, we demonstrate that exogenous attention increases 2nd-order contrast sensitivity at the attended location, while decreasing it at unattended locations, relative to a neutral condition. By manipulating both 1st- and 2nd-order spatial frequency, we find that the effects of attention depend both on 2nd-order spatial frequency of the stimulus and the observer’s 2nd-order spatial resolution at the target location. At parafoveal locations, attention enhances 2nd-order contrast sensitivity to high, but not to low 2nd-order spatial frequencies; at peripheral locations attention also enhances sensitivity to low 2nd-order spatial frequencies. Control experiments rule out the possibility that these effects might be due to an increase in contrast sensitivity at the 1st-order stage of visual processing. Thus, exogenous attention affects 2nd-order contrast sensitivity at both attended and unattended locations. PMID:21356228

  15. The next generation of epidermal growth factor receptor tyrosine kinase inhibitors in the treatment of lung cancer.

    PubMed

    Steuer, Conor E; Khuri, Fadlo R; Ramalingam, Suresh S

    2015-04-15

    The discovery of "driver" genomic alterations in patients with non-small cell lung cancer (NSCLC) has dramatically changed the field of thoracic oncology in recent years. The best understood of these molecular drivers are those involving the epidermal growth factor receptor (EGFR), which when aberrantly activated are integral to the development of a subset of NSCLC tumors. First-generation and second-generation tyrosine kinase inhibitors (TKIs) specific to the activated EGFR have shown significant efficacy and have brought about the era of targeted therapy for NSCLC. The most common resistance mechanism is a threonine-to-methionine substitution (T790M) in exon 20 of the EGFR gene. Although the previous standard of care in patients with EGFR-mutated NSCLC that progressed on initial TKI therapy was chemotherapy, third-generation EGFR TKIs have now been developed and have yielded promising results for this population of patients with NSCLC. This article reviews the emerging data regarding third-generation agents in the treatment of patients with advanced NSCLC. PMID:25521095

  16. Heat shock protein 90 and tyrosine kinase regulate eNOS NO* generation but not NO* bioactivity.

    PubMed

    Ou, Jingsong; Fontana, Jason T; Ou, Zhijun; Jones, Deron W; Ackerman, Allan W; Oldham, Keith T; Yu, Jun; Sessa, William C; Pritchard, Kirkwood A

    2004-02-01

    An increase in the association of heat shock protein 90 (HSP90) with endothelial nitric oxide (NO) synthase (eNOS) is well recognized for increasing NO (NO*) production. Despite the progress in this field, the mechanisms by which HSP90 modulates eNOS remain unclear due, in part, to the fact that geldanamycin (GA) redox cycles to generate superoxide anion (O(2)(-*) and the fact that inhibiting HSP90 with GA or radicicol (RAD) destabilizes tyrosine kinases that rely on the chaperone for maturation. In this report, we determine the extent to which these side effects alter vascular and endothelial cell function in physiologically relevant systems and in cultured endothelial cells. Vascular endothelial growth factor (VEGF)-stimulated vascular permeability, as measured by Evans blue leakage in the ears of male Swiss mice in vivo, and acetylcholine-induced vasodilation of isolated, pressurized mandibular arterioles from male C57BL6 mice ex vivo were attenuated by N(omega)-nitro-L-arginine methyl ester (L-NAME), GA, and RAD. Z-1[N-(2-aminoethyl)-N-(2-ammonoethyl)amino]diazen-1-ium-1,2-dioate (DETA-NONOate), a slow releasing NO. donor, increased vasodilation of arterioles pretreated with GA, RAD, and L-NAME equally well except at 10(-5) M, the highest concentration used, where vasodilation was greater in pressurized arterioles treated with L-NAME than in arterioles pretreated with GA or RAD alone. Both GA and RAD reduced NO* release from stimulated endothelial cell cultures and increased O(2)(-*) production in the endothelium of isolated aortas by an L-NAME-inhibitable mechanism. Pretreatment with RAD increased stimulated O(2)(-*) production from eNOS, whereas pretreatment with genistein (GE), a broad-spectrum tyrosine kinase inhibitor, did not; however, pretreatment with GE + RAD resulted in a super-induced state of uncoupled eNOS activity upon stimulation. These data suggest that the tyrosine kinases, either directly or indirectly, and HSP90-dependent signaling pathways

  17. 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.

  18. Florida Investigates 2nd Possible Local Transmission of Zika Virus

    MedlinePlus

    ... html Florida Investigates 2nd Possible Local Transmission of Zika Virus If confirmed, cases would be first instances ... investigating a second possible case of locally transmitted Zika infection. On Tuesday, the first possible case of ...

  19. 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.

  20. Directed differentiation of postnatal hippocampal neural stem cells generates nuclear receptor related-1 protein- and tyrosine hydroxylase-expressing cells

    PubMed Central

    Ding, Yinxiu; Zhang, Zixin; Ma, Jiangbo; Xia, Hechun; Wang, Yin; Liu, Yinming; Ma, Quanrui; Sun, Tao; Liu, Juan

    2016-01-01

    Parkinson's disease (PD) is a severe neurodegenerative disorder. Although the detailed underlying molecular mechanism remains to be elucidated, the major pathological feature of PD is the loss of dopaminergic (DA) neurons of the substantia nigra. The use of donor stem cells to replace DA neurons may be a key breakthrough in the treatment of PD. In the present study, the growth kinetics of hippocampal neural stem cells (Hip-NSCs) isolated from postnatal mice and cultured in vitro were observed, specifically the generation of cells expressing DA neuronal markers nuclear receptor related-1 protein (Nurr1) and tyrosine hydroxylase (TH). It was revealed that Hip-NSCs differentiated primarily into astrocytes when cultured in serum-containing medium. However, in low serum conditions, the number of βIII tubulin-positive neurons increased markedly. The proportion of Nurr1-positive cells and TH-positive neurons, significantly increased with increasing duration of directed differentiation of Hip-NSCs (P=0.0187 and 0.0254, respectively). The results of the present study reveal that Hip-NSCs may be induced to differentiate in vitro into neurons expressing Nurr1 and TH, known to be critical regulators of DA neuronal fate. Additionally, their expression may be necessary to facilitate neuronal maturation in vitro. These data suggest that Hip-NSCs may serve as a source of DA neurons for cell therapy in patients diagnosed with PD. PMID:27432537

  1. Outcome of treatment of chronic myeloid leukemia with second-generation tyrosine kinase inhibitors after imatinib failure.

    PubMed

    Cornelison, A Megan; Kantarjian, Hagop; Cortes, Jorge; Jabbour, Elias

    2011-06-01

    Although imatinib revolutionized the management of chronic myeloid leukemia (CML), recent data indicate a transformation in the treatment approach likely in the near future. For patients whose CML does not respond to standard-dose imatinib therapy, increasing the imatinib dose is a second-line option. However, high-dose imatinib is not an appropriate approach for patients experiencing drug toxicity, and there remain questions concerning the durability of responses achieved with this strategy. Alternative second-line options include the newer tyrosine kinase inhibitors (TKIs) such as dasatinib and nilotinib. A substantial amount of long-term data for these agents is available. Although both are potent and specific BCR-ABL TKIs, dasatinib and nilotinib exhibit unique pharmacological profiles and response patterns relative to different patient characteristics, such as disease stage and BCR-ABL mutational status. The superiority of second-generation TKIs over imatinib in newly diagnosed disease has been recognized as well. They induce high and rapid rates of cytogenetic and molecular response, with less progression to advanced forms of disease in comparison with imatinib. Several investigational agents specific for those patients with the T315I mutation remain under evaluation. The future of CML therapy may include early use of these potent agents to help more patients achieve molecular remission and potentially be a path to a CML cure. PMID:22035738

  2. 2nd PEGS Annual Symposium on Antibodies for Cancer Therapy

    PubMed Central

    Ho, Mitchell; Royston, Ivor; Beck, Alain

    2012-01-01

    The 2nd Annual Antibodies for Cancer Therapy symposium, organized again by Cambridge Healthtech Institute as part of the Protein Engineering Summit, was held in Boston, USA from April 30th to May 1st, 2012. Since the approval of the first cancer antibody therapeutic, rituximab, fifteen years ago, eleven have been approved for cancer therapy, although one, gemtuzumab ozogamicin, was withdrawn from the market.  The first day of the symposium started with a historical review of early work for lymphomas and leukemias and the evolution from murine to human antibodies. The symposium discussed the current status and future perspectives of therapeutic antibodies in the biology of immunoglobulin, emerging research on biosimilars and biobetters, and engineering bispecific antibodies and antibody-drug conjugates. The tumor penetration session was focused on the understanding of antibody therapy using ex vivo tumor spheroids and the development of novel agents targeting epithelial junctions in solid tumors. The second day of the symposium discussed the development of new generation recombinant immunotoxins with low immunogenicity, construction of chimeric antigen receptors, and the proof-of-concept of ‘photoimmunotherapy’. The preclinical and clinical session presented antibodies targeting Notch signaling and chemokine receptors.  Finally, the symposium discussed emerging technologies and platforms for therapeutic antibody discovery. PMID:22864478

  3. Ortho- and meta-tyrosine formation from phenylalanine in human saliva as a marker of hydroxyl radical generation during betel quid chewing.

    PubMed

    Nair, U J; Nair, J; Friesen, M D; Bartsch, H; Ohshima, H

    1995-05-01

    The habit of betel quid chewing, common in South-East Asia and the South Pacific islands, is causally associated with an increased risk of oral cancer. Reactive oxygen species formed from polyphenolic betel quid ingredients and lime at alkaline pH have been implicated as the agents responsible for DNA and tissue damage. To determine whether hydroxyl radical (HO.) is generated in the human oral cavity during chewing of betel quid, the formation of o- and m-tyrosine from L-phenylalanine was measured. Both o- and m-tyrosine were formed in vitro in the presence of extracts of areca nut and/or catechu, transition metal ions such as Cu2+ and Fe2+ and lime or sodium carbonate (alkaline pH). Omission of any of these ingredients from the reaction mixture significantly reduced the yield of tyrosines. Hydroxyl radical scavengers such as ethanol, D-mannitol and dimethylsulfoxide inhibited the phenylalanine oxidation in a dose-dependent fashion. Five volunteers chewed betel quid consisting of betel leaf, areca nut, catechu and slaked lime (without tobacco). Their saliva, collected after chewing betel quid, contained high concentrations of p-tyrosine, but no appreciable amounts of o- or m-tyrosine. Saliva samples from the same subjects after chewing betel quid to which 20 mg phenylalanine had been added contained o- and m-tyrosine at concentrations ranging from 1010 to 3000 nM and from 1110 to 3140 nM respectively. These levels were significantly higher (P < 0.005) than those of subjects who kept phenylalanine in the oral cavity without betel quid, which ranged from 14 to 70 nM for o-tyrosine and from 10 to 35 nM for m-tyrosine. These studies clearly demonstrate that the HO. radical is formed in the human oral cavity during betel quid chewing and is probably implicated in the genetic damage that has been observed in oral epithelial cells of chewers. PMID:7767985

  4. Role played by paxillin and paxillin tyrosine phosphorylation in hepatocyte growth factor/sphingosine-1-phosphate-mediated reactive oxygen species generation, lamellipodia formation, and endothelial barrier function

    PubMed Central

    Usatyuk, Peter V.; Jacobson, Jeffrey; Cress, Anne E.; Garcia, Joe G. N.; Salgia, Ravi; Natarajan, Viswanathan

    2015-01-01

    Abstract Paxillin is a multifunctional and multidomain focal adhesion adaptor protein. It serves as an important scaffolding protein at focal adhesions by recruiting and binding to structural and signaling molecules. Paxillin tyrosine phosphorylation at Y31 and Y118 is important for paxillin redistribution to focal adhesions and angiogenesis. Hepatocyte growth factor (HGF) and sphingosine-1-phosphate (S1P) are potent stimulators of lamellipodia formation, a prerequisite for endothelial cell migration. The role played by paxillin and its tyrosine phosphorylated forms in HGF- or S1P-induced lamellipodia formation and barrier function is unclear. HGF or S1P stimulated lamellipodia formation, tyrosine phosphorylation of paxillin at Y31 and Y118, and c-Abl in human lung microvascular endothelial cells (HLMVECs). Knockdown of paxillin with small interfering RNA (siRNA) or transfection with paxillin mutants (Y31F or Y118F) mitigated HGF- or S1P-induced lamellipodia formation, translocation of p47phox to lamellipodia, and reactive oxygen species (ROS) generation in HLMVECs. Furthermore, exposure of HLMVECs to HGF or S1P stimulated c-Abl-mediated tyrosine phosphorylation of paxillin at Y31 and Y118 in a time-dependent fashion, and down-regulation of c-Abl with siRNA attenuated HGF- or S1P-mediated lamellipodia formation, translocation of p47phox to lamellipodia, and endothelial barrier enhancement. In vivo, knockdown of paxillin with siRNA in mouse lungs attenuated ventilator-induced lung injury. Together, these results suggest that c-Abl-mediated tyrosine phosphorylation of paxillin at Y31 and Y118 regulates HGF- or S1P-mediated lamellipodia formation, ROS generation in lamellipodia, and endothelial permeability. PMID:26697169

  5. 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.

  6. 2nd Quarter Transportation Report FY 2014

    SciTech Connect

    Gregory, L.

    2014-07-30

    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.

  7. 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…

  8. 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. ...

  9. 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…

  10. Clinical efficacy of second generation tyrosine kinase inhibitor and 5-azacytidine combination in chronic myelogenous leukaemia in myeloid blast crisis.

    PubMed

    Ghez, David; Micol, Jean-Baptiste; Pasquier, Florence; Auger, Nathalie; Saada, Véronique; Spentchian, Marc; Ianotto, Jean-Christophe; Bourhis, Jean-Henri; Bennaceur-Griscelli, Anelyse; Terré, Christine; Castaigne, Sylvie; Rigaudeau, Sophie; Rousselot, Philippe; de Botton, Stéphane

    2013-11-01

    Even in the tyrosine kinase inhibitors era, the prognosis of patients with chronic myeloid leukaemia in myeloid blast crisis remains dismal with few patients surviving longer than 6 months. Here we report the cases of 5 patients treated with the combination of 5-azacytidine and tyrosine kinase inhibitors for myeloid blast crisis CML. All patients achieved a complete haematological response including two with a complete cytogenetic and major molecular response. Two patients underwent an allogeneic stem cell transplantation. One died from relapse 34 months from diagnosis. The second is alive and free from disease at 11 months from diagnosis. The other 3 patients are still in complete haematological response after 15, 24 and 33 months of follow-up. These results suggest that the combination has a significant activity in myeloid blast crisis and may increase survival. PMID:23968731

  11. Technical Issues Map for the NHI System Interface and Support Systems Area: 2nd Quarter FY07

    SciTech Connect

    Steven R. Sherman

    2007-03-01

    This document provides a mapping of technical issues associated with development of the Next Generation Nuclear Plant (NGNP) intermediate heat transport loop and nuclear hydrogen plant support systems to the work that has been accomplished or is currently underway in the 2nd quarter of FY07.

  12. Safety of a second-generation tyrosine kinase inhibitor and novel targeted therapy for the treatment of a patient with chronic myeloid leukemia and multiple myeloma.

    PubMed

    Katzel, Jed A; Lee-Ma, Annette; Vesole, David H

    2015-09-01

    The prevalence of chronic myeloid leukemia and multiple myeloma has increased in recent years partly because of an improved therapeutic armamentarium for both conditions. Likewise, understanding the complexity inherent in designing combination treatment strategies will become increasingly prescient in the coming years. We describe, to the best of our knowledge, the first reported patient to be treated with second-generation tyrosine kinase inhibitor therapy while on novel therapy for myeloma. The combination was well tolerated and effective for the treatment of chronic myeloid leukemia and concurrent myeloma. PMID:26111050

  13. The transient nature of 2nd-order stereopsis.

    PubMed

    Hess, Robert F; Wilcox, Laurie M

    2008-05-01

    There are currently two competing dichotomies used to describe how local stereoscopic information is processed by the human visual system. The first is in terms of the type of the spatial filtering operations used to extract relevant image features prior to stereoscopic analysis (i.e. 1st- vs 2nd-order stereo; [Hess, R. F., & Wilcox, L. M. (1994). Linear and non-linear filtering in stereopsis. Vision Research, 34, 2431-2438]). The second is in terms of the temporal properties of the mechanisms used to process stereoscopic information (i.e. sustained vs transient stereo; [Schor, C. M., Edwards, M., & Pope, D. R. (1998). Spatial-frequency and contrast tuning of the transient-stereopsis system. Vision Research, 38(20), 3057-3068]). Here we compare the dynamics of 1st- and 2nd-order stereopsis using several types of stimuli and find a clear dissociation in which 1st-order stimuli exhibit sustained properties while 2nd-order patterns show more transient properties. Our results and analyses unify and simplify two complimentary bodies of work. PMID:18407312

  14. The latest therapeutic strategies after resistance to first generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) in patients with non-small cell lung cancer (NSCLC)

    PubMed Central

    Xu, Meng; Xie, Yiqun; Ni, Songshi

    2015-01-01

    First-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), gefitinib and erlotinib, produce reliable responses and survival benefits in selected patients with advanced non-small cell lung cancer (NSCLC). Unfortunately, most patients who initially respond to first-line therapy with EGFR TKIs will experience disease progression in 1-2 years. To overcome the resistance of EGFR TKIs, the potent resistance mechanisms and novel therapeutic strategies have been developed. T790M mutation and activation of bypass signaling pathway are identified the predominant mechanisms of acquired resistance to TKIs. Several approaches have shown promise, such as next-generation EGFR TKIs, immunotherapy, and combinational therapies. And the limited clinical data suggest that all drugs are acceptable safe. Additionally, this review will also focus on the increasingly importance of re-biopsy at the time of disease progression, and the matching effective therapies is related to the identification of specific molecular types of tumors. PMID:26015938

  15. Two 2nd Circuit decisions represent mixed bag on insurance.

    PubMed

    2000-01-21

    The 2nd U.S. Circuit Court of Appeals in New York issued two important rulings within a week on the extent to which the Americans with Disabilities Act (ADA) regulates insurance practices. [Name removed] v. Allstate Life Insurance Co. was a plaintiff-friendly decision, finding that the insurance company illegally refused to sell life insurance to a married couple because of their mental disability, major depression. [Name removed]. v. Israel Discount Bank of New York was more defendant friendly and tackled the issue of whether the ADA permits different benefit caps for mental and physical disabilities. PMID:11367226

  16. HER2 mutated breast cancer responds to treatment with single agent neratinib, a second generation HER2/EGFR tyrosine kinase inhibitor

    PubMed Central

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

    2015-01-01

    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. In this case report, we describe 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 function 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 is 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 cancer, suggesting that clinical trials of neratinib or neratinib-based combinations for HER2 mutated solid tumors is warranted. PMID:26358790

  17. 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. PMID:26358790

  18. The crystal structure of ^7Li2ND

    NASA Astrophysics Data System (ADS)

    Tsubota, Masami; Sorby, Magnus H.; Hino, Satoshi; Ichikawa, Takayuki; Hauback, Bjorn C.; Kojima, Yoshitsugu

    2008-03-01

    Recently much attention has been given to reversible hydrogen storage materials possessing high gravimetric capacity. Lithium amide/imide systems are promising candidates. Chen et al.[1] found that a mixture of lithium amide and lithium hydride can reversibly store hydrogen up to 6.5 mass% forming lithium imide (Li2NH). Among them, the crystal structure of Li2NH is still controversial. Balogh et al.[2] have reported a cubic structure model. However, this model differs significantly from theoretical structure models. In this work, the crystal structure of the isotopically substituted ^7Li2ND has been investigated by powder neutron and synchrotron X-ray diffraction experiments. In our data some peaks, which should be a single peak for cubic symmetry, were obviously split indicating a lower symmetry than cubic for lithium imide. The structure of ^7Li2ND will be described. [1] P. Chen et al., J. Phys. Chem. B 107 (2003) 10967. [2] M.P. Balogh et al., J. Alloys Compd. 420 (2006) 326.

  19. 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

  20. Overcoming resistance to first/second generation epidermal growth factor receptor tyrosine kinase inhibitors and ALK inhibitors in oncogene-addicted advanced non-small cell lung cancer.

    PubMed

    Romanidou, Ourania; Landi, Lorenza; Cappuzzo, Federico; Califano, Raffaele

    2016-05-01

    Epidermal growth factor receptor (EGFR) activating mutations and anaplastic lymphoma kinase (ALK) gene rearrangement in advanced non-small cell lung cancer (NSCLC) represent the two oncogenic events with an impact on current clinical practice. EGFR tyrosine kinase inhibitors (TKIs) and crizotinib are the standard of care for the treatment of EGFR mutant and ALK gene rearranged advanced NSCLC patients. Unfortunately, despite initial clinical benefit, acquired resistance to EGFR-TKIs or crizotinib usually develops after an average of 10-12 months of treatment. The aim of this review is to describe the mechanisms of resistance to first/second generation EGFR-TKIs and crizotinib. In particular, we focus on strategies to overcome resistance due to secondary EGFR T790M mutation and mutations of the ALK domain. PMID:27239236

  1. Overcoming resistance to first/second generation epidermal growth factor receptor tyrosine kinase inhibitors and ALK inhibitors in oncogene-addicted advanced non-small cell lung cancer

    PubMed Central

    Romanidou, Ourania; Landi, Lorenza; Cappuzzo, Federico; Califano, Raffaele

    2016-01-01

    Epidermal growth factor receptor (EGFR) activating mutations and anaplastic lymphoma kinase (ALK) gene rearrangement in advanced non-small cell lung cancer (NSCLC) represent the two oncogenic events with an impact on current clinical practice. EGFR tyrosine kinase inhibitors (TKIs) and crizotinib are the standard of care for the treatment of EGFR mutant and ALK gene rearranged advanced NSCLC patients. Unfortunately, despite initial clinical benefit, acquired resistance to EGFR-TKIs or crizotinib usually develops after an average of 10–12 months of treatment. The aim of this review is to describe the mechanisms of resistance to first/second generation EGFR-TKIs and crizotinib. In particular, we focus on strategies to overcome resistance due to secondary EGFR T790M mutation and mutations of the ALK domain. PMID:27239236

  2. 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

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

    PubMed

    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 2(nd) and 3(rd) 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- + orthotyrosine)/ 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

  4. Use of second- and third-generation tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia: an evolving treatment paradigm.

    PubMed

    Jabbour, Elias; Kantarjian, Hagop; Cortes, Jorge

    2015-06-01

    Although imatinib remains the gold standard for first-line treatment of chronic myeloid leukemia (CML), increasing recognition of imatinib resistance and intolerance has led to the development of additional tyrosine kinase inhibitors (TKIs), which have demonstrated effectiveness as salvage therapies or alternative first-line treatments. Although additional options represent progress, the availability of 3 second-generation TKIs (dasatinib, nilotinib, and bosutinib) and 1 third-generation TKI (ponatinib) has added complexity to the treatment paradigm for CML, particularly CML in the chronic phase. Two second-generation agents (dasatinib and nilotinib) are approved for use as first-line and subsequent therapy. Thus, the appropriate sequencing of TKIs is a frequent quandary, and is incompletely addressed in clinical guidelines. Here, we review studies that might guide selection of a second- or third-generation TKI after failure of TKI therapy in patients with chronic-phase CML. These studies evaluate prognostic factors such as first-line cytogenetic response and BCR-ABL1 mutation status, which might help physicians identify patients who are likely to respond to second-generation TKIs, and those for whom ponatinib or an investigational agent might be more appropriate. We summarize evidence to date that suggests that use of a second-generation TKI as third-line therapy confers limited value in most CML patients, and we also explore the utility of current event-free survival versus traditional outcomes to predict long-term benefits of sequential TKI use. Finally, we present 3 case studies to illustrate how prognostic factors and other considerations (eg, tolerability) can be used to individualize subsequent therapy in cases of TKI resistance or intolerance. PMID:25971713

  5. Sulfone-stabilized carbanions for the reversible covalent capture of a posttranslationally-generated cysteine oxoform found in protein tyrosine phosphatase 1B (PTP1B).

    PubMed

    Parsons, Zachary D; Ruddraraju, Kasi Viswanatharaju; Santo, Nicholas; Gates, Kent S

    2016-06-15

    Redox regulation of protein tyrosine phosphatase 1B (PTP1B) involves oxidative conversion of the active site cysteine thiolate into an electrophilic sulfenyl amide residue. Reduction of the sulfenyl amide by biological thiols regenerates the native cysteine residue. Here we explored fundamental chemical reactions that may enable covalent capture of the sulfenyl amide residue in oxidized PTP1B. Various sulfone-containing carbon acids were found to react readily with a model peptide sulfenyl amide via attack of the sulfonyl carbanion on the electrophilic sulfur center in the sulfenyl amide. Both the products and the rates of these reactions were characterized. The results suggest that capture of a peptide sulfenyl amide residue by sulfone-stabilized carbanions can slow, but not completely prevent, thiol-mediated generation of the corresponding cysteine-containing peptide. Sulfone-containing carbon acids may be useful components in the construction of agents that knock down PTP1B activity in cells via transient covalent capture of the sulfenyl amide oxoform generated during insulin signaling processes. PMID:27132865

  6. c-MYC Generates Repair Errors via Increased Transcription of Alternative-NHEJ Factors, LIG3 and PARP1, in Tyrosine Kinase-activated Leukemias

    PubMed Central

    Muvarak, Nidal; Kelley, Shannon; Robert, Carine; Baer, Maria R.; Perrotti, Danilo; Gambacorti-Passerini, Carlo; Civin, Curt; Scheibner, Kara; Rassool, Feyruz

    2015-01-01

    Leukemias expressing the constitutively activated tyrosine kinases (TKs) BCR-ABL1 and FLT3/ITD activate signaling pathways that increase genomic instability through generation of reactive oxygen species (ROS), DNA double-strand breaks (DSBs) and error-prone repair. The non-homologous end-joining (NHEJ) pathway is a major pathway for DSB repair and is highly aberrant in TK-activated-leukemias; an alternative form of NHEJ (ALT-NHEJ) predominates, evidenced by increased expression of DNA ligase IIIα (LIG3) and poly (ADP-ribose) polymerase (PARP1), increased frequency of large genomic deletions, and repair using DNA sequence microhomologies. This study, for the first time, demonstrates that the TK target c-MYC plays a role in transcriptional activation and subsequent expression of LIG3 and PARP1 and contributes to the increased error-prone repair observed in TK-activated leukemias. c-MYC negatively regulates microRNAs miR-150 and miR-22 which demonstrate an inverse correlation with LIG3 and PARP1 expression in primary and cultured leukemia cells and chronic myelogenous leukemia (CML) human patient samples. Notably, inhibition of c-MYC and overexpression of miR-150 and -22 decreases ALT-NHEJ activity. Thus, BCR-ABL1 or FLT3/ITD induces c-MYC expression leads to genomic instability via augmented expression of ALT-NHEJ repair factors that generate repair errors. PMID:25828893

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

    NASA Astrophysics Data System (ADS)

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

    2014-02-01

    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.

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

    PubMed

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

    2014-02-01

    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. PMID:24593593

  9. The Second Stellar Spectrum and the non-LTE Problem of the 2nd Kind

    NASA Astrophysics Data System (ADS)

    Trujillo Bueno, Javier

    2009-09-01

    This paper presents an overview of the radiative transfer problem of calculating the spectral line intensity and polarization that emerges from a (generally magnetized) astrophysical plasma composed of atoms and molecules whose excitation state is significantly influenced by radiative transitions produced by an anisotropic radiation field. The numerical solution of this non-LTE problem of the 2nd kind is facilitating the physical understanding of the second solar spectrum and the exploration of the complex magnetism of the extended solar atmosphere, but much more could be learned if high-sensitivity polarimeters were developed also for the present generation of night-time telescopes. Interestingly, I find that the population ratio between the levels of some resonance line transitions can be efficiently modulated by the inclination of a weak magnetic field when the anisotropy of the incident radiation is significant, something that could provide a new diagnostic tool in astrophysics.

  10. [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. PMID:18227902

  11. 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.

  12. APTWG: 2nd Asia-Pacific Transport Working Group Meeting

    NASA Astrophysics Data System (ADS)

    Dong, J. Q.; Shi, Y. J.; Tamura, N.; Jhang, Hogun; Watanabe, T.-H.; Ding, X. T.

    2013-02-01

    This conference report summarizes the contributions to and discussions at the 2nd Asia-Pacific Transport Working Group Meeting held in Chengdu, China, from 15 to 18 May 2012. The topics of the meeting were organized under five main headings: momentum transport, non-locality in transport, edge turbulence and L-H transition, three-dimensional effects on transport physics, and particle, momentum and heat pinches. It is found that lower hybrid wave and ion cyclotron wave induce co-current rotation while electron cyclotron wave induces counter-current rotation. A four-stage imaging for low (L) to high (H) confinement transition gradually emerges and a more detailed verification is urgently expected. The new edge-localized modes mitigation technique with supersonic molecular beam injection was approved to be effective to some extent on HL-2A and KSTAR. It is also found that low collisionality, trapped electron mode to ion temperature gradient transition (or transition of higher to lower density and temperature gradients), fuelling and lithium coating are in favour of inward pinch of particles in tokamak plasmas.

  13. Do chronic myeloid leukemia patients with late "warning" responses benefit from "watch and wait" or switching therapy to a second generation tyrosine kinase inhibitor?

    PubMed

    García-Gutiérrez, Valentin; Puerta, Jose Manuel; Maestro, Begoña; Casado Montero, Luis Felipe; Muriel, Alfonso; Molina Hurtado, Jose Ramon; Perez-Encinas, Manuel; Moreno Romero, Maria Victoria; Suñol, Pere Barba; Sola Garcia, Ricardo; De Paz, Raquel; Ramirez Sanchez, Maria Jose; Osorio, Santiago; Mata Vazquez, Maria Isabel; Martinez López, Joaquin; Sastre, Jose Luis; Portero, Maria de Los Angles; Bautista, Guiomar; Duran Nieto, Maria Soledad; Giraldo, Pilar; Jimenez Jambrina, Margarita; Burgaleta, Carmen; Ruiz Aredondo, Joaquin; Peñarrubia, Maria Jesús; Requena, Maria José; Fernández Valle, María Del Carmen; Calle, Carmen; Paz Coll, Antonio; Hernández-Rivas, Jose Ángel; Franco Osorio, Rafael; Cano, Pilar; Tallón Pérez, David; Fernández de la Mata, Margarita; Garrido, Pilar López; Steegmann, Juan Luis

    2014-11-01

    In the latest recommendations for the management of chronic-phase chronic myeloid leukemia suboptimal responses have been reclassified as "warning responses." In contrast to previous recommendations current guidance advises close monitoring without changing therapy. We have identified 198 patients treated with first-line imatinib, with a warning response after 12 months of treatment (patients with a complete cytogenetic response but no major molecular response [MMR]). One hundred and forty-six patients remained on imatinib, while 52 patients changed treatment to a second generation tyrosine kinase inhibitor (2GTKI). Changing therapy did not correlate with an increase in overall survival or progression-free survival. Nevertheless, a significant improvement was observed in the probability of a MMR: 24% vs. 42% by 12 months and 43% vs. 64% by 24 months (P = 0.002); as well as the probability of achieving a deep molecular responses (MR(4.5) ): 1% vs. 17% and 7% vs. 23% by 12 and 24 months, respectively (P = <0.001) .The treatment change to 2GTKI remained safe; however, we have observed a 19% of treatment discontinuation due to side effects. We have observed an improvement of molecular responses after changing treatment to 2GTKI in patients with late suboptimal response treated with imatinib first line. However, these benefits were not correlated with an improvement of progression free survival or overall survival. PMID:25059397

  14. 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

  15. Examples to Accompany "Descriptive Cataloging of Rare Books, 2nd Edition."

    ERIC Educational Resources Information Center

    Association of Coll. and Research Libraries, Chicago, IL.

    This book is intended to be used with "Descriptive Cataloging of Rare Books," 2nd edition (DCRB) as an illustrative aid to catalogers and others interested in or needing to interpret rare book cataloging. As such, it is to be used in conjunction with the rules it illustrates, both in DCRB and in "Anglo-American Cataloging Rules," 2nd edition…

  16. 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.

  17. 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

  18. 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. PMID:26397863

  19. Next-generation sequencing for sensitive detection of BCR-ABL1 mutations relevant to tyrosine kinase inhibitor choice in imatinib-resistant patients

    PubMed Central

    Soverini, Simona; De Benedittis, Caterina; Polakova, Katerina Machova; Linhartova, Jana; Castagnetti, Fausto; Gugliotta, Gabriele; Papayannidis, Cristina; Mancini, Manuela; Klamova, Hana; Salvucci, Marzia; Crugnola, Monica; Iurlo, Alessandra; Albano, Francesco; Russo, Domenico; Rosti, Gianantonio; Cavo, Michele; Baccarani, Michele; Martinelli, Giovanni

    2016-01-01

    In chronic myeloid leukemia (CML) and Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) patients who fail imatinib treatment, BCR-ABL1 mutation profiling by Sanger sequencing (SS) is recommended before changing therapy since detection of specific mutations influences second-generation tyrosine kinase inhibitor (2GTKI) choice. We aimed to assess i) in how many patients who relapse on second-line 2GTKI therapy next generation sequencing (NGS) may track resistant mutations back to the sample collected at the time of imatinib resistance, before 2GTKI start (switchover sample) and ii) whether low level mutations identified by NGS always undergo clonal expansion. To this purpose, we used NGS to retrospectively analyze 60 imatinib-resistant patients (CML, n = 45; Ph+ ALL, n = 15) who had failed second-line 2GTKI therapy and had acquired BCR-ABL1 mutations (Group 1) and 25 imatinib-resistant patients (CML, n = 21; Ph+ ALL, n = 4) who had responded to second-line 2GTKI therapy, for comparison (Group 2). NGS uncovered that in 26 (43%) patients in Group 1, the 2GTKI-resistant mutations that triggered relapse were already detectable at low levels in the switchover sample (median mutation burden, 5%; range 1.1%–18.4%). Importantly, none of the low level mutations detected by NGS in switchover samples failed to expand whenever the patient received the 2GTKI to whom they were insensitive. In contrast, no low level mutation that was resistant to the 2GTKI the patients subsequently received was detected in the switchover samples from Group 2. NGS at the time of imatinib failure reliably identifies clinically relevant mutations, thus enabling a more effective therapeutic tailoring. PMID:26980736

  20. 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

  1. Clinical efficacy of second-generation tyrosine kinase inhibitors in imatinib-resistant gastrointestinal stromal tumors: a meta-analysis of recent clinical trials

    PubMed Central

    Wu, Lile; Zhang, Zhongqiang; Yao, Hongliang; Liu, Kuijie; Wen, Yu; Xiong, Li

    2014-01-01

    Background Primary and secondary resistance to imatinib, a selective receptor tyrosine kinase inhibitor (TKI), is a serious clinical problem in the control of advanced gastrointestinal stromal tumors (GIST). Here we report on a meta-analysis we performed to evaluate the efficacy of second-generation TKIs in the treatment of patients with imatinib-resistant GIST. Methods Randomized controlled trials evaluating the clinical efficacy of second-generation TKIs were identified by searching PubMed and EMBASE from 2000 to February 2014. Outcomes subjected to analysis were progression-free survival and overall survival. Statistical analyses were performed using Review Manager version 5.1.0 (Cochrane Collaboration, Oxford, UK). Weighted hazard ratios (HR) with 95% confidence intervals (CIs) were calculated for the outcomes. Fixed-effects or random-effects models were used, depending on the degree of heterogeneity across the selected studies. Results Three randomized controlled trials were selected for meta-analysis. Among imatinib-resistant or imatinib-intolerant patients, 541 received second-generation TKIs (sunitinib, nilotinib, or regorafenib) and 267 controls received placebo or best supportive care. Progression-free survival was significantly improved in the TKI-treated group (HR 0.38; 95% CI 0.24–0.59; P<0.0001). No statistically significant difference was detected in overall survival between the treatment group and the control group (HR 0.85; 95% CI 0.71–1.03; P=0.09). In the subgroup of patients who were resistant or intolerant to both imatinib and sunitinib, TKI therapy (nilotinib or regorafenib) improved progression-free survival (HR 0.40; 95% CI 0.19–0.84; P=0.02) but not overall survival (HR 0.83; 95% CI 0.63–1.08; P=0.17). Regorafenib was shown to be effective in terms of progression-free survival across different subpopulations of patients who were resistant to both imatinib and sunitinib. Conclusion Second-generation TKIs (sunitinib, nilotinib, and

  2. 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

  3. 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.

  4. 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

  5. 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

  6. MAGAZINE E30. VIEW FROM BETWEEN 1ST AND 2ND BLAST WALL ...

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

    MAGAZINE E-30. VIEW FROM BETWEEN 1ST AND 2ND BLAST WALL LOOKING TO THE REAR OF THE MAGAZINE. - Naval Magazine Lualualei, Waikele Branch, Tunnel Magazine Type, Waikakalaua & Kipapa Gulches, Pearl City, Honolulu County, HI

  7. 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

  8. 12. Bldg #13, 2nd floor, interior stone walls w/windows and ...

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

    12. Bldg #13, 2nd floor, interior stone walls w/windows and bent pipe thru wall L and light bulbs in ceiling, to NE - Lawrence Machine Shop, Building No. 13, Union & Canal Streets, Lawrence, Essex County, MA

  9. 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

  10. 2nd U.S. Case of Bacteria Resistant to Last-Resort Antibiotic

    MedlinePlus

    ... news/fullstory_159807.html 2nd U.S. Case of Bacteria Resistant to Last-Resort Antibiotic Scientists concerned it ... the United States who was infected with a bacteria that is resistant to an antibiotic of last ...

  11. Front elevation of Rostrum with 2nd Division American Expeditionary Force ...

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

    Front elevation of Rostrum with 2nd Division American Expeditionary Force Monument in foreground, view to northwest - Cypress Hills National Cemetery, Jamaica Avenue Unit, 625 Jamaica Avenue, Brooklyn, Kings County, NY

  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. 73. VIEW OF NORTHWEST SIDE OF 2ND TEE, LOOKING NORTHWEST, ...

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

    73. VIEW OF NORTHWEST SIDE OF 2ND TEE, LOOKING NORTHWEST, SHOWING STEPPED PLATFORM, BENCHES, AND LIGHT STANDARDS - Huntington Beach Municipal Pier, Pacific Coast Highway at Main Street, Huntington Beach, Orange County, CA

  14. 21. VIEW FROM INTERIOR OF 2ND FLOOR ARCHED WINDOW WITH ...

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

    21. VIEW FROM INTERIOR OF 2ND FLOOR ARCHED WINDOW WITH HOLLOW STEEL SASH AND POLISHED PLATE WIRE GLASS. THIS WINDOW IS AT THE FRONT OF THE BUILDING. - Pacific Telephone & Telegraph Company Building, 1519 Franklin Street, Oakland, Alameda County, CA

  15. The 2nd-order Post-Newtonian Orbit Equation of Light

    NASA Astrophysics Data System (ADS)

    Xiao, Yu; Fei, Bao-Jun; Sun, Wei-Jin; Ji, Cheng-Xiang

    2008-10-01

    Based on the 2nd-order post-Newtonian approximation under the DSX frame of the general relativity theory, the 2nd-order post-Newtonian orbital equation of light in the axis-symmetrical stationary spacetime is derived, and from this, the angle of deflection of light propagating in the equatorial plane is derived. The obtained results are consistent with those of the Schwarzchild and Kerr metrics within the limits of measuring precision.

  16. Severe weather phenomena: SQUALL LINES The case of July 2nd 2009

    NASA Astrophysics Data System (ADS)

    Paraschivescu, Mihnea; Tanase, Adrian

    2010-05-01

    The wind intensity plays an important role, among the dangerous meteorological phenomena, to produce negative effects on the economy and the social activities, particularly when the wind is about to turn into a storm. During the past years one can notice an increase of wind frequency and intensity due to climate changes and, consequently, as a result of the extreme meteorological phenomena not only on a planetary level but also on a regional one. Although dangerous meteorological phenomena cannot be avoided, since they are natural, nevertheless they can be anticipated and decision making institutions and mass media can be informed. This is the reason why, in this paper, we set out to identify the synoptic conditions that led to the occurrence of the severe storm case in Bucharest on July 2nd, 2009, as well as the matrices that generate such cases. At the same time we sought to identify some indications evidence especially from radar data so as to lead to the improvement of the time interval between the nowcasting warning and the actual occurrence of the phenomenon.

  17. Receptor Tyrosine Kinase and Tyrosine Kinase Inhibitors

    PubMed Central

    Mirshafiey, Abbas; Ghalamfarsa, Ghasem; Asghari, Babak

    2014-01-01

    Receptor tyrosine kinases (RTKs) are essential components of signal transduction pathways that mediate cell-to-cell communication and their function as relay points for signaling pathways. They have a key role in numerous processes that control cellular proliferation and differentiation, regulate cell growth and cellular metabolism, and promote cell survival and apoptosis. Recently, the role of RTKs including TCR, FLT-3, c-Kit, c-Fms, PDGFR, ephrin, neurotrophin receptor, and TAM receptor in autoimmune disorder, especially rheumatoid arthritis and multiple sclerosis has been suggested. In multiple sclerosis pathogenesis, RTKs and their tyrosine kinase enzymes are selective important targets for tyrosine kinase inhibitor (TKI) agents. TKIs, compete with the ATP binding site of the catalytic domain of several tyrosine kinases, and act as small molecules that have a favorable safety profile in disease treatment. Up to now, the efficacy of TKIs in numerous animal models of MS has been demonstrated, but application of these drugs in human diseases should be tested in future clinical trials. PMID:25337443

  18. 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.

  19. 11 Years of Cloud Characteristics from SEVIRI: 2nd Edition of the CLAAS Dataset by CMSAF

    NASA Astrophysics Data System (ADS)

    Finkensieper, Stephan; Stengel, Martin; Fokke Meirink, Jan; van Zadelhoff, Gerd-Jan; Kniffka, Anke

    2016-04-01

    Spatiotemporal variability of clouds is an important aspect of the climate system. Therefore climate data records of cloud properties are valuable to many researchers in the climate community. The passive SEVIRI imager onboard the geostationary Meteosat Second Generation satellites is well suited for the needs of cloud retrievals as it provides measurements in 12 spectral channels every 15 minutes and thus allows for capturing both the spatial and the temporal variability of clouds. However, requirements on climate data records are high in terms of record length and homogeneity, so that intercalibration and homogenization among the available SEVIRI instruments becomes a crucial factor. We present the 2nd edition of the CLoud Property DAtAset using SEVIRI (CLAAS-2) generated within the EUMETSAT Satellite Application Facility on Climate Monitoring (CMSAF), that is temporally extended and qualitatively improved compared to the 1st edition. CLAAS-2 covers the time period 2004-2014 and features cloud mask, cloud top properties, cloud phase, cloud type, and microphysical cloud properties on the complete SEVIRI disc in 15-minute temporal resolution. Temporally and spatially averaged quantities, mean diurnal cycles and monthly histograms are included as well. CLAAS-2 was derived from a homogenized data basis, obtained by intercalibrating visible and infrared SEVIRI radiances (of Meteosat 8, 9 and 10) with MODIS, using state-of-the-art retrieval schemes. In addition to the dataset characteristics, we will present validation results using CALIPSO as reference observations. The CLAAS-2 dataset will allow for a large variety of applications of which some will be indicated in our presentation, with focus on determining diurnal to seasonal cycles, spatially resolved frequencies of cloud properties as well as showing the potential for using CLAAS-2 data for model process studies.

  20. Physics design of the DARHT 2nd axis accelerator cell

    SciTech Connect

    Chen, Y J; Houck, T L; Reginato, L J; Shang, C C; Yu, S S

    1999-08-19

    The next generation of radiographic machines based on induction accelerators require very high brightness electron beams to realize the desired x-ray spot size and intensity. This high brightness must be maintained throughout the beam transport, from source to x-ray converter target. The accelerator for the second-axis of the Dual Axis Radiographic Hydrodynamic Test (DARHT) facility is being designed to accelerate a 4-kA, 2-{micro}s pulse of electrons to 20 MeV. After acceleration, the 2-{micro}s pulse will be chopped into a train of four 50-ns pulses with variable temporal spacing by rapidly deflecting the beam between a beam stop and the final transport section. The short beam pulses will be focused onto an x-ray converter target generating four radiographic pulses within the 2-{micro}s window. Beam instability due to interaction with the accelerator cells can very adversely effect the beam brightness and radiographic pulse quality. This paper describes the various issues considered in the design of the accelerator cell with emphasis on transverse impedance and minimizing beam instabilities.

  1. 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.

  2. Four-dimensional investigation of the 2nd order volume autocorrelation technique

    NASA Astrophysics Data System (ADS)

    Faucher, O.; Tzallas, P.; Benis, E. P.; Kruse, J.; Peralta Conde, A.; Kalpouzos, C.; Charalambidis, D.

    2009-10-01

    The 2nd order volume autocorrelation technique, widely utilized in directly measuring ultra-short light pulses durations, is examined in detail via model calculations that include three-dimensional integration over a large ionization volume, temporal delay and spatial displacement of the two beams of the autocorrelator at the focus. The effects of the inherent displacement to the 2nd order autocorrelation technique are demonstrated for short and long pulses, elucidating the appropriate implementation of the technique in tight focusing conditions. Based on the above investigations, a high accuracy 2nd order volume autocorrelation measurement of the duration of the 5th harmonic of a 50 fs long laser pulse, including the measurement of the carrier wavelength oscillation, is presented.

  3. Regional Observations of North Korea Explosions: 1st and 2nd Tests

    NASA Astrophysics Data System (ADS)

    Chi, Heon Cheol; Shin, Jin Soo; Lee, Hee-Il; Park, Jung Ho; Sheen, Dong-Hoon; Kim, Geunyoung; Kim, Tea Sung; Che, Il-Young; Lim, In-Seub

    2010-05-01

    Through data exchanging with China, Russia and Japan, KIGAM could monitor North Korea explosion tests in near real time with azimuthally full coverage from the test site. Except for the East Sea (Japan Sea) side, the seismic stations are distributed uniformly along the boundaries of North Korea and adjacent countries. The error ellipses of epicentral determination of test site for 1st and 2nd tests showed almost identical pattern if they were separately calculated with the same configuration of stations. But the combined use of the 1st and the 2nd test data showed that the 2nd test site was moved approximately 2 Km westward from 1st site. The Pn/Lg spectral ratio clearly discriminate these events from two nearby natural earthquakes above 4 Hz. Full moment tensor inversion also indicate the 2nd test had a very large isotropic component. But mb-Ms discrimination, which has been considered one of the most reliable discriminants for separating explosions and earthquakes, did not show apparently the known pattern of explosion for both tests. Body wave magnitude, mb(Pn) of the 2nd test, which was evaluated as 4.5 by KIGAM, varies with directional location of stations widely from 4.1 to 5.2. The magnitude obtained from Lg, mb(Lg), showed narrow variation between 4.3 to 4.7 with the average of 4.5. In the case of both 1st and 2nd tests, both mb(Pn) and mb(Lg) showed equivalently large variation with directional station location. These variations are mainly due to lateral variation of crustal structures surrounding the test site. Remarkably mb(Lg) showed very linear relationship with mb(Pn). By considering attenuation characteristics according to the propagation path, the variations could be effectively reduced. The cut-off frequencies of P wave of both tests showed no or negligible difference even though the estimated yield of the 2nd test were much larger than that of the 1st one. The ratio of P-wave amplitudes of two tests showed from 2 to 3.1 times. Correspondingly the

  4. Monitoring North Korea Explosions: Status and Result of 1st and 2nd Tests (Invited)

    NASA Astrophysics Data System (ADS)

    Chi, H.; Lee, H.; Shin, J.; Park, J.; Sheen, D.; Kim, G.; Che, I.; Lim, I.; Kim, T.

    2009-12-01

    Through data exchanging with China, Russia and Japan, KIGAM could monitor North Korea explosion tests in near real time with azimuthal full coverage from the test site. Except for the East Sea (Japan Sea) side, the seismic stations are distributed uniformly along the boundaries of North Korea and adjacent countries, and only stations with the distance of 200 to 550 Km from the test site were considered. Irrespective of azimuthal directions of stations from the test site, the conventional discrimination, Pn/Lg spectral ratio clearly showed that both tests were explosion. But mb-Ms discrimination did not show apparently the known pattern of explosion for both tests. Body wave magnitude, mb(Pn) of 2nd test, which was evaluated as 4.5 by KIGAM, varies with directional location of stations widely from 4.1 to 5.2. The magnitude obtained from Lg, mb(Lg), showed narrow variation between 4.3 to 4.7 with the average of 4.5. In the case of 1st test, both mb(Pn) and mb(Lg) showed equivalently large variation with directional station location. The error ellipses of epicentral determination of test site for 1st and 2nd tests showed almost identical pattern if they were separately calculated with the same configuration of stations. But the combined use of 1st and 2nd test data showed that 2nd test site was moved approximately 2 Km westward from 1st site. The cut-off frequencies of P wave of 1st and 2nd tests showed no or negligible difference even though the estimated yield of 2nd test were much larger than that of 1st one. The ratio of 1st and 2nd P-wave amplitudes showed from 2 to 3.1 times. Correspondingly the estimated energy or yield were ranged from 4 to roughly 10 times. KIGAM evaluated the yield of 2nd test were 8 times in the average larger than that of 1st one.

  5. 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.

  6. 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

  7. Monoclonal antibodies to individual tyrosine-phosphorylated protein substrates of oncogene-encoded tyrosine kinases

    SciTech Connect

    Kanner, S.B.; Reynolds, A.B.; Vines, R.R.; Parsons, J.T. )

    1990-05-01

    Cellular transformation by oncogenic retroviruses encoding protein tyrosine kinases coincides with the tyrosine-specific phosphorylation of multiple protein substrates. Previous studies have shown that tyrosine phosphorylation of a protein of 120 kDa, p120, correlated with src transformation in chicken embryo fibroblasts. Additionally, the authors previously identified two phosphotyrosine-containing cellular proteins, p130 and p110, that formed stable complexes with activated variants of pp60{sup src}, the src-encoded tyrosine kinase. To study transformation-relevant tyrosine kinase substrates, they have generated monoclonal antibodies to individual tyrosine phosphoproteins, including p130, p120, p110, and five additional phosphoproteins (p210, p125, p118, p85, and p185/p64). These antibodies detected several of the same tyrosine phosphoproteins in chicken embryo fibroblasts transformed by avian retroviruses Y73 and CT10, encoding the yes and crk oncogenes, respectively. Protein substrates in mouse, rat, hamster, and human cells overexpressing activated variants of chicken pp60{sup src} were also detected by several of the monoclonal antibodies.

  8. 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)

  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. 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...

  11. 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.

  12. 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.

  13. 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.…

  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. 70. VIEW OF LIFEGUARD TOWER ON SOUTHEAST SIDE OF 2ND ...

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

    70. VIEW OF LIFEGUARD TOWER ON SOUTHEAST SIDE OF 2ND TEE (LEFT) AND NORTHWEST SIDE OF TEE (RIGHT), WITH VIEW OF PILINGS, LOOKING SOUTH-SOUTHWEST - Huntington Beach Municipal Pier, Pacific Coast Highway at Main Street, Huntington Beach, Orange County, CA

  16. 71. VIEW OF NORTHWEST SIDE OF 2ND TEE (LEFT), SHOWING ...

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

    71. VIEW OF NORTHWEST SIDE OF 2ND TEE (LEFT), SHOWING VIEW OF PILINGS, LIFEGURD TOWER ON SOUTHEAST SIDE OF TEE (RIGHT), LOOKING EAST-NORTHEAST - Huntington Beach Municipal Pier, Pacific Coast Highway at Main Street, Huntington Beach, Orange County, CA

  17. Individual Differences In The School Performance of 2nd-Grade Children Born to Low-Income Adolescent Mothers

    ERIC Educational Resources Information Center

    Apiwattanalunggarn, Kunlakarn Lekskul; Luster, Tom

    2005-01-01

    The purpose of this study was to investigate factors that contribute to individual differences in the school performance of 2nd-grade children born to adolescent mothers. The sample of this study was 90 low-income adolescent mothers and their children. Data were collected from the adolescent mothers and their first-born children, now in 2nd grade,…

  18. 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.

  19. Validation of the 2nd Generation Proteasome Inhibitor Oprozomib for Local Therapy of Pulmonary Fibrosis.

    PubMed

    Semren, Nora; Habel-Ungewitter, Nunja C; Fernandez, Isis E; Königshoff, Melanie; Eickelberg, Oliver; Stöger, Tobias; Meiners, Silke

    2015-01-01

    Proteasome inhibition has been shown to prevent development of fibrosis in several organs including the lung. However, effects of proteasome inhibitors on lung fibrosis are controversial and cytotoxic side effects of the overall inhibition of proteasomal protein degradation cannot be excluded. Therefore, we hypothesized that local lung-specific application of a novel, selective proteasome inhibitor, oprozomib (OZ), provides antifibrotic effects without systemic toxicity in a mouse model of lung fibrosis. Oprozomib was first tested on the human alveolar epithelial cancer cell line A549 and in primary mouse alveolar epithelial type II cells regarding its cytotoxic effects on alveolar epithelial cells and compared to the FDA approved proteasome inhibitor bortezomib (BZ). OZ was less toxic than BZ and provided high selectivity for the chymotrypsin-like active site of the proteasome. In primary mouse lung fibroblasts, OZ showed significant anti-fibrotic effects, i.e. reduction of collagen I and α smooth muscle actin expression, in the absence of cytotoxicity. When applied locally into the lungs of healthy mice via instillation, OZ was well tolerated and effectively reduced proteasome activity in the lungs. In bleomycin challenged mice, however, locally applied OZ resulted in accelerated weight loss and increased mortality of treated mice. Further, OZ failed to reduce fibrosis in these mice. While upon systemic application OZ was well tolerated in healthy mice, it rather augmented instead of attenuated fibrotic remodelling of the lung in bleomycin challenged mice. To conclude, low toxicity and antifibrotic effects of OZ in pulmonary fibroblasts could not be confirmed for pulmonary fibrosis of bleomycin-treated mice. In light of these data, the use of proteasome inhibitors as therapeutic agents for the treatment of fibrotic lung diseases should thus be considered with caution. PMID:26340365

  20. The new 2nd-generation laser station at Santiago de Cuba

    NASA Astrophysics Data System (ADS)

    Masevich, A. G.; Chepurnov, B. D.; Fundora, M.; del Pino, J.; Kautzleben, H.

    The new laser-radar station at Santiago de Cuba was equipped in cooperation between the Academies of Sciences of the USSR, Cuba and the G.D.R. The system is based on a modified satellite-tracking camera (SBG). Its basic concept and the technical performance are similar to the laser-radar station of the Central Institute for Physics of the Earth, Potsdam. During a first 6-weeks-observation campaign (Dec. 1985 - Jan. 1986), 70 satellite passes (including 40 passes of the geodynamical satellite LAGEOS) were obtained.

  1. 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…

  2. 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. PMID:22939601

  3. Validation of the 2nd Generation Proteasome Inhibitor Oprozomib for Local Therapy of Pulmonary Fibrosis

    PubMed Central

    Semren, Nora; Habel-Ungewitter, Nunja C.; Fernandez, Isis E.; Königshoff, Melanie; Eickelberg, Oliver; Stöger, Tobias; Meiners, Silke

    2015-01-01

    Proteasome inhibition has been shown to prevent development of fibrosis in several organs including the lung. However, effects of proteasome inhibitors on lung fibrosis are controversial and cytotoxic side effects of the overall inhibition of proteasomal protein degradation cannot be excluded. Therefore, we hypothesized that local lung-specific application of a novel, selective proteasome inhibitor, oprozomib (OZ), provides antifibrotic effects without systemic toxicity in a mouse model of lung fibrosis. Oprozomib was first tested on the human alveolar epithelial cancer cell line A549 and in primary mouse alveolar epithelial type II cells regarding its cytotoxic effects on alveolar epithelial cells and compared to the FDA approved proteasome inhibitor bortezomib (BZ). OZ was less toxic than BZ and provided high selectivity for the chymotrypsin-like active site of the proteasome. In primary mouse lung fibroblasts, OZ showed significant anti-fibrotic effects, i.e. reduction of collagen I and α smooth muscle actin expression, in the absence of cytotoxicity. When applied locally into the lungs of healthy mice via instillation, OZ was well tolerated and effectively reduced proteasome activity in the lungs. In bleomycin challenged mice, however, locally applied OZ resulted in accelerated weight loss and increased mortality of treated mice. Further, OZ failed to reduce fibrosis in these mice. While upon systemic application OZ was well tolerated in healthy mice, it rather augmented instead of attenuated fibrotic remodelling of the lung in bleomycin challenged mice. To conclude, low toxicity and antifibrotic effects of OZ in pulmonary fibroblasts could not be confirmed for pulmonary fibrosis of bleomycin-treated mice. In light of these data, the use of proteasome inhibitors as therapeutic agents for the treatment of fibrotic lung diseases should thus be considered with caution. PMID:26340365

  4. Integrated vehicle test bed for IVHM systems on 2nd generation RLV

    NASA Technical Reports Server (NTRS)

    James, M. L.; Baroth, E.; Mellinger, L.; Park, H.; Stough, T.; Brown, S. A.; Meyer, C. M.

    2003-01-01

    The IVTB concept is to validate spacecraft system designs and evaluate new technologies; its focus is to identify and resolve problems at the early stages of development and facilitate new technology transfer.

  5. 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.

  6. 2nd-Order CESE Results For C1.1: Transonic Ringleb 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 (an unstructured Navier-Stokes solver coded in C++ with serial and parallel versions available.) 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.

  7. 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.

  8. [Employment and education in the 2nd economic and social development plan of Togo].

    PubMed

    Dovi-sodemekou, F B

    1985-01-01

    Togo is a developing country whose population is increasing at the rapid rate of 2.7%/year. Economic development is therefore a necessity to ensure at least an average standard of living. Plans of development include objectives of structural societal changes, including improvements in education and employment. This study analyzes the evolution of population activities. It identifies obstacles to the improvement of education and employment. The investigation examines the employment and education situation before adoption of the 2nd plan of Togo and predicts the probable evolution of the situation. Despite the priority accorded to agriculture, the 2nd plan appears to give greater importance to industry. The industrial and commercial sector has witnessed a 65.2% investment increase, whereas the rural sector had an investment increase of 11.8%. The 2nd plan, in view of its relation to the evolution of economic activities, took into account the demand for manual labor. In the private sector, industries should occupy an important position. The dualism of a modern and a traditional sector is considered a cause of underdevelopment. The modern sector should be developed in order to suppress the traditional sector and allow progress in society. As a result of this approach, agriculture is given a 2ndary role. PMID:12267415

  9. Very large millimeter/submillimeter array toward search for 2nd Earth

    NASA Astrophysics Data System (ADS)

    Iguchi, Satoru; Saito, Masao

    2012-09-01

    ALMA (Atacama Large Millimeter/submillimeter Array) is a revolutionary radio telescope and its early scientific operation has just started. It is expected that ALMA will resolve several cosmic questions and will give us a new cosmic view. Our passion for astronomy naturally goes beyond ALMA because we believe that the 21st-century astronomy should pursue the new scientific frontier. In this conference, we propose a project of the future radio telescope to search for habitable planets and finally detect 2nd Earth as a migratable planet. Detection of 2nd Earth is one of the ultimate dreams not only for astronomers but also for every human being. To directly detect 2nd Earth, we have to carefully design the sensitivity and angular resolution of the telescope by conducting trade-off analysis between the confusion limit and the minimum detectable temperature. The result of the sensitivity analysis is derived assuming an array that has sixty-four (64) 50-m antennas with 25-μm surface accuracy mainly located within the area of 300 km (up to 3000 km), dual-polarization SSB receivers with the best noise temperature performance achieved by ALMA or better, and IF bandwidth of 128 or 256 GHz.. We temporarily name this telescope "Very Large Millimeter/Submillimeter Array (VLMSA)". Since this sensitivity is extremely high, we can have a lot of chances to study the galaxy, star formation, cosmology and of course the new scientific frontier.

  10. 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.

  11. 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

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

    PubMed Central

    Yasuda, Hiroyuki; 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

    2015-01-01

    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. PMID:26515464

  13. 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.

  14. 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

  15. 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

  16. [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. PMID:27426066

  17. Easy Glide in a Coarse-Grained Mg-2Zn-2Nd Alloy

    NASA Astrophysics Data System (ADS)

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

    2016-08-01

    Compression tests were performed at 673 K (400 °C) on a Mg-2Zn-2Nd alloy at the strain rates of 0.1, 0.01, and 0.001/s. The 0.1 and 0.01/s flow curves displayed work hardening to a peak stress at around 0.2 true strain. However, testing at 0.001/s led to steady-state flow at about 22 MPa from 0.03 true strain onwards. Such a steady-state flow is attributed to the predominance of basal slip under these conditions.

  18. The ratio of 2nd to 4th digit length: a new predictor of disease predisposition?

    PubMed

    Manning, J T; Bundred, P E

    2000-05-01

    The ratio between the length of the 2nd and 4th digits is: (a) fixed in utero; (b) lower in men than in women; (c) negatively related to testosterone and sperm counts; and (d) positively related to oestrogen concentrations. Prenatal levels of testosterone and oestrogen have been implicated in infertility, autism, dyslexia, migraine, stammering, immune dysfunction, myocardial infarction and breast cancer. We suggest that 2D:4D ratio is predictive of these diseases and may be used in diagnosis, prognosis and in early life-style interventions which may delay the onset of disease or facilitate its early detection. PMID:10859702

  19. [Infected chorionic hematoma as a cause of infection in the 2nd trimester].

    PubMed

    Weigel, M; Friese, K; Schmitt, W; Strittmatter, H J; Melchert, F

    1992-12-01

    Superinfected subchorionic haematomas are a rare septic focus in the 2nd trimenon. Symptoms being unspecific, the diagnosis has to be made by exclusion, in most cases. As the changes of a successful treatment of the manifest infection is poor, antibiotic prophylaxis as well as close laboratory controls and early antibiotic therapy should be discussed after sonographic diagnosis of an intrauterine haematoma. Two of our three patients reported on having suffered a miscarriage; only one pregnancy could be maintained after spontaneous depletion of the infected haemorrhage. PMID:1490559

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

    PubMed

    Higgins, Stephen T

    2015-11-01

    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 policy makers 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

  1. Efficacy and Safety of rAAV2-ND4 Treatment for Leber's Hereditary Optic Neuropathy.

    PubMed

    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

  2. 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. PMID:26334946

  3. 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

  4. Mechanism of assembly of the dimanganese-tyrosyl radical cofactor of class Ib ribonucleotide reductase: Enzymatic generation of superoxide is required for tyrosine oxidation via a Mn(III)Mn(IV) intermediate

    PubMed Central

    Cotruvo, Joseph A.; Stich, Troy A.; Britt, R. David; Stubbe, JoAnne

    2013-01-01

    Ribonucleotide reductases (RNRs) utilize radical chemistry to reduce nucleotides to deoxynucleotides in all organisms. In the class Ia and Ib RNRs, this reaction requires a stable tyrosyl radical (Y•) generated by oxidation of a reduced dinuclear metal cluster. The FeIII2-Y• cofactor in the NrdB subunit of the class Ia RNRs can be generated by self-assembly from FeII2-NrdB, O2, and a reducing equivalent. By contrast, the structurally homologous class Ib enzymes require a MnIII2-Y• cofactor in their NrdF subunit. MnII2-NrdF does not react with O2, but it binds the reduced form of a conserved flavodoxin-like protein, NrdIhq, which, in the presence of O2, reacts to form the MnIII2-Y• cofactor. Here we investigate the mechanism of assembly of the MnIII2-Y• cofactor in Bacillus subtilis NrdF. Cluster assembly from MnII2-NrdF, NrdIhq, and O2 has been studied by stopped flow absorption and rapid freeze quench EPR spectroscopies. The results support a mechanism in which NrdIhq reduces O2 to O2•− (40-48 s−1, 0.6 mM O2), the O2•− channels to and reacts with MnII2-NrdF to form a MnIIIMnIV intermediate (2.2 ± 0.4 s−1), and the MnIIIMnIV species oxidizes tyrosine to Y• (0.08-0.15 s−1). Controlled production of O2•− by NrdIhq during class Ib RNR cofactor assembly both circumvents the unreactivity of the MnII2 cluster with O2 and satisfies the requirement for an “extra” reducing equivalent in Y• generation. PMID:23402532

  5. Antacid Use and De Novo Brain Metastases in Patients with Epidermal Growth Factor Receptor-Mutant Non-Small Cell Lung Cancer Who Were Treated Using First-Line First-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors

    PubMed Central

    Chen, Yu-Mu; Lai, Chien-Hao; Chang, Huang-Chih; Chao, Tung-Ying; Tseng, Chia-Cheng; Fang, Wen-Feng; Wang, Chin-Chou; Chung, Yu-Hsiu; Wang, Yi-Hsi; Su, Mao-Chang; Liu, Shih-Feng; Huang, Kuo-Tung; Chen, Hung-Chen; Chang, Ya-Chun; Lin, Meng-Chih

    2016-01-01

    Background Antacid treatments decrease the serum concentrations of first-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), although it is unknown whether antacids affect clinical outcomes. As cerebrospinal fluid concentrations of TKIs are much lower than serum concentrations, we hypothesized that this drug-drug interaction might affect the prognosis of patients with de novo brain metastases. Materials and Methods This retrospective study evaluated 269 patients with EGFR-mutant non-small cell lung cancer (NSCLC) who had been diagnosed between December 2010 and December 2013, and had been treated using first-line first-generation EGFR-TKIs. Among these patients, we identified patients who concurrently used H2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) as antacids. Patients who exhibited >30% overlap between the use of TKIs and antacids were considered antacid users. Results Fifty-seven patients (57/269, 21.2%) were antacid users, and antacid use did not significantly affect progression-free survival (PFS; no antacids: 11.2 months, H2RAs: 9.4 months, PPIs: 6.7 months; p = 0.234). However, antacid use significantly reduced overall survival (OS; no antacids: 25.0 months, H2RAs: 15.5 months, PPIs: 11.3 months; p = 0.002). Antacid use did not affect PFS for various metastasis sites, although antacid users with de novo brain metastases exhibited significantly shorter OS, compared to non-users (11.8 vs. 16.3 months, respectively; p = 0.041). Antacid use did not significantly affect OS in patients with bone, liver, or pleural metastases. Conclusion Antacid use reduced OS among patients with EGFR-mutant NSCLC who were treated using first-line first-generation EGFR-TKIs, and especially among patients with de novo brain metastases. PMID:26894507

  6. 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. PMID:25756742

  7. 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

  8. Tetragonal ZrO2:Nd3+ nanosphere: Combustion synthesis, luminescence and photoacoustic spectroscopy

    NASA Astrophysics Data System (ADS)

    Gupta, Santosh K.; Chandrasekhar, D.; Kadam, R. M.

    2015-12-01

    Nanocrystalline ZrO2:Nd3+ was synthesised using gel-combustion method and characterized systematically using X-ray diffraction (XRD) and transmission electron microscopy (TEM). Through this route we can stabilize metastable tetragonal phase at 500 °C through addition of 1 mol % Nd3+ which is technologically more important. Optical characterization of the sample was done using photoluminescence (PL) and photoacoustic spectroscopy (PAS). PL studies shows an intense and optimum stimulated emission cross section of 1065 nm peak corresponding to 4F3/2 → 4I11/2 which and thus it can be a probable laser material. PAS is used to investigate electronic absorption of Nd3 in zirconia. Various covalency parameters like nephelauxetic ratio (β), covalency factor (b1/2) and Sinha parameter (δ) were evaluated for pure oxide powder and as well as for Nd3+ doped zirconia.

  9. International symposium on peripheral nerve repair and regeneration and 2nd club Brunelli meeting

    PubMed Central

    2010-01-01

    The International Symposium "Peripheral Nerve Repair and Regeneration and 2nd Club Brunelli Meeting" was held on December 4-5, 2009 in Turin, Italy (Organizers: Bruno Battiston, Stefano Geuna, Isabelle Perroteau, Pierluigi Tos). Interest in the study of peripheral nerve regeneration is very much alive because complete recovery of nerve function almost never occurs after nerve reconstruction and, often, the clinical outcome is rather poor. Therefore, there is a need for defining innovative strategies for improving the success of recovery after nerve lesion and repair and this meeting was intended to discuss, from a multidisciplinary point of view, some of today's most important issues in this scientific field, arising from both basic and clinical neurosciences. PMID:20214775

  10. International symposium on peripheral nerve repair and regeneration and 2nd club Brunelli meeting.

    PubMed

    Turgut, Mehmet; Geuna, Stefano

    2010-01-01

    The International Symposium "Peripheral Nerve Repair and Regeneration and 2nd Club Brunelli Meeting" was held on December 4-5, 2009 in Turin, Italy (Organizers: Bruno Battiston, Stefano Geuna, Isabelle Perroteau, Pierluigi Tos). Interest in the study of peripheral nerve regeneration is very much alive because complete recovery of nerve function almost never occurs after nerve reconstruction and, often, the clinical outcome is rather poor. Therefore, there is a need for defining innovative strategies for improving the success of recovery after nerve lesion and repair and this meeting was intended to discuss, from a multidisciplinary point of view, some of today's most important issues in this scientific field, arising from both basic and clinical neurosciences. PMID:20214775

  11. 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.

  12. Glass fiber laser at 1. 36. mu. m from SiO sub 2 :Nd

    SciTech Connect

    Hakimi, F.; Po, H.; Tumminelli, R.; McCollum, B.C.; Zenteno, L.; Cho, N.M.; Snitzer, E. )

    1989-10-01

    By adding 14 mol % P{sub 2}O{sub 5} to the core of a SiO{sub 2}:Nd fiber, laser emission was obtained at 1.36 {mu}m. From the fluorescent spectra and laser thresholds for the {sup 4}{ital F}{sub 3/2} to {sup 4}{ital I}{sub 11/2} and {sup 4}{ital F}{sub 3/2} to {sup 4}{ital I}{sub 3/2} transitions, the net gain at 1.36 {mu}m is 0.024 dB/mW, and the ratio of excited-state absorption (the {sup 4}{ital F}{sub 3/2} to {sup 4}{ital G}{sub 1/2} transition) to stimulated emission is estimated to be 0.78.

  13. 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.

  14. [Measurement report on the horizontal position relationship between the umbilicus and the 2nd lum- bar spinal process in adults].

    PubMed

    Zhao, Jingyi; Fu, Liyuan; Wang, Yueqi; Qiu, Wenqi; Yao, Miaojie; Zhao, Baixiao; Guo, Changqing

    2016-04-01

    The impact factors were explored to determine the horizontal positional relationship between the umbilicus and the 2nd lumbar spinal process in adults and to verify the accuracy of the localization of Shenshu (BL 23) via the umbilicus. The position of the umbilicus and the 2nd lumbar spinal process was measured in 100 participants and the data were analyzed through SPSS 20.0 software. It was found that the umbilicus and the 2nd lumbar process were not positioned horizontally. The positional relationship of these two sites was not apparently correlated with gender, age, body weight, body height, BMI, waistline and discomfort of lumbar region. The umbilicus was commonly and posteriorly projected on the site between the 4th and 5th lumbar vertebra. It is explained that the localization of Shenshu (BL23) via the umbilicus is not accurate. PMID:27352498

  15. 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 (

  16. Activation of the IGF1R pathway potentially mediates acquired resistance to mutant-selective 3rd-generation EGF receptor tyrosine kinase inhibitors in advanced non-small cell lung cancer.

    PubMed

    Park, Ji Hyun; Choi, Yun Jung; Kim, Seon Ye; Lee, Jung-Eun; Sung, Ki Jung; Park, Sojung; Kim, Woo Sung; Song, Joon Seon; Choi, Chang-Min; Sung, Young Hoon; Rho, Jin Kyung; Lee, Jae Cheol

    2016-04-19

    Mutant-selective, 3rd-generation EGFR-TKIs were recently developed to control lung cancer cells harboring T790M-mediated resistance. However, the development of resistance to these novel drugs seems inevitable. Thus, we investigated the mechanism of acquired resistance to the mutant-selective EGFR-TKI WZ4002. We established five WZ4002-resistant cells, derived from cells harboring both EGFR and T790M mutations by long-term exposure to increasing doses of WZ4002. Compared with the parental cells, all resistant cells showed 10-100-folds higher resistance to WZ4002, as well as cross-resistance to other mutant-selective inhibitors. Among them, three resistant cells (HCC827/WR, PC-9/WR and H1975/WR) showed dependency on EGFR signaling, but two other cells (PC-9/GR/WR and PC-9/ER/WR) were not. Notably, insulin-like growth factor-1 receptor (IGF1R) was aberrantly activated in PC-9/GR/WR cells in phospho-receptor tyrosine kinase array, consistently accompanied by loss of IGF binding protein-3 (IGFBP3). Down-regulation of IGF1R by shRNA, as well as inhibition of IGF1R activity either by AG-1024 (a small molecule IGF1R inhibitor) or BI 836845 (a monoclonal anti-IGF1/2 blocking antibody), restored the sensitivity to WZ4002 both in vitro and xenograft. Taken together, these results suggest that activation of the IGF1R pathway associated with IGFBP3 loss can induce an acquired resistance to the mutant-selective EGFR-TKI, WZ4002. Therefore, a combined therapy of IGF1R inhibitors and mutant-selective EGFR-TKIs might be a viable treatment strategy for overcoming acquired resistance. PMID:26980747

  17. Activation of the IGF1R pathway potentially mediates acquired resistance to mutant-selective 3rd-generation EGF receptor tyrosine kinase inhibitors in advanced non-small cell lung cancer

    PubMed Central

    Park, Ji Hyun; Choi, Yun Jung; Kim, Seon Ye; Lee, Jung-Eun; Sung, Ki Jung; Park, Sojung; Kim, Woo Sung; Song, Joon Seon; Choi, Chang-Min; Sung, Young Hoon; Rho, Jin Kyung; Lee, Jae Cheol

    2016-01-01

    Mutant-selective, 3rd-generation EGFR-TKIs were recently developed to control lung cancer cells harboring T790M-mediated resistance. However, the development of resistance to these novel drugs seems inevitable. Thus, we investigated the mechanism of acquired resistance to the mutant-selective EGFR-TKI WZ4002. We established five WZ4002-resistant cells, derived from cells harboring both EGFR and T790M mutations by long-term exposure to increasing doses of WZ4002. Compared with the parental cells, all resistant cells showed 10–100-folds higher resistance to WZ4002, as well as cross-resistance to other mutant-selective inhibitors. Among them, three resistant cells (HCC827/WR, PC-9/WR and H1975/WR) showed dependency on EGFR signaling, but two other cells (PC-9/GR/WR and PC-9/ER/WR) were not. Notably, insulin-like growth factor-1 receptor (IGF1R) was aberrantly activated in PC-9/GR/WR cells in phospho-receptor tyrosine kinase array, consistently accompanied by loss of IGF binding protein-3 (IGFBP3). Down-regulation of IGF1R by shRNA, as well as inhibition of IGF1R activity either by AG-1024 (a small molecule IGF1R inhibitor) or BI 836845 (a monoclonal anti-IGF1/2 blocking antibody), restored the sensitivity to WZ4002 both in vitro and xenograft. Taken together, these results suggest that activation of the IGF1R pathway associated with IGFBP3 loss can induce an acquired resistance to the mutant-selective EGFR-TKI, WZ4002. Therefore, a combined therapy of IGF1R inhibitors and mutant-selective EGFR-TKIs might be a viable treatment strategy for overcoming acquired resistance. PMID:26980747

  18. 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")…

  19. 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;…

  20. 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…

  1. The Influence of Neighborhood Density and Word Frequency on Phoneme Awareness in 2nd and 4th Grades

    ERIC Educational Resources Information Center

    Hogan, Tiffany P.; Bowles, Ryan P.; Catts, Hugh W.; Storkel, Holly L.

    2011-01-01

    Purpose: The purpose of this study was to test the hypothesis that two lexical characteristics--neighborhood density and word frequency--interact to influence performance on phoneme awareness tasks. Methods: Phoneme awareness was examined in a large, longitudinal dataset of 2nd and 4th grade children. Using linear logistic test model, the relation…

  2. 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…

  3. Iron metabolism in African American women during the 2nd and 3rd trimester of a high-risk pregnancy

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Objective: To examine iron metabolism during the 2nd and 3rd trimester in African American women classified as a high-risk pregnancy. Design: Longitudinal. Setting: Large, university-based, urban Midwestern medical center. Participants: Convenience sample of 47 African American women classified a...

  4. 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…

  5. Phase Relations of the CaO-SiO2-Nd2O3 System and the Implication for Rare Earths Recycling

    NASA Astrophysics Data System (ADS)

    Le, Thu Hoai; Malfliet, Annelies; Blanpain, Bart; Guo, Muxing

    2016-03-01

    CaO-SiO2-Nd2O3 slags were equilibrated at 1773 K and 1873 K (1500 °C and 1600 °C) for 24 hours in Ar, and quenched in water to determine the operative phase relations. The composition and crystallinity of the phases in equilibrium were determined by EPMA-WDS and EBSD, respectively. Based on these analyses, the liquid stability region was accurately determined, and a large part of the isothermal section of the phase diagram was constructed. Data resulting from this work can be used to generate a thermodynamic database for rare-earth oxide-containing systems and to support further investigation on separation of rare earths from metallurgical slags or other residues through high-temperature processing.

  6. Phase Relations of the CaO-SiO2-Nd2O3 System and the Implication for Rare Earths Recycling

    NASA Astrophysics Data System (ADS)

    Le, Thu Hoai; Malfliet, Annelies; Blanpain, Bart; Guo, Muxing

    2016-06-01

    CaO-SiO2-Nd2O3 slags were equilibrated at 1773 K and 1873 K (1500 °C and 1600 °C) for 24 hours in Ar, and quenched in water to determine the operative phase relations. The composition and crystallinity of the phases in equilibrium were determined by EPMA-WDS and EBSD, respectively. Based on these analyses, the liquid stability region was accurately determined, and a large part of the isothermal section of the phase diagram was constructed. Data resulting from this work can be used to generate a thermodynamic database for rare-earth oxide-containing systems and to support further investigation on separation of rare earths from metallurgical slags or other residues through high-temperature processing.

  7. 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

  8. 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.

  9. 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.

  10. 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.

  11. Transient 2(nd) Degree Av Block Mobitz Type II: A Rare Finding in Dengue Haemorrhagic Fever.

    PubMed

    Nigam, Ashwini Kumar; Singh, Omkar; Agarwal, Ayush; Singh, Amit K; Yadav, Subhash

    2015-05-01

    Dengue has been a major problem as endemic occurs almost every year and causes a state of panic due to lack of proper diagnostic methods and facilities for proper management. Patients presenting with classical symptoms are easy to diagnose, however as a large number of cases occur every year, a number of cases diagnosed with dengue fever on occasion presents with atypical manifestations, which cause extensive evaluation of the patients, unnecessary referral to higher centre irrespective of the severity and therefore a rough idea of these manifestations must be present in the backdrop in order to prevent these problems. Involvement of cardiovascular system in dengue has been reported in previous studies, and they are usually benign and self-limited. The importance of study of conduction abnormalities is important as sometimes conduction blocks are the first sign of acute myocarditis in patients of Dengue Hemorrhagic Fever in shock. We present here a case of 2(nd) Degree Mobitz Type II atrioventricular AV block in a case of Dengue Hemorrhagic fever reverting to the normal rhythm in recovery phase and no signs thereafter on follow up. PMID:26155512

  12. 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.

  13. 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)…

  14. 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

  15. 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

  16. 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.

  17. Mechanosensitivity of the 2nd Kind: TGF-β Mechanism of Cell Sensing the Substrate Stiffness

    PubMed Central

    Cockerill, Max; Rigozzi, Michelle K.; Terentjev, Eugene M.

    2015-01-01

    Cells can sense forces applied to them, but also the stiffness of their environment. These are two different phenomena, and here we investigate the mechanosensitivity of the 2nd kind: how the cell can measure an elastic modulus at a single point of adhesion—and how the cell can receive and interpret the chemical signal released from the sensor. Our model uses the example of large latent complex of TGF-β as a sensor. Stochastic theory gives the rate of breaking of latent complex, which initiates the signaling feedback loop after the active TGF-β release and leads to a change of cell phenotype driven by the α-smooth muscle actin. We investigate the dynamic and steady-state behaviors of the model, comparing them with experiments. In particular, we analyse the timescale of approach to the steady state, the stability of the non-linear dynamical system, and how the steady-state concentrations of the key markers vary depending on the elasticity of the substrate. We discover a crossover region for values of substrate elasticity closely corresponding to that of the fibroblast to myofibroblast transition. We suggest that the cell could actively vary the parameters of its dynamic feedback loop to ‘choose’ the position of the transition region and the range of substrate elasticity that it can detect. In this way, the theory offers the unifying mechanism for a variety of phenomena, such as the myofibroblast conversion in fibrosis of wounds and lungs and smooth muscle cell dysfunction in cardiac disease. PMID:26448620

  18. 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.

  19. 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

  20. 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

  1. A novel nonreceptor tyrosine kinase, Srm: cloning and targeted disruption.

    PubMed Central

    Kohmura, N; Yagi, T; Tomooka, Y; Oyanagi, M; Kominami, R; Takeda, N; Chiba, J; Ikawa, Y; Aizawa, S

    1994-01-01

    We have isolated a novel nonreceptor tyrosine kinase, Srm, that maps to the distal end of chromosome 2. It has SH2, SH2', and SH3 domains and a tyrosine residue for autophosphorylation in the kinase domain but lacks an N-terminal glycine for myristylation and a C-terminal tyrosine which, when phosphorylated, suppresses kinase activity. These are structural features of the recently identified Tec family of nonreceptor tyrosine kinases. The Srm N-terminal unique domain, however, lacks the structural characteristics of the Tec family kinases, and the sequence similarity is highest to Src in the SH region. The expression of two transcripts is rather ubiquitous and changes according to tissue and developmental stage. Mutant mice were generated by gene targeting in embryonic stem cells but displayed no apparent phenotype as in mutant mice expressing Src family kinases. These results suggest that Srm constitutes a new family of nonreceptor tyrosine kinases that may be redundant in function. Images PMID:7935409

  2. 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. PMID:21660238

  3. Neurobehavioral Evaluation System (NES): comparative performance of 2nd-, 4th-, and 8th-grade Czech children.

    PubMed

    Otto, D A; Skalik, I; House, D E; Hudnell, H K

    1996-01-01

    The Neurobehavioral Evaluation System was designed for field studies of workers, but many NES tests can be performed satisfactorily by children as young as 7 or 8 years old and a few tests, such as simple reaction time, can be performed by preschool children. However, little comparative data from children of different ages or grade levels are available. Studies of school children in the Czech Republic indicate that 2nd-grade children could perform the following NES tests satisfactorily: Finger Tapping, Visual Digit Span. Continuous Performance, Symbol-Digit Substitution, Pattern Comparison, and simpler conditions of Switching Attention. Comparative scores of boys and girls from the 2nd, 4th, and 8th grades and power analyses to estimate appropriate sample size were presented. Performance varied systematically with grade level and gender. Larger samples were needed with younger children to achieve comparable levels of statistical power. Gender comparisons indicated that boys responded faster, but made more errors than girls. PMID:8866533

  4. 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.

  5. 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…

  6. 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

  7. 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

  8. Structural basis of tubulin tyrosination by tubulin tyrosine ligase.

    PubMed

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

    2013-02-01

    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

  9. 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

  10. 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

  11. 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. PMID:26104693

  12. 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

  13. 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

  14. 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

  15. 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.

  16. 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,...

  17. 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.

  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. Receptor tyrosine kinase targeting in multicellular spheroids.

    PubMed

    Breslin, Susan; O'Driscoll, Lorraine

    2015-01-01

    While growing cells as a monolayer is the traditional method for cell culture, the incorporation of multicellular spheroids into experimental design is becoming increasingly popular. This is due to the understanding that cells grown as spheroids tend to replicate the in vivo situation more reliably than monolayer cells. Thus, the use of multicellular spheroids may be more clinically relevant than monolayer cell cultures. Here, we describe methods for multicellular 3D spheroid generation that may be used to provide samples for receptor tyrosine kinase (and other protein) detection. Methods described include the forced-floating poly-HEMA method, the hanging-drop method, and the use of ECM to form multicellular 3D spheroids. PMID:25319898

  20. Complexity of Receptor Tyrosine Kinase Signal Processing

    PubMed Central

    Volinsky, Natalia; Kholodenko, Boris N.

    2013-01-01

    Our knowledge of molecular mechanisms of receptor tyrosine kinase (RTK) signaling advances with ever-increasing pace. Yet our understanding of how the spatiotemporal dynamics of RTK signaling control specific cellular outcomes has lagged behind. Systems-centered experimental and computational approaches can help reveal how overlapping networks of signal transducers downstream of RTKs orchestrate specific cell-fate decisions. We discuss how RTK network regulatory structures, which involve the immediate posttranslational and delayed transcriptional controls by multiple feed forward and feedback loops together with pathway cross talk, adapt cells to the combinatorial variety of external cues and conditions. This intricate network circuitry endows cells with emerging capabilities for RTK signal processing and decoding. We illustrate how mathematical modeling facilitates our understanding of RTK network behaviors by unraveling specific systems properties, including bistability, oscillations, excitable responses, and generation of intricate landscapes of signaling activities. PMID:23906711

  1. Order and disorder in Ca 2ND 0.90H 0.10-A structural and thermal study

    NASA Astrophysics Data System (ADS)

    Verbraeken, Maarten C.; Suard, Emmanuelle; Irvine, John T. S.

    2011-08-01

    The structure of calcium nitride hydride and its deuterided form has been re-examined at room temperature and studied at high temperature using neutron powder diffraction and thermal analysis. When synthesised at 600 °C, a mixture of both ordered and disordered Ca 2ND 0.90H 0.10 phases results. The disordered phase is the minor component and has a primitive rocksalt structure (spacegroup Fm3 m) with no ordering of D/N on the anion sites and the ordered phase is best described using the rhombohedral spacegroup R-3 m with D and N arranged in alternate layers in (111) planes. This mixture of ordered and disordered phases exists up to 580 °C, at which the loss of deuterium yields Ca 2ND 0.85 with the disappearance of the disordered phase. In the new ordered phase there exists a similar content of vacancies on both anion sites; to achieve this balance, a little N transfers onto the D site, whereas there is no indication of D transferring onto the N-sites. These observations are thought to indicate that the D/N ordering is difficult to achieve with fully occupied anion sites. It has previously been reported that Ca 2ND has an ordered cubic cell with alternating D and N sites in the [100] directions [1]; however, for the samples studied herein, there were clearly two coexisting phases with apparent broadening/splitting of the primitive peaks but not for the ordered peaks. The rhombohedral phase was in fact metrically cubic; however, all the observed peaks were consistent with the rhombohedral unit cell with no peaks requiring the larger ordered cubic unit cell to be utilised. Furthermore this rhombohedral cell displays the same form of N-D ordering as the Sr and Ba analogues, which are metrically rhombohedral.

  2. 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

  3. [Combined Anterior and Posterior Surgical Approaches for Resection of a 2nd-rib Chondrosarcoma Occupying the Superior Sulcus].

    PubMed

    Shinohara, Yoshikazu; Anraku, Masaki; Saito, Noriyuki; Fukumoto, Kento; Kobayashi, Hiroshi; Shinoda, Yusuke; Chikuda, Hirotaka; Nakajima, Jun

    2016-06-01

    A 77-year-old man with right chest wall chondrosarcoma invading vertebral bodies underwent resection. Computed tomography (CT) showed that the tumor occupied the right superior sulcus, and was close to mediastinal organs including the trachea and esophagus. We adopted a combined anterior and posterior approaches that made safe and curative resection possible. In the anterior approach, we dissected and mobilized the neurovascular structures and neighboring organs from the tumor. A-4 cm gutter on the ventral side of the 1st, 2nd, and 3rd thoracic vertebral bodies was created for safe resection. By the subsequent posterior approach, successful resection was achieved without violating tumor margins. PMID:27246126

  4. 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

  5. Quantitative metabolic profiles of 2nd and 3rd trimester human amniotic fluid using 1H HR-MAS spectroscopy

    PubMed Central

    Cohn, Brad R.; Zhao, Shoujun; Kornak, John; Zhang, Vickie Y.; Iman, Rahwa; Kurhanewicz, John; Vahidi, Kiarash; Yu, Jingwei; Caughey, Aaron B.; Swanson, Mark G.

    2016-01-01

    Object To establish and compare normative metabolite concentrations in 2nd and 3rd trimester human amniotic fluid samples in an effort to reveal metabolic biomarkers of fetal health and development. Materials and methods Twenty-one metabolite concentrations were compared between 2nd (15–27 weeks gestation, N = 23) and 3rd (29–39 weeks gestation, N = 27) trimester amniotic fluid samples using 1H high resolution magic angle spinning (HR-MAS) spectroscopy. Data were acquired using the electronic reference to access in vivo concentrations method and quantified using a modified semi-parametric quantum estimation algorithm modified for high-resolution ex vivo data. Results Sixteen of 21 metabolite concentrations differed significantly between 2nd and 3rd trimester groups. Betaine (0.00846±0.00206 mmol/kg vs. 0.0133±0.0058 mmol/kg, P <0.002) and creatinine (0.0124±0.0058 mmol/kg vs. 0.247±0.011 mmol/kg, P <0.001) concentrations increased significantly, while glucose (5.96±1.66 mmol/kg vs. 2.41±1.69 mmol/kg, P <0.001), citrate (0.740±0.217 mmol/kg vs. 0.399±0.137 mmol/kg, P <0.001), pyruvate (0.0659±0.0103 mmol/kg vs. 0.0299±0.286 mmol/kg, P <0.001), and numerous amino acid (e.g. alanine, glutamate, isoleucine, leucine, lysine, and valine) concentrations decreased significantly with advancing gestation. A stepwise multiple linear regression model applied to 50 samples showed that gestational age can be accurately predicted using combinations of alanine, glucose and creatinine concentrations. Conclusion These results provide key normative data for 2nd and 3rd trimester amniotic fluid metabolite concentrations and provide the foundation for future development of magnetic resonance spectroscopy (MRS) biomarkers to evaluate fetal health and development. PMID:19779747

  6. Cisplatin stimulates protein tyrosine phosphorylation in macrophages.

    PubMed

    Kumar, R; Shrivastava, A; Sodhi, A

    1995-03-01

    Cisplatin [cis-dichlorodiamine platinum (II)], a potent anti-tumor compound, stimulates immune responses by activating monocyte-macrophages and other cells of the immune system. The mechanism by which cisplatin activates these cells is poorly characterized. Since protein tyrosine phosphorylation appears to be a major intracellular signalling event that mediates cellular responses, we examined whether cisplatin alters tyrosine phosphorylation in macrophages. We found that cisplatin increased tyrosine phosphorylation of several proteins in peritoneal macrophages and in P388D1 and IC-21 macrophage cell lines. Treatment of macrophages with tyrosine kinase inhibitors, genestein and lavendustin A, inhibited cisplatin-stimulated protein tyrosine phosphorylation in macrophages. Macrophages treated with cisplatin also exhibit increased fluorescence with anti-phosphotyrosine-FITC antibody. These data indicate that protein tyrosine phosphorylation plays a role in cisplatin-induced activation of macrophages. PMID:7539662

  7. 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

  8. 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 (

  9. 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.

  10. 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. PMID:26369537

  11. 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

  12. 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.

  13. Surface-emitting quantum cascade laser with 2nd-order metal-semiconductor gratings for single-lobe emission

    NASA Astrophysics Data System (ADS)

    Boyle, C.; Sigler, C.; Kirch, J. D.; Lindberg, D.; Earles, T.; Botez, D.; Mawst, L. J.

    2016-03-01

    Grating-coupled, surface-emitting (GCSE) quantum-cascade lasers (QCLs) are demonstrated with high-power, single-lobe surface emission. A 2nd-order Au-semiconductor distributed-feedback (DFB)/ distributed-Bragg-reflector (DBR) grating is used for feedback and out-coupling. The DFB and DBR grating regions are 2.55 mm- and 1.28 mm-long, respectively, for a total grating length of 5.1 mm. The lasers are designed to operate in a symmetric longitudinal mode by causing resonant coupling of the guided optical mode to the antisymmetric surface-plasmon modes of the 2nd-order metal/semiconductor grating. In turn, the antisymmetric longitudinal modes are strongly absorbed by the metal in the grating, causing the symmetric longitudinal mode to be favored to lase, which produces a single lobe beam over a grating duty-cycle range of 36-41 %. Simulations indicate that the symmetric mode is always favored to lase, independent of the random phase of residual reflections from the device's cleaved ends. Peak pulsed output powers of ~ 0.4 W were measured with single-lobe, single-mode operation near 4.75 μm.

  14. 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

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

    PubMed

    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

  16. 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.

  17. Literacy: The Key to Success. A Literacy Handbook, 2nd Edition.

    ERIC Educational Resources Information Center

    Mid-York Library System, Utica, NY.

    Designed to provide a comprehensive literacy reference for public libraries, this handbook presents a glossary of terms, background information on functional literacy, and brief reviews of 14 additional topics: (1) literacy statistics; (2) adult performance levels; (3) the problem of adult education; (4) illiteracy generates itself; (5) about…

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

    SciTech Connect

    White, J.S.; Witman, P.M.; Harbaugh, L.; Rubow, L.N.; Horazak, D.A.

    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.

  19. Project DEEP STEAM 2nd and 3rd quarter reports, April 1-September 30, 1981

    SciTech Connect

    Moreno, J.B.; Aeschliman, D.P.; Clay, R.G.; Lee, D.O.; Marshall, B.W.; Muir, J.F.

    1982-03-01

    The objective of Project DEEP STEAM is to develop the technology required to economically produce heavy oil from deep reservoirs. The tasks included in this project are development of thermally efficient delivery systems and downhole steam-generation systems. During the period April 1-September 30, 1981, activity was completed on the development of a low-pressure-combustion, indirect-contact downhole generator (Rocketdyne), and effort continued on two high-pressure, direct-contact designs (Foster-Miller Associates, Sandia National Laboratories). Field testing of the Sandia design began in the Wilmington Field at Long Beach, California. This was the first test of a high-pressure, direct-contact downhole steam generator in a deep well. Development of a second Sandia design, using pure oxygen as the oxidizer, was initiated. Progress continued on the Min-Stress II packer concept at L'Garde, Inc., and on the extruded metal packer at Foster-Miller. A new insulant test series was begun at the Tacoma test tower. The instrumented bare-string steam injection test in Canada, initiated in cooperation with Husky Oil in the last report period, was successfully completed in early May. A redesigned test program to allow simultaneous testing of several different insulated tubulars is scheduled for October 1981.

  20. 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.

  1. 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.

  2. Morgenröthe or business as usual: a personal account of the 2nd Annual EULAR Congress, Prague

    PubMed Central

    Wollheim, Frank A

    2001-01-01

    The 2nd Annual European League Against Rheumatism (EULAR) Congress, held in Prague, 13–16 June 2001, was an impressive event with a record turnout of 8300 delegates. It offered a large variety of first-class state of the art lectures by some 180 invited worldwide speakers. Several new and ongoing therapeutic developments were discussed. The aim to attract the young scientific community was only partly achieved, and the dependence on industry posed some problems. The organization, however, was a big improvement compared with the previous congress in this series. The number of submitted abstracts was relatively low (1200) compared with the number of delegates. Accommodation of satellite symposia and organization of poster sessions remain problem areas of this meeting. The Annual EULAR Congress emerges as one of the two most important annual congresses of rheumatology, the other being the American College of Rheumatology meeting.

  3. 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.

  4. CRACking ion channel targets: 2nd annual Ion Channel Targets Conference. 12-13 September 2006, Boston, MA, USA.

    PubMed

    Mathes, Chris

    2007-01-01

    The 2nd Annual Ion Channel Targets (ICT) Conference (by Select Bioscience LLC) was held in Boston on 12-13 September 2006. A healthy mixture of scientists from pharma, biotech and academic sectors attended the meeting. The speaker list reflected this mixture. In general, the conference focused on new ion channel targets and the methods for studying them in detail. Keynote lectures from Professors David Clapham (Harvard Medical School, USA) and Reinhold Penner (University of Hawaii, USA) set the tone by highlighting recent findings with a voltage-gated proton channel (Clapham), cation channel in sperm (Clapham) and the calcium-release-activated calcium channel (Penner). Also described at ICT were voltage-gated sodium, potassium, transmembrane-receptor-potential channels, as well as ligand-gated nicotinic acetylcholine (nAChR) and GABA type A receptors. PMID:17150038

  5. The influence of neighborhood density and word frequency on phoneme awareness in 2nd and 4th grades

    PubMed Central

    Hogan, Tiffany P.; Bowles, Ryan P.; Catts, Hugh W.; Storkel, Holly L.

    2010-01-01

    Purpose The purpose of this study was to test the hypothesis that two lexical characteristics – neighborhood density and word frequency – interact to influence performance on phoneme awareness tasks. Methods Phoneme awareness was examined in a large, longitudinal dataset of 2nd and 4th grade children. Using linear logistic test model, the relation between words' neighborhood density, word frequency, and phoneme awareness performance was examined across grades while covarying type and place of deletion. Results A predicted interaction was revealed: words from dense neighborhoods or those with high frequency were more likely to yield correct phoneme awareness responses across grades. Conclusions Findings support an expansion to the lexical restructuring model to include interactions between neighborhood density and word frequency to account for phoneme awareness. PMID:20691979

  6. 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. PMID:26298195

  7. 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

  8. 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

  9. 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

  10. 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.

  11. Treatment patterns, overall survival, healthcare resource use and costs in elderly Medicare beneficiaries with chronic myeloid leukemia using second-generation tyrosine kinase inhibitors as second-line therapy.

    PubMed

    Smith, B Douglas; Liu, Jun; Latremouille-Viau, Dominick; Guerin, Annie; Fernandez, Daniel; Chen, Lei

    2016-05-01

    Objective Though the median age at diagnosis is 64 years, few studies focus on elderly (≥65 years) patients with chronic myeloid leukemia (CML). This study examines healthcare outcomes among elderly Medicare beneficiaries with CML who started nilotinib or dasatinib after imatinib. Research design and methods Patients were identified in the Medicare Research Identifiable Files (2006-2012) and had continuous Medicare Parts A, B, and D coverage. Main outcome measures Treatment patterns, overall survival (OS), monthly healthcare resource utilization and medical costs were measured from the second-line tyrosine kinase inhibitor (TKI) initiation (index date) to end of Medicare coverage. Results Despite similar adherence, dasatinib patients (N = 379) were more likely to start on the recommended dose (74% vs. 53%; p < 0.001), and to have dose reductions (21% vs. 11%, adjusted hazard ratio [HR] = 1.94; p = 0.002) or dose increases (9% vs. 7%; adjusted HR = 1.81; p = 0.048) than nilotinib patients (N = 280). Fewer nilotinib patients discontinued (59% vs. 67%; adjusted HR = 0.80; p = 0.026) or switched to another TKI (21% vs. 29%; adjusted HR = 0.72; p = 0.044) than dasatinib patients. Nilotinib patients had longer median OS (>4.9 years vs. 4.0 years; p = 0.032) and 37% lower mortality risk than dasatinib patients (adjusted HR = 0.63; p = 0.008). Nilotinib patients had 23% fewer inpatient admissions, 30% fewer emergency room visits, 13% fewer outpatient visits (all p < 0.05), and lower monthly medical costs (by $513, p = 0.024) than dasatinib patients. Limitations Lack of clinical assessment (disease phase and response to first-line therapy) and retrospective nature of study (unobservable potential confounding factors, non-randomized treatment choice). Conclusions In the current study of elderly CML patients, initiation of second-line TKIs frequently occurs at doses lower than the recommended starting doses and

  12. 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

  13. Simultaneous Identification of Tyrosine Phosphorylation and Sulfation Sites Utilizing Tyrosine-Specific Bromination

    NASA Astrophysics Data System (ADS)

    Kim, Jong-Seo; Song, Si-Uk; Kim, Hie-Joon

    2011-11-01

    Tyrosine phosphorylation and sulfation play many key roles in the cell. Isobaric phosphotyrosine and sulfotyrosine residues in peptides were determined by mass spectrometry using phosphatase or sulfatase to remove the phosphate or the sulfate group. Unique Br signature was introduced to the resulting tyrosine residues by incubation with 32% HBr at -20 °C for 20 min. MS/MS analysis of the brominated peptide enabled unambiguous determination of the phosphotyrosine and the sulfotyrosine sites. When phosphotyrosine and sulfotyrosine as well as free tyrosine were present in the same peptide, they could be determined simultaneously using either phosphatase or sulfatase following acetylation of the free tyrosine.

  14. 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

  15. 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.

  16. A chimeric tyrosine/tryptophan hydroxylase. The tyrosine hydroxylase regulatory domain serves to stabilize enzyme activity.

    PubMed

    Mockus, S M; Kumer, S C; Vrana, K E

    1997-08-01

    The neurotransmitter biosynthetic enzymes, tyrosine hydroxylase (TH), and tryptophan hydroxylase (TPH) are each composed of an amino-terminal regulatory domain and a carboxyl-terminal catalytic domain. A chimeric hydroxylase was generated by coupling the regulatory domain of TH (TH-R) to the catalytic domain of TPH (TPH-C) and expressing the recombinant enzyme in bacteria. The chimeric junction was created at proline 165 in TH and proline 106 in TPH because this residue is within a conserved five amino-acid span (ValProTrpPhePro) that defines the beginning of the highly homologous catalytic domains of TH and TPH. Radioenzymatic activity assays demonstrated that the TH-R/TPH-C chimera hydroxylates tryptophan, but not tyrosine. Therefore, the regulatory domain does not confer substrate specificity. Although the TH-R/TPH-C enzyme did serve as a substrate for protein kinase (PKA), activation was not observed following phosphorylation. Phosphorylation studies in combination with kinetic data provided evidence that TH-R does not exert a dominant influence on TPH-C. Stability assays revealed that, whereas TH exhibited a t1/2 of 84 min at 37 degrees C, TPH was much less stable (t1/2 = 28.3 min). The stability profile of TH-R/TPH-C, however, was superimposable on that of TH. Removal of the regulatory domain (a deletion of 165 amino acids from the N-terminus) of TH rendered the catalytic domain highly unstable, as demonstrated by a t1/2 of 14 min. The authors conclude that the regulatory domain of TH functions as a stabilizer of enzyme activity. As a corollary, the well-characterized instability of TPH may be attributed to the inability of its regulatory domain to stabilize the catalytic domain. PMID:9356925

  17. De novo design of VEGFR-2 tyrosine kinase inhibitors based on a linked-fragment approach.

    PubMed

    Liu, Yi-Zhou; Wang, Xiao-Li; Wang, Xin-Ying; Yu, Ri-Lei; Liu, Dong-Qing; Kang, Cong-Min

    2016-09-01

    Vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitors have been demonstrated to possess substantial antitumor activity. VEGFR-2 tyrosine kinase inhibitors are crucial for development of antitumor drugs. Based on the crystal structure of VEGFR-2 tyrosine kinase, a linked-fragment strategy was employed to design novel VEGFR-2 tyrosine kinase inhibitors, and 1000 compounds were generated in this process. Absorption, distribution, metabolism, excretion and toxicity (ADMET) were used to screen the 1000 compounds, and 59 compounds were acceptable. Scaffold hopping was then used for further screening, and only four compounds were obtained in this way. Then, the binding energy of the four molecules to VEGFR-2 tyrosine kinase was calculated using molecular docking, and their values were found to be lower than that of Sorafenib. Finally, molecular dynamics simulations were performed on the complex of the compound with the lowest binding energy with VEGFR-2 tyrosine kinase, and the binding model was analyzed. At the end, four chemical entities with novel structures were obtained, and were suggested for experimental testing in future studies. PMID:27558799

  18. Workshop report on the 2nd Joint ENCCA/EuroSARC European bone sarcoma network meeting: integration of clinical trials with tumour biology

    PubMed Central

    2014-01-01

    This is the report of the 2nd Joint ENCCA/EuroSARC European Bone Sarcoma Network Meeting held in Leiden, The Netherlands, on 26-27 September 2013, bringing together preclinical and clinical investigators on bone sarcoma. The purpose of this workshop was to present the achievements of biological research and clinical trials in bone sarcomas and to stimulate crosstalk.

  19. 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…

  20. 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.

  1. Growth, structure, and optical properties of a self-activated crystal: Na2Nd2O(BO3)2

    NASA Astrophysics Data System (ADS)

    Shan, Faxian; Zhang, Guochun; Yao, Jiyong; Xu, Tianxiang; Zhang, Xinyuan; Fu, Ying; Wu, Yicheng

    2015-08-01

    A self-activated crystal Na2Nd2O(BO3)2 has been grown from the Na2O-Nd2O3-B2O3-NaF system. Its structure was determined by single crystal X-ray diffraction, and verified by infrared spectrum and inductively coupled plasma optical emission spectrometry. Na2Nd2O(BO3)2 crystallizes in the monoclinic crystal system, space group P21/c with unit-cell parameters a = 10.804 Å, b = 6.421 Å, c = 10.450 Å, β = 117.95°, Z = 4, and V = 640.4 Å3. Its absorption and emission spectra were measured at room temperature. Based on the absorption spectrum, the spontaneous transition probabilities, fluorescence branch ratio, and the radiation lifetime of 4F3/2 state were calculated. The emission properties under the 355 nm excitation were also evaluated. The electronic structure of Na2Nd2O(BO3)2 was calculated by the first-principles method. The obtained results show that Na2Nd2O(BO3)2 may be a promising microchip laser material.

  2. Summary of the 2nd International Symposium on Arthrogryposis, St. Petersburg, Russia, September 17-19, 2014.

    PubMed

    Hall, Judith G; Agranovich, Olga; Ogranovich, Alga; Pontén, Eva; Pontén, Ava; van Bosse, Harold J P

    2015-06-01

    Enormous progress has been made in understanding the etiology and therapies for arthrogryposis (multiple congenital contractures). A 2nd International Symposium on Arthrogryposis was sponsored by the Turner Institute in St. Petersburg, Russia. Olga Agranovich, Head of the Arthrogryposis Department of the Turner Institute, organized this special meeting. Care providers from multiple disciplines from all over the world representing 18 nations attended. Participants included: Pediatric orthopedic specialists, rehabilitation physicians, occupational therapists, physical therapists, medical geneticists, neurologists, craniofacial physicians, psychologists, developmental biologists, as well as representatives from parent support groups. The 1st symposium established the need for a collaborative and interdisciplinary approach to the treatment of arthrogryposis, engagement of parent support organizations, and the aim for more research. The Second Symposium highlighted the continuing need for more research on various therapies, identification of different types of arthrogryposis, standardized descriptions of severity, development of new orthotics, improved prenatal diagnosis, and studying adult outcome. Major progress has been made on both upper and lower limb treatments. PMID:25847824

  3. Long-term monitoring of the human intestinal microbiota from the 2nd week to 13 years of age.

    PubMed

    Endo, Akihito; Pӓrtty, Anna; Kalliomӓki, Marko; Isolauri, Erika; Salminen, Seppo

    2014-08-01

    Microbial contact begins prior to birth and continues rapidly thereafter. Few long term follow-up studies have been reported and we therefore characterized the development of intestinal microbiota of ten subjects from the 2nd week of life to 13 years of age. PCR-denaturing gradient gel electrophoresis combined with several bacterial group-specific primer sets demonstrated the colonization steps of defined bacterial groups in the microbiota. Bifidobacterium species were seen throughout the test period in all subjects. Bacteroides fragilis group and Blautia coccoides-Eubacterium rectale group species were not detected in several subjects during the first 6 months of life but were commonly seen after 12 months of life. Streptococcus group appeared during early life but was not seen in several subjects at the age of 13 years. Although a few species were linked with the increasing age, major bacterial species in the groups did not change dramatically. Rather considerable changes were found in the relative abundances of each bacterial species. Clustering analysis of total bacterial flora indicated that the microbiota changed considerably between 6 months and 12 months of life, and, at the age of 12 months, the intestinal microbiota was already converted toward a profile characteristic of an adult microbiota. Probiotic supplementation in the beginning of life did not have major impacts on later microbiota development. PMID:24933584

  4. Study on microstructure and properties of extruded Mg-2Nd-0.2Zn alloy as potential biodegradable implant material.

    PubMed

    Li, Junlei; Tan, Lili; Wan, Peng; Yu, Xiaoming; Yang, Ke

    2015-04-01

    Mg-2Nd-0.2Zn (NZ20) alloy was prepared for the application as biodegradable implant material in this study. The effects of the extrusion process on microstructure, mechanical and corrosion properties of the alloy were investigated. The as-cast alloy was composed of α-Mg matrix and Mg12Nd eutectic compound. The solution treatment could lead to the Mg12Nd phase dissolution and the grain coarsening. The alloy (E1) preheated at 380°C for 1h and extruded at 390°C presents fine grains with amounts of tiny Mg12Nd particles uniformly dispersed throughout the boundaries and the interior of the grains. The alloy (E2) preheated at 480°C for 1h and extruded at 500°C exhibits relatively larger grains with few nano-scale Mg12Nd phase particles dispersed. The alloy of E1, compared with E2, showed relatively lower corrosion rate, higher yield strength and slightly lower elongation. PMID:25686968

  5. [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. PMID:26455002

  6. 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.

  7. 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.

  8. Enhanced Deficits in Long-Term Potentiation in the Adult Dentate Gyrus with 2nd Trimester Ethanol Consumption

    PubMed Central

    Helfer, Jennifer L.; White, Emily R.; Christie, Brian R.

    2012-01-01

    Ethanol exposure during pregnancy can cause structural and functional changes in the brain that can impair cognitive capacity. The hippocampal formation, an area of the brain strongly linked with learning and memory, is particularly vulnerable to the teratogenic effects of ethanol. In the present experiments we sought to determine if the functional effects of developmental ethanol exposure could be linked to ethanol exposure during any single trimester-equivalent. Ethanol exposure during the 1st or 3rd trimester-equivalent produced only minor changes in synaptic plasticity in adult offspring. In contrast, ethanol exposure during the 2nd trimester equivalent resulted in a pronounced decrease in long-term potentiation, indicating that the timing of exposure influences the severity of the deficit. Together, the results from these experiments demonstrate long-lasting alterations in synaptic plasticity as the result of developmental ethanol exposure and dependent on the timing of exposure. Furthermore, these results allude to neural circuit malfunction within the hippocampal formation, perhaps relating to the learning and memory deficits observed in individuals with fetal alcohol spectrum disorders. PMID:23227262

  9. A neutron powder diffraction study of ND 3 intercalated titanium disulfide, 3 R-TiS 2ND 3

    NASA Astrophysics Data System (ADS)

    Bouwmeester, H. J. M.; Wiegers, G. A.

    1988-10-01

    Neutron powder diffraction of rhombohedral 3 R-TiS 2ND 3 ( a = 3.419 Å, c = 27.03 Å at 300 K, space group R overline3m ) has shown that ND 3 molecules and ND +4 ions, present in a ratio of about 5 to 1 from chemical and physical evidence, occupy statistically the trigonal-prismatic holes between TiS 2 sandwiches. One cannot distinguish between ND 3 and ND +4. Powder intensities calculated for a model with spherically symmetric ND 3 molecules (corresponding to isotropically rotating ND 3 and ND +4) in the trigonal-prismatic holes were in reasonable agreement with the observed intensities. Attempts to obtain information on the precise orientation of ND 3 and ND +4 in the TiS 2 lattice using refinements with structure factors were not successful; the reliability R factor was 0.093 for spherical symmetric ND 3 molecules with nitrogen in the center of the trigonal-prismatic holes.

  10. Near infrared emission and energy transfer in Eu2+ - Nd3+ co-doped Ca2BO3Cl

    NASA Astrophysics Data System (ADS)

    Talewar, R. A.; Joshi, C. P.; Moharil, S. V.

    2016-05-01

    Novel near infrared (NIR) emitting phosphor, Ca2BO3Cl:Eu2+, Nd3+ was synthesized by conventional solid-state reaction and characterized with X-ray diffraction, photoluminescence emission, photoluminescence excitation spectra and fluorescence decay measurements. When excited with 400 nm, the phosphor gives broadband emission at 560 nm, which corresponds to the allowed 5d → 4f transition of Eu2+ and an intense NIR emissions in the range 800-1400 nm, which are assigned to the characteristic 4I9/2,11/2,13/2 transitions of Nd3+ ions. The dependence of visible and NIR emissions, decay lifetime and the energy transfer efficiency (ηETE) were investigated in detail. The luminescence spectra, both in visible (VIS) and NIR regions, and decay lifetime curves of Eu2+ have been measured to prove energy transfer (ET) from Eu2+ to Nd3+. These results demonstrate the possibility for enhancing the photovoltaic conversion efficiency of silicon solar cell by modifying the absorption and utilizing the UV to blue part of the solar spectrum where the efficiency of c-Silicon solar cell is low.

  11. 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.

  12. Electrocradiographic Qrs Axis, Q Wave and T-wave Changes in 2nd and 3rd Trimester of Normal Pregnancy

    PubMed Central

    S., Chandrasekharappa; Brid, S.V

    2014-01-01

    Background: Pregnancy although a physiological phenomena affects all the functions of the maternal body and brings about remarkable changes in the cardiovascular system. The cardiovascular changes and many of the physiological adaptations of normal pregnancy alter the physical findings thus, sometimes misleading the diagnosis of heart disease. Pregnancy also brings about various changes in the electrocardiogram, further confusing with that of heart disease. This study is undertaken to highlight the effect of normal pregnancy on the QRS axis, Q wave and T-wave of the Electrocardiogram and thereby helps us to distinguish it from that of pathological changes. Objectives: To study the effect of normal pregnancy on the QRS axis, Q wave and T-wave in the electrocardiogram and to compare with that of normal non pregnant women. Materials and Methods: Fifty normal pregnant women in 2nd and 3rd trimester each between 20– 35 y of age and 50 normal non pregnant women of the same age group were selected for the study. A 12 lead ECG was recorded by using ECG machine with special emphasis on QRS axis, Q wave and T-wave changes and all the parameters were analysed. Results: The ECG changes observed in our study include, deviation of QRS axis towards left as pregnancy advanced, significant increased incidence of occurrence of prominent Q waves in lead II, III and avF in pregnant group (p < 0.05 ) and, T-wave abnormalities like flat and inverted T-waves in lead III, V1 – V3 were more frequent in pregnant group ( p<0.05 ) than in non pregnant group. Conclusion:Normal pregnancy brings about various changes in ECG. These changes during pregnancy should be interpretated with caution by the physicians. It is necessary to understand the normal physiological changes which in turn help us in better management of those with cardiac disease. PMID:25386425

  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. Histone tyrosine phosphorylation comes of age

    PubMed Central

    Singh, Rakesh Kumar

    2011-01-01

    Histones were discovered over a century ago and have since been found to be the most extensively post-translationally modified proteins, although tyrosine phosphorylation of histones had remained elusive until recently. The year 2009 proved to be a landmark year for histone tyrosine (Y) phosphorylation as five research groups independently discovered this modification. Three groups describe phosphorylation of Y142 in the variant histone H2A.X, where it may be involved in the cellular decision making process to either undergo DNA repair or apoptosis in response to DNA damage. Further, one group suggests that phosphorylation of histone H3 on Y99 is crucial for its regulated proteolysis in yeast, while another found that Y41 phosphorylation modulates chromatin architecture and oncogenesis in mammalian cells. These pioneering studies provide the initial conceptual framework for further analyses of the diverse roles of tyrosine phosphorylation on different histones, with far reaching implications for human health and disease. PMID:20935492

  15. Cell signaling by receptor-tyrosine kinases

    PubMed Central

    Lemmon, Mark A.; Schlessinger, Joseph

    2010-01-01

    Recent structural studies of receptor tyrosine kinases (RTKs) have revealed unexpected diversity in the mechanisms of their activation by growth factor ligands. Strategies for inducing dimerization by ligand binding are surprisingly diverse, as are mechanisms that couple this event to activation of the intracellular tyrosine kinase domains. As our understanding of these details becomes increasingly sophisticated, it provides an important context for therapeutically countering the effects of pathogenic RTK mutations in cancer and other diseases. Much remains to be learned, however, about the complex signaling networks downstream from RTKs and how alterations in these networks are translated into cellular responses. PMID:20602996

  16. Studies of Nondefective Adenovirus 2-Simian Virus 40 Hybrid Viruses III. Base Composition, Molecular Weight, and Conformation of the Ad2+ND1 Genome

    PubMed Central

    Crumpacker, Clyde S.; Henry, Patrick H.; Kakefuda, Tuyoski; Rowe, Wallace P.; Levin, Myron J.; Lewis, Andrew M.

    1971-01-01

    The nondefective adenovirus 2 (Ad2)-simian virus 40 (SV40) hybrid virus, Ad2+ND1, differs from the defective Ad-SV40 hybrid populations previously described, in that this hybrid virus can replicate without the aid of nonhybrid adenovirus helper. Consequently, the deoxyribonucleic acid (DNA) from this virus, which can be obtained free of nonhybrid adenovirus DNA, is well suited for biophysical studies on Ad-SV40 hybrid DNA. Such studies have been performed and demonstrate Ad2+ND1 DNA to have a buoyant density (1.715 g/cm3) and thermal denaturation profile (Tm = 75.1 C) almost identical with nonhybrid Ad2 DNA. Furthermore, its molecular weight, as determined by analytical zone sedimentation and electron microscopy, was 22 × 106 to 25 × 106 daltons, which is also very similar to that determined for Ad2. Electron micrographs showed all of the hybrid molecules to be double-stranded and linear. By using this determination of the molecular weight of Ad2+ND1 DNA and assuming that 1% of this molecule consists of covalently linked SV40 DNA (see companion paper), we calculate that the hybrid DNA molecule contains 220 × 103 to 250 × 103 daltons of SV40 DNA, or the equivalent of one-tenth of the SV40 genome. PMID:4323710

  17. 21 CFR 582.5920 - Tyrosine.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Tyrosine. 582.5920 Section 582.5920 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS SUBSTANCES GENERALLY RECOGNIZED AS SAFE Nutrients and/or Dietary Supplements...

  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. Bombesin, vasopressin, and endothelin rapidly stimulate tyrosine phosphorylation in intact Swiss 3T3 cells

    SciTech Connect

    Zachary, I.; Gil, J.; Lehmann, W.; Sinnett-Smith, J.; Rozengurt, E. )

    1991-06-01

    The mitogenic neuropeptides bombesin and vasopressin markedly increased tyrosine and serine phosphorylation of multiple substrates in quiescent Swiss 3T3 fibroblasts, including two major bands of M{sub r} 90,000 and 115,000. Tyrosine phosphorylation of these proteins was increased as judged by immunoprecipitation of {sup 32}P{sub i}-labeled cells and immunoblotting of unlabeled cells with monoclonal antiphosphotyrosine antibodies, elution with phenyl phosphate, and phospho amino acid analysis. Phosphotyrosyl proteins generated by bombesin and vasopressin did not correspond either by apparent molecular weight or by immunological and biochemical criteria to several known tyrosine kinase substrates, including phospholipase C{sub {gamma}}, the microtubule-associated protein 2 kinase, GTPase-activating protein, or phosphatidylinositol kinase. The effect was rapid (within seconds), concentration dependent, and inhibited by specific receptor antagonists for both bombesin and vasopressin. The endothelin-related peptide, vasoactive intestinal contractor, also elicited a rapid and concentration-dependent tyrosine/serine phosphorylation of a similar set of substrates. These results demonstrate that neuropeptides, acting through receptors linked to GTP-binding proteins, stimulate tyrosine phosphorylation of a common set of substrates in quiescent Swiss 3T3 cells and suggest the existence of an additional signal transduction pathway in neuropeptide-induced mitogenesis.

  20. 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.

  1. 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.

  2. 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. PMID:16623137

  3. Dimerization mediated through a leucine zipper activates the oncogenic potential of the met receptor tyrosine kinase.

    PubMed Central

    Rodrigues, G A; Park, M

    1993-01-01

    Oncogenic activation of the met (hepatocyte growth factor/scatter factor) receptor tyrosine kinase involves a genomic rearrangement that generates a hybrid protein containing tpr-encoded sequences at its amino terminus fused directly to the met-encoded receptor kinase domain. Deletion of Tpr sequences abolishes the transforming ability of this protein, implicating this region in oncogenic activation. We demonstrate, by site-directed mutagenesis and coimmunoprecipitation experiments, that a leucine zipper motif within Tpr mediates dimerization of the tpr-met product and is essential for the transforming activity of the met oncogene. By analogy with ligand-stimulated activation of receptor tyrosine kinases, we propose that constitutive dimerization mediated by a leucine zipper motif within Tpr is responsible for oncogenic activation of the Met kinase. The possibility that this mechanism of activation represents a paradigm for a class of receptor tyrosine kinase oncogenes activated by DNA rearrangement is discussed. Images PMID:8413267

  4. EDITORIAL: Selected Papers from OMS'07, the 2nd Topical Meeting of the European Optical Society on Optical Microsystems (OMS)

    NASA Astrophysics Data System (ADS)

    Rendina, Ivo; Fazio, Eugenio; Ferraro, Pietro

    2008-06-01

    OMS'07 was the 2nd Topical Meeting of the European Optical Society (EOS) on Optical Microsystems (OMS). It was organized by the EOS in the frame of its international topical meeting activity, and after the success of the inaugural meeting was once again held in Italy, 30 September to 3 October 2007, amidst the wonderful scenery of the Island of Capri. The local organizing committee was composed of researchers from `La Sapienza' University in Rome and the National Council of Research (CNR) in Naples, Italy. A selected group of leading scientists in the field formed the international scientific committee. The conference was fully dedicated to the most recent advancements carried out in the field of optical microsystems. More then 150 scientists coming from five continents attended the conference and more than 100 papers were presented, organized into the following sessions: Photonic cystals and metamaterials Optofluidic microsystems and devices Optical microsystems and devices New characterization methods for materials and devices Application of optical systems Optical sources and photodetectors Optical resonators Nonlinear optic devices Micro-optical devices. Four keynote lecturers were invited for the Plenary sessions: Federico Capasso, Harvard University, USA; Bahram Javidi, University of Connecticut, USA (Distinguished Lecturer, Emeritus of LEOS--IEEE Society); Demetri Psaltis, EPFL, Lausanne, Switzerland; Ammon Yariv, California Institute of Technology, USA. Furthermore, 21 invited speakers opened each session of the conference with their talks. In addition a special session was organized to celebrate eighty years of the Isituto Nazionale di Ottica Applicata (INOA) of CNR. The special invited speaker for this session was Professor Theodor W Hänsch (Nobel Prize in Physics, 2005), who gave a lecture entitled `What can we do with optical frequency combs?' In this special issue of Journal of Optics A: Pure and Applied Optics, a selection of the most interesting

  5. 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

  6. Thermochemistry of glasses along the 2NdAlO3 3SiO2 join

    NASA Astrophysics Data System (ADS)

    Zhang, Yahong; Navrotsky, Alexandra; Tangeman, Jean A.; Weber, J. K. Richard

    2003-08-01

    Five Nd-aluminosilicate glasses along the 2NdAlO3-3SiO2 join were synthesized using conventional drop-quench techniques. A sixth glass, with the end-member NdAlO3 composition, required synthesis by containerless liquid-phase processing methods to avoid crystallization. Enthalpies of drop solution (DeltaHds) and formation (DeltaHf) for the Nd-aluminosilicate glasses and the NdAlO3-composition end-member glass were measured in molten 2PbO-B2O3 at 1078 K in a twin Calvet type calorimeter. Values for DeltaHds for the Nd-aluminosilicate glasses increase with decreasing silica content from 130.7 +/- 1.5 to 149.6 +/- 0.6 kJ mol-1. Similarly, values of DeltaHf increase with decreasing silica content from 41.0 +/- 2.0 to 59.0 +/- 1.6 kJ mol-1. Values of DeltaHds and DeltaHf for NdAlO3-composition glass were measured as 99.3 +/- 0.9 and 139.2 +/- 2.1 kJ mol-1, respectively. Using transposed temperature drop calorimetry, the enthalpy of vitrification for NdAlO3-composition glass was measured as 69.5 +/- 0.9 kJ mol-1 relative to the stable crystalline neodymium aluminium perovskite (NdAlO3) phase. Enthalpies of mixing were calculated based on amorphous end members; the strongly negative values support the absence of immiscibility in this system. Differential scanning calorimetry was used to determine glass transition (Tg) and crystallization (Tx) temperatures, as well as values for the configurational heat capacity (DeltaCP(Tg)) and the temperature range of the supercooled liquid interval (DeltaT(SCL)). The NdAlO3-composition glass showed no evidence of a glass transition prior to crystallization; only a single exotherm was observed, the onset of which occurred at 1045 K. For the Nd-aluminosilicates, values of Tg and DeltaT(SCL) increase with increasing silica content, from 1128 to 1139 K and from ~95 to ~175 K, respectively. Values of (DeltaCP(Tg)) increase with decreasing silica content, from ~27 to ~75 J/g fw lowastK, reflecting the increasing fragility and decreasing

  7. Conservation and early expression of zebrafish tyrosine kinases support the utility of zebrafish as a model for tyrosine kinase biology.

    PubMed

    Challa, Anil Kumar; Chatti, Kiranam

    2013-09-01

    Tyrosine kinases have significant roles in cell growth, apoptosis, development, and disease. To explore the use of zebrafish as a vertebrate model for tyrosine kinase signaling and to better understand their roles, we have identified all of the tyrosine kinases encoded in the zebrafish genome and quantified RNA expression of selected tyrosine kinases during early development. Using profile hidden Markov model analysis, we identified 122 zebrafish tyrosine kinase genes and proposed unambiguous gene names where needed. We found them to be organized into 39 nonreceptor and 83 receptor type, and 30 families consistent with human tyrosine kinase family assignments. We found five human tyrosine kinase genes (epha1, bmx, fgr, srm, and insrr) with no identifiable zebrafish ortholog, and one zebrafish gene (yrk) with no identifiable human ortholog. We also found that receptor tyrosine kinase genes were duplicated more often than nonreceptor tyrosine kinase genes in zebrafish. We profiled expression levels of 30 tyrosine kinases representing all families using direct digital detection at different stages during the first 24 hours of development. The profiling experiments clearly indicate regulated expression of tyrosine kinases in the zebrafish, suggesting their role during early embryonic development. In summary, our study has resulted in the first comprehensive description of the zebrafish tyrosine kinome. PMID:23234507

  8. Conservation and Early Expression of Zebrafish Tyrosine Kinases Support the Utility of Zebrafish as a Model for Tyrosine Kinase Biology

    PubMed Central

    Challa, Anil Kumar

    2013-01-01

    Abstract Tyrosine kinases have significant roles in cell growth, apoptosis, development, and disease. To explore the use of zebrafish as a vertebrate model for tyrosine kinase signaling and to better understand their roles, we have identified all of the tyrosine kinases encoded in the zebrafish genome and quantified RNA expression of selected tyrosine kinases during early development. Using profile hidden Markov model analysis, we identified 122 zebrafish tyrosine kinase genes and proposed unambiguous gene names where needed. We found them to be organized into 39 nonreceptor and 83 receptor type, and 30 families consistent with human tyrosine kinase family assignments. We found five human tyrosine kinase genes (epha1, bmx, fgr, srm, and insrr) with no identifiable zebrafish ortholog, and one zebrafish gene (yrk) with no identifiable human ortholog. We also found that receptor tyrosine kinase genes were duplicated more often than nonreceptor tyrosine kinase genes in zebrafish. We profiled expression levels of 30 tyrosine kinases representing all families using direct digital detection at different stages during the first 24 hours of development. The profiling experiments clearly indicate regulated expression of tyrosine kinases in the zebrafish, suggesting their role during early embryonic development. In summary, our study has resulted in the first comprehensive description of the zebrafish tyrosine kinome. PMID:23234507

  9. Epidermal growth factor receptor tyrosine kinase inhibitors for non-small cell lung cancer

    PubMed Central

    Asami, Kazuhiro; Atagi, Shinji

    2014-01-01

    First-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), including gefitinib and erlotinib, have proven to be highly effective agents for advanced non-small cell lung cancer (NSCLC) in patients harboring an activating EGFR mutation such as the exon 19 deletion mutation and L858R. Although those reversible small molecular targeted agents provide a significant response and survival benefit, all responders eventually acquire resistance. Second-generation EGFR-targeting agents, such as irreversible EGFR/HER2 tyrosine kinase inhibitors and pan-HER TKIs, may improve survival further and be useful for patients who acquired resistance to first-generation EGFR-TKIs. This review discusses novel therapeutic strategies for EGFR-mutated advanced NSCLC using first- and second-generation EGFR-TKIs. PMID:25302168

  10. Zebrafish tyrosine hydroxylase 2 gene encodes tryptophan hydroxylase.

    PubMed

    Ren, Guiqi; Li, Song; Zhong, Hanbing; Lin, Shuo

    2013-08-01

    The primary pathological hallmark of Parkinson disease (PD) is the profound loss of dopaminergic neurons in the substantia nigra pars compacta. To facilitate the understanding of the underling mechanism of PD, several zebrafish PD models have been generated to recapitulate the characteristics of dopaminergic (DA) neuron loss. In zebrafish studies, tyrosine hydroxylase 1 (th1) has been frequently used as a molecular marker of DA neurons. However, th1 also labels norepinephrine and epinephrine neurons. Recently, a homologue of th1, named tyrosine hydroxylase 2 (th2), was identified based on the sequence homology and subsequently used as a novel marker of DA neurons. In this study, we present evidence that th2 co-localizes with serotonin in the ventral diencephalon and caudal hypothalamus in zebrafish embryos. In addition, knockdown of th2 reduces the level of serotonin in the corresponding th2-positive neurons. This phenotype can be rescued by both zebrafish th2 and mouse tryptophan hydroxylase 1 (Tph1) mRNA as well as by 5-hydroxytryptophan, the product of tryptophan hydroxylase. Moreover, the purified Th2 protein has tryptophan hydroxylase activity comparable with that of the mouse TPH1 protein in vitro. Based on these in vivo and in vitro results, we conclude that th2 is a gene encoding for tryptophan hydroxylase and should be used as a marker gene of serotonergic neurons. PMID:23754283

  11. Tyrosine and carboxyl protonation changes in the bacteriorhodopsin photocycle. 2. Tyrosine-26 and -64

    SciTech Connect

    Roepe, P.; Scherrer, P.; Ahl, P.L.; Gupta, S.K.D.; Bogomolni, R.A.; Herzfeld, J.; Rothschild, K.J.

    1987-10-20

    Low-temperature Fourier transform infrared (FTIR) and UV difference spectroscopies combined with selective tyrosine nitration and tyrosine isotopic labeling have been used to investigate the participation of tyrosines-26 and -64 in the bacteriorhodopsin (bR) photocycle. Nitration of Tyr-26 has no detectable effect on the FTIR or UV difference spectra of the BR/sub 570/ ..-->.. K/sub 630/ or BR/sub 570/ ..-->.. M/sub 412/ transitions. In contrast, nitration of Tyr-64 causes changes in both the FTIR and UV spectra of these transitions. However, this nitration does not alter tyrosine peaks in the FTIR difference spectra which have previously been associated with the protonation of a tyrosinate by K/sub 630/ and the deprotonation of a tyrosine by M/sub 412/. Instead, Tyr-64 nitration appears to affect other tyrosine peaks. These results and changes in UV difference spectra upon Tyr-64 nitration are consistent with the deprotonation of Tyr-64 by M/sub 412/ as concluded previously. Effects on chromophore vibrations caused by Tyr-64 nitration are unaltered upon reducing the nitrotyrosine to aminotyrosine with sodium dithionite. Finally, nitro-Tyr-64 causes a shift in the frequency of a positive peak at 1739 cm/sup -1/ in the BR/sub 570/ ..-->.. M/sub 412/ FTIR difference spectrum which reflects the protonation of a carboxyl-containing residue. The shift does not occur for samples containing amino-Tyr-64. These data suggest that Tyr-64 may interact with this carboxyl group.

  12. Defining the role of tyrosine and rational tuning of oxidase activity by genetic incorporation of unnatural tyrosine analogs.

    PubMed

    Yu, Yang; Lv, Xiaoxuan; Li, Jiasong; Zhou, Qing; Cui, Chang; Hosseinzadeh, Parisa; Mukherjee, Arnab; Nilges, Mark J; Wang, Jiangyun; Lu, Yi

    2015-04-15

    While a conserved tyrosine (Tyr) is found in oxidases, the roles of phenol ring pKa and reduction potential in O2 reduction have not been defined despite many years of research on numerous oxidases and their models. These issues represent major challenges in our understanding of O2 reduction mechanism in bioenergetics. Through genetic incorporation of unnatural amino acid analogs of Tyr, with progressively decreasing pKa of the phenol ring and increasing reduction potential, in the active site of a functional model of oxidase in myoglobin, a linear dependence of both the O2 reduction activity and the fraction of H2O formation with the pKa of the phenol ring has been established. By using these unnatural amino acids as spectroscopic probe, we have provided conclusive evidence for the location of a Tyr radical generated during reaction with H2O2, by the distinctive hyperfine splitting patterns of the halogenated tyrosines and one of its deuterated derivatives incorporated at the 33 position of the protein. These results demonstrate for the first time that enhancing the proton donation ability of the Tyr enhances the oxidase activity, allowing the Tyr analogs to augment enzymatic activity beyond that of natural Tyr. PMID:25672571

  13. Isolation and characterization of the human tyrosine hydroxylase gene: identification of 5' alternative splice sites responsible for multiple mRNAs

    SciTech Connect

    O'Malley, K.L.; Anhalt, M.J.; Martin, B.M.; Kelsoe, J.R.; Winfield, S.L.; Ginns, E.I.

    1987-11-03

    A full-length genomic clone for human tyrosine hydroxylase (L-tyrosine, tetrahydropteridine:oxygen oxidoreductase, EC 1.14.16.2) has been isolated. A human brain genomic library constructed in EMBL3 was screened by using a rat cDNA for tyrosine hydroxylase as a probe. Out of one million recombinant phage, one clone was identified that hybridized to both 5' and 3' rat cDNA probes. Restriction endonuclease mapping, Southern blotting, and sequence analysis revealed that, like its rodent counterpart, the human gene is single copy, contains 13 primary exons, and spans approximately 8 kilobases (kb). In contrast to the rat gene, human tyrosine hydroxylase undergoes alternative RNA processing within intron 1, generating at least three distinct mRNAs. A comparison of the human tyrosine hydroxylase and phenylalanine hydroxylase genes indicates that although both probably evolved from a common ancestral gene, major changes in the size of introns have occurred since their divergence.

  14. 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.

  15. [Influence of hypocaloric diet with addition of a vitamin-mineral complex on status of patients with obesity 1st and 2nd degrees].

    PubMed

    Sharafetdinov, Kh Kh; Plotnikova, O A; Zykina, V V; Mal'tsev, G Iu; Sokol'nikov, A A; Kaganov, B S

    2011-01-01

    Addition of a vitamin-mineral complex (VMC) to a standard hypocaloric diet leads to a positive dynamics of antropometric characteristics in patients with obesity 1st and 2nd degrees which is comparable to effectiveness of standard dietotherapy (dietary treatment) traditionally used in complex treatment of obesity. Addition of 1,8 mg of vitamin B2 as part of VMC to a hypocaloric diet is shown to be inadequate in eradication of marginal provision of riboflavin when using diets reduced in calories. PMID:22232885

  16. Methods to monitor classical protein-tyrosine phosphatase oxidation

    PubMed Central

    Karisch, Robert; Neel, Benjamin G.

    2012-01-01

    SUMMARY Reactive oxygen species (ROS), particularly H2O2, act as intracellular second messengers in many signaling pathways. Protein-tyrosine phosphatases (PTPs) are now believed to be important targets of ROS. PTPs contain a conserved catalytic cysteine with an unusually low pKa. This property allows PTPs to execute nucleophilic attack on substrate phosphotyrosyl residues, but also renders them highly susceptible to oxidation. Reversible oxidation, which inactivates PTPs, is emerging as an important cellular regulatory mechanism and might contribute to human diseases, including cancer. Given their potential toxicity, it seems likely that ROS generation is highly controlled within cells to restrict oxidation to those PTPs that must be inactivated for signaling to proceed. Thus, identifying ROS-inactivated PTPs could be tantamount to finding the PTP(s) that critically regulate a specific signaling pathway. This article provides an overview of the methods currently available to identify and quantify PTP oxidation and outlines future challenges in redox signaling. PMID:22577968

  17. 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

  18. PREFACE: 2nd International Conference on Particle Physics in memoriam Engin Arık and her Colleagues

    NASA Astrophysics Data System (ADS)

    Çetin, Serkant Ali; Jenni, Peter; Erkcan Özcan, Veysi; Nefer Şenoğuz, Vedat

    2012-02-01

    The 2nd International Conference on Particle Physics in memoriam Engin Arık and her Colleagues: Fatma Şenel Boydağ, İskender Hikmet, Mustafa Fidan, Berkol Doğan and Engin Abat was held at Doğuş University, İstanbul, Turkey on 20-25 June 2011. The conference was organized jointly by the Doğuş and Boğaziçi Universities, with support from CERN and the Turkish Academy of Sciences. This was the second International Conference on Particle Physics (ICPP) organized in memory of Engin Arık and her Colleagues who lost their lives in the tragic plane accident on November 30 2007, on their way to the workshop of the Turkish Accelerator Center (TAC) Project. The first of this conference series was held on 27-31 October 2008 at Boğaziçi University, İstanbul, Turkey. The conference is intended to be repeated every two years in Istanbul as a Conference Series under the name 'ICPP-Istanbul'. Professor Engin Arık had a pioneering role in experimental particle physics in Turkey, and was an inspiring teacher to many colleagues. She led the Turkish participation in experiments at CERN such as CHARMII, SMC, CHORUS, ATLAS and CAST. One of her latest involvements was in the national project to design the Turkish Accelerator Center with the collaboration of 10 Turkish universities including Doğuş and Boğaziçi. Our dear colleagues not only participated in the TAC project but also collaborated on the ATLAS (E Arık, E Abat and B Doğan) and CAST (E Arık, F Şenel Boydağ, İ Hikmet and B Doğan) experiments. We believe that the ICPP-Istanbul conference series has been, and will always be, a way to commemorate them in a most appropriate context. The topics covered in ICPP-Istanbul-II were 'LHC Physics and Tevatron Results', 'Neutrinos and Dark Matter', 'Particle Factories' and 'Accelerator Physics and Future TeV Scale Colliders'. The main emphasis was on the recent experimental results in high-energy physics with discussions on expectations from existing or future

  19. Hyperfine structure and lifetime measurements in the 4s2nd 2D3/2 Rydberg sequence of Ga I by time-resolved laser spectroscopy

    NASA Astrophysics Data System (ADS)

    Liu, Chunqing; Tian, Yanshan; Yu, Qi; Bai, Wanshuang; Wang, Xinghao; Wang, Chong; Dai, Zhenwen

    2016-05-01

    The hyperfine structure (HFS) constants of the 4s2nd 2D3/2 (n=6-18) Rydberg sequence and the 4s26p 2P3/2 level for two isotopes of 69Ga and 71Ga atoms were measured by means of the time-resolved laser-induced fluorescence (TR-LIF) technique and the quantum beat method. The observed hyperfine quantum beat spectra were analyzed and the magnetic-dipole HFS constants A as well as the electric-quadrupole HFS constants B of these levels were obtained by Fourier transform and a program for multiple regression analysis. Also using TR-LIF method radiative lifetimes of the above sequence states were determined at room temperature. The measured lifetime values range from 69 to 2279 ns with uncertainties no more than 10%. To our knowledge, the HFS constants of this Rydberg sequence and the lifetimes of the 4s2nd 2D3/2 (n=10-18) levels are reported for the first time. Good agreement between our results and the previous is achieved.

  20. 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.

  1. 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. PMID:17161592

  2. Perturbations of tyrosine metabolism promote the indolepyruvate pathway via tryptophan in host and microbiome.

    PubMed

    Gertsman, Ilya; Gangoiti, Jon A; Nyhan, William L; Barshop, Bruce A

    2015-03-01

    The drug nitisinone (NTBC) is used to treat tyrosinemia type I, and more recently has been also used for the treatment of another disorder of tyrosine metabolism, alkaptonuria. While studying the dose effects of NTBC treatment on alkaptonuria, untargeted metabolomics revealed perturbations in a completely separate pathway, that of tryptophan metabolism. Significant elevations in several indolic compounds associated with the indolepyruvate pathway of tryptophan metabolism were present in NTBC-treated patient sera and correlated with elevations of an intermediate of tyrosine metabolism. Indolic compounds of this pathway have long been associated with commensal bacterial and plant metabolism. These exogenous sources of indoles have been more recently implicated in affecting mammalian cell function and disease. We studied the correlation of these indolic compounds in other disorders of tyrosine metabolism including tyrosinemia types I and II as well as transient tyrosinemia, and demonstrated that 4-hydroxyphenylpyruvate (4-HPP) was directly responsible for the promotion of this pathway. We then investigated the regulation of the indolepyruvate pathway and the role of 4-HPP further in both mammalian cells and intestinal microbial cultures. We demonstrated that several of the indolic products, including indolepyruvate and indolelactate, were in fact generated by human cell metabolism, while the downstream indole metabolite, indolecarboxaldehyde, was produced exclusively by microbial cultures of human gut flora. This study describes a symbiotic perturbation in host and microbiome tryptophan metabolism in response to elevations related to defects of tyrosine metabolism and concomitant drug treatment. PMID:25680927

  3. The Tyrosine Kinome Dictates Breast Cancer Heterogeneity and Therapeutic Responsiveness.

    PubMed

    Ha, Jacqueline R; Siegel, Peter M; Ursini-Siegel, Josie

    2016-09-01

    Phospho-tyrosine signaling networks control numerous biological processes including cellular differentiation, cell growth and survival, motility, and invasion. Aberrant regulation of the tyrosine kinome is a hallmark of malignancy and influences all stages of breast cancer progression, from initiation to the development of metastatic disease. The success of specific tyrosine kinase inhibitors strongly validates the clinical relevance of tyrosine phosphorylation networks in breast cancer pathology. However, a significant degree of redundancy exists within the tyrosine kinome. Numerous receptor and cytoplasmic tyrosine kinases converge on a core set of signaling regulators, including adaptor proteins and tyrosine phosphatases, to amplify pro-tumorigenic signal transduction pathways. Mutational activation, amplification, or overexpression of one or more components of the tyrosine kinome represents key contributing events responsible for the tumor heterogeneity that is observed in breast cancers. It is this molecular heterogeneity that has become the most significant barrier to durable clinical responses due to the development of therapeutic resistance. This review focuses on recent literature that supports a prominent role for specific components of the tyrosine kinome in the emergence of unique breast cancer subtypes and in shaping breast cancer plasticity, sensitivity to targeted therapies, and the eventual emergence of acquired resistance. J. Cell. Biochem. 117: 1971-1990, 2016. © 2016 Wiley Periodicals, Inc. PMID:27392311

  4. Potential sites of CFTR activation by tyrosine kinases.

    PubMed

    Billet, Arnaud; Jia, Yanlin; Jensen, Timothy J; Hou, Yue-Xian; Chang, Xiu-Bao; Riordan, John R; Hanrahan, John W

    2016-05-01

    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

  5. 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.

  6. 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.

  7. Spatial and Temporal Regulation of Receptor Tyrosine Kinase Activation and Intracellular Signal Transduction.

    PubMed

    Bergeron, John J M; Di Guglielmo, Gianni M; Dahan, Sophie; Dominguez, Michel; Posner, Barry I

    2016-06-01

    Epidermal growth factor (EGF) and insulin receptor tyrosine kinases (RTKs) exemplify how receptor location is coupled to signal transduction. Extracellular binding of ligands to these RTKs triggers their concentration into vesicles that bud off from the cell surface to generate intracellular signaling endosomes. On the exposed cytosolic surface of these endosomes, RTK autophosphorylation selects the downstream signaling proteins and lipids to effect growth factor and polypeptide hormone action. This selection is followed by the recruitment of protein tyrosine phosphatases that inactivate the RTKs and deliver them by membrane fusion and fission to late endosomes. Coincidentally, proteinases inside the endosome cleave the EGF and insulin ligands. Subsequent inward budding of the endosomal membrane generates multivesicular endosomes. Fusion with lysosomes then results in RTK degradation and downregulation. Through the spatial positioning of RTKs in target cells for EGF and insulin action, the temporal extent of signaling, attenuation, and downregulation is regulated. PMID:27023845

  8. Tyrosine kinase BMX phosphorylates phosphotyrosine-primed motif mediating the activation of multiple receptor tyrosine kinases.

    PubMed

    Chen, Sen; Jiang, Xinnong; Gewinner, Christina A; Asara, John M; Simon, Nicholas I; Cai, Changmeng; Cantley, Lewis C; Balk, Steven P

    2013-05-28

    The nonreceptor tyrosine kinase BMX (bone marrow tyrosine kinase gene on chromosome X) is abundant in various cell types and activated downstream of phosphatidylinositol-3 kinase (PI3K) and the kinase Src, but its substrates are unknown. Positional scanning peptide library screening revealed a marked preference for a priming phosphorylated tyrosine (pY) in the -1 position, indicating that BMX substrates may include multiple tyrosine kinases that are fully activated by pYpY sites in the kinase domain. BMX phosphorylated focal adhesion kinase (FAK) at Tyr⁵⁷⁷ subsequent to its Src-mediated phosphorylation at Tyr⁵⁷⁶. Loss of BMX by RNA interference or by genetic deletion in mouse embryonic fibroblasts (MEFs) markedly impaired FAK activity. Phosphorylation of the insulin receptor in the kinase domain at Tyr¹¹⁸⁹ and Tyr¹¹⁹⁰, as well as Tyr¹¹⁸⁵, and downstream phosphorylation of the kinase AKT at Thr³⁰⁸ were similarly impaired by BMX deficiency. However, insulin-induced phosphorylation of AKT at Ser⁴⁷³ was not impaired in Bmx knockout MEFs or liver tissue from Bmx knockout mice, which also showed increased insulin-stimulated glucose uptake, possibly because of decreased abundance of the phosphatase PHLPP (PH domain leucine-rich repeat protein phosphatase). Thus, by identifying the pYpY motif as a substrate for BMX, our findings suggest that BMX functions as a central regulator among multiple signaling pathways mediated by tyrosine kinases. PMID:23716717

  9. Bruton tyrosine kinase inhibition in chronic lymphocytic leukemia.

    PubMed

    Maddocks, Kami; Jones, Jeffrey A

    2016-04-01

    Chronic lymphocytic leukemia (CLL) is the most common adult leukemia and remains incurable outside of the setting of allogeneic stem cell transplant. While the standard therapy for both initial and relapsed CLL has traditionally included monoclonal antibody therapy in combination with chemotherapy, there are patients with high-risk disease features including unmutated IgVH, del(11q22) and del(17p13) that are associated with poor overall responses to these therapies with short time to relapse and shortened overall survival. Additionally, many of these therapies have a high rate of infectious toxicity in a population already at increased risk. Targeting the B-cell receptor (BCR) signaling pathway has emerged as a promising therapeutic advance in a variety of B-cell malignancies, including CLL. Bruton agammaglobulinemia tyrosine kinase (Btk) is a tyrosine kinase in the BCR pathway critical to the survival of both normal and malignant B cells and inhibition of this kinase has shown to block the progression of CLL. Ibrutinib, a first in class oral inhibitor of Btk, has shown promise as a very effective agent in the treatment of CLL-in both relapsed and upfront therapy, alone and in combination with other therapies, and in patients of all-risk disease-which has led to its approval in relapsed CLL and as frontline therapy in patients with the high-risk del(17p13) disease. Several studies are ongoing to evaluate the efficacy and safety of ibrutinib in combination with chemotherapy as frontline treatment for CLL and investigation into newer-generation Btk inhibitors is also underway. PMID:27040703

  10. 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

  11. Identification and characterization of 2nd generation Invader Locked Nucleic Acids (LNAs) for mixed-sequence recognition of double-stranded DNA

    PubMed Central

    Sau, Sujay P.; Madsen, Andreas S.; Podbevsek, Peter; Andersen, Nicolai K.; Kumar, T. Santhosh; Andersen, Sanne; Rathje, Rie L.; Anderson, Brooke A.; Guenther, Dale C.; Karmakar, Saswata; Kumar, Pawan; Plavec, Janez; Wengel, Jesper

    2013-01-01

    Development of synthetic agents that recognize double-stranded DNA (dsDNA) is a long-standing goal that is inspired by the promise for tools that detect, regulate and modify genes. Progress has been made with triplex-forming oligonucleotides, PNAs, and polyamides, but substantial efforts are currently devoted to the development of alternative strategies that overcome limitations observed with the classic approaches. In 2005, we introduced Invader Locked Nucleic Acids (LNAs), i.e., double-stranded probes that are activated for mixed-sequence recognition of dsDNA through modification with ‘+1 interstrand zippers’ of 2’-N-(pyren-1-yl)methyl-2’-amino-α-L-LNA monomers. Despite promising preliminary results, progress has been slow due to the synthetic complexity of the building blocks. Here, we describe a study that led to the identification of two simpler classes of Invader monomers. We compare thermal denaturation characteristics of double-stranded probes featuring different interstrand zippers of pyrene-functionalized monomers based on 2’-amino-α-L-LNA, 2’-N-methyl-2’-amino-DNA, and RNA scaffolds. Insights from fluorescence spectroscopy, molecular modeling and NMR spectroscopy are used to elucidate the structural factors that govern probe activation. We demonstrate that probes with +1 zippers of 2’-O-(pyren-1-yl)methyl-RNA or 2’-N-methyl-2’-N-(pyren-1-yl)methyl-2’-amino-DNA monomers recognize DNA hairpins with similar efficiency as original Invader LNAs. Access to synthetically simple monomers will accelerate the use of Invader-mediated dsDNA-recognition for applications in molecular biology and nucleic acid diagnostics. PMID:24032477

  12. 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,…

  13. 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.

  14. Recent Observations of Clouds and Precipitation by the Airborne Precipitation Radar 2nd Generation in Support of the GPM and ACE Missions

    NASA Technical Reports Server (NTRS)

    Durden, Stephen L.; Tanelli, Simone; Im, Eastwood

    2012-01-01

    In this paper we illustrate the unique dataset collected during the Global Precipitation Measurement Cold-season Precipitation Experiment (GCPEx, US/Canada Jan/Feb 2012). We will focus on the significance of these observations for the development of algorithms for GPM and ACE, with particular attention to classification and retrievals of frozen and mixed phase hydrometeors.

  15. Microtubule-associated protein 1B interaction with tubulin tyrosine ligase contributes to the control of microtubule tyrosination.

    PubMed

    Utreras, Elías; Jiménez-Mateos, Eva Maria; Contreras-Vallejos, Erick; Tortosa, Elena; Pérez, Mar; Rojas, Sebastián; Saragoni, Lorena; Maccioni, Ricardo B; Avila, Jesús; González-Billault, Christian

    2008-01-01

    Microtubule-associated protein 1B (MAP1B) is the first microtubule-associated protein to be expressed during nervous system development. MAP1B belongs to a large family of proteins that contribute to the stabilization and/or enhancement of microtubule polymerization. These functions are related to the control of the dynamic properties of microtubules. The C-terminal domain of the neuronal alpha-tubulin isotype is characterized by the presence of an acidic polypeptide, with the last amino acid being tyrosine. This tyrosine residue may be enzymatically removed from the protein by an unknown carboxypeptidase activity. Subsequently, the tyrosine residue is again incorporated into this tubulin by another enzyme, tubulin tyrosine ligase, to yield tyrosinated tubulin. Because neurons lacking MAP1B have a reduced proportion of tyrosinated microtubules, we analyzed the possible interaction between MAP1B and tubulin tyrosine ligase. Our results show that these proteins indeed interact and that the interaction is not affected by MAP1B phosphorylation. Additionally, neurons lacking MAP1B, when exposed to drugs that reversibly depolymerize microtubules, do not fully recover tyrosinated microtubules upon drug removal. These results suggest that MAP1B regulates tyrosination of alpha-tubulin in neuronal microtubules. This regulation may be important for general processes involved in nervous system development such as axonal guidance and neuronal migration. PMID:18075266

  16. Inhibition of biofilm formation by D-tyrosine: Effect of bacterial type and D-tyrosine concentration.

    PubMed

    Yu, Cong; Li, Xuening; Zhang, Nan; Wen, Donghui; Liu, Charles; Li, Qilin

    2016-04-01

    D-Tyrosine inhibits formation and triggers disassembly of bacterial biofilm and has been proposed for biofouling control applications. This study probes the impact of D-tyrosine in different biofilm formation stages in both G+ and G- bacteria, and reveals a non-monotonic correlation between D-tyrosine concentration and biofilm inhibition effect. In the attachment stage, cell adhesion was studied in a flow chamber, where D-tyrosine caused significant reduction in cell attachment. Biofilms formed by Pseudomonas aeruginosa and Bacillus subtilis were characterized by confocal laser scanning microscopy as well as quantitative analysis of cellular biomass and extracellular polymeric substances. D-Tyrosine exhibited strong inhibitive effects on both biofilms with an effective concentration as low as 5 nM; the biofilms responded to D-tyrosine concentration change in a non-monotonic, bi-modal pattern. In addition, D-tyrosine showed notable and different impact on EPS production by G+ and G- bacteria. Extracellular protein was decreased in P. aeruginosa biofilms, but increased in those of B. subtilis. Exopolysaccharides production by P. aeruginosa was increased at low concentrations and reduced at high concentrations while no impact was found in B. subtilis. These results suggest that distinct mechanisms are at play at different D-tyrosine concentrations and they may be species specific. Dosage of D-tyrosine must be carefully controlled for biofouling control applications. PMID:26854605

  17. 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.

  18. Tyrosine for the treatment of depression.

    PubMed

    Gelenberg, A J; Gibson, C J

    1984-01-01

    The two most widely held biochemical models of depression--the catecholamine (CA) and indoleamine (IA) hypotheses--explain depression as a result of deficient transmission of the CA norepinephrine (NE) or the IA serotonin (5-hydroxytryptamine, 5-HT) respectively. Until recently, all drugs used to treat depression appeared to enhance neurotransmission in one or both of these systems, which was used to explain their antidepressant actions (Gelenberg and Klerman, 1978). In fact, it was this action of antidepressants that gave rise to the models of depression. Another way to increase brain levels of NE and 5-HT, and potentially to increase presynaptic activity, would be the systemic administration of the precursors of the neurotransmitters, an approach something like organic gardening in the brain. For this purpose, the 5-HT precursors tryptophan and 5-hydroxtryptophan (5-HTP), and the NE precursors tyrosine and dihydroxyphenylalanine (DOPA), have been administered to depressed patients. This paper reviews some of the theoretical background and clinical experience with the precursor strategy, focusing primarily on work with L-tyrosine. All four precursors as possible antidepressants have been recently reviewed (Gelenberg, 1982). PMID:6443584

  19. The Extended Family of Protein Tyrosine Phosphatases.

    PubMed

    Alonso, Andrés; Nunes-Xavier, Caroline E; Bayón, Yolanda; Pulido, Rafael

    2016-01-01

    In higher eukaryotes, the Tyr phosphorylation status of cellular proteins results from the coordinated action of Protein Tyrosine Kinases (PTKs) and Protein Tyrosine Phosphatases (PTPs). PTPs have emerged as highly regulated enzymes with diverse substrate specificity, and proteins with Tyr-dephosphorylation or Tyr-dephosphorylation-like properties can be clustered as the PTPome. This includes proteins from the PTP superfamily, which display a Cys-based catalytic mechanism, as well as enzymes from other gene families (Asp-based phosphatases, His-based phosphatases) that have converged in protein Tyr-dephosphorylation-related functions by using non-Cys-based catalytic mechanisms. Within the Cys-based members of the PTPome, classical PTPs dephosphorylate specific phosphoTyr (pTyr) residues from protein substrates, whereas VH1-like dual-specificity PTPs dephosphorylate pTyr, pSer, and pThr residues, as well as nonproteinaceous substrates, including phosphoinositides and phosphorylated carbohydrates. In addition, several PTPs have impaired catalytic activity as a result of amino acid substitutions at their active sites, but retain regulatory functions related with pTyr signaling. As a result of their relevant biological activity, many PTPs are linked to human disease, including cancer, neurodevelopmental, and metabolic diseases, making these proteins important drug targets and molecular markers in the clinic. Here, a brief overview on the biochemistry and physiology of the different groups of proteins that belong to the mammalian PTPome is presented. PMID:27514797

  20. Bruton tyrosine kinase (Btk) suppresses osteoblastic differentiation.

    PubMed

    Kaneshiro, Shoichi; Ebina, Kosuke; Shi, Kenrin; Yoshida, Kiyoshi; Otsuki, Dai; Yoshikawa, Hideki; Higuchi, Chikahisa

    2015-09-01

    The Tec family of nonreceptor tyrosine kinases has been shown to play a key role in inflammation and bone destruction. Bruton tyrosine kinase (Btk) has been the most widely studied because of its critical role in B cells. Furthermore, recent evidence has demonstrated that blocking Btk signaling is effective in ameliorating lymphoma progression and experimental arthritis. The role of Btk in osteoblastic differentiation has not been well elucidated. In this study, we demonstrated the role of Btk in osteoblastic differentiation and investigated the effects of a Btk inhibitor on osteoblastic differentiation in mouse preosteoblastic MC3T3-E1 cells, primary calvarial osteoblasts, and bone marrow stromal ST2 cells. Btk expression was detected in all three cell lines. Btk inhibition stimulated mRNA expression of osteoblastic markers (alkaline phosphatase, osteocalcin, and osterix) and promoted mineralization of the extracellular matrix. In addition, Btk knockdown caused increased mRNA expression of osteoblastic markers. Furthermore, Btk inhibition suppressed the phosphorylation of mitogen-activated protein kinase (MAPK), nuclear factor kappa B (NFκB), and protein kinase Cα (PKCα). Our results indicate that Btk may regulate osteoblastic differentiation through the MAPK, NFκB, and PKCα signaling pathways. PMID:25230818

  1. Receptor Tyrosine Kinases with Intracellular Pseudokinase Domains

    PubMed Central

    Mendrola, Jeannine M.; Shi, Fumin; Park, Jin H.; Lemmon, Mark A.

    2013-01-01

    As with other groups of protein kinases, approximately 10% of the receptor tyrosine kinases (RTKs) in the human proteome contain intracellular pseudokinases that lack one or more conserved catalytically important residues. These include ErbB3, a member of the epidermal growth factor receptor (EGFR) family, and a series of unconventional Wnt receptors. We recently showed that, despite its reputation as a pseudokinase, the ErbB3 tyrosine kinase domain (TKD) does retain significant – albeit weak – kinase activity. This led us to suggest that a subgroup of RTKs may be able to signal even with very inefficient kinases. Recent work suggests that this is not the case, however. Other pseudokinase RTKs have not revealed significant kinase activity, and mutations that impair ErbB3’s weak kinase activity have not so far been found to exhibit signaling defects. These findings therefore point to models in which the TKDs of pseudokinase RTKs participate in receptor signaling by allosterically regulating associated kinases (such as ErbB3 regulation of ErbB2) and/or function as regulated ‘scaffolds’ for other intermolecular interactions central to signal propagation. Further structural and functional studies – particularly of the pseudokinase RTKs involved in Wnt signaling – are required to shed new light on these intriguing signaling mechanisms. PMID:23863174

  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. Structural and magnetic study of order-disorder behavior in the double perovskites Ba2Nd1-xMnxMoO6.

    PubMed

    Coomer, Fiona C; Cussen, Edmund J

    2014-01-21

    The synthesis and structural and magnetic characterization of the site-ordered double perovskites, Ba2Nd1-xMnxMoO6, 0 < x ≤ 1, are reported in order to show the effect of doping Jahn-Teller active, S = 1/2, Mo(5+) into the structure of Ba2MnMoO6, which exhibits anomalous long-range antiferromagnetic order. Rietveld refinements against room temperature neutron powder diffraction data indicate that the tetragonal distortion present in the Ba2NdMoO6 end member persists to x ≤ 0.3. This is predominantly manifested as a tilting of the MO6 octahedra, and there is no evidence of any structural phase transitions on cooling to 1.5 K. For x > 0.3, no deviation from the ideal cubic Fm3̅m symmetry is observed. Furthermore, dc-susceptibility measurements confirm that Mn(2+) is being doped onto the Nd(3+) site, and the associated oxidation of Mo(5+) to Mo(6+). For all compositions, the Curie-Weiss paramagnetic behavior above 150 K indicates negative Weiss constants that range from -24(2) and -85(2) K. This net antiferromagnetic interaction is weakest when x ≈ 0.5, where the disorder in cation site occupancy and competition with ferromagnetic interactions is the greatest. Despite these strong antiferromagnetic interactions, there is no evidence in the dc-susceptibility of a bulk cancellation of spins for x > 0.05. Low-temperature neutron diffraction measurements indicate that there is no long-range magnetic order for 0.1 ≤ x < 0.9. Ba2Nd0.10Mn0.90MoO6 exhibits additional Bragg scattering at 2 K, indicative of long-range antiferromagnetic ordering of the Mn(2+) cations, with a propagation vector k = (1/2, 1/2, 1/2). The scattering intensities can be modeled using a noncollinear magnetic structure with the Mn(2+) moments orientated antiferromagnetically along the four different ⟨111⟩ directions. PMID:24392887

  4. 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

  5. Protein tyrosine nitration of mitochondrial carbamoyl phosphate synthetase 1 and its functional consequences.

    PubMed

    Takakusa, Hideo; Mohar, Isaac; Kavanagh, Terrance J; Kelly, Edward J; Kaspera, Rüdiger; Nelson, Sidney D

    2012-03-30

    Mitochondria are the primary locus for the generation of reactive nitrogen species including peroxynitrite and subsequent protein tyrosine nitration. Protein tyrosine nitration may have important functional and biological consequences such as alteration of enzyme catalytic activity. In the present study, mouse liver mitochondria were incubated with peroxynitrite, and the mitochondrial proteins were separated by 1D and 2D gel electrophoresis. Nitrotyrosinylated proteins were detected with an anti-nitrotyrosine antibody. One of the major proteins nitrated by peroxynitrite was carbamoyl phosphate synthetase 1 (CPS1) as identified by LC-MS protein analysis and Western blotting. The band intensity of nitration normalized to CPS1 was increased in a peroxynitrite concentration-dependent manner. In addition, CPS1 activity was decreased by treatment with peroxynitrite in a peroxynitrite concentration- and time-dependent manner. The decreased CPS1 activity was not recovered by treatment with reduced glutathione, suggesting that the decrease of the CPS1 activity is due to tyrosine nitration rather than cysteine oxidation. LC-MS analysis of in-gel digested samples, and a Popitam-based modification search located 5 out of 36 tyrosine residues in CPS1 that were nitrated. Taken together with previous findings regarding CPS1 structure and function, homology modeling of mouse CPS1 suggested that nitration at Y1450 in an α-helix of allosteric domain prevents activation of CPS1 by its activator, N-acetyl-l-glutamate. In conclusion, this study demonstrated the tyrosine nitration of CPS1 by peroxynitrite and its functional consequence. Since CPS1 is responsible for ammonia removal in the urea cycle, nitration of CPS1 with attenuated function might be involved in some diseases and drug-induced toxicities associated with mitochondrial dysfunction. PMID:22402285

  6. Nephrin Tyrosine Phosphorylation Is Required to Stabilize and Restore Podocyte Foot Process Architecture.

    PubMed

    New, Laura A; Martin, Claire E; Scott, Rizaldy P; Platt, Mathew J; Keyvani Chahi, Ava; Stringer, Colin D; Lu, Peihua; Samborska, Bozena; Eremina, Vera; Takano, Tomoko; Simpson, Jeremy A; Quaggin, Susan E; Jones, Nina

    2016-08-01

    Podocytes are specialized epithelial cells of the kidney blood filtration barrier that contribute to permselectivity via a series of interdigitating actin-rich foot processes. Positioned between adjacent projections is a unique cell junction known as the slit diaphragm, which is physically connected to the actin cytoskeleton via the transmembrane protein nephrin. Evidence indicates that tyrosine phosphorylation of the intracellular tail of nephrin initiates signaling events, including recruitment of cytoplasmic adaptor proteins Nck1 and Nck2 that regulate actin cytoskeletal dynamics. Nephrin tyrosine phosphorylation is altered in human and experimental renal diseases characterized by pathologic foot process remodeling, prompting the hypothesis that phosphonephrin signaling directly influences podocyte morphology. To explore this possibility, we generated and analyzed knockin mice with mutations that disrupt nephrin tyrosine phosphorylation and Nck1/2 binding (nephrin(Y3F/Y3F) mice). Homozygous nephrin(Y3F/Y3F) mice developed progressive proteinuria accompanied by structural changes in the filtration barrier, including podocyte foot process effacement, irregular thickening of the glomerular basement membrane, and dilated capillary loops, with a similar but later onset phenotype in heterozygous animals. Furthermore, compared with wild-type mice, nephrin(Y3F/Y3F) mice displayed delayed recovery in podocyte injury models. Profiling of nephrin tyrosine phosphorylation dynamics in wild-type mice subjected to podocyte injury indicated site-specific differences in phosphorylation at baseline, injury, and recovery, which correlated with loss of nephrin-Nck1/2 association during foot process effacement. Our results define an essential requirement for nephrin tyrosine phosphorylation in stabilizing podocyte morphology and suggest a model in which dynamic changes in phosphotyrosine-based signaling confer plasticity to the podocyte actin cytoskeleton. PMID:26802179

  7. 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...

  8. What's new with the flu? Reflections regarding the management and prevention of influenza from the 2nd New Zealand Influenza Symposium, November 2015.

    PubMed

    Charania, Nadia A; Mansoor, Osman D; Murfitt, Diana; Turner, Nikki M

    2016-01-01

    Influenza is a common respiratory viral infection. Seasonal outbreaks of influenza cause substantial morbidity and mortality that burdens healthcare services every year. The influenza virus constantly evolves by antigenic drift and occasionally by antigenic shift, making this disease particularly challenging to manage and prevent. As influenza viruses cause seasonal outbreaks and also have the ability to cause pandemics leading to widespread social and economic losses, focused discussions on improving management and prevention efforts is warranted. The Immunisation Advisory Centre (IMAC) hosted the 2nd New Zealand Influenza Symposium (NZiS) in November 2015. International and national participants discussed current issues in influenza management and prevention. Experts in the field presented data from recent studies and discussed the ecology of influenza viruses, epidemiology of influenza, methods of prevention and minimisation, and experiences from the 2015 seasonal influenza immunisation campaign. The symposium concluded that although much progress in this field has been made, many areas for future research remain. PMID:27607085

  9. 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. PMID:24737964

  10. 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

  11. Tyrosine kinase inhibitors and the thyroid.

    PubMed

    Sherman, Steven I

    2009-12-01

    Protein tyrosine kinase inhibitors (TKIs) have emerged as significant targets for novel cancer therapies. For patients with differentiated or medullary carcinomas unresponsive to conventional treatments, multiple novel therapies primarily targeting angiogenesis have entered clinical trials. Partial response rates up to 30% have been reported in single-agent studies, but prolonged disease stabilisation is more commonly seen. The most successful agents target the vascular endothelial growth factor receptors. Sorafenib and sunitinib have had promising preliminary results reported and are being used selectively for patients who do not qualify for clinical trials. Treatment for patients with metastatic or advanced thyroid carcinoma now emphasises clinical trial opportunities for novel agents with considerable promise. Adverse effects on thyroid function and thyroid hormone metabolism have also been seen with several TKIs, necessitating prospective thyroid function testing for all patients starting therapy. PMID:19942148

  12. The Ror receptor tyrosine kinase family.

    PubMed

    Forrester, W C

    2002-01-01

    Receptor tyrosine kinases (RTKs) participate in numerous developmental decisions. Ror RTKs are a family of orphan receptors that are related to muscle specific kinase (MuSK) and Trk neurotrophin receptors. MuSK assembles acetylcholine receptors at the neuromuscular junction, and Trk receptors function in the developing nervous system (reviewed in [3-5]). Rors have been identified in nematodes, insects and mammals. Recent studies have begun to shed light on Ror function during development. In most species, Rors are expressed in many tissue types during development. Analyses of mutants that are defective in the single nematode Ror demonstrate a role in cell migration and in orienting cell polarity. Mice lacking one of the two Ror gene products display defects in bone and heart formation. Similarly, two different human bone development disorders, dominant brachydactyly B and recessive Robinow syndrome, result from mutations in one of the human Ror genes. PMID:11846036

  13. Antibodies directed against receptor tyrosine kinases

    PubMed Central

    FAUVEL, Bénédicte; Yasri, Aziz

    2014-01-01

    Approximately 30 therapeutic monoclonal antibodies have already been approved for cancers and inflammatory diseases, and monoclonal antibodies continue to be one of the fastest growing classes of therapeutic molecules. Because aberrant signaling by receptor tyrosine kinases (RTKs) is a commonly observed factor in cancer, most of the subclasses of RTKs are being extensively studied as potential targets for treating malignancies. The first two RTKs that have been targeted by antibody therapy, with five currently marketed antibodies, are the growth factor receptors EGFR and HER2. However, due to systemic side effects, refractory patients and the development of drug resistance, these treatments are being challenged by emerging therapeutics. This review examines current monoclonal antibody therapies against RTKs. After an analysis of agents that have already been approved, we present an analysis of antibodies in clinical development that target RTKs. Finally, we highlight promising RTKs that are emerging as new oncological targets for antibody-based therapy. PMID:24859229

  14. 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. PMID:25257259

  15. The tyrosine kinase FER is responsible for the capacitation-associated increase in tyrosine phosphorylation in murine sperm.

    PubMed

    Alvau, Antonio; Battistone, Maria Agustina; Gervasi, Maria Gracia; Navarrete, Felipe A; Xu, Xinran; Sánchez-Cárdenas, Claudia; De la Vega-Beltran, Jose Luis; Da Ros, Vanina G; Greer, Peter A; Darszon, Alberto; Krapf, Diego; Salicioni, Ana Maria; Cuasnicu, Patricia S; Visconti, Pablo E

    2016-07-01

    Sperm capacitation is required for fertilization. At the molecular level, this process is associated with fast activation of protein kinase A. Downstream of this event, capacitating conditions lead to an increase in tyrosine phosphorylation. The identity of the tyrosine kinase(s) mediating this process has not been conclusively demonstrated. Recent experiments using stallion and human sperm have suggested a role for PYK2 based on the use of small molecule inhibitors directed against this kinase. However, crucially, loss-of-function experiments have not been reported. Here, we used both pharmacological inhibitors and genetically modified mice models to investigate the identity of the tyrosine kinase(s) mediating the increase in tyrosine phosphorylation in mouse sperm. Similar to stallion and human, PF431396 blocks the capacitation-associated increase in tyrosine phosphorylation. Yet, sperm from Pyk2(-/-) mice displayed a normal increase in tyrosine phosphorylation, implying that PYK2 is not responsible for this phosphorylation process. Here, we show that PF431396 can also inhibit FER, a tyrosine kinase known to be present in sperm. Sperm from mice targeted with a kinase-inactivating mutation in Fer failed to undergo capacitation-associated increases in tyrosine phosphorylation. Although these mice are fertile, their sperm displayed a reduced ability to fertilize metaphase II-arrested eggs in vitro. PMID:27226326

  16. The Structure of L-Tyrosine 2,3-Aminomutase frmo the C-1027 Enediyne Antitumor Antibiotic Biosynthetic Pathway

    SciTech Connect

    Christianson,C.; Montavon, T.; Van Lanen, S.; Shen, B.; Bruner, S.

    2007-01-01

    The SgcC4 L-tyrosine 2,3-aminomutase (SgTAM) catalyzes the formation of (S)-{beta}-tyrosine in the biosynthetic pathway of the enediyne antitumor antibiotic C-1027. SgTAM is homologous to the histidine ammonia lyase family of enzymes whose activity is dependent on the methylideneimidazole-5-one (MIO) cofactor. Unlike the lyase enzymes, SgTAM catalyzes additional chemical transformations resulting in an overall stereospecific 1,2-amino shift in the substrate L-tyrosine to generate (S)-{beta}-tyrosine. Previously, we provided kinetic, spectroscopic, and mutagenesis data supporting the presence of MIO in the active site of SgTAM [Christenson, S. D.; Wu, W.; Spies, A.; Shen, B.; and Toney, M. D. (2003) Biochemistry 42, 12708-12718]. Here we report the first X-ray crystal structure of an MIO-containing aminomutase, SgTAM, and confirm the structural homology of SgTAM to ammonia lyases. Comparison of the structure of SgTAM to the L-tyrosine ammonia lyase from Rhodobacter sphaeroides provides insight into the structural basis for aminomutase activity. The results show that SgTAM has a closed active site well suited to retain ammonia and minimize the formation of lyase elimination products. The amino acid determinants for substrate recognition and catalysis can be predicted from the structure, setting the framework for detailed mechanistic investigations.

  17. The structure of L-tyrosine 2,3-aminomutase from the C-1027 enediyne antitumor antibiotic biosynthetic pathway.

    PubMed

    Christianson, Carl V; Montavon, Timothy J; Van Lanen, Steven G; Shen, Ben; Bruner, Steven D

    2007-06-19

    The SgcC4 l-tyrosine 2,3-aminomutase (SgTAM) catalyzes the formation of (S)-beta-tyrosine in the biosynthetic pathway of the enediyne antitumor antibiotic C-1027. SgTAM is homologous to the histidine ammonia lyase family of enzymes whose activity is dependent on the methylideneimidazole-5-one (MIO) cofactor. Unlike the lyase enzymes, SgTAM catalyzes additional chemical transformations resulting in an overall stereospecific 1,2-amino shift in the substrate l-tyrosine to generate (S)-beta-tyrosine. Previously, we provided kinetic, spectroscopic, and mutagenesis data supporting the presence of MIO in the active site of SgTAM [Christenson, S. D.; Wu, W.; Spies, A.; Shen, B.; and Toney, M. D. (2003) Biochemistry 42, 12708-12718]. Here we report the first X-ray crystal structure of an MIO-containing aminomutase, SgTAM, and confirm the structural homology of SgTAM to ammonia lyases. Comparison of the structure of SgTAM to the l-tyrosine ammonia lyase from Rhodobacter sphaeroides provides insight into the structural basis for aminomutase activity. The results show that SgTAM has a closed active site well suited to retain ammonia and minimize the formation of lyase elimination products. The amino acid determinants for substrate recognition and catalysis can be predicted from the structure, setting the framework for detailed mechanistic investigations. PMID:17516659

  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. Global Analysis of Human Nonreceptor Tyrosine Kinase Specificity Using High-Density Peptide Microarrays

    PubMed Central

    2015-01-01

    Protein kinases phosphorylate substrates in the context of specific phosphorylation site sequence motifs. The knowledge of the specific sequences that are recognized by kinases is useful for mapping sites of phosphorylation in protein substrates and facilitates the generation of model substrates to monitor kinase activity. Here, we have adapted a positional scanning peptide library method to a microarray format that is suitable for the rapid determination of phosphorylation site motifs for tyrosine kinases. Peptide mixtures were immobilized on glass slides through a layer of a tyrosine-free Y33F mutant avidin to facilitate the analysis of phosphorylation by radiolabel assay. A microarray analysis provided qualitatively similar results in comparison with the solution phase peptide library “macroarray” method. However, much smaller quantities of kinases were required to phosphorylate peptides on the microarrays, which thus enabled a proteome scale analysis of kinase specificity. We illustrated this capability by microarray profiling more than 80% of the human nonreceptor tyrosine kinases (NRTKs). Microarray results were used to generate a universal NRTK substrate set of 11 consensus peptides for in vitro kinase assays. Several substrates were highly specific for their cognate kinases, which should facilitate their incorporation into kinase-selective biosensors. PMID:25164267

  20. 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. PMID:25449685

  1. 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…

  2. 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.

  3. D Modeling of Headstones of the 2ND and 3RD Century by Low Cost Photogrammetric Techniques

    NASA Astrophysics Data System (ADS)

    Landes, T.; Waton, M.-D.; Alby, E.; Gourvez, S.; Lopes, B.

    2013-07-01

    As a dozen headstones have been discovered during excavations in south Alsace, archaeologists stored them in the Regional Directorate of Cultural Affairs in Strasbourg. In order to complete the survey they are used to practice by hand on the steles, they asked the INSA Strasbourg to reconstruct at least the 7 figured sandstones in 3D. The high accuracy required by the archaeologists can be reached by an expensive technique using laserscanning system. Aim of the current work is to look for an alternative method and (if appropriate) low cost software allowing to provide a similar quality and a sufficient level of details. The 3D reconstruction of the headstones based exclusively on multiple images processing is presented. The step of point cloud generation is detailed because it determines the final product quality. Therefore, an assessment of the produced point cloud has been performed through comparison to a reference point cloud obtained by laser scanning technique. The steps leading to the photo-realistic textured 3D models of the headstones are presented and the software used for that are evaluated. The final product respects the accuracy requirement of 1 mm desired by the archaeologists.

  4. International Conference on Small and Special Electrical Machines, 2nd, London, England, September 22-24, 1981, Proceedings

    NASA Astrophysics Data System (ADS)

    Papers are presented on recent research concerning small and special electrical machines, including machine selection and environmental aspects; induction motors; stepping motors and drives; actuators, torque motors, and couplers; hysteresis and reluctance motors; synchronous motors and generators (including permanent magnet); control schemes and servo machines; and dc motors (including permanent magnet and brushless). Topics examined include the reliability of small ironless rotor dc motors, a new form of induction motor for fan drives, a study of the components of interbar voltage and magnetic field at the surface of small skewed diecast aluminum rotors, the microprocessor control of a step motor with various inertia loads, the synchronization of reluctance motor without pole-slipping, and the normal force in linear stepping motors. Also discussed are a direct simulation method using magnetic equivalent circuits for converter-fed reluctance machines, the synchronous performance of a single-phase machine with induced excitation, the application of design and analysis in small machines for aircraft, the microprocessor control of an inverter-driven reluctance motor, an electric main propulsion drive for a remotely piloted vehicle, and small dc motors with controllable electronic commutators. No individual items are abstracted in this volume

  5. pH regulation of an egg cortex tyrosine kinase.

    PubMed

    Jiang, W P; Veno, P A; Wood, R W; Peaucellier, G; Kinsey, W H

    1991-07-01

    Fertilization of the echinoderm egg is known to result in the phosphorylation, on tyrosine, of a high-molecular-weight cortical protein (HMWCP) localized in the egg cortex. Studies using various parthenogenic agents indicate that this phosphorylation event occurs in response to the alkaline shift in cytoplasmic pHi which normally occurs 1 to 2 min after fertilization. In the present study, the purified egg cell surface complex was used as in vitro system to determine whether a small alkaline shift in pH, such as occurs upon fertilization, could stimulate the activity of the egg cortex-associated tyrosine kinase toward endogenous protein substrates. The results demonstrated that the cell surface complex is highly enriched in a tyrosine kinase activity which accounts for the majority of the protein kinase activity in this preparation. The activity of this tyrosine kinase toward the HMWCP and other cortical proteins was highly dependent on pH over the range pH 6.8 to 7.3. This indicates that the fertilization-associated change in cytoplasmic pH would be sufficient to trigger increased tyrosine phosphorylation of the high-molecular-weight cortical protein in vivo. The regulation of tyrosine phosphorylation by small changes in pH represents a novel control mechanism in which a tyrosine protein kinase may act as a pH-sensitive transducer. PMID:2060713

  6. Tyrosine depletion lowers in vivo DOPA synthesis in ventral hippocampus.

    PubMed

    Bongiovanni, Rodolfo; Kyser, Abby N; Jaskiw, George E

    2012-12-01

    In vivo dopamine synthesis in the medial prefrontal cortex of the rat is sensitive to the availability of tyrosine. Whether other limbic cortical dopamine terminal regions are similarly tyrosine-dependent is not known. In this study we examined the effects of tyrosine depletion on dopamine synthesis and catecholamine levels in the ventral hippocampus. A tyrosine- and phenylalanine-free neutral amino acid mixture was used to lower brain tyrosine levels in rats undergoing in vivo microdialysis. In one group, NSD-1015 was included in perfusate to permit measurement of DOPA levels. In a second group, NSD-1015 was not included in perfusate so that catecholamine levels could be assayed. Tyrosine depletion significantly lowered DOPA levels in the NSD-1015 treated group and lowered DOPAC but not dopamine or noradrenaline levels in the group not exposed to NSD-1015. We conclude that while catecholamine synthesis in the ventral hippocampus declines when tyrosine availability is lowered, under basal conditions, compensatory mechanisms are able to maintain stable extracellular catecholamine levels. PMID:23022716

  7. 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.

  8. Genetic alterations of protein tyrosine phosphatases in human cancers

    PubMed Central

    Zhao, Shuliang; Sedwick, David; Wang, Zhenghe

    2014-01-01

    Protein tyrosine phosphatases (PTPs) are enzymes that remove phosphate from tyrosine residues in proteins. Recent whole-exome sequencing of human cancer genomes reveals that many PTPs are frequently mutated in a variety of cancers. Among these mutated PTPs, protein tyrosine phosphatase T (PTPRT) appears to be the most frequently mutated PTP in human cancers. Beside PTPN11 which functions as an oncogene in leukemia, genetic and functional studies indicate that most of mutant PTPs are tumor suppressor genes. Identification of the substrates and corresponding kinases of the mutant PTPs may provide novel therapeutic targets for cancers harboring these mutant PTPs. PMID:25263441

  9. 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.

  10. Excellence and evidence in staffing: a data-driven model for excellence in staffing (2nd edition).

    PubMed

    Baggett, Margarita; Batcheller, Joyce; Blouin, Ann Scott; Behrens, Elizabeth; Bradley, Carol; Brown, Mary J; Brown, Diane Storer; Bolton, Linda Burnes; Borromeo, Annabelle R; Burtson, Paige; Caramanica, Laura; Caspers, Barbara A; Chow, Marilyn; Christopher, Mary Ann; Clarke, Sean P; Delucas, Christine; Dent, Robert L; Disser, Tony; Eliopoulos, Charlotte; Everett, Linda Q; Garcia, Amy; Glassman, Kimberly; Goodwin, Susan; Haagenson, Deb; Harper, Ellen; Harris, Kathy; Hoying, Cheryl L; Hughes-Rease, Marsha; Kelly, Lesly; Kiger, Anna J; Kobs-Abbott, Ann; Krueger, Janelle; Larson, Jackie; March, Connie; Martin, Deborah Maust; Mazyck, Donna; Meenan, Penny; McGaffigan, Patricia; Myers, Karen K; Nell, Kate; Newcomer, Britta; Cathy, Rick; O'Rourke, Maria; Rosa, Billy; Rose, Robert; Rudisill, Pamela; Sanford, Kathy; Simpson, Roy L; Snowden, Tami; Strickland, Bob; Strohecker, Sharon; Weems, Roger B; Welton, John; Weston, Marla; Valentine, Nancy M; Vento, Laura; Yendro, Susan

    2014-01-01

    The Patient Protection and Affordable Care Act (PPACA, 2010) and the Institute of Medicine's (IOM, 2011) Future of Nursing report have prompted changes in the U.S. health care system. This has also stimulated a new direction of thinking for the profession of nursing. New payment and priority structures, where value is placed ahead of volume in care, will start to define our health system in new and unknown ways for years. One thing we all know for sure: we cannot afford the same inefficient models and systems of care of yesterday any longer. The Data-Driven Model for Excellence in Staffing was created as the organizing framework to lead the development of best practices for nurse staffing across the continuum through research and innovation. Regardless of the setting, nurses must integrate multiple concepts with the value of professional nursing to create new care and staffing models. Traditional models demonstrate that nurses are a commodity. If the profession is to make any significant changes in nurse staffing, it is through the articulation of the value of our professional practice within the overall health care environment. This position paper is organized around the concepts from the Data-Driven Model for Excellence in Staffing. The main concepts are: Core Concept 1: Users and Patients of Health Care, Core Concept 2: Providers of Health Care, Core Concept 3: Environment of Care, Core Concept 4: Delivery of Care, Core Concept 5: Quality, Safety, and Outcomes of Care. This position paper provides a comprehensive view of those concepts and components, why those concepts and components are important in this new era of nurse staffing, and a 3-year challenge that will push the nursing profession forward in all settings across the care continuum. There are decades of research supporting various changes to nurse staffing. Yet little has been done to move that research into practice and operations. While the primary goal of this position paper is to generate research

  11. Studying N-linked glycosylation of receptor tyrosine kinases.

    PubMed

    Itkonen, Harri M; Mills, Ian G

    2015-01-01

    Metabolic alterations have been identified as a frequent event in cancer. This is often associated with increased flux through glycolysis, and also a secondary pathway to glycolysis, hexosamine biosynthetic pathway (HBP). HBP provides substrate for N-linked glycosylation, which occurs in the endoplasmic reticulum and the Golgi apparatus. N-linked glycosylation supports protein folding and correct sorting of proteins to plasma membrane and secretion. This process generates complex glycoforms, which can be recognized by other proteins and glycosylation of receptor tyrosine kinases (RTK) can also regulate their plasma-membrane retention time. Of special interest for experimental biologists, plants produce proteins, termed lectins, which bind with high specificity to glyco-conjugates. For the purposes of molecular biology, plant lectins can be conjugated to different moieties, such as agarose beads, which enable precipitation of specifically glycosylated proteins. In this chapter, we describe in detail how to perform pull-down experiments with commercially available lectins to identify changes in the glycosylation of RTKs. PMID:25319893

  12. 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. PMID:26096795

  13. Redox and zinc signalling pathways converging on protein tyrosine phosphatases.

    PubMed

    Bellomo, Elisa; Hogstrand, Christer; Maret, Wolfgang

    2014-10-01

    Zinc ions, though redox-inert, have either pro-antioxidant or pro-oxidant functions at critical junctures in redox metabolism and redox signalling. They are released from cells and in cells, e.g. from metallothionein, a protein that transduces redox signals into zinc signals (1). The released zinc ions inhibit enzymes such as protein tyrosine phosphatases (PTPs), key regulatory enzymes of cellular phosphorylation signalling. The Ki(Zn) value for inhibition of receptor PTPB is 21pM (2). The binding is about as tight as the binding of zinc to zinc metalloenzymes and suggests tonic zinc inhibition. PTP1-B (PTPN1), an enzyme regulating the insulin and leptin receptors and involved in cancer and diabetes pathobiochemistry, has a Ki(Zn) value of about 5nM (3). Zinc ions bind to the enzyme in the closed conformation when additional metal-binding ligands are brought into the vicinity of the active site. In contrast, redox reactions target cysteines in the active sites of PTPs in the open conformation. This work provides a molecular basis how hydrogen peroxide and free zinc ions generated by growth factor signalling stimulate phosphorylation signalling differentially. (Supported by the Biotechnology and Biological Sciences Research Council UK, grant BB/K001442/1.). PMID:26461422

  14. Mutation of a Cuticle Protein Gene, BmCPG10, Is Responsible for Silkworm Non-Moulting in the 2nd Instar Mutant

    PubMed Central

    Zhao, Qiaoling; Kang, Lequn; Xia, Dingguo; Qiu, Zhiyong; Tang, Shunming; Li, Muwang; Shen, Xingjia; Zhang, Guozheng

    2016-01-01

    In the silkworm, metamorphosis and moulting are regulated by ecdysone hormone and juvenile hormone. The subject in the present study is a silkworm mutant that does not moult in the 2nd instar (nm2). Genetic analysis indicated that the nm2 mutation is controlled by a recessive gene and is homozygous lethal. Based on positional cloning, nm2 was located in a region approximately 275 kb on the 5th linkage group by eleven SSR polymorphism markers. In this specific range, according to the transcriptional expression of thirteen genes and cloning, the relative expression level of the BmCPG10 gene that encodes a cuticle protein was lower than the expression level of the wild-type gene. Moreover, this gene’s structure differs from that of the wild-type gene: there is a deletion of 217 bp in its open reading frame, which resulted in a change in the protein it encoded. The BmCPG10 mRNA was detectable throughout silkworm development from the egg to the moth. This mRNA was low in the pre-moulting and moulting stages of each instar but was high in the gluttonous stage and in newly exuviated larvae. The BmCPG10 mRNA showed high expression levels in the epidermis, head and trachea, while the expression levels were low in the midgut, Malpighian tubule, prothoracic gland, haemolymph and ventral nerve cord. The ecdysone titre was determined by ELISA, and the results demonstrated that the ecdysone titre of nm2 larvae was lower than that of the wild-type larvae. The nm2 mutant could be rescued by feeding 20-hydroxyecdysone, cholesterol and 7—dehydrocholesterol (7dC), but the rescued nm2 only developed to the 4th instar and subsequently died. The moulting time of silkworms could be delayed by BmCPG10 RNAi. Thus, we speculated that the mutation of BmCPG10 was responsible for the silkworm mutant that did not moult in the 2nd instar. PMID:27096617

  15. Mutation of a Cuticle Protein Gene, BmCPG10, Is Responsible for Silkworm Non-Moulting in the 2nd Instar Mutant.

    PubMed

    Wu, Fan; Wang, Pingyang; Zhao, Qiaoling; Kang, Lequn; Xia, Dingguo; Qiu, Zhiyong; Tang, Shunming; Li, Muwang; Shen, Xingjia; Zhang, Guozheng

    2016-01-01

    In the silkworm, metamorphosis and moulting are regulated by ecdysone hormone and juvenile hormone. The subject in the present study is a silkworm mutant that does not moult in the 2nd instar (nm2). Genetic analysis indicated that the nm2 mutation is controlled by a recessive gene and is homozygous lethal. Based on positional cloning, nm2 was located in a region approximately 275 kb on the 5th linkage group by eleven SSR polymorphism markers. In this specific range, according to the transcriptional expression of thirteen genes and cloning, the relative expression level of the BmCPG10 gene that encodes a cuticle protein was lower than the expression level of the wild-type gene. Moreover, this gene's structure differs from that of the wild-type gene: there is a deletion of 217 bp in its open reading frame, which resulted in a change in the protein it encoded. The BmCPG10 mRNA was detectable throughout silkworm development from the egg to the moth. This mRNA was low in the pre-moulting and moulting stages of each instar but was high in the gluttonous stage and in newly exuviated larvae. The BmCPG10 mRNA showed high expression levels in the epidermis, head and trachea, while the expression levels were low in the midgut, Malpighian tubule, prothoracic gland, haemolymph and ventral nerve cord. The ecdysone titre was determined by ELISA, and the results demonstrated that the ecdysone titre of nm2 larvae was lower than that of the wild-type larvae. The nm2 mutant could be rescued by feeding 20-hydroxyecdysone, cholesterol and 7-dehydrocholesterol (7dC), but the rescued nm2 only developed to the 4th instar and subsequently died. The moulting time of silkworms could be delayed by BmCPG10 RNAi. Thus, we speculated that the mutation of BmCPG10 was responsible for the silkworm mutant that did not moult in the 2nd instar. PMID:27096617

  16. Development of China Hydrogeology Exploring Techniques in 30 Years --Comparison of Handbook of Hydrogeology of 1st and 2nd Edition

    NASA Astrophysics Data System (ADS)

    Tong, Y.

    2013-12-01

    Handbook of Hydrogeology (2nd edition) is supported by one program from China Geological Survey (CGS): Research of Technical Methods of Hydrogeological Survey and Revision of Handbook of Hydrogeology. It is a reference book for those who are engaged in hydrogeological survey and research in China and covers fundamental principles, theories, survey and exploring techniques, and traditional experiences and achievements in hydrogeology. By comparing the 1st (1978) and 2nd (2012) edition of Handbook of Hydrogeology (in Chinese), this paper analyses the development of China hydrogeological survey and exploring techniques in last 30 years, especially the great change and progress in survey techniques of hydro-remote sensing and hydro-geophysical prospecting. In the first edition of Handbook of Hydrogeology, hydro-remote sensing was only mentioned as an interpretation of aerial pictures in a hydrogeological way, but had not yet formed an independent system and discipline. In the second edition, hydro-remote sensing is an important and independent chapter as one of the hydrogeological techniques. In it, various survey techniques of hydro-remote sensing and types and features of remote sensing data are classified. General systems of interpretation marks of remote sensing images are established, including marks of landform and Quaternary sediment, bedrock, structure types, water yield property, environmental elements of hydrogeology, aquifer group and so on. Systematic workflow is constructed, esp. in remote sensing images mapping and interpreting techniques. GPS and GIS are integrated into remote sensing. Remote sensing exploring instruments and interpreting softwares are also introduced and classified. Although hydro-geophysical prospecting, in the first edition of Handbook of Hydrogeology, was one independent chapter, there were only 10 exploring techniques. Equipments and instruments were simple and lagged in comparison to those in the second edition. The precision and

  17. Tyrosine hydroxylase deficiency with severe clinical course.

    PubMed

    Zafeiriou, D I; Willemsen, M A; Verbeek, M M; Vargiami, E; Ververi, A; Wevers, R

    2009-05-01

    Tyrosine hydroxylase (TH) deficiency is a rare autosomal recessive disorder mapped to chromosome 11p15.5. Its clinical expression varies with presentations as dopa-responsive dystonia (recessive Segawa's disease), dopa-responsive infantile parkinsonism, dopa-responsive spastic paraplegia, progressive infantile encephalopathy or dopa-non-responsive dystonia. We describe a 7-year-old boy with progressive infantile encephalopathy and non-responsiveness to dopamine. The patient demonstrated generalized hypotonia, pyramidal tract dysfunction and temperature instability after the second month of life. Dystonia, tremor and oculogyric crises complicated the clinical picture during the following months. Neurotransmitter analysis in CSF disclosed almost undetectable levels of HVA and MHPG, whereas serum prolactin was profoundly increased. Subsequent molecular analysis revealed homozygosity for a missense mutation (c.707T>C) in the TH gene. l-Dopa therapy in both high and low doses resulted in massive hyperkinesias, while substitution with selegiline exerted only a mild beneficial effect. Today, at the age of 7 years, the patient demonstrates severe developmental retardation with marked trunkal hypotonia, hypokinesia and occasionally dystonic and/or hyperkinetic crises. He is the third Greek patient with TH deficiency to be reported. Since all three patients carry the same pathogenetic mutation, a founder effect is suspected. PMID:19282209

  18. 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

  19. Structure of tyrosine aminotransferase from Leishmania infantum

    PubMed Central

    Moreno, M. A.; Abramov, A.; Abendroth, J.; Alonso, A.; Zhang, S.; Alcolea, P. J.; Edwards, T.; Lorimer, D.; Myler, P. J.; Larraga, V.

    2014-01-01

    The trypanosomatid parasite Leishmania infantum is the causative agent of visceral leishmaniasis (VL), which is usually fatal unless treated. VL has an incidence of 0.5 million cases every year and is an important opportunistic co-infection in HIV/AIDS. Tyrosine aminotransferase (TAT) has an important role in the metabolism of trypanosomatids, catalyzing the first step in the degradation pathway of aromatic amino acids, which are ultimately converted into their corresponding l-2-oxoacids. Unlike the enzyme in Trypanosoma cruzi and mammals, L. infantum TAT (LiTAT) is not able to transaminate ketoglutarate. Here, the structure of LiTAT at 2.35 Å resolution is reported, and it is confirmed that the presence of two Leishmania-specific residues (Gln55 and Asn58) explains, at least in part, this specific reactivity. The difference in substrate specificity between leishmanial and mammalian TAT and the importance of this enzyme in parasite metabolism suggest that it may be a useful target in the development of new drugs against leishmaniasis. PMID:24817714

  20. 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.

  1. Enantiomeric Interactions between Liquid Crystals and Organized Monolayers of Tyrosine-Containing Dipeptides

    PubMed Central

    Bai, Yiqun; Abbott, Nicholas L.

    2011-01-01

    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 (5CB) and TL205 (a mixture of mesogens containing cyclohexane-fluorinated biphenyls and fluorinated terphenyls)) on monolayers of either 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 dominate 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. PMID:22091988

  2. Synthesis, structural characterization, and electrical properties of new oxygen-deficient tetragonal tungsten bronzes Ba2NdTi(2+x)Nb(3-x)O(15-x/2).

    PubMed

    Prades, Marta; Masó, Nahum; Beltrán, Héctor; Cordoncillo, Eloisa; West, Anthony R

    2013-02-18

    Oxygen-deficient tetragonal tungsten bronzes ceramics with general formula Ba(2)NdTi(2+x)Nb(3-x)O(15-x/2) (0 ≤ x ≤ 1) have been prepared by low temperature solvothermal synthesis with final firing of ceramics at 1100-1300 °C in air. Rietveld refinement of X-ray powder diffraction (XRD) and neutron powder diffraction (ND) data at room temperature of Ba(2)NdTi(3)Nb(2)O(14.5) shows that Ba and Nd are ordered on the 15-coordinate and 12-coordinate sites, respectively, Ti and Nb are disordered nonrandomly over the two octahedral sites, and oxygen vacancies locate preferentially in the coordination sphere of Nd and Ti/Nb(2) atoms. Variable frequency impedance measurements show that samples are poor electronic conductors with activation energies ∼0.8-1.7 eV, conductivities ∼1 × 10(-5) S cm(-1) at ∼725 °C and with some evidence of oxide ion conduction at high x values. Composition dependence of the dielectric properties shows a transition from classic ferroelectric behavior with Ba(2)NdTi(2)Nb(3)O(15) to a relaxor-like behavior with Ba(2)NdTi(3)Nb(2)O(14.5). At intermediate compositions, both a first-order phase transition and relaxor-like behavior are observed. PMID:23360368

  3. Creating a Culture of Human Rights, Democracy and Peace in the New Millennium. Proceedings of the International Conference on Children's Rights Education (2nd, Victoria, British Columbia, August 18-22, 2001).

    ERIC Educational Resources Information Center

    Blanchet-Cohen, Natasha; Hart, Stuart; Cook, Philip

    The 2nd International Conference on Children's Rights in Education hosted approximately 150 child-centered international policy makers, who discussed the implications and implementation of children's rights to guide educational policy, research, and practice. This report presents an annotated agenda of the conference proceedings and, based on the…

  4. 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 and…

  5. [Side effect management of tyrosine kinase inhibitors in urology : Hypertension].

    PubMed

    Sikic, D; Meidenbauer, N; Lieb, V; Keck, B

    2016-07-01

    Tyrosine kinase inhibitors like sunitinib, sorafenib, pazopanib or axintinib are regarded the standard of care in the systemic therapy of metastatic renal cell carcinoma. However, the many side effects associated with this therapy pose challenges for the treating physician and the patient. This review offers an overview of the classification and the treatment of hypertension, which is one of the major side effects induced by all tyrosine kinase inhibitors, in order to improve treatment efficacy and patient compliance. PMID:27146871

  6. 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.

  7. 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.

  8. 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. PMID:19280672

  9. Data and performances evaluation of the SPIDIA-DNA Pan-European External Quality Assessment: 2nd SPIDIA-DNA laboratory report

    PubMed Central

    Malentacchi, Francesca; Pizzamiglio, Sara; Ibrahim-Gawel, Hady; Pazzagli, Mario; Verderio, Paolo; Ciniselli, Chiara Maura; Wyrich, Ralf; Gelmini, Stefania

    2016-01-01

    Within the EU-SPIDIA project (www.spidia.eu), the quality parameters of blood genomic DNA were defined [SPIDIA-DNA: an External Quality Assessment for the pre-analytical phase of blood samples used for DNA-based analyses – [1]; Influence of pre-analytical procedures on genomic DNA integrity in blood samples: the SPIDIA experience – [2]; Combining qualitative and quantitative imaging evaluation for the assessment of genomic DNA integrity: the SPIDIA experience – [3]. DNA quality parameters were used to evaluate the laboratory performance within an External Quality Assessment (EQA) [Second SPIDIA-DNA External Quality Assessment (EQA): Influence of pre-analytical phase of blood samples on genomic DNA quality – [4]. These parameters included DNA purity and yield by UV spectrophotometric measurements, the presence of PCR interferences by Kineret software and genomic DNA integrity analysis by Pulsed Field Gel Electrophoresis. Here we present the specific laboratory report of the 2nd SPIDIA-DNA EQA as an example of data and performances evaluation. PMID:26949730

  10. 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

  11. 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

  12. Giant dielectric permittivity caused by carrier hopping in a layered cuprate Bi 2Ba 2Nd 1.6Ce 0.4Cu 2O 10+ δ

    NASA Astrophysics Data System (ADS)

    Xu, Xiaofeng; Cao, Guanghan; Jiao, Zhengkuan

    2004-12-01

    The ceramic sample of a layered cuprate Bi 2Ba 2Nd 1.6Ce 0.4Cu 2O 10+ δ, so-called Ba-based Bi-2222 compound was studied by the measurement of the temperature (80-300 K) and the frequency (20-10 6 Hz) dependence of the complex dielectric permittivity. The dielectric constant was measured as high as ˜1000 at 1 kHz and 300 K with relatively low dissipation factor. However, it decreases systematically with decreasing temperature or with increasing frequency due to the dipolar relaxation process. This thermally activated relaxation process plays a dominant role for the low frequency dielectric response. Furthermore, the frequency-dependent ac conductivity was found to obey the power law σ=Aω. The results were interpreted in terms of Pike's model of hopping transport of localized charge carriers which yields explicitly the ω behavior and the temperature dependence of s. And we calculated the ionization energy of localized carriers W=0.35 eV for the present sample.

  13. 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

  14. 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. PMID:22364877

  15. Influence of long-term altered gravity on the swimming performance of developing cichlid fish: including results from the 2nd German Spacelab Mission D-2

    NASA Astrophysics Data System (ADS)

    Rahmann, H.; Hilbig, R.; Flemming, J.; Slenzka, K.

    This study presents qualitative and quantitative data concerning gravity-dependent changes in the swimming behaviour of developing cichlid fish larvae (Oreochromis mossambicus) after a 9 resp. 10 days exposure to increased acceleration (centrifuge experiments), to reduced gravity (fast-rotating clinostat), changed accelerations (parabolic air craft flights) and to near weightlessness (2nd German Spacelab Mission D-2). Changes of gravity initially cause disturbances of the swimming performance of the fish larvae. With prolonged stay in orbit a step by step normalisation of the swimming behaviour took place in the fish. After return to 1g earth conditions no somersaulting or looping could be detected concerning the fish, but still slow and disorientated movements as compared to controls occurred. The fish larvae adapted to earth gravity within 3-5 days. Fish seem to be in a distinct early developmental stages extreme sensitive and adaptable to altered gravity. However, elder fish either do not react or show compensatory behaviour e.g. escape reactions.

  16. Pharmacophore modeling for protein tyrosine phosphatase 1B inhibitors.

    PubMed

    Bharatham, Kavitha; Bharatham, Nagakumar; Lee, Keun Woo

    2007-05-01

    A three dimensional chemical feature based pharmacophore model was developed for the inhibitors of protein tyrosine phosphatase 1B (PTP1B) using the CATALYST software, which would provide useful knowledge for performing virtual screening to identify new inhibitors targeted toward type II diabetes and obesity. A dataset of 27 inhibitors, with diverse structural properties, and activities ranging from 0.026 to 600 microM, was selected as a training set. Hypol, the most reliable quantitative four featured pharmacophore hypothesis, was generated from a training set composed of compounds with two H-bond acceptors, one hydrophobic aromatic and one ring aromatic features. It has a correlation coefficient, RMSD and cost difference (null cost-total cost) of 0.946, 0.840 and 65.731, respectively. The best hypothesis (Hypol) was validated using four different methods. Firstly, a cross validation was performed by randomizing the data using the Cat-Scramble technique. The results confirmed that the pharmacophore models generated from the training set were valid. Secondly, a test set of 281 molecules was scored, with a correlation of 0.882 obtained between the experimental and predicted activities. Hypol performed well in correctly discriminating the active and inactive molecules. Thirdly, the model was investigated by mapping on two PTP1B inhibitors identified by different pharmaceutical companies. The Hypol model correctly predicted these compounds as being highly active. Finally, docking simulations were performed on few compounds to substantiate the role of the pharmacophore features at the binding site of the protein by analyzing their binding conformations. These multiple validation approaches provided confidence in the utility of this pharmacophore model as a 3D query for virtual screening to retrieve new chemical entities showing potential as potent PTP1B inhibitors. PMID:17615669

  17. Advanced IRFPAs for next-generation sensors

    NASA Astrophysics Data System (ADS)

    Caulfield, John T.; Fletcher, Christopher L.; Graham, Roger W.; Patten, Elizabeth A.; Pham, Le T.; Pierce, Gregory; Scribner, Dean A.; Skele, Martins; Taylor, Scott M.; Trautfield, Walter C.

    2004-08-01

    Raytheon Vision Systems (RVS) has invented and demonstrated a new class of advanced focal plane arrays. These Advanced FPAs are sometimes called 3rd Generation or "Next Generation" FPAs because they have integrated onto the FPA the ability to sense multiple IR spectrums, have improved resolution and performance, and conduct image processing on the FPA ROIC. These next generation of FPAs are allowing more functionality and the detection of a more diverse set of data than previously possible with 2nd Gen FPAs. Examples and history of advanced next generation FPAs are reviewed including RVS"s Multispectral, Uncooled, Adaptive Sensors and other advanced sensors.

  18. Endogenous reactive oxygen species content and modulation of tyrosine phosphorylation during sperm capacitation.

    PubMed

    Donà, G; Fiore, C; Tibaldi, E; Frezzato, F; Andrisani, A; Ambrosini, G; Fiorentin, D; Armanini, D; Bordin, L; Clari, G

    2011-10-01

    Generation of controlled amounts of reactive oxygen species (ROS) and phosphorylation of protein tyrosine (Tyr) residues are two main cellular changes involved in sperm capacitation. This study examined the relationship between tyrosine-phosphorylation (Tyr-P) and endogenous ROS production during sperm capacitation, and correlated them with both sperm motility and functionality expressed as acrosome-reacted cells. Immediate ROS generation was observed to peak after a 45-min incubation, followed by a rapid decrease in ROS content and successive regeneration of the ROS peak in 3 h and later. These two peaks were directly correlated with both the Tyr-P process involving sperm heads and tails, and the acrosome reaction (69 ± 8% and 65 ± 4%, respectively). The period of low-ROS content resulted in low Tyr-P patterns, located exclusively in the cell midpiece, and drastic reduction in acrosome-reacted cells. Ascorbic acid addition inhibited both Tyr-P patterns and acrosome reactions, whereas NADPH induced high ROS generation, with Tyr-P patterns located only on sperm tails, and prevented the acrosome reaction. Sperm hyperactivation was insensitive to ROS content. This is an important parameter for evaluation of sperm capacitation, which is achieved only when both ROS generation reaches a peak and Tyr-P involves the sperm head. PMID:20738429

  19. Energy handbook, 2nd edition

    SciTech Connect

    Loftness, R.L.

    1984-01-01

    This handbook provides a compilation of data on world energy resources, utilization, and costs. The principle emphasis is on the U.S. in recent decades, but there is extensive information of the rest of the world and some data for not only recent centuries but also for the past millenium, while over 20 percent of the volume presents projections for the future. Tables, charts, and curves occupy about 90 percent of the page space while perhaps 10 percent is devoted to text that explains and qualifies the quantitative material.

  20. Diagnostic imaging, 2nd edition

    SciTech Connect

    Armstrong, P.; Wastie, M.L.

    1987-01-01

    This book discusses ultrasound radionuclide examinations, and computed tomography in an integrated, comprehensive account of conventional radiology. The authors describe the signs of each modality and how to apply this information in diagnosing diseases. A practical approach to the topic of radiology shows the reader how to use films to reach diagnoses and how to relate this field to the clinical problems that are of prime interest.

  1. 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.

  2. 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.

  3. Ocean Science, 2nd ed

    SciTech Connect

    Stowe, K.

    1983-01-01

    An introductory treatment of all of the major areas of oceanographic studies including geological, physical, chemical, and biological aspects, ocean-atmosphere interactions, marine geology, and marine resources. Presents clear, concise explanations of ocean behavior and its properties. Explains the history behind specific aspects of the ocean environment. Includes considerably expanded sections on estuaries and marine biology, and chapters on marine ecology. Contents-The Earth. Plate Tectonics. The Ocean Bottom. Sediment Materials. Sediment Processes and Distributions. Properties of Ocean Waves. Waves and Tides. Beaches. The Components of Seawater--Part 1. The Components of Seawater--Part 2. The Ocean and Our Climate. The Earth's Rotation and Atmospheric Circulation. Ocean Surface Currents. Deep Ocean Currents and Water Masses. Seas and Estuaries. Biological Productivity in The Oceans. The Spectrum of Marine Organisms. Marine Ecology. Distributions and Lifestyles of Marine Organisms. Ocean Food Resources. Ocean Energy and Mineral Resources.

  4. 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.

  5. Are Striatal Tyrosine Hydroxylase Interneurons Dopaminergic?

    PubMed Central

    Xenias, Harry S.; Ibáñez-Sandoval, Osvaldo; Koós, Tibor

    2015-01-01

    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. PMID:25904808

  6. 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

  7. Inhibition of human neutrophil responses by alpha-cyano-3,4-dihydroxythiocinnamamide; a protein-tyrosine kinase inhibitor.

    PubMed Central

    Dryden, P.; Duronio, V.; Martin, L.; Hudson, A. T.; Salari, H.

    1992-01-01

    1. Activation of neutrophils results in increased tyrosine phosphorylation of several proteins that may have important roles in receptor/effector coupling. In this study, the effect of a protein tyrosine kinase inhibitor on receptor-mediated neutrophil activation by platelet-activating factor (PAF), leukotriene, B4 (LTB4) and N-formylmethionylleucylphenylalanine (FMLP) is investigated. 2. alpha-Cyano-3,4-dihydroxythiocinnamamide dose-dependently inhibited intracellular calcium release and superoxide generation from human neutrophils activated by 1 microM LTB4, PAF, and FMLP. 3. In the presence of cytochalasin B, FMLP stimulated elastase release from neutrophils was also inhibited to unstimulated levels by 5 min pretreatment with alpha-cyano-3,4-dihydroxythiocinnamamide. 4. The inhibitory action of alpha-cyano-3,4-dihydroxythiocinnamamide was found to be at or upstream of phospholipase C activation, blocking both phosphatidylinositol hydrolysis and protein kinase C activation. alpha-Cyano-3,4-dihydroxythiocinnamamide did not affect agonist receptor binding sites or receptor affinity in neutrophils. 5. Immunoblot analysis demonstrated the tyrosine phosphorylation of proteins of 41, 56, 66, and 104 kDa in neutrophils treated with agonists. Treatment of neutrophils with alpha-cyano-3,4-dihydroxythiocinnamamide prior to stimulation with chemoattractants reduced tyrosine phosphorylation of the above phosphoproteins. 6. These results indicate that alpha-cyano-3,4-dihydroxythiocinnamamide might be a useful agent in characterizing the essential proteins and biochemical pathways that regulate neutrophil activation. PMID:1504749

  8. 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

  9. 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

  10. Improvement of Measurement Accuracy of Strain of Thin Film by CCD Camera with a Template Matching Method Using the 2ND-ORDER Polynomial Interpolation

    NASA Astrophysics Data System (ADS)

    Park, Jun-Hyub; Shin, Myung-Soo; Kang, Dong-Joong; Lim, Sung-Jo; Ha, Jong-Eun

    In this study, a system for non-contact in-situ measurement of strain during tensile test of thin films by using CCD camera with marking surface of specimen by black pen was implemented as a sensing device. To improve accuracy of measurement when CCD camera is used, this paper proposed a new method for measuring strain during tensile test of specimen with micrometer size. The size of pixel of CCD camera determines resolution of measurement, but the size of pixel can not satisfy the resolution required in tensile test of thin film because the extension of the specimen is very small during the tensile test. To increase resolution of measurement, the suggested method performs an accurate subpixel matching by applying 2nd order polynomial interpolation method to the conventional template matching. The algorithm was developed to calculate location of subpixel providing the best matching value by performing single dimensional polynomial interpolation from the results of pixel-based matching at a local region of image. The measurement resolution was less than 0.01 times of original pixel size. To verify the reliability of the system, the tensile test for the BeNi thin film was performed, which is widely used as a material in micro-probe tip. Tensile tests were performed and strains were measured using the proposed method and also the capacitance type displacement sensor for comparison. It is demonstrated that the new strain measurement system can effectively describe a behavior of materials after yield during the tensile test of the specimen at microscale with easy setup and better accuracy.

  11. 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. PMID:25765308

  12. 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

  13. Structural characterisation of tyrosine-nitrated peptides by ultraviolet and infrared matrix-assisted laser desorption/ionisation Fourier transform ion cyclotron resonance mass spectrometry.

    PubMed

    Petre, Brínduşa-Alina; Youhnovski, Nikolay; Lukkari, Juho; Weber, Reinhold; Przybylski, Michael

    2005-01-01

    Nitration of tyrosine residues in proteins may occur in cells upon oxidative stress and inflammation processes mediated through generation of reactive nitroxyl from peroxynitrite. Tyrosine nitration from oxidative pathways may generate cytotoxic species that cause protein dysfunction and pathogenesis. A number of protein nitrations in vivo have been reported and some specific Tyrosine nitration sites have been recently identified using mass spectrometric methods. High-resolution Fourier transform ion cyclotron resonance mass spectrometry (MALDI) FT-ICR-MS) is shown here to be a highly efficient method in the determination of protein nitrations. Following the identification of nitration of the catalytic site Tyr-430 residue of bovine prostacyclin synthase, we synthesised several model peptides containing both unmodified tyrosine and 3-nitro-tyrosine residues, using solid-phase peptide synthesis (SPPS). The structures of the nitrotyrosine peptides were characterised both by ESI- and by matrix-assisted laser desorption/ionisation (MALDI)-FT-ICR-MS, using a standard ultraviolet (UV) nitrogen nitrogen laser and a 2.97 microm Nd-YAG infrared laser. Using UV-MALDI-MS, 3-nitrotyrosyl-peptides were found to undergo extensive photochemical fragmentation at the nitrophenyl group, which may hamper or prevent the unequivocal identification of Tyr-nitrations in cellular proteins. In contrast, infrared-MALDI-FT-ICR-MS did not produce fragmentation of molecular ions of Tyr-nitrated peptides. PMID:16322657

  14. Enrichment and detection of tyrosine-nitrated proteins.

    PubMed

    Dekker, Frank; Abello, Nicolas; Wisastra, Rosalina; Bischoff, Rainer

    2012-08-01

    Nitrotyrosine is a post-translationally modified amino acid with distinctly different properties than tyrosine or any other of the genetically encoded amino acids. Detecting proteins containing nitrotyrosine is the first step towards a better understanding of the role of nitrotyrosine in health and disease. Moreover, quantifying the extent of nitrotyrosine and determining its location in a protein forms the basis for a better understanding of the effect of tyrosine nitration on biological function. Described in this unit is a method to detect tyrosine-nitrated proteins in tissue sections and on western blots after creating a fluorescent complex between aminotyrosine, salicylaldehyde, and Al(3+). In addition, an approach is detailed for labeling aminotyrosine with biotin to enrich peptides from complex samples. Both methods require reduction of nitrotyrosine to aminotyrosine, which can be achieved with sodium dithionite or hemin plus dithiothreitol. PMID:22851496

  15. Cysteine mutations cause defective tyrosine phosphorylation in MEGF10 myopathy

    PubMed Central

    Mitsuhashi, Satomi; Mitsuhashi, Hiroaki; Alexander, Matthew S; Sugimoto, Hiroyuki; Kang, Peter B

    2013-01-01

    Recessive mutations in MEGF10 are known to cause a congenital myopathy in humans. Two mutations in the extracellular EGF-like domains of MEGF10, C326R and C774R, were associated with decreased tyrosine phosphorylation of MEGF10 in vitro. Y1030 was identified to be the major tyrosine phosphorylation site in MEGF10 and is phosphorylated at least in part by c-Src. Overexpression of wild-type MEGF10 enhanced C2C12 myoblast proliferation, while overexpression of Y1030F mutated MEGF10 did not. We conclude that MEGF10-mediated signaling via tyrosine phosphorylation helps to regulate myoblast proliferation. Defects in this signaling pathway may contribute to the disease mechanism of MEGF10 myopathy. PMID:23954233

  16. 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. PMID:26492832

  17. Characterization of the PEST family protein tyrosine phosphatase BDP1.

    PubMed

    Kim, Y W; Wang, H; Sures, I; Lammers, R; Martell, K J; Ullrich, A

    1996-11-21

    Using a polymerase chain reaction (PCR) amplification strategy, we identified a novel protein tyrosine phosphatase (PTPase) designated Brain Derived Phosphatase (BDP1). The full length sequence encoded an open reading frame of 459 amino acids with no transmembrane domain and had a calculated molecular weight of 50 kDa. The predicted amino acid sequence contained a PEST motif and accordingly, BDP1 shared the greatest homology with members of the PTP-PEST family. When transiently expressed in 293 cells BDP1 hydrolyzed p-Nitrophenylphosphate, confirming it as a functional protein tyrosine phosphatase. Northern blot analysis indicated that BDP1 was expressed not only in brain, but also in colon and several different tumor-derived cell lines. Furthermore, BDP1 was found to differentially dephosphorylate autophosphorylated tyrosine kinases which are known to be overexpressed in tumor tissues. PMID:8950995

  18. L-tyrosine administration increases acetylcholinesterase activity in rats.

    PubMed

    Ferreira, Gabriela K; Carvalho-Silva, Milena; Gonçalves, Cinara L; Vieira, Júlia S; Scaini, Giselli; Ghedim, Fernando V; Deroza, Pedro F; Zugno, Alexandra I; Pereira, Talita C B; Oliveira, Giovanna M T; Kist, Luiza W; Bogo, Maurício R; Schuck, Patrícia F; Ferreira, Gustavo C; Streck, Emilio L

    2012-12-01

    Tyrosinemia is a rare genetic disease caused by mutations on genes that codify enzymes responsible for tyrosine metabolism. Considering that tyrosinemics patients usually present symptoms associated with central nervous system alterations that ranges from slight decreases in intelligence to severe mental retardation, we decided to investigate whether acute and chronic administration of L-tyrosine in rats would affect acetylcholinesterase mRNA expression and enzymatic activity during their development. In our acute protocol, Wistar rats (10 and 30 days old) were killed one hour after a single intraperitoneal L-tyrosine injection (500 mg/kg) or saline. Chronic administration consisted of L-tyrosine (500 mg/kg) or saline injections 12 h apart for 24 days in Wistar rats (7 days old) and rats were killed 12 h after last injection. Acetylcholinesterase activity was measured by Ellman's method and acetylcholinesterase expression was carried out by a semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR) assay. We observed that acute (10 and 30 days old rats) and chronic L-tyrosine administration increased acetylcholinesterase activity in serum and all tested brain areas (hippocampus, striatum and cerebral cortex) when compared to control group. Moreover, there was a significant decrease in mRNA levels of acetylcholinesterase in hippocampus was observed after acute protocol (10 and 30 days old rats) and in striatum after chronic protocol. In case these alterations also occur in the brain of the patients, our results may explain, at least in part, the neurological sequelae associated with high plasma concentrations of tyrosine seen in patients affected by tyrosinemia type II. PMID:23046746

  19. Modular engineering of L-tyrosine production in Escherichia coli.

    PubMed

    Juminaga, Darmawi; Baidoo, Edward E K; Redding-Johanson, Alyssa M; Batth, Tanveer S; Burd, Helcio; Mukhopadhyay, Aindrila; Petzold, Christopher J; Keasling, Jay D

    2012-01-01

    Efficient biosynthesis of L-tyrosine from glucose is necessary to make biological production economically viable. To this end, we designed and constructed a modular biosynthetic pathway for L-tyrosine production in E. coli MG1655 by encoding the enzymes for converting erythrose-4-phosphate (E4P) and phosphoenolpyruvate (PEP) to L-tyrosine on two plasmids. Rational engineering to improve L-tyrosine production and to identify pathway bottlenecks was directed by targeted proteomics and metabolite profiling. The bottlenecks in the pathway were relieved by modifications in plasmid copy numbers, promoter strength, gene codon usage, and the placement of genes in operons. One major bottleneck was due to the bifunctional activities of quinate/shikimate dehydrogenase (YdiB), which caused accumulation of the intermediates dehydroquinate (DHQ) and dehydroshikimate (DHS) and the side product quinate; this bottleneck was relieved by replacing YdiB with its paralog AroE, resulting in the production of over 700 mg/liter of shikimate. Another bottleneck in shikimate production, due to low expression of the dehydroquinate synthase (AroB), was alleviated by optimizing the first 15 codons of the gene. Shikimate conversion to L-tyrosine was improved by replacing the shikimate kinase AroK with its isozyme, AroL, which effectively consumed all intermediates formed in the first half of the pathway. Guided by the protein and metabolite measurements, the best producer, consisting of two medium-copy-number, dual-operon plasmids, was optimized to produce >2 g/liter L-tyrosine at 80% of the theoretical yield. This work demonstrates the utility of targeted proteomics and metabolite profiling in pathway construction and optimization, which should be applicable to other metabolic pathways. PMID:22020510

  20. 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.

  1. Biosynthesis of brominated tyrosine metabolites by Aplysina fistularis.

    PubMed

    Carney, J R; Rinehart, K L

    1995-07-01

    The biosynthesis of brominated tyrosine metabolites by the marine sponge Aplysina fistularis was investigated. [U-14C]-L-Tyrosine, [U-14C]-L-3-bromotyrosine, and [U-14C]-L-3,5-dibromotyrosine were incorporated into both dibromoverongiaquinol [1] and aeroplysinin-1 [2], and [methyl-14C]methionine was specifically incorporated into the O-methyl group group of 2. [Methyl-14C]-L-O-methyltyrosine, [methyl-14C]-L-3,5-dibromo-O-methyltyrosine, and several putative nitrile precursors were not incorporated into 1 or 2. PMID:7561906

  2. Growth and characterisation of ?-tyrosine-doped TGS crystals

    NASA Astrophysics Data System (ADS)

    Meera, K.; Aravazhi, S.; Santhana Raghavan, P.; Ramasamy, P.

    2000-04-01

    Single crystals of L-tyrosine-doped triglycine sulphate (LTTGS) were grown by low-temperature solution method. Morphological changes were observed on the grown crystals. Crystalline quality and cell parameter values were determined using rocking curve and powder X-ray diffraction analysis. The presence of L-tyrosine in LTTGS was estimated qualitatively by FTIR analysis. Microhardness studies carried out using Leitz Weitzler hardness tester at room temperature showed a decrease due to doping. Domain studies on b-cut plates were observed using scanning electron microscopy.

  3. Cell-free expression of functional receptor tyrosine kinases

    PubMed Central

    He, Wei; Scharadin, Tiffany M.; Saldana, Matthew; Gellner, Candice; Hoang-Phou, Steven; Takanishi, Christina; Hura, Gregory L.; Tainer, John A; Carraway III, Kermit L.; Henderson, Paul T.; Coleman, Matthew A.

    2015-01-01

    Receptor tyrosine kinases (RTKs) play critical roles in physiological and pathological processes, and are important anticancer drug targets. In vitro mechanistic and drug discovery studies of full-length RTKs require protein that is both fully functional and free from contaminating proteins. Here we describe a rapid cell-free and detergent-free co-translation method for producing full-length and functional ERBB2 and EGFR receptor tyrosine kinases supported by water-soluble apolipoprotein A-I based nanolipoprotein particles. PMID:26274523

  4. 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. PMID:20071031

  5. Gender Disparities in the Presentation, Management and Outcomes of Acute Coronary Syndrome Patients: Data from the 2nd Gulf Registry of Acute Coronary Events (Gulf RACE-2)

    PubMed Central

    Shehab, Abdulla; Al-Dabbagh, Bayan; AlHabib, Khalid F.; Alsheikh-Ali, Alawi A.; Almahmeed, Wael; Sulaiman, Kadhim; Al-Motarreb, Ahmed; Nagelkerke, Nicolaas; Suwaidi, Jassim Al; Hersi, Ahmad; Faleh, Hussam Al; Asaad, Nidal; Saif, Shukri Al; Amin, Haitham

    2013-01-01

    Background Gender-related differences in mortality of acute coronary syndrome (ACS) have been reported. The extent and causes of these differences in the Middle-East are poorly understood. We studied to what extent difference in outcome, specifically 1-year mortality are attributable to demographic, baseline clinical differences at presentation, and management differences between female and male patients. Methodology/Principal Findings Baseline characteristics, treatment patterns, and 1-year mortality of 7390 ACS patients in 65 hospitals in 6 Arabian Gulf countries were evaluated during 2008–2009, as part of the 2nd Gulf Registry of Acute Coronary Events (Gulf RACE-2). Women were older (61.3±11.8 vs. 55.6±12.4; P<0.001), more overweight (BMI: 28.1±6.6 vs. 26.7±5.1; P<0.001), and more likely to have a history of hypertension, hyperlipidemia or diabetes. Fewer women than men received angiotensin-converting enzyme inhibitors (ACE), aspirin, clopidogrel, beta blockers or statins at discharge. They also underwent fewer invasive procedures including angiography (27.0% vs. 34.0%; P<0.001), percutaneous coronary intervention (PCI) (10.5% vs. 15.6%; P<0.001) and reperfusion therapy (6.9% vs. 20.2%; P<0.001) than men. Women were at higher unadjusted risk for in-hospital death (6.8% vs. 4.0%, P<0.001) and heart failure (HF) (18% vs. 11.8%, P<0.001). Both 1-month and 1-year mortality rates were higher in women than men (11% vs. 7.4% and 17.3% vs. 11.4%, respectively, P<0.001). Both baseline and management differences contributed to a worse outcome in women. Together these variables explained almost all mortality disparities. Conclusions/Significance Differences between genders in mortality appeared to be largely explained by differences in prognostic variables and management patterns. However, the origin of the latter differences need further study. PMID:23405162

  6. An Intensive Post Event Campaign (IPEC) on the extreme flash flood which affected the Starzel river (Germany) on the 2nd of June 2008

    NASA Astrophysics Data System (ADS)

    Gaume, E.

    2009-04-01

    On the 2nd of June 2008 in the evening, the Zollernabkreis region, located 50 kilometers South from Stuttgart (Germany), was affected by extreme thunderstorms which induced large flash floods. The most severely affected area appeared to be the upper Starzel river catchment (130 km2) where the extraordinary flood caused large damages in two towns (Hechingen and Jungingen) and killed 3 people. The data collected immediately after the flood event are impressive: 75 mm of rainfall accumulated within 1 hour near Hechingen and up to 240 mm within 55 minutes measured on a private gauge in the town of Jungingen. These first elements led to the organization of an intensive post event campaign (IPEC) with two objectives: 1) to validate and complement the existing data on rainfall and runoff, 2) to analyze the dominant rainfall-runoff processes during such an extreme event. The field campaign took place in November 2008 and involved 11 scientists from various European research institutions contributing to the European research project Hydrate as well as hydrologists from the regional administration. 36 river cross-sections were surveyed in the affected watershed to map the discharges; detailed accounts of the flood in Jungingen as well as films and pictures were collected to establish the timing of the flood; and the available radar, rainfall and stream gauge measurements were verified. The main outcomes of this IPEC are the following: • The discharge mapping revealed very high spatial heterogeneities. The flood volumes were essentially produced on a very limited part of the catchment area: a 5 km2 area upstream Jungingen and about 10 km2 area for the whole Starzel watershed. • In this area, very high unit discharges were estimated - between 12 and 15 m3/s/km2. These values imply surprisingly low runoff rates (about 20%) according to the estimated rainfall intensities - which were validated during the field survey. • Such localized intense events do not appear to be

  7. 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

  8. ZDHHC3 Tyrosine Phosphorylation Regulates Neural Cell Adhesion Molecule Palmitoylation.

    PubMed

    Lievens, Patricia Marie-Jeanne; Kuznetsova, Tatiana; Kochlamazashvili, Gaga; Cesca, Fabrizia; Gorinski, Natalya; Galil, Dalia Abdel; Cherkas, Volodimir; Ronkina, Natalia; Lafera, Juri; Gaestel, Matthias; Ponimaskin, Evgeni; Dityatev, Alexander

    2016-09-01

    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

  9. Purification of a specific reversible tyrosine-O-phosphate phosphatase.

    PubMed Central

    Fukami, Y; Lipmann, F

    1982-01-01

    A phosphatase specific for tyrosine-O-phosphate (Tyr-P) was separated from several nonspecific phosphatases present in the third instar larvae of Drosophila melanogaster. The enzyme hydrolyzed L-Tyr-P, with an apparent Km of 0.14 mM, but not D-Tyr-P after being freed from hydrolytic activity toward p-nitrophenyl phosphate, the common phosphatase substrate. Such purified preparations also catalyzed a reversible phosphate transfer reaction from unlabeled Tyr-P to [3H]tyrosine. The transfer activity was L4-14% of the hydrolytic activity, depending on the initial concentration of tyrosine (0.25-4.0 mM). The two activities coincided throughout purification. However, they differed in pH optimum, that of hydrolysis being 6.5-7 and that of phosphate transfer being 7.7.5. The two activities were also differentially inhibited by 1-p-bromotetramisole oxalate in the presence of EDTA and by Mn2+. Addition of Mg2+ did not affect either hydrolysis or phosphate transfer, but 5 mM Zn2+ was 65% inhibitory to both. Sodium fluoride strongly inhibited both reactions, and this inhibition was reversed by EDTA, while EDTA itself had no effect. Pi had no effect and no detectable incorporation of 32Pi into Tyr-P was observed, indicating that the phosphate transfer reaction is not a simple reversal of hydrolysis. No ATP-linked phosphorylation of tyrosine was found. PMID:6181504

  10. The mitochondrial ATPase. Evidence for a single essential tyrosine residue.

    PubMed

    Ferguson, S J; Lloyd, W J; Lyons, M H; Radda, G K

    1975-05-01

    1. Evidence is presented which indicates that inactivation of the mitochondrial ATPase from bovine heart by the reagent 4-chloro-7-nitrobenzofurazan results from modification of one tyrosine residue per enzyme molecule. Activity can be restored by a variety of sulphydryl reagents. 2. In sodium dodecyl sulphate, the nitrogenzofurazan group on tyrosine is transfered to newly exposed sulphydryl groups on the enzyme. 3. The rate of transfer of the nitrobenzofurazan moiety from theenzyme to sulphydryl compounds is compared with that for transfer from the model compound N-acetyl-tyrosine-0(7-nitrobenzo-furazan) ethyl ester, the synthesis and properties of which are also described. 4. The ligands ATP and ADP exert a protective effect on the rate of reaction between the mitochondrial ATPase and 4-chloro-7-nitrobenzofurazan. The variation in rate of this reaction with change in pH has also been examined and a pKa of 9.5 estimated for the tyrosine residue. 5. The modification does not prevent substrate binding as judged by changes in the fluorescence of aurovertin, an antibiotic with specific affinity for mitochondiral ATPases. 6. When the ATPase activity of submitochondrial particles is inhibited by 4-chloro-7-nitrobenzo-furazan, there is a parallel decrease in the extent of the energy-linked fluorescence enhancement of 1-anilino-naphthalene-8-sulphonate induced by ATP hydrolysis. Both ATPase activity and the fluorescence enhancement are restored by sluphydryl reagents. PMID:238839

  11. Inhibition of Bcr serine kinase by tyrosine phosphorylation.

    PubMed Central

    Liu, J; Wu, Y; Ma, G Z; Lu, D; Haataja, L; Heisterkamp, N; Groffen, J; Arlinghaus, R B

    1996-01-01

    The first exon of the BCR gene encodes a new serine/threonine protein kinase. Abnormal fusion of the BCR and ABL genes, resulting from the formation of the Philadelphia chromosome (Ph), is the hallmark of Ph-positive leukemia. We have previously demonstrated that the Bcr protein is tyrosine phosphorylated within first-exon sequences by the Bcr-Abl oncoprotein. Here we report that in addition to tyrose 177 (Y-177), Y-360 and Y283 are phosphorylated in Bcr-Abl proteins in vitro. Moreover, Bcr tyrosine 360 is phosphorylated in vivo within both Bcr-Abl and Bcr. Bcr mutant Y177F had a greatly reduced ability to transphosphorylate casein and histone H1, whereas Bcr mutants Y177F and Y283F had wild-type activities. In contrast, the Y360F mutation had little effect on Bcr's autophosphorylation activity. Tyrosine-phosphorylated Bcr, phosphorylated in vitro by Bcr-Abl, was greatly inhibited in its serine/threonine kinase activity, impairing both auto- and transkinase activities of Bcr. Similarly, the isolation of Bcr from cells expressing Bcr-Abl under conditions that preserve phosphotyrosine residues also reduced Bcr's kinase activity. These results indicate that tyrosine 360 of Bcr is critical for the transphosphorylation activity of Bcr and that in Ph-positive leukemia, Bcr serine/threonine kinase activity is seriously impaired. PMID:8622703

  12. Old Tyrosine Kinase Inhibitors and Newcomers in Gastrointestinal Cancer Treatment.

    PubMed

    Erika, Giordani; Federica, Zoratto; Martina, Strudel; Anselmo, Papa; Luigi, Rossi; Marina, Minozzi; Davide, Caruso; Eleonora, Zaccarelli; Monica, Verrico; Silverio, Tomao

    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. PMID:26278713

  13. 21 CFR 862.1730 - Free tyrosine test system.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 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....

  14. 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....

  15. 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....

  16. 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....

  17. 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....

  18. p120 Catenin-Associated Fer and Fyn Tyrosine Kinases Regulate β-Catenin Tyr-142 Phosphorylation and β-Catenin-α-Catenin Interaction

    PubMed Central

    Piedra, Jose; Miravet, Susana; Castaño, Julio; Pálmer, Héctor G.; Heisterkamp, Nora; García de Herreros, Antonio; Duñach, Mireia

    2003-01-01

    β-Catenin has a key role in the formation of adherens junction through its interactions with E-cadherin and α-catenin. We show here that interaction of β-catenin with α-catenin is regulated by the phosphorylation of β-catenin Tyr-142. This residue can be phosphorylated in vitro by Fer or Fyn tyrosine kinases. Transfection of these kinases to epithelial cells disrupted the association between both catenins. We have also examined whether these kinases are involved in the regulation of this interaction by K-ras. Stable transfectants of the K-ras oncogene in intestinal epithelial IEC18 cells were generated which show little α-catenin-β-catenin association with respect to control clones; this effect is accompanied by increased Tyr-142 phosphorylation and activation of Fer and Fyn kinases. As reported for Fer, Fyn kinase is constitutively bound to p120 catenin; expression of K-ras induces the phosphorylation of p120 catenin on tyrosine residues increasing its affinity for E-cadherin and, consequently, promotes the association of Fyn with the adherens junction complex. Yes tyrosine kinase also binds to p120 catenin but only upon activation, and stimulates Fer and Fyn tyrosine kinases. These results indicate that p120 catenin acts as a docking protein facilitating the activation of Fer/Fyn tyrosine kinases by Yes and demonstrate the role of these p120 catenin-associated kinases in the regulation of β-catenin-α-catenin interaction. PMID:12640114

  19. The tyrosine kinase p60c-src regulates the fast gate of the cystic fibrosis transmembrane conductance regulator chloride channel.

    PubMed Central

    Fischer, H; Machen, T E

    1996-01-01

    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. PMID:8968578

  20. Development of a 5-plex SILAC Method Tuned for the Quantitation of Tyrosine Phosphorylation Dynamics

    PubMed Central

    Tzouros, Manuel; Golling, Sabrina; Avila, David; Lamerz, Jens; Berrera, Marco; Ebeling, Martin; Langen, Hanno; Augustin, Angélique

    2013-01-01

    The propagation of phosphorylation downstream of receptor tyrosine kinases is a key dynamic cellular event involved in signal transduction, which is often deregulated in disease states such as cancer. Probing phosphorylation dynamics is therefore crucial for understanding receptor tyrosine kinases' function and finding ways to inhibit their effects. MS methods combined with metabolic labeling such as stable isotope labeling with amino acids in cell culture (SILAC) have already proven successful in deciphering temporal phosphotyrosine perturbations. However, they are limited in terms of multiplexing, and they also are time consuming, because several experiments need to be performed separately. Here, we introduce an innovative approach based on 5-plex SILAC that allows monitoring of phosphotyrosine signaling perturbations induced by a drug treatment in one single experiment. Using this new labeling strategy specifically tailored for phosphotyrosines, it was possible to generate the time profiles for 318 unique phosphopeptides belonging to 215 proteins from an erlotinib-treated breast cancer cell line model. Hierarchical clustering of the time profiles followed by pathway enrichment analysis highlighted epidermal growth factor receptor (EGFR or ErbB1) and ErbB2 signaling as the major pathways affected by erlotinib, thereby validating the method. Moreover, based on the similarity of its time profile to those of other proteins in the ErbB pathways, the phosphorylation at Tyr453 of protein FAM59A, a recently described adaptor of EGFR, was confirmed as tightly involved in the signaling cascade. The present investigation also demonstrates the remote effect of EGFR inhibition on ErbB3 phosphorylation sites such as Tyr1289 and Tyr1328, as well as a potential feedback effect on Tyr877 of ErbB2. Overall, the 5-plex SILAC is a straightforward approach that extends sample multiplexing and builds up the arsenal of methods for tyrosine phosphorylation dynamics. PMID:23882028

  1. Protein Tyrosine Nitration and Thiol Oxidation by Peroxynitrite—Strategies to Prevent These Oxidative Modifications

    PubMed Central

    Daiber, Andreas; Daub, Steffen; Bachschmid, Markus; Schildknecht, Stefan; Oelze, Matthias; Steven, Sebastian; Schmidt, Patrick; Megner, Alexandra; Wada, Masayuki; Tanabe, Tadashi; Münzel, Thomas; Bottari, Serge; Ullrich, Volker

    2013-01-01

    The reaction product of nitric oxide and superoxide, peroxynitrite, is a potent biological oxidant. The most important oxidative protein modifications described for peroxynitrite are cysteine-thiol oxidation and tyrosine nitration. We have previously demonstrated that intrinsic heme-thiolate (P450)-dependent enzymatic catalysis increases the nitration of tyrosine 430 in prostacyclin synthase and results in loss of activity which contributes to endothelial dysfunction. We here report the sensitive peroxynitrite-dependent nitration of an over-expressed and partially purified human prostacyclin synthase (3.3 μM) with an EC50 value of 5 μM. Microsomal thiols in these preparations effectively compete for peroxynitrite and block the nitration of other proteins up to 50 μM peroxynitrite. Purified, recombinant PGIS showed a half-maximal nitration by 10 μM 3-morpholino sydnonimine (Sin-1) which increased in the presence of bicarbonate, and was only marginally induced by freely diffusing NO2-radicals generated by a peroxidase/nitrite/hydrogen peroxide system. Based on these observations, we would like to emphasize that prostacyclin synthase is among the most efficiently and sensitively nitrated proteins investigated by us so far. In the second part of the study, we identified two classes of peroxynitrite scavengers, blocking either peroxynitrite anion-mediated thiol oxidations or phenol/tyrosine nitrations by free radical mechanisms. Dithiopurines and dithiopyrimidines were highly effective in inhibiting both reaction types which could make this class of compounds interesting therapeutic tools. In the present work, we highlighted the impact of experimental conditions on the outcome of peroxynitrite-mediated nitrations. The limitations identified in this work need to be considered in the assessment of experimental data involving peroxynitrite. PMID:23567270

  2. 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. PMID:27085377

  3. Effects of tyrosine-26 and tyrosine-64 nitration on the photoreactions of bacteriorhodopsin

    NASA Technical Reports Server (NTRS)

    Scherrer, P.; Stoeckenius, W.

    1985-01-01

    The photoreactions of nitrated bacteriorhodopsin (bR) are examined. Flash-induced difference spectra of bR, bR with aminotyrosine in position 26 (bR-N26R) and bR with aminotyrosine in position 64 are analyzed. It is observed that changes in the actinic wavelength (from 520 to 500 or 580 nm) have no affect on the shape of the spectra and the formation and decay kinetics of the O and M intermediates. Nitration of tyrosine-64 decreases the chromophore absorbance, shifts the absorption maximum to 535 nm, and affects photocycle kinetics independent of the pK of its phenolic group. Light-dark adaptation spectra for bR are studied. The kinetics of the M and O intermediates in bR with nitrotyrosine in position 64 (bR-N64) and bR with aminotyrosine in position 64 and bR with nitrotyrosine in position 26 and bR-N26R are described and compared to bR; the pH dependence and M and O decay rates are considered. The deprotonation of bR-N64 during the photoreaction cycle and the effects of nitration on the activity of proton pumping are investigated.

  4. Asymmetric Tyrosine Kinase Arrangements in Activation or Autophosphorylation of Receptor Tyrosine Kinases

    SciTech Connect

    J Bae; J Schlessinger

    2011-12-31

    Receptor tyrosine kinases (RTKs) play important roles in the control of many cellular processes including cell proliferation, cell adhesion, angiogenesis, and apoptosis. Ligand-induced dimerization of RTKs leads to autophosphorylation and activation of RTKs. Structural studies have shown that while isolated ectodomains of several RTKs form symmetric dimers the isolated cytoplasmic kinase domains of epidermal growth factor receptor (EGFR) and fibroblast growth factor receptor (FGFR) form asymmetric dimers during their activation. Binding of one kinase molecule of EGFR to a second kinase molecule asymmetrically leads to stimulation of kinase activity and enhanced autophosphorylation. Furthermore, the structures of the kinase domain of FGFR1 and FGFR2 reveal the formation of asymmetric interfaces in the processes of autophosphorylation at their specific phosphotyrosine (pY) sites. Disruption of asymmetric dimer interface of EGFR leads to reduction in enzymatic activity and drastic reduction of autophosphorylation of FGFRs in ligandstimulated live cells. These studies demonstrate that asymmetric dimer formation is as a common phenomenon critical for activation and autophosphorylation of RTKs.

  5. MOLCAS 7: the next generation.

    PubMed

    Aquilante, Francesco; De Vico, Luca; Ferré, Nicolas; Ghigo, Giovanni; Malmqvist, Per-Ake; Neogrády, Pavel; Pedersen, Thomas Bondo; Pitonák, Michal; Reiher, Markus; Roos, Björn O; Serrano-Andrés, Luis; Urban, Miroslav; Veryazov, Valera; Lindh, Roland

    2010-01-15

    Some of the new unique features of the MOLCAS quantum chemistry package version 7 are presented in this report. In particular, the Cholesky decomposition method applied to some quantum chemical methods is described. This approach is used both in the context of a straight forward approximation of the two-electron integrals and in the generation of so-called auxiliary basis sets. The article describes how the method is implemented for most known wave functions models: self-consistent field, density functional theory, 2nd order perturbation theory, complete-active space self-consistent field multiconfigurational reference 2nd order perturbation theory, and coupled-cluster methods. The report further elaborates on the implementation of a restricted-active space self-consistent field reference function in conjunction with 2nd order perturbation theory. The average atomic natural orbital basis for relativistic calculations, covering the whole periodic table, are described and associated unique properties are demonstrated. Furthermore, the use of the arbitrary order Douglas-Kroll-Hess transformation for one-component relativistic calculations and its implementation are discussed. This section especially focuses on the implementation of the so-called picture-change-free atomic orbital property integrals. Moreover, the ElectroStatic Potential Fitted scheme, a version of a quantum mechanics/molecular mechanics hybrid method implemented in MOLCAS, is described and discussed. Finally, the report discusses the use of the MOLCAS package for advanced studies of photo chemical phenomena and the usefulness of the algorithms for constrained geometry optimization in MOLCAS in association with such studies. PMID:19499541

  6. Redundant and selective roles for erythropoietin receptor tyrosines in erythropoiesis in vivo.

    PubMed

    Longmore, G D; You, Y; Molden, J; Liu, K D; Mikami, A; Lai, S Y; Pharr, P; Goldsmith, M A

    1998-02-01

    Cytokine receptors have been shown in cell culture systems to use phosphotyrosine residues as docking sites for certain signal transduction intermediates. Studies using various cellular backgrounds have yielded conflicting information about the importance of such residues. The present studies were undertaken to determine whether or not tyrosine residues within the erythropoietin receptor (EPOR) are essential for biologic activity during hematopoiesis in vivo. A variant of the EPOR was constructed that contains both a substitution (R129C) causing constitutive receptor activation as well as replacement of all eight cytoplasmic tyrosines by phenylalanines (cEPORYF). A comparison between animals exposed to recombinant retroviruses expressing cEPOR and cEPORYF showed that efficient red blood cell (RBC) development in vivo is dependent on the pressence of tyrosine residues in the cytoplasmic domain of the EPOR. In addition, an inefficient EPOR tyrosine independent pathway supporting RBC development was detected. Tyrosine add-back mutants showed that multiple individual tyrosines have the capacity to restore full erythropoietic potential to the EPOR as determined in whole animals. The analysis of primary erythroid progenitors transduced with the various cEPOR tyrosine mutants and tyrosine add-backs showed that only tyrosine 343 (Y1) and tyrosine 479 (Y8) were capable of supporting immature burst-forming unit-erythroid progenitor development. Thus, this receptor is characterized by striking functional redundancy of tyrosines in a biologically relevant context. However, selective tyrosine residues may be uniquely important for early signals supporting erythroid development. PMID:9446647

  7. Integrin Ligation Results in Nephrin Tyrosine Phosphorylation In Vitro

    PubMed Central

    Verma, Rakesh; Venkatareddy, Madhusudan; Kalinowski, Anne; Patel, Sanjeevkumar R.; Garg, Puneet

    2016-01-01

    Nephrin is expressed at the basolateral aspect of podocytes and is an important signaling protein at the glomerular slit diaphragm. In vitro studies have demonstrated that Nephrin phosphorylation-dependent signaling is able to assemble a protein complex that is able to polymerize actin. However, proximal signaling events that result in nephrin tyrosine phosphorylation are not well understood. Nephrin deletion in mice and human nephrin mutations result in developmental failure of the podocyte intercellular junction resutling in proteinuria. This has been presumed to be due to a failure to respond to an external polarized cue in the absence of nephrin or a failure to transduce an outside-in signal in patients with nephrin mutations. The nephrin extracellular domain binds to itself or neph1 across the foot process intercellular junction. Nephrin is tyrosine phosphorylation-silent in healthy glomeruli when presumably the nephrin extracellular domain is in an engaged state. These observations raise the possibility of an alternate proximal signaling mechanism that might be responsible for nephrin tyrosine phosphorylation. Here we present data showing that integrin engagement at the basal aspect of cultured podocytes results in nephrin tyrosine phosphorylation. This is abrogated by incubating podocytes with an antibody that prevents integrin β1 ligation and activation in response to binding to extracellular matrix. Furthermore, nephrin tyrosine phosphorylation was observed in podocytes expressing a membrane-targeted nephrin construct that lacks the extracellular domain. We propose, integrin-activation based signaling might be responsible for nephrin phosphorylation rather than engagment of the nephrin extracellular domain by a ligand. PMID:26848974

  8. Inverse correlation between tyrosine phosphorylation and collagenase production in chondrocytes.

    PubMed Central

    Cruz, T F; Mills, G; Pritzker, K P; Kandel, R A

    1990-01-01

    Collagenase production by chondrocytes appears to play a major role in the development of osteoarthritis. Although the mechanisms regulating collagenase production by chondrocytes are not known, incubation of bovine chondrocytes in serum markedly decreases collagenase production. Since serum has been demonstrated to increase levels of phosphotyrosine (P-Tyr) in several cell types, we determined the effect of altering intracellular levels of P-Tyr on collagenase production. Both orthovanadate, a potent inhibitor of tyrosine phosphatases, and serum caused a marked increase in tyrosine phosphorylation. The increase in P-Tyr was associated with a decrease in the production of collagenase, suggesting that two processes may be linked. Orthovanadate caused an increase in P-Tyr in the absence of serum, suggesting that P-Tyr levels in resting chondrocytes are regulated through activity of both tyrosine kinases and phosphatases. Orthovanadate and serum induced a synergistic increase in P-Tyr levels, suggesting that serum functions through increasing kinase activity rather than decreasing phosphatase activity. In the absence of serum, concentrations of orthovanadate which maximally inhibited collagenase production primarily increased phosphorylation of a 36 kDa protein, suggesting that the phosphorylation of this protein may play a major role in regulating collagenase production. Orthovanadate had limited effects on chondrocyte proteoglycan synthesis, morphology or viability in the presence or absence of serum, suggesting that the decrease in collagenase production was not due to non-specific inhibition of protein synthesis or cellular toxicity. Inhibition of tyrosine phosphatases by orthovanadate or activation of tyrosine kinases by addition of serum correlated with the inhibition of collagenase production. Images Fig. 1. Fig. 2. PMID:1697163

  9. Properties of the humic-like material arising from the photo-transformation of l-tyrosine.

    PubMed

    Berto, Silvia; De Laurentiis, Elisa; Tota, Tiziana; Chiavazza, Enrico; Daniele, Pier Giuseppe; Minella, Marco; Isaia, Marco; Brigante, Marcello; Vione, Davide

    2016-03-01

    The UVB photolysis of l-tyrosine yields species with fluorescence and absorption spectra that are very similar to those of humic substances. By potentiometric measurements, chemical modeling and the application of NMR, mass spectrometry and laser flash photolysis, it was possible to get insights into the structural and chemical properties of the compounds derived by the l-tyrosine phototransformation. The photolytic process follows aromatic-ring hydroxylation and dimerization. The latter is presumably linked with the photoinduced generation of tyrosyl (phenoxy-type) radicals, which have a marked tendency to dimerize and possibly oligomerize. Interestingly, photoinduced transformation gives compounds with protogenic and complexation capabilities similar to those of the humic substances that occur naturally in surface waters. This finding substantiates a new and potentially important abiotic (photolytic) pathway for the formation of humic compounds in surface-water environments. PMID:26748008

  10. Co-expression of protein tyrosine kinases EGFR-2 and PDGFRβ with protein tyrosine phosphatase 1B in Pichia pastoris.

    PubMed

    Tu, Pham Ngoc; Wang, Yamin; Cai, Menghao; Zhou, Xiangshan; Zhang, Yuanxing

    2014-02-28

    The regulation of protein tyrosine phosphorylation is mediated by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs) and is essential for cellular homeostasis. Coexpression of PTKs with PTPs in Pichia pastoris was used to facilitate the expression of active PTKs by neutralizing their apparent toxicity to cells. In this study, the gene encoding phosphatase PTP1B with or without a blue fluorescent protein or peroxisomal targeting signal 1 was cloned into the expression vector pAG32 to produce four vectors. These vectors were subsequently transformed into P. pastoris GS115. The tyrosine kinases EGFR-2 and PDGFRβ were expressed from vector pPIC3.5K and were fused with a His-tag and green fluorescent protein at the N-terminus. The two plasmids were transformed into P. pastoris with or without PTP1B, resulting in 10 strains. The EGFR-2 and PDGFRβ fusion proteins were purified by Ni(2+) affinity chromatography. In the recombinant P. pastoris, the PTKs co-expressed with PTP1B exhibited higher kinase catalytic activity than did those expressing the PTKs alone. The highest activities were achieved by targeting the PTKs and PTP1B into peroxisomes. Therefore, the EGFR-2 and PDGFRβ fusion proteins expressed in P. pastoris may be attractive drug screening targets for anticancer therapeutics. PMID:24248091

  11. Antitumor Effect of the Tyrosine Kinase Inhibitor Nilotinib on Gastrointestinal Stromal Tumor (GIST) and Imatinib-Resistant GIST Cells

    PubMed Central

    Sako, Hiroyuki; Fukuda, Kazumasa; Saikawa, Yoshiro; Nakamura, Rieko; Takahashi, Tsunehiro; Wada, Norihito; Kawakubo, Hirohumi; Takeuchi, Hiroya; Ohmori, Tai; Kitagawa, Yuko

    2014-01-01

    Despite the benefits of imatinib for treating gastrointestinal stromal tumors (GIST), the prognosis for high risk GIST and imatinib-resistant (IR) GIST remains poor. The mechanisms of imatinib resistance have not yet been fully clarified. The aim of the study was to establish imatinib-resistant cell lines and investigate nilotinib, a second generation tyrosine kinase inhibitor (TKI), in preclinical models of GIST and imatinib-resistant GIST. For a model of imatinib-resistant GIST, we generated resistant cells from GK1C and GK3C cell lines by exposing them to imatinib for 6 months. The parent cell lines GK1C and GK3C showed imatinib sensitivity with IC50 of 4.59±0.97 µM and 11.15±1.48 µM, respectively. The imatinib-resistant cell lines GK1C-IR and GK3C-IR showed imatinib resistance with IC50 values of 11.74±0.17 µM (P<0.001) and 41.37±1.07 µM (P<0.001), respectively. The phosphorylation status of key cell signaling pathways, receptor tyrosine kinase KIT (CD117), platelet-derived growth factor receptor alpha (PDGFRA) and downstream signaling kinases: serine-threonine kinase Akt (AKT) and extracellular signal-regulated kinase 1/2 (ERK1/2) or the non-receptor tyrosine kinase: proto-oncogene tyrosine-protein kinase Src (SRC), was analyzed in established cell lines and ERK1/2 phosphorylation was found to be increased compared to the parental cells. Nilotinib demonstrated significant antitumor efficacy against GIST xenograft lines and imatinib-resistant GIST cell lines. Thus, nilotinib may have clinical potential for patients with GIST or imatinib-resistant GIST. PMID:25221952

  12. Tyrosine Kinase Inhibitors in Ph+ Chronic Myeloid Leukemia Therapy: a Review.

    PubMed

    Shah, Krupa; Parikh, Sonia; Rawal, Rakesh

    2016-01-01

    Chronic myeloid leukaemia (CML) is a clonal myeloproliferative hematopoietic stem cell disorder. Deregulated BCRABL fusion tyrosine kinase activity is the main cause of CML disease pathogenesis, making BCRABL an ideal target for inhibition. Current tyrosine kinase inhibitors (TKIs) designed to inhibit BCRABL oncoprotein activity, have completely transformed the prognosis of CML. Interruption of TKI treatment leads to minimal residual disease reside (MRD), thought to reside in TKIinsensitive leukaemia stem cells which remain a potential reservoir for disease relapse. This highlights the need to develop new therapeutic strategies for CML either as small molecule master TKIs or phytopharmaceuticals derived from nature to achieve chronic molecular remission. This review outlines the past, present and future therapeutic approaches for CML including coverage of relevant mechanisms, whether ABL dependent or independent, and epigenetic factors responsible for developing resistance against TKIs. Appearance of mutant clones along the course of therapy either preexisting or induced due to therapy is still a challenge for the clinician. A proposed invitro model of generating colony forming units from CML stem cells derived from diagnostic samples seems to be achievable in the era of high throughput technology which can take care of single cell genomic profiling. PMID:27509925

  13. Protein tyrosine phosphatase PTPN14 is a regulator of lymphatic function and choanal development in humans.

    PubMed

    Au, Audrey C; Hernandez, Paolo A; Lieber, Ernest; Nadroo, Ali M; Shen, Yu-Ming; Kelley, Kevin A; Gelb, Bruce D; Diaz, George A

    2010-09-10

    The lymphatic vasculature is essential for the recirculation of extracellular fluid, fat absorption, and immune function and as a route of tumor metastasis. The dissection of molecular mechanisms underlying lymphangiogenesis has been accelerated by the identification of tissue-specific lymphatic endothelial markers and the study of congenital lymphedema syndromes. We report the results of genetic analyses of a kindred inheriting a unique autosomal-recessive lymphedema-choanal atresia syndrome. These studies establish linkage of the trait to chromosome 1q32-q41 and identify a loss-of-function mutation in PTPN14, which encodes a nonreceptor tyrosine phosphatase. The causal role of PTPN14 deficiency was confirmed by the generation of a murine Ptpn14 gene trap model that manifested lymphatic hyperplasia with lymphedema. Biochemical studies revealed a potential interaction between PTPN14 and the vascular endothelial growth factor receptor 3 (VEGFR3), a receptor tyrosine kinase essential for lymphangiogenesis. These results suggest a unique and conserved role for PTPN14 in the regulation of lymphatic development in mammals and a nonconserved role in choanal development in humans. PMID:20826270

  14. Management of Chronic Myeloid Leukemia Patients Resistant to Tyrosine Kinase Inhibitors Treatment

    PubMed Central

    Wieczorek, Agnieszka; Uharek, Lutz

    2015-01-01

    Chronic myeloid leukemia (CML) is a myeloproliferative disorder associated with a characteristic chromosomal translocation called the Philadelphia chromosome. This oncogene is generated by the fusion of breakpoint cluster region (BCR) and Abelson leukemia virus (ABL) genes and encodes a novel fusion gene translating into a protein with constitutive tyrosine kinase activity. The discovery and introduction of tyrosine kinase inhibitors (TKIs) irreversibly changed the landscape of CML treatment, leading to dramatic improvement in long-term survival rates. The majority of patients with CML in the chronic phase have a life expectancy comparable with that of healthy age-matched individuals. Although an enormous therapeutic improvement has been accomplished, there are still some unresolved issues in the treatment of patients with CML. One of the most important problems is based on the fact that TKIs can efficiently target proliferating mature cells but do not eradicate leukemic stem cells, allowing persistence of the malignant clone. Owing to the resistance mechanisms arising during the course of the disease, treatment with most of the approved BCR-ABL1 TKIs may become ineffective in a proportion of patients. This article highlights the different molecular mechanisms of acquired resistance being developed during treatment with TKIs as well as the pharmacological strategies to overcome it. Moreover, it gives an overview of novel drugs and therapies that are aiming in overcoming drug resistance, loss of response, and kinase domain mutations. PMID:26917943

  15. Tyrosine Administration Decreases Vulnerability to Ventricular Fibrillation in the Normal Canine Heart

    NASA Astrophysics Data System (ADS)

    Scott, Neal A.; Desilva, Regis A.; Lown, Bernard; Wurtman, Richard J.

    1981-02-01

    Intravenous infusion of tyrosine (1, 2, or 4 milligrams per kilogram) for 20 to 30 minutes caused dose-dependent increases in the ventricular fibrillation threshold in normal dogs. Administration of valine, a neutral amino acid that competes with tyrosine for uptake at the blood-brain barrier, in a dose equimolar to the most effective dose of tyrosine, slightly decreased the ventricular fibrillation threshold when given alone and significantly blocked elevation of the ventricular fibrillation threshold after tyrosine infusion. Hence, tyrosine, presumably acting in the central nervous system, can protect against certain ventricular arrhythmias.

  16. Subcutaneous L-tyrosine elicits cutaneous analgesia in response to local skin pinprick in rats.

    PubMed

    Hung, Ching-Hsia; Chiu, Chong-Chi; Liu, Kuo-Sheng; Chen, Yu-Wen; Wang, Jhi-Joung

    2015-10-15

    The purpose of the study was to estimate the ability of L-tyrosine to induce cutaneous analgesia and to investigate the interaction between L-tyrosine and the local anesthetic lidocaine. After subcutaneously injecting the rats with L-tyrosine and lidocaine in a dose-dependent manner, cutaneous analgesia (by blocking the cutaneous trunci muscle reflex-CTMR) was evaluated in response to the local pinprick. The drug-drug interaction was analyzed by using an isobolographic method. We showed that both L-tyrosine and lidocaine produced dose-dependent cutaneous analgesia. On the 50% effective dose (ED50) basis, the rank of drug potency was lidocaine (5.09 [4.88-5.38] μmol)>L-tyrosine (39.1 [36.5-41.8] μmol) (P<0.05). At the equipotent doses (ED25, ED50, and ED75), the duration of cutaneous analgesia caused by L-tyrosine lasted longer than that caused by lidocaine (P<0.01). Lidocaine co-administered with L-tyrosine exhibited an additive effect on infiltrative cutaneous analgesia. Our pre-clinical study demonstrated that L-tyrosine elicits the local/cutaneous analgesia, and the interaction between L-tyrosine and lidocaine is additive. L-tyrosine has a lower potency but much greater duration of cutaneous analgesia than lidocaine. Adding L-tyrosine to lidocaine preparations showed greater duration of cutaneous analgesia compared with lidocaine alone. PMID:26376025

  17. High-permittivity microwave dielectric ceramics based on (1 - x)(Li1/2Nd1/2)TiO3-xCaTiO3

    NASA Astrophysics Data System (ADS)

    Zhang, Weijun; Chen, Xingyu; Jia, Aiqing; Bai, Shuxin

    2015-04-01

    Microwave (MW) dielectric ceramics in (1 - x)(Li1/2Nd1/2)TiO3-xCaTiO3 (0.2 ≤ x ≤ 0.8) composition were prepared through the conventional solid-state reaction. X-ray diffraction (XRD) analysis and scanning electron microscopy (SEM) combined with energy dispersive X-ray analysis (EDX) indicated that the matrix phase was a continuous solid solution with orthorhombic perovskite structure. A minor amount of secondary phase was detected only in the composition of x = 0.7 and 0.8. The (1 - x)(Li1/2Nd1/2)TiO3-xCaTiO3 ceramics showed a very high permittivity of 118-153 and reasonable Q × f0 values of 2360-5930 GHz as x increased from 0.2 to 0.8. The temperature coefficient of resonant frequency (τf) of the samples increased with increasing x value and was approximately linearly proportional to ɛr. Bi4B2O9 addition effectively tailored the τf of (1 - x)(Li1/2Nd1/2)TiO3-xCaTiO3 ceramics to near zero at low temperature, and induced no degradation of Q × f0 value. The x = 0.3 composition with 20 wt.%Bi4B2O9 addition sintered at 1050°C exhibited dielectric properties of ɛr = 112.4, Q × f0 = 2414 GHz and τf = 8.9 ppm/°C.

  18. Targeting Angiogenesis in Colorectal Cancer: Tyrosine Kinase Inhibitors.

    PubMed

    Kircher, Sheetal Mehta; Nimeiri, Halla S; Benson, Al B

    2016-01-01

    Colorectal cancer is commonly diagnosed throughout the world, and treatment options have greatly expanded over the last 2 decades. Targeting angiogenesis has been a major focus of study in a variety of malignancy types. Targeting angiogenesis has been achieved by several mechanisms in colorectal cancer, including use of antiangiogenic small molecule tyrosine kinase inhibitors (TKIs). There have been many attempts and failures to prove efficacy of TKIs in the treatment of colorectal cancer including sorafenib, sunitinib, vatalanib, and tivozanib. Regorafenib was the first TKI to demonstrate efficacy and is an orally active inhibitor of angiogenic (including the vascular endothelial growth factor receptors 1, 2, and 3), stromal, and oncogenic receptor tyrosine kinases. There are ongoing investigations of both regorafenib and ninetanib; however, there remains a critical need to better understand novel combinations with TKIs that could prove more efficacious than available options. PMID:27341596

  19. Stabilization and purification of tyrosine aminotransferase from rat liver.

    PubMed

    Hargrove, J L

    1990-01-01

    Purification of unmodified tyrosine aminotransferase from rat liver requires that the activity of cathepsin T be minimized, and that losses of enzyme due to dilution or oxidation by prevented. The enzyme was stabilized by pyridoxal 5'-phosphate, dithiothreitol, and potassium phosphate, but was destabilized by L-tyrosine or L-glutamate. A rapid, efficient method for purification of this enzyme included the following steps: twenty-fold induction with a high-casein diet plus dexamethasone phosphate administered in the drinking water; a heat step (65 degrees C) followed by precipitation from 0.20 M sucrose at pH 5.0; and small-scale chromatography on DEAE-cellulose, hydroxyapatite and CM-Sephadex C50 at pH 6.0. These steps yielded more than 10 mg of native enzyme from 35 rats, with a recovery of 68% of the initial activity. PMID:1973296

  20. Bone sialoprotein II synthesized by cultured osteoblasts contains tyrosine sulfate

    SciTech Connect

    Ecarot-Charrier, B.; Bouchard, F.; Delloye, C. )

    1989-11-25

    Isolated mouse osteoblasts that retain their osteogenic activity in culture were incubated with (35S) sulfate. Two radiolabeled proteins, in addition to proteoglycans, were extracted from the calcified matrix of osteoblast cultures. All the sulfate label in both proteins was in the form of tyrosine sulfate as assessed by amino acid analysis and thin layer chromatography following alkaline hydrolysis. The elution behavior on DEAE-Sephacel of the major sulfated protein and the apparent Mr on sodium dodecyl sulfate gels were characteristic of bone sialoprotein II extracted from rat. This protein was shown to cross-react with an antiserum raised against bovine bone sialoprotein II, indicating that bone sialoprotein II synthesized by cultured mouse osteoblasts is a tyrosine-sulfated protein. The minor sulfated protein was tentatively identified as bone sialoprotein I or osteopontin based on its elution properties on DEAE-Sephacel and anomalous behavior on sodium dodecyl sulfate gels similar to those reported for rat bone sialoprotein I.

  1. Tailoring Tyrosine Kinase Inhibitors to Fit the Lung Cancer Genome

    PubMed Central

    Looyenga, Brendan D; Cherni, Irene; MacKeigan, Jeffrey P; Weiss, Glen J

    2011-01-01

    Tyrosine kinase inhibitors (TKIs) have been in use as cancer therapeutics for nearly a decade, and their utility in targeting specific malignancies with defined genetic lesions has proven to be remarkably effective. Recent efforts to characterize the spectrum of genetic lesions found in non-small cell lung carcinoma (NSCLC) have provided important insights into the molecular basis of this disease and have also revealed a wide array of tyrosine kinases that might be effectively targeted for rationally designed therapies. The findings of these studies, however, also provide a cautionary tale about the limitations of single-agent therapies, which fail to account for the genetic heterogeneity and pathway redundancy that characterize advanced NSCLC. Emergence of drug resistance mechanisms to specific TKIs, such as gefitinib and erlotinib, suggests that more sophisticated chemotherapeutic paradigms that target multiple pathways at the same time will be required to effectively treat this disease. PMID:21461169

  2. The role of nitisinone in tyrosine pathway disorders.

    PubMed

    Lock, Edward; Ranganath, Lakshminarayan R; Timmis, Oliver

    2014-11-01

    Nitisinone 2-(2-nitro-4-trifluoromethylbenzoyl)cyclohexane-1,3-dione (NTBC), an effective herbicide, is the licensed treatment for the human condition, hereditary tyrosinaemia type 1 (HT-1). Its mode of action interrupts tyrosine metabolism through inhibition of 4-hydroxyphenylpyruvate dioxygenase (HPPD). Nitisinone is a remarkable safe drug to use with few side effects reported. Therefore, we propose that it should be investigated as a potential treatment for other disorders of tyrosine metabolism. These include alkaptonuria (AKU), a rare disease resulting is severe, early-onset osteoarthritis. We present a case study from the disease, and attempts to use the drug both off-label and in clinical research through the DevelopAKUre consortium. PMID:25266991

  3. Oxidation of Tyrosine-Phosphopeptides by Titanium Dioxide Photocatalysis.

    PubMed

    Ruokolainen, Miina; Ollikainen, Elisa; Sikanen, Tiina; Kotiaho, Tapio; Kostiainen, Risto

    2016-06-22

    Protein phosphorylation has a key role in cell regulation. Oxidation of proteins, in turn, is related to many diseases and to aging, but the effects of phosphorylation on the oxidation of proteins and peptides have been rarely studied. The aim of this study was to examine the mechanistic effect of phosphorylation on peptide oxidation induced by titanium dioxide photocatalysis. The effect of phosphorylation was compared between nonphosphorylated and tyrosine phosphorylated peptides using electrospray tandem mass spectrometry. We observed that tyrosine was the most preferentially oxidized amino acid, but the oxidation reaction was significantly inhibited by its phosphorylation. The study also shows that titanium dioxide photocatalysis provides a fast and easy method to study oxidation reactions of biomolecules, such as peptides. PMID:27268440

  4. Tyrosine phosphorylation of RAS by ABL allosterically enhances effector binding

    PubMed Central

    Ting, Pamela Y.; Johnson, Christian W.; Fang, Cong; Cao, Xiaoqing; Graeber, Thomas G.; Mattos, Carla; Colicelli, John

    2015-01-01

    RAS proteins are signal transduction gatekeepers that mediate cell growth, survival, and differentiation through interactions with multiple effector proteins. The RAS effector RAS- and RAB-interacting protein 1 (RIN1) activates its own downstream effectors, the small GTPase RAB5 and the tyrosine kinase Abelson tyrosine-protein kinase (ABL), to modulate endocytosis and cytoskeleton remodeling. To identify ABL substrates downstream of RAS-to-RIN1 signaling, we examined human HEK293T cells overexpressing components of this pathway. Proteomic analysis revealed several novel phosphotyrosine peptides, including Harvey rat sarcoma oncogene (HRAS)-pTyr137. Here we report that ABL phosphorylates tyrosine 137 of H-, K-, and NRAS. Increased RIN1 levels enhanced HRAS-Tyr137 phosphorylation by nearly 5-fold, suggesting that RAS-stimulated RIN1 can drive ABL-mediated RAS modification in a feedback circuit. Tyr137 is well conserved among RAS orthologs and is part of a transprotein H-bond network. Crystal structures of HRASY137F and HRASY137E revealed conformation changes radiating from the mutated residue. Although consistent with Tyr137 participation in allosteric control of HRAS function, the mutations did not alter intrinsic GTP hydrolysis rates in vitro. HRAS-Tyr137 phosphorylation enhanced HRAS signaling capacity in cells, however, as reflected by a 4-fold increase in the association of phosphorylated HRASG12V with its effector protein RAF proto-oncogene serine/threonine protein kinase 1 (RAF1). These data suggest that RAS phosphorylation at Tyr137 allosterically alters protein conformation and effector binding, providing a mechanism for effector-initiated modulation of RAS signaling.—Ting, P. Y., Johnson, C. W., Fang, C., Cao, X., Graeber, T. G., Mattos, C., Colicelli, J. Tyrosine phosphorylation of RAS by ABL allosterically enhances effector binding. PMID:25999467

  5. Comparative Analysis of Mutant Tyrosine Kinase Chemical Rescue†

    PubMed Central

    Muratore, Kathryn E.; Seeliger, Markus A.; Wang, Zhihong; Fomina, Dina; Neiswinger, Johnathan; Havranek, James J.; Baker, David; Kuriyan, John; Cole, Philip A.

    2009-01-01

    Protein tyrosine kinases are critical cell signaling enzymes. These enzymes have a highly conserved Arg residue in their catalytic loop which is present two residues or four residues downstream from an absolutely conserved Asp catalytic base. Prior studies on protein tyrosine kinases Csk and Src revealed the potential for chemical rescue of catalytically-deficient mutant kinases (Arg to Ala mutations) by small diamino compounds, particularly imidazole, however the potency and efficiency of rescue was greater for Src. This current study further examines the structural and kinetic basis of rescue for mutant Src as compared to mutant Abl tyrosine kinase. An X-ray crystal structure of R388A Src revealed the surprising finding that a histidine residue of the N-terminus of a symmetry-related kinase inserts into the active site of the adjacent Src and mimics the hydrogen bonding pattern seen in wild-type protein tyrosine kinases. Abl R367A shows potent and efficient rescue more comparable to Src, even though its catalytic loop is more like that of Csk. Various enzyme redesigns of the active sites indicate that the degree and specificity of rescue is somewhat flexible, but the overall properties of the enzymes and rescue agents play an overarching role. The newly discovered rescue agent 2-aminoimidazole is about as efficient as imidazole in rescuing R/A Src and Abl. Rate vs. pH studies with these imidazole analogs suggest that the protonated imidazolium is the preferred form for chemical rescue, consistent with structural models. The efficient rescue seen with mutant Abl points to the potential of this approach to be used effectively to analyze Abl phosphorylation pathways in cells. PMID:19260709

  6. Characterization of Phospho-(Tyrosine)-Mimetic Calmodulin Mutants

    PubMed Central

    Stateva, Silviya R.; Salas, Valentina; Benaim, Gustavo; Menéndez, Margarita; Solís, Dolores; Villalobo, Antonio

    2015-01-01

    Calmodulin (CaM) phosphorylated at different serine/threonine and tyrosine residues is known to exert differential regulatory effects on a variety of CaM-binding enzymes as compared to non-phosphorylated CaM. In this report we describe the preparation and characterization of a series of phospho-(Y)-mimetic CaM mutants in which either one or the two tyrosine residues present in CaM (Y99 and Y138) were substituted to aspartic acid or glutamic acid. It was expected that the negative charge of the respective carboxyl group of these amino acids mimics the negative charge of phosphate and reproduce the effects that distinct phospho-(Y)-CaM species may have on target proteins. We describe some physicochemical properties of these CaM mutants as compared to wild type CaM, after their expression in Escherichia coli and purification to homogeneity, including: i) changes in their electrophoretic mobility in the absence and presence of Ca2+; ii) ultraviolet (UV) light absorption spectra, far- and near-UV circular dichroism data; iii) thermal stability in the absence and presence of Ca2+; and iv) Tb3+-emitted fluorescence upon tyrosine excitation. We also describe some biochemical properties of these CaM mutants, such as their differential phosphorylation by the tyrosine kinase c-Src, and their action as compared to wild type CaM, on the activity of two CaM-dependent enzymes: cyclic nucleotide phosphodiesterase 1 (PDE1) and endothelial nitric oxide synthase (eNOS) assayed in vitro. PMID:25830911

  7. Novel Bruton’s tyrosine kinase inhibitors currently in development

    PubMed Central

    D’Cruz, Osmond J; Uckun, Fatih M

    2013-01-01

    Bruton’s tyrosine kinase (Btk) is intimately involved in multiple signal-transduction pathways regulating survival, activation, proliferation, and differentiation of B-lineage lymphoid cells. Btk is overexpressed and constitutively active in several B-lineage lymphoid malignancies. Btk has emerged as a new antiapoptotic molecular target for treatment of B-lineage leukemias and lymphomas. Preclinical and early clinical results indicate that Btk inhibitors may be useful in the treatment of leukemias and lymphomas. PMID:23493945

  8. Lysine residues direct the chlorination of tyrosines in YXXK motifs of apolipoprotein A-I when hypochlorous acid oxidizes high density lipoprotein.

    PubMed

    Bergt, Constanze; Fu, Xiaoyun; Huq, Nabiha P; Kao, Jeff; Heinecke, Jay W

    2004-02-27

    Oxidized lipoproteins may play an important role in the pathogenesis of atherosclerosis. Elevated levels of 3-chlorotyrosine, a specific end product of the reaction between hypochlorous acid (HOCl) and tyrosine residues of proteins, have been detected in atherosclerotic tissue. Thus, HOCl generated by the phagocyte enzyme myeloperoxidase represents one pathway for protein oxidation in humans. One important target of the myeloperoxidase pathway may be high density lipoprotein (HDL), which mobilizes cholesterol from artery wall cells. To determine whether activated phagocytes preferentially chlorinate specific sites in HDL, we used tandem mass spectrometry (MS/MS) to analyze apolipoprotein A-I that had been oxidized by HOCl. The major site of chlorination was a single tyrosine residue located in one of the protein's YXXK motifs (where X represents a nonreactive amino acid). To investigate the mechanism of chlorination, we exposed synthetic peptides to HOCl. The peptides encompassed the amino acid sequences YKXXY, YXXKY, or YXXXY. MS/MS analysis demonstrated that chlorination of tyrosine in the peptides that contained lysine was regioselective and occurred in high yield if the substrate was KXXY or YXXK. NMR and MS analyses revealed that the N(epsilon) amino group of lysine was initially chlorinated, which suggests that chloramine formation is the first step in tyrosine chlorination. Molecular modeling of the YXXK motif in apolipoprotein A-I demonstrated that these tyrosine and lysine residues are adjacent on the same face of an amphipathic alpha-helix. Our observations suggest that HOCl selectively targets tyrosine residues that are suitably juxtaposed to primary amino groups in proteins. This mechanism might enable phagocytes to efficiently damage proteins when they destroy microbial proteins during infection or damage host tissue during inflammation. PMID:14660678

  9. Ligand-induced IFN gamma receptor tyrosine phosphorylation couples the receptor to its signal transduction system (p91).

    PubMed Central

    Greenlund, A C; Farrar, M A; Viviano, B L; Schreiber, R D

    1994-01-01

    Herein we report that interferon-gamma (IFN gamma) induces the rapid and reversible tyrosine phosphorylation of the IFN gamma receptor. Using a panel of receptor intracellular domain mutants, we show that a membrane-proximal LPKS sequence (residues 266-269) is required for ligand-induced tyrosine kinase activation and/or kinase-receptor association and biological responsiveness, and a functionally critical membrane-distal tyrosine residue (Y440) is a target of the activated enzyme. The biological significance of Y440 phosphorylation was demonstrated by showing that a receptor-derived nonapeptide corresponding to receptor residues 436-444 and containing phosphorylated Y440 bound specifically to p91, blocked p91 phosphorylation and inhibited the generation of an active p91-containing transcription factor complex. In contrast, nonphosphorylated wild-type, phosphorylated mutant, or phosphorylated irrelevant peptides did not. Moreover, the phosphorylated Y440-containing peptide did not interact with a related but distinct latent transcription factor (p113) which is activatible by IFN alpha but not IFN gamma. These results thus document the specific and inducible association of p91 with the phosphorylated IFN gamma receptor and thereby elucidate the mechanism by which ligand couples the IFN gamma receptor to its signal transduction system. Images PMID:8156998

  10. Transformation of erythroid progenitors by viral and cellular tyrosine kinases.

    PubMed

    Beug, H; Schroeder, C; Wessely, O; Deiner, E; Meyer, S; Ischenko, I D; Hayman, M J

    1995-08-01

    Recently, two different normal avian erythroid progenitors were described. They differ in the receptor tyrosine kinases they express and in their ability to undergo self-renewal in culture. A common progenitor, termed stem cell factor (SCF) progenitor, expresses the receptor for avian SCF c-Kit, and undergoes short-term self-renewal when grown in the presence of avian SCF. A second progenitor, referred to as SCF/transforming growth factor-alpha progenitor, coexpresses c-Kit and the avian epidermal growth factor receptor homologue c-ErbB. These progenitors undergo sustained self-renewal when grown in the presence of transforming growth factor-alpha plus estradiol. The phenotype of the normal SCF/transforming growth factor-alpha progenitors closely corresponded to that of erythroid cells transformed by the tyrosine kinase oncogenes v-erbB or v-sea. This suggested that these cells, but not the SCF progenitors, would be the target cells for erythroblast transformation by these oncogenes. However, we demonstrate that both progenitor cells can be transformed by the v-erbB and v-sea oncogenes and also by the ligand-activated proto-oncogene product c-ErbB. We conclude that the target cell specificity of certain tyrosine kinase oncoproteins for erythroid cells is a reflection of their ability to provide signals for self-renewal that normally emanate from the endogenous c-ErbB protein. PMID:8547228

  11. cap alpha. -Methyl-p-tyrosine shifts circadian temperature rhythms

    SciTech Connect

    Cahill, A.L.; Ehret, C.F.

    1982-09-01

    ..cap alpha..-Methyl-p-tyrosine shifts the acrophase (time of highest temperature) of the circadian temperature rhythm of the rat to earlier or later times of day depending on the phase of the cicadian cycle at which the drug is administered. When ..cap alpha..-methyl-p-tyrosine methyl ester HCl is injected intraperitoneally at a dose of 100 mg/kg late in the projected 8-h light phase, the acrophase of the intraperitoneal temperature rhythm is delayed by up to 3 h.However, when the same dose of drug is given 9-10 h into the projected 16-h dark phase of the daily cycle, the acrophase of the temperature rhythm occurs about 2 h earlier than expected. The times of ..cap alpha..-methyl-p-tyrosine administration leading to maximal phase delays or advances are correlated with the times of minimal and maximal turnover of norepinephrine in the hypothalamus. These results suggest that changing rates of norepinephrine turnover in the hypothalamus may regulate the circadian temperature rhythm in rats. The results also emphasize the fact that the effects of drugs may vary as a function of the time of administration. This fact must be taken into account in pharmacologic testing.

  12. MERTK receptor tyrosine kinase is a therapeutic target in melanoma

    PubMed Central

    Schlegel, Jennifer; Sambade, Maria J.; Sather, Susan; Moschos, Stergios J.; Tan, Aik-Choon; Winges, Amanda; DeRyckere, Deborah; Carson, Craig C.; Trembath, Dimitri G.; Tentler, John J.; Eckhardt, S. Gail; Kuan, Pei-Fen; Hamilton, Ronald L.; Duncan, Lyn M.; Miller, C. Ryan; Nikolaishvili-Feinberg, Nana; Midkiff, Bentley R.; Liu, Jing; Zhang, Weihe; Yang, Chao; Wang, Xiaodong; Frye, Stephen V.; Earp, H. Shelton; Shields, Janiel M.; Graham, Douglas K.

    2013-01-01

    Metastatic melanoma is one of the most aggressive forms of cutaneous cancers. Although recent therapeutic advances have prolonged patient survival, the prognosis remains dismal. C-MER proto-oncogene tyrosine kinase (MERTK) is a receptor tyrosine kinase with oncogenic properties that is often overexpressed or activated in various malignancies. Using both protein immunohistochemistry and microarray analyses, we demonstrate that MERTK expression correlates with disease progression. MERTK expression was highest in metastatic melanomas, followed by primary melanomas, while the lowest expression was observed in nevi. Additionally, over half of melanoma cell lines overexpressed MERTK compared with normal human melanocytes; however, overexpression did not correlate with mutations in BRAF or RAS. Stimulation of melanoma cells with the MERTK ligand GAS6 resulted in the activation of several downstream signaling pathways including MAPK/ERK, PI3K/AKT, and JAK/STAT. MERTK inhibition via shRNA reduced MERTK-mediated downstream signaling, reduced colony formation by up to 59%, and diminished tumor volume by 60% in a human melanoma murine xenograft model. Treatment of melanoma cells with UNC1062, a novel MERTK-selective small-molecule tyrosine kinase inhibitor, reduced activation of MERTK-mediated downstream signaling, induced apoptosis in culture, reduced colony formation in soft agar, and inhibited invasion of melanoma cells. This work establishes MERTK as a therapeutic target in melanoma and provides a rationale for the continued development of MERTK-targeted therapies. PMID:23585477

  13. Direct Binding of GTP Cyclohydrolase and Tyrosine Hydroxylase

    PubMed Central

    Bowling, Kevin M.; Huang, Zhinong; Xu, Dong; Ferdousy, Faiza; Funderburk, Christopher D.; Karnik, Nirmala; Neckameyer, Wendi; O'Donnell, Janis M.

    2008-01-01

    The signaling functions of dopamine require a finely tuned regulatory network for rapid induction and suppression of output. A key target of regulation is the enzyme tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis, which is activated by phosphorylation and modulated by the availability of its cofactor, tetrahydrobiopterin. The first enzyme in the cofactor synthesis pathway, GTP cyclohydrolase I, is activated by phosphorylation and inhibited by tetrahydrobiopterin. We previously reported that deficits in GTP cyclohydrolase activity in Drosophila heterozygous for mutant alleles of the gene encoding this enzyme led to tightly corresponding diminution of in vivo tyrosine hydroxylase activity that could not be rescued by exogenous cofactor. We also found that the two enzymes could be coimmunoprecipitated from tissue extracts and proposed functional interactions between the enzymes that extended beyond provision of cofactor by one pathway for another. Here, we confirm the physical association of these enzymes, identifying interacting regions in both, and we demonstrate that their association can be regulated by phosphorylation. The functional consequences of the interaction include an increase in GTP cyclohydrolase activity, with concomitant protection from end-product feedback inhibition. In vivo, this effect would in turn provide sufficient cofactor when demand for catecholamine synthesis is greatest. The activity of tyrosine hydroxylase is also increased by this interaction, in excess of the stimulation resulting from phosphorylation alone. Vmax is elevated, with no change in Km. These results demonstrate that these enzymes engage in mutual positive regulation. PMID:18801743

  14. 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. PMID:12237126

  15. Protein tyrosine phosphorylation during meiotic divisions of starfish oocytes

    SciTech Connect

    Peaucellier, G.; Andersen, A.C.; Kinsey, W.H. )

    1990-04-01

    We have used an antibody specific for phosphotyrosine to investigate protein phosphorylation on tyrosine during hormone-induced maturation of starfish oocytes. Analysis of immunoprecipitates from cortices of in vivo labeled Marthasterias glacialis oocytes revealed the presence of labeled phosphotyrosine-containing proteins only after hormone addition. Six major phosphoproteins of 195, 155, 100, 85, 45, and 35 kDa were detected. Total activity in immunoprecipitates increased until first polar body emission and was greatly reduced upon completion of meiosis but some proteins exhibited different kinetics. The labeling of the 155-kDa protein reached a maximum at germinal vesicle breakdown, while the 35-kDa appeared later and disappeared after polar body emission. Similar results were obtained with Asterias rubens oocytes. In vitro phosphorylation of cortices showed that tyrosine kinase activity is a major protein kinase activity in this fraction, the main endogenous substrate being a 68-kDa protein. The proteins phosphorylated on tyrosine in vitro were almost similar in extracts from oocytes treated or not with the hormone.

  16. Involvement of the Tyrosine Kinase Fer in Cell Adhesion

    PubMed Central

    Rosato, Roberto; Veltmaat, Jacqueline M.; Groffen, John; Heisterkamp, Nora

    1998-01-01

    The Fer protein belongs to the fes/fps family of nontransmembrane receptor tyrosine kinases. Lack of success in attempts to establish a permanent cell line overexpressing it at significant levels suggested a strong negative selection against too much Fer protein and pointed to a critical cellular function for Fer. Using a tetracycline-regulatable expression system, overexpression of Fer in embryonic fibroblasts was shown to evoke a massive rounding up, and the subsequent detachment of the cells from the substratum, which eventually led to cell death. Induction of Fer expression coincided with increased complex formation between Fer and the cadherin/src-associated substrate p120cas and elevated tyrosine phosphorylation of p120cas. β-Catenin also exhibited clearly increased phosphotyrosine levels, and Fer and β-catenin were found to be in complex. Significantly, although the levels of α-catenin, β-catenin, and E-cadherin were unaffected by Fer overexpression, decreased amounts of α-catenin and β-catenin were coimmunoprecipitated with E-cadherin, demonstrating a dissolution of adherens junction complexes. A concomitant decrease in levels of phosphotyrosine in the focal adhesion-associated protein p130 was also observed. Together, these results provide a mechanism for explaining the phenotype of cells overexpressing Fer and indicate that the Fer tyrosine kinase has a function in the regulation of cell-cell adhesion. PMID:9742093

  17. Eph-mediated tyrosine phosphorylation of citron kinase controls abscission.

    PubMed

    Jungas, Thomas; Perchey, Renaud T; Fawal, Mohamad; Callot, Caroline; Froment, Carine; Burlet-Schiltz, Odile; Besson, Arnaud; Davy, Alice

    2016-08-29

    Cytokinesis is the last step of cell division, culminating in the physical separation of daughter cells at the end of mitosis. Cytokinesis is a tightly regulated process that until recently was mostly viewed as a cell-autonomous event. Here, we investigated the role of Ephrin/Eph signaling, a well-known local cell-to-cell communication pathway, in cell division. We show that activation of Eph signaling in vitro leads to multinucleation and polyploidy, and we demonstrate that this is caused by alteration of the ultimate step of cytokinesis, abscission. Control of abscission requires Eph kinase activity, and Src and citron kinase (CitK) are downstream effectors in the Eph-induced signal transduction cascade. CitK is phosphorylated on tyrosines in neural progenitors in vivo, and Src kinase directly phosphorylates CitK. We have identified the specific tyrosine residues of CitK that are phosphorylated and show that tyrosine phosphorylation of CitK impairs cytokinesis. Finally, we show that, similar to CitK, Ephrin/Eph signaling controls neuronal ploidy in the developing neocortex. Our study indicates that CitK integrates intracellular and extracellular signals provided by the local environment to coordinate completion of cytokinesis. PMID:27551053

  18. eps15, a novel tyrosine kinase substrate, exhibits transforming activity.

    PubMed Central

    Fazioli, F; Minichiello, L; Matoskova, B; Wong, W T; Di Fiore, P P

    1993-01-01

    An expression cloning method which allows direct isolation of cDNAs encoding substrates for tyrosine kinases was applied to the study of the epidermal growth factor (EGF) receptor (EGFR) signaling pathway. A previously undescribed cDNA was isolated and designated eps15. The structural features of the predicted eps15 gene product allow its subdivision into three domains. Domain I contains signatures of a regulatory domain, including a candidate tyrosine phosphorylation site and EF-hand-type calcium-binding domains. Domain II presents the characteristic heptad repeats of coiled-coil rod-like proteins, and domain III displays a repeated aspartic acid-proline-phenylalanine motif similar to a consensus sequence of several methylases. Antibodies specific for the eps15 gene product recognize two proteins: a major species of 142 kDa and a minor component of 155 kDa, both of which are phosphorylated on tyrosine following EGFR activation by EGF in vivo. EGFR is also able to directly phosphorylate the eps15 product in vitro. In addition, phosphorylation of the eps15 gene product in vivo is relatively receptor specific, since the erbB-2 kinase phosphorylates it very inefficiently. Finally, overexpression of eps15 is sufficient to transform NIH 3T3 cells, thus suggesting that the eps15 gene product is involved in the regulation of mitogenic signals. Images PMID:7689153

  19. Phosphorylation of caveolin-1 on tyrosine-14 induced by ROS enhances palmitate-induced death of beta-pancreatic cells.

    PubMed

    Wehinger, Sergio; Ortiz, Rina; Díaz, María Inés; Aguirre, Adam; Valenzuela, Manuel; Llanos, Paola; Mc Master, Christopher; Leyton, Lisette; Quest, Andrew F G

    2015-05-01

    A considerable body of evidence exists implicating high levels of free saturated fatty acids in beta pancreatic cell death, although the molecular mechanisms and the signaling pathways involved have not been clearly defined. The membrane protein caveolin-1 has long been implicated in cell death, either by sensitizing to or directly inducing apoptosis and it is normally expressed in beta cells. Here, we tested whether the presence of caveolin-1 modulates free fatty acid-induced beta cell death by reexpressing this protein in MIN6 murine beta cells lacking caveolin-1. Incubation of MIN6 with palmitate, but not oleate, induced apoptotic cell death that was enhanced by the presence of caveolin-1. Moreover, palmitate induced de novo ceramide synthesis, loss of mitochondrial transmembrane potential and reactive oxygen species (ROS) formation in MIN6 cells. ROS generation promoted caveolin-1 phosphorylation on tyrosine-14 that was abrogated by the anti-oxidant N-acetylcysteine or the incubation with the Src-family kinase inhibitor, PP2 (4-amino-5-(4-chlorophenyl)-7(dimethylethyl)pyrazolo[3,4-d]pyrimidine). The expression of a non-phosphorylatable caveolin-1 tyrosine-14 to phenylalanine mutant failed to enhance palmitate-induced apoptosis while for MIN6 cells expressing the phospho-mimetic tyrosine-14 to glutamic acid mutant caveolin-1 palmitate sensitivity was comparable to that observed for MIN6 cells expressing wild type caveolin-1. Thus, caveolin-1 expression promotes palmitate-induced ROS-dependent apoptosis in MIN6 cells in a manner requiring Src family kinase mediated tyrosine-14 phosphorylation. PMID:25572853

  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. Protein Tyrosine Phosphatase φ Regulates Paxillin Tyrosine Phosphorylation and Mediates Colony-Stimulating Factor 1-Induced Morphological Changes in Macrophages

    PubMed Central

    Pixley, Fiona J.; Lee, Pierre S. W.; Condeelis, John S.; Stanley, E. Richard

    2001-01-01

    Removal of colony-stimulating factor 1 (CSF-1) causes macrophages to round up and to increase their expression of protein tyrosine phosphatase φ (PTPφ). This is accompanied by the disruption of focal complexes and the formation of ruffles. Here we have overexpressed wild-type (WT) PTPφ and a phosphatase-inactive (C325S) mutant in a macrophage cell line in the presence and absence of CSF-1. In the presence of CSF-1, WT PTPφ induces cell rounding and ruffle formation, while C325S PTPφ has no effect. In contrast, in CSF-1-starved cells, C325S PTPφ behaves in a dominant negative fashion, preventing rounding and ruffling. Furthermore, C325S PTPφ increases adhesion in cycling cells, while WT PTPφ enhances motility. In WT PTPφ-overexpressing cells, the focal contact protein paxillin is selectively depleted from focal complexes and specifically dephosphorylated on tyrosine. In contrast, paxillin is hyperphosphorylated in C325S PTPφ-expressing cells. Moreover, a complex containing PTPφ, paxillin, and a paxillin-associated tyrosine kinase, Pyk2, can be immunoprecipitated from macrophage lysates, and the catalytic domain of PTPφ selectively binds paxillin and Pyk2 in vitro. Although PTPφ and Pyk2 do not colocalize with paxillin in focal complexes, all three proteins are colocalized in dorsal ruffles. The results suggest that paxillin is dephosphorylated by PTPφ in dorsal ruffles, using Pyk2 as a bridging molecule, resulting in a reduced pool of tyrosine-phosphorylated paxillin available for incorporation into focal complexes, thereby mediating CSF-1 regulation of macrophage morphology, adhesion, and motility. PMID:11238916

  2. Tyrosine Phosphorylation and Dephosphorylation in Burkholderia cenocepacia Affect Biofilm Formation, Growth under Nutritional Deprivation, and Pathogenicity

    PubMed Central

    Andrade, Angel; Tavares-Carreón, Faviola; Khodai-Kalaki, Maryam

    2015-01-01

    Burkholderia cenocepacia, a member of the B. cepacia complex (Bcc), is an opportunistic pathogen causing serious chronic infections in patients with cystic fibrosis. Tyrosine phosphorylation has emerged as an important posttranslational modification modulating the physiology and pathogenicity of Bcc bacteria. Here, we investigated the predicted bacterial tyrosine kinases BCAM1331 and BceF and the low-molecular-weight protein tyrosine phosphatases BCAM0208, BceD, and BCAL2200 of B. cenocepacia K56-2. We show that BCAM1331, BceF, BCAM0208, and BceD contribute to biofilm formation, while BCAL2200 is required for growth under nutrient-limited conditions. Multiple deletions of either tyrosine kinase or low-molecular-weight protein tyrosine phosphatase genes resulted in the attenuation of B. cenocepacia intramacrophage survival and reduced pathogenicity in the Galleria mellonella larval infection model. Experimental evidence indicates that BCAM1331 displays reduced tyrosine autophosphorylation activity compared to that of BceF. With the artificial substrate p-nitrophenyl phosphate, the phosphatase activities of the three low-molecular-weight protein tyrosine phosphatases demonstrated similar kinetic parameters. However, only BCAM0208 and BceD could dephosphorylate BceF. Further, BCAL2200 became tyrosine phosphorylated in vivo and catalyzed its autodephosphorylation. Together, our data suggest that despite having similar biochemical activities, low-molecular-weight protein tyrosine phosphatases and tyrosine kinases have both overlapping and specific roles in the physiology of B. cenocepacia. PMID:26590274

  3. Effects of hemorrhagic hypotension on tyrosine concentrations in rat spinal cord and plasma

    NASA Technical Reports Server (NTRS)

    Conlay, L. A.; Maher, T. J.; Roberts, C. H.; Wurtman, R. J.

    1988-01-01

    Tyrosine is the precursor for catecholamine neurotransmitters. When catecholamine-containing neurons are physiologically active (as sympathoadrenal cells are in hypotension), tyrosine administration increases catecholamine synthesis and release. Since hypotension can alter plasma amino acid composition, the effects of an acute hypotensive insult on tyrosine concentrations in plasma and spinal cord were examined. Rats were cannulated and bled until the systolic blood pressure was 50 mmHg, or were kept normotensive for 1 h. Tyrosine and other large neutral amino acids (LNAA) known to compete with tyrosine for brain uptake were assayed in plasma and spinal cord. The rate at which intra-arterial (H-3)tyrosine disappeared from the plasma was also estimated in hemorrhaged and control rats. In plasma of hemorrhaged animals, both the tyrosine concentration and the tyrosine/LNAA ratio was elevated; moreover, the disappearance of (H-3)tyrosine was slowed. Tyrosine concentrations also increased in spinal cords of hemorrhaged-hypotensive rats when compared to normotensive controls. Changes in plasma amino acid patterns may thus influence spinal cord concentrations of amino acid precursors for neurotransmitters during the stress of hemorrhagic shock.

  4. Para-Tyrosine Supplementation Improves Insulin- and Liraglutide- Induced Vasorelaxation in Cholesterol-Fed Rats.

    PubMed

    Sélley, Eszter; Kun, Szilárd; Kürthy, Mária; Kovács, Tibor; Wittmann, István; Molnár, Gergo A

    2015-01-01

    Former data of our workgroup indicated that the accumulation of oxidized amino acids (meta- and ortho-tyrosine) due to oxidative stress may play an important role in the impaired insulininduced vasoactive properties of different arterial segments. There are evidences, that incorporation of these amino acids into cellular proteins leads to certain hormonal resistances, which might be restored by supplementation with the physiologic isoform, para-tyrosine. Rats in the control group were kept on a regular diet, rats in the cholesterol-fed group received high-fat diet, while the third group of rats received high-fat diet with para-tyrosine supplementation for 16 weeks. Plasma cholesterol level was significantly higher in the cholesterol-fed group, while the level of cholesterol in the cholesterol+para-tyrosine group did not differ significantly from that of the controls. Plasma level of insulin after glucose stimulation was decreased in the cholesterol-fed group, while that in the para-tyrosine supplemented group did not differ significantly from the controls. Vascular para-, meta- and ortho-tyrosine content was measured with HPLC. Elevated vascular meta-tyrosine/para-tyrosine ratio of cholesterol fed rats could be avoided by para-tyrosine supplementation. Vascular response of the thoracic aorta to insulin and liraglutide was assessed by a DMT multi-myograph. Cholesterol feeding resulted in vascular insulin-and liraglutide resistance, which was restored by para-tyrosine supplementation. Incorporation of the oxidative stress induced pathological tyrosine isoforms leads to vascular-hormone-resistances. We show that the physiological amino acid para-tyrosine is capable of restoring hypercholesterolemia-induced increased meta-tyrosine content of the vascular wall, thus attenuating functional vascular damage. PMID:26202368

  5. SPS 91 - Power from space; Proceedings of the 2nd International Symposium, Ecole Superieure d'Electricite, Gif-sur-Yvette, France, Aug. 27-30, 1991

    NASA Astrophysics Data System (ADS)

    Various papers on the concept of Solar Power Satellites (SPS) are presented. The general topics addressed include: global energy issues; SPS demonstration projects; extraterrestrial materials; power generation, conversion, and storage; environmental issues; development strategies.

  6. 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.

  7. Expression of receptor protein tyrosine phosphatase δ, PTPδ, in mouse central nervous system.

    PubMed

    Shishikura, Maria; Nakamura, Fumio; Yamashita, Naoya; Uetani, Noriko; Iwakura, Yoichiro; Goshima, Yoshio

    2016-07-01

    Protein tyrosine phosphate δ (PTPδ), one of the receptor type IIa protein tyrosine phosphates, is known for its roles in axon guidance, synapse formation, cell adhesion, and tumor suppression. Alternative splicing of this gene generates at least four (A-D) isoforms; however, the major isoform in vivo is yet to be determined. The protein localization has neither been revealed. We have generated anti-mouse PTPδ-specific monoclonal antibody and analyzed the protein expression in wild-type and Ptpδ knockout mice. Immunoblot analysis of various organs revealed that neuronal tissues express both C-and D-isoforms of PTPδ, whereas non-neuronal tissues express only C-isoform. Immunohistochemistry of wild-type or Ptpδ heterozygous sections showed that olfactory bulb, cerebral cortex, hippocampus, cerebellum, and several nuclei in brain stem exhibit moderate to strong positive signals. These signals were absent in Ptpδ knockout specimens. Higher magnification revealed differences between expression patterns of PTPδ mRNA and its protein product. In hippocampus, weak mRNA expression in CA1 stratum pyramidale but strong immunostaining in the stratum lacunosum moleculare was observed, suggesting the axonal expression of PTPδ in the entorhinal cortical afferents. Olfactory mitral cells exhibited mRNA expression in cell bodies and protein localization in their dendritic fields, glomerular and external plexiform layers. Nissl staining showed that the external plexiform layer was reduced in Ptpδ knockout mice. Golgi-impregnation confirmed the poor dendritic growth of homozygous mitral cells. These results suggest that PTPδ may localize in axons as well as in dendrites to regulate their elaboration in the central nervous system. PMID:27026654

  8. 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

  9. The Biological Buffer, Bicarbonate/CO2, Potentiates H2O2-Mediated Inactivation of Protein Tyrosine Phosphatases

    PubMed Central

    Zhou, Haiying; Singh, Harkewal; Parsons, Zachary D.; Lewis, Sarah M.; Bhattacharya, Sanjib; Seiner, Derrick R.; LaButti, Jason N.; Reilly, Thomas J.; Tanner, John J.; Gates, Kent S.

    2012-01-01

    Hydrogen peroxide is a cell signaling agent that inactivates protein tyrosine phosphatases (PTPs) via oxidation of their catalytic cysteine residue. PTPs are inactivated rapidly during H2O2-mediated cellular signal transduction processes but, paradoxically, hydrogen peroxide is a rather sluggish PTP inactivator in vitro. Here we present evidence that the biological buffer, bicarbonate/CO2, potentiates the ability of H2O2 to inactivate PTPs. The results of biochemical experiments and high resolution crystallographic analysis are consistent with a mechanism involving oxidation of the catalytic cysteine residue by peroxymonocarbonate generated via the reaction of H2O2 with HCO3 −/CO2. PMID:21913686

  10. Intracellular Growth Is Dependent on Tyrosine Catabolism in the Dimorphic Fungal Pathogen Penicillium marneffei

    PubMed Central

    Boyce, Kylie J.; McLauchlan, Alisha; Schreider, Lena; Andrianopoulos, Alex

    2015-01-01

    During infection, pathogens must utilise the available nutrient sources in order to grow while simultaneously evading or tolerating the host’s defence systems. Amino acids are an important nutritional source for pathogenic fungi and can be assimilated from host proteins to provide both carbon and nitrogen. The hpdA gene of the dimorphic fungus Penicillium marneffei, which encodes an enzyme which catalyses the second step of tyrosine catabolism, was identified as up-regulated in pathogenic yeast cells. As well as enabling the fungus to acquire carbon and nitrogen, tyrosine is also a precursor in the formation of two types of protective melanin; DOPA melanin and pyomelanin. Chemical inhibition of HpdA in P. marneffei inhibits ex vivo yeast cell production suggesting that tyrosine is a key nutrient source during infectious growth. The genes required for tyrosine catabolism, including hpdA, are located in a gene cluster and the expression of these genes is induced in the presence of tyrosine. A gene (hmgR) encoding a Zn(II)2-Cys6 binuclear cluster transcription factor is present within the cluster and is required for tyrosine induced expression and repression in the presence of a preferred nitrogen source. AreA, the GATA-type transcription factor which regulates the global response to limiting nitrogen conditions negatively regulates expression of cluster genes in the absence of tyrosine and is required for nitrogen metabolite repression. Deletion of the tyrosine catabolic genes in the cluster affects growth on tyrosine as either a nitrogen or carbon source and affects pyomelanin, but not DOPA melanin, production. In contrast to other genes of the tyrosine catabolic cluster, deletion of hpdA results in no growth within macrophages. This suggests that the ability to catabolise tyrosine is not required for macrophage infection and that HpdA has an additional novel role to that of tyrosine catabolism and pyomelanin production during growth in host cells. PMID:25812137

  11. Effects of systemic L-tyrosine on dopamine release from rat corpus striatum and nucleus accumbens

    NASA Technical Reports Server (NTRS)

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

    1988-01-01

    Intracerebral dialysis was used to monitor extracellular fluid from rat striatum and nucleus accumbens following the intraperitoneal administration of tyrosine. Dopamine concentrations in dialysates from both the striatum and the nucleus accumbens increased significantly in response to the tyrosine. The magnitude of the tyrosine effect was greater in the nucleus accumbens than in the striatum. Hence, mesolimbic dopaminergic neurons may be especially responsive to precursor availability.

  12. Managing side effects of tyrosine kinase inhibitor therapy to optimize adherence in patients with chronic myeloid leukemia: the role of the midlevel practitioner.

    PubMed

    Cornelison, Megan; Jabbour, Elias J; Welch, Mary Alma

    2012-01-01

    In the last decade, the development of imatinib, a tyrosine kinase inhibitor, has brought about unprecedented change in the way newly diagnosed, chronic-phase chronic myeloid leukemia patients are treated. Two next-generation tyrosine kinase inhibitors, nilotinib and dasatinib, were initially indicated for imatinib-resistant or imatinib-intolerant chronic myeloid leukemia patients and recently received approval from the Food and Drug Administration for treatment of newly diagnosed, chronic-phase chronic myeloid leukemia patients. In comparison with the previous standards of care, benefits with these three tyrosine kinase inhibitors have included more rapid response rates, increased survival, and fewer side effects. The improved long-term outcomes have altered the approach to management of chronic myeloid leukemia from a progressive fatal disease with a poor prognosis to a chronic condition similar to diabetes or hypertension. Prolonged survival increases the need for patient education, support, monitoring, and assistance with adverse event management. Even low-grade side effects can adversely affect patients' quality of life and, therefore, require prompt attention to prevent long-term complications or suboptimal outcomes. New evidence has indicated that patient adherence to tyrosine kinase inhibitor therapy is essential to successful treatment. Midlevel practitioners can help to optimize outcomes by educating patients regarding the importance of adherence, performing regular monitoring, helping patients to understand their test results, and aggressively managing treatment-related side effects. PMID:22244674

  13. Targeted Disruption of Tyrosylprotein Sulfotransferase-2, an Enzyme that Catalyzes Post-Translational Protein Tyrosine O-Sulfation, Causes Male Infertility*

    PubMed Central

    Borghei, Atefeh; Ouyang, Ying-Bin; Westmuckett, Andrew D.; Marcello, Matthew R.; Landel, Carlisle P.; Evans, Janice P.; Moore, Kevin L.

    2006-01-01

    Tyrosine O-sulfation is a post-translational modification mediated by one of two Golgi tyrosylprotein sulfotransferases (TPST-1 and -2) expressed in all mammalian cells. Tyrosine sulfation plays an important role in the function of some known TPST substrates by enhancing protein-protein interactions. To explore the role of these enzymes in vivo, and gain insight into other potential TPST substrates, TPST-2 deficient mice were generated by targeted disruption of the Tpst2 gene. Tpst2+/- mice appear normal and, when interbred, yield litters of normal size with a Mendelian distribution of the targeted mutation. Tpst2-/- mice have moderately delayed growth, but appear healthy and attain normal body weight by 10 weeks of age. In contrast to Tpst1-/- males that have normal fertility, Tpst2-/- males are infertile. Tpst2-/- sperm are normal in number, morphology, and motility in normal media and appear to capacitate and undergo acrosomal exocytosis normally. However, they are severely defective in their motility in viscous media and in their ability to fertilize zona pellucida (ZP)-intact eggs. Adhesion of Tpst2-/- sperm to the egg plasma membrane is reduced compared to wild type sperm, but sperm-egg fusion is similar or even increased. These data strongly suggest that tyrosine sulfation of unidentified substrate(s) play a crucial role in these processes and document for the first time the critical importance of post-translational tyrosine sulfation in male fertility. PMID:16469738

  14. Genomic organization of Bruton`s tyrosine kinase

    SciTech Connect

    Rohrer, J.; Conley, M.E.

    1994-09-01

    Bruton`s tyrosine kinase (Btk), is a nonreceptor tyrosine kinase that has been identified as the defective gene in X-linked agammaglobulinemia (XLA). XLA patients have profound hypogammaglobulinemia and markedly reduced numbers of B cells while their T cell and phagocyte numbers remain normal. To determine the genomic organization of Btk, intron/exon borders were identified by sequencing cosmid DNA using cDNA primers. Nineteen exons spanning 37 kb of genomic DNA were identified. All the intron/exon splice junctions followed the GT/AG rule. The translational ATG start codon was in exon 2 which was 6 kb downstream of exon 1. Exon 19, 519 bp in length and 3.8 kb distal to exon 18, was the largest exon and included the 450 bp of the 3{prime} untranslated region. Exons 6 through 18 formed the largest cluster of exons with no intron being longer than 1550 bp. There was no apparent correlation between the exon boundaries of Btk and the functional domains of the protein or the exon boundaries of src, the nonreceptor protein tyrosine kinase prototype. The region 500 bp upstream of the presumed transcriptional start site was sequenced and found to have a G+C content of 52%. No TATA-type promoter elements in the -20 bp to -30 bp region were identified. However, at position -48 bp, a TGTGAA motif was found that bears some similarity to the TATA box. This sequence was preceded by a perfect inverted CCAAT box at position -90 bp. Three retinoic acid binding sites were also identified at positions -50 bp, -83 bp and -197 bp. Defining the genomic structure of Btk will permit us to identify regulatory elements in this gene and to identify mutations in genomic DNA of patients with XLA.

  15. Tyrosine Aminotransferase: Biochemical and Structural Properties and Molecular Dynamics Simulations

    SciTech Connect

    P Mehere; Q Han; J Lemkul; C Vavricka; H Robinson; D Bevan; J Li

    2011-12-31

    Tyrosine aminotransferase (TAT) catalyzes the transamination of tyrosine and other aromatic amino acids. The enzyme is thought to play a role in tyrosinemia type II, hepatitis and hepatic carcinoma recovery. The objective of this study is to investigate its biochemical and structural characteristics and substrate specificity in order to provide insight regarding its involvement in these diseases. Mouse TAT (mTAT) was cloned from a mouse cDNA library, and its recombinant protein was produced using Escherichia coli cells and purified using various chromatographic techniques. The recombinant mTAT is able to catalyze the transamination of tyrosine using {alpha}-ketoglutaric acid as an amino group acceptor at neutral pH. The enzyme also can use glutamate and phenylalanine as amino group donors and p-hydroxy-phenylpyruvate, phenylpyruvate and alpha-ketocaproic acid as amino group acceptors. Through macromolecular crystallography we have determined the mTAT crystal structure at 2.9 {angstrom} resolution. The crystal structure revealed the interaction between the pyridoxal-5'-phosphate cofactor and the enzyme, as well as the formation of a disulphide bond. The detection of disulphide bond provides some rational explanation regarding previously observed TAT inactivation under oxidative conditions and reactivation of the inactive TAT in the presence of a reducing agent. Molecular dynamics simulations using the crystal structures of Trypanosoma cruzi TAT and human TAT provided further insight regarding the substrate-enzyme interactions and substrate specificity. The biochemical and structural properties of TAT and the binding of its cofactor and the substrate may help in elucidation of the mechanism of TAT inhibition and activation.

  16. Tyrosine aminotransferase: biochemical and structural properties and molecular dynamics simulations

    SciTech Connect

    Mehere, P.; Robinson, H.; Han, Q.; Lemkul, J. A.; Vavricka, C. J.; Bevan, D. R.; Li, J.

    2010-11-01

    Tyrosine aminotransferase (TAT) catalyzes the transamination of tyrosine and other aromatic amino acids. The enzyme is thought to play a role in tyrosinemia type II, hepatitis and hepatic carcinoma recovery. The objective of this study is to investigate its biochemical and structural characteristics and substrate specificity in order to provide insight regarding its involvement in these diseases. Mouse TAT (mTAT) was cloned from a mouse cDNA library, and its recombinant protein was produced using Escherichia coli cells and purified using various chromatographic techniques. The recombinant mTAT is able to catalyze the transamination of tyrosine using {alpha}-ketoglutaric acid as an amino group acceptor at neutral pH. The enzyme also can use glutamate and phenylalanine as amino group donors and p-hydroxy-phenylpyruvate, phenylpyruvate and alpha-ketocaproic acid as amino group acceptors. Through macromolecular crystallography we have determined the mTAT crystal structure at 2.9 {angstrom} resolution. The crystal structure revealed the interaction between the pyridoxal-5'-phosphate cofactor and the enzyme, as well as the formation of a disulphide bond. The detection of disulphide bond provides some rational explanation regarding previously observed TAT inactivation under oxidative conditions and reactivation of the inactive TAT in the presence of a reducing agent. Molecular dynamics simulations using the crystal structures of Trypanosoma cruzi TAT and human TAT provided further insight regarding the substrate-enzyme interactions and substrate specificity. The biochemical and structural properties of TAT and the binding of its cofactor and the substrate may help in elucidation of the mechanism of TAT inhibition and activation.

  17. PROCEEDINGS OF THE STATIONARY SOURCE COMBUSTION SYMPOSIUM (2ND) HELD IN NEW ORLEANS, LA. ON AUGUST 29-SEPTEMBER 1, 1977. VOLUME II. UTILITY AND LARGE INDUSTRIAL BOILERS

    EPA Science Inventory

    ;Contents: Field testing--application of combustion modification to power generating combustion sources; Analysis of NOx control in stationary sources; Overfire air technology for tangentially fired utility boilers burning western U.S. coal; The EPRI program on NOx control using ...

  18. Character Education Connections for School, Home and Community: A Guide for Integrating Character Education. Grades Pre-K through 12. 2nd Edition.

    ERIC Educational Resources Information Center

    Stirling, Diane

    This character education guide, for grades Pre-K through 12, presents field-generated, field-tested ideas for integrating character education with daily learning. The ideas are varied in design, scope, and developmental levels and range from half-hour lessons to school-wide events to year-long courses. Each unit (50 in all) is built on particular…

  19. ENVIRONMENTAL PROTECTION AGENCY (EPA) FINE PARTICLE SCRUBBER SYMPOSIUM (2ND) HELD IN NEW ORLEANS, LOUISIANA ON MAY 2-3, 1977

    EPA Science Inventory

    The report presents the proceedings, including introductory remarks and 16 technical papers, of the Second Fine Particle Scrubber Symposium, held May 2-3, 1977, in New Orleans. Sponsored by the U.S. Environmental Protection Agency, the symposium was held to stimulate and generate...

  20. Involvement of the N-terminal unique domain of Chk tyrosine kinase in Chk-induced tyrosine phosphorylation in the nucleus

    SciTech Connect

    Nakayama, Yuji; Kawana, Akiko; Igarashi, Asae; Yamaguchi, Naoto . E-mail: nyama@p.chiba-u.ac.jp

    2006-07-15

    Chk tyrosine kinase phosphorylates Src-family kinases and suppresses their kinase activity. We recently showed that Chk localizes to the nucleus as well as the cytoplasm and inhibits cell proliferation. In this study, we explored the role of the N-terminal unique domain of Chk in nuclear localization and Chk-induced tyrosine phosphorylation in the nucleus. In situ binding experiments showed that the N-terminal domain of Chk was associated with the nucleus and the nuclear matrix. The presence of the N-terminal domain of Chk led to a fourfold increase in cell population exhibiting Chk-induced tyrosine phosphorylation in the nucleus. Expression of Chk but not kinase-deficient Chk induced tyrosine phosphorylation of a variety of proteins ranging from 23 kDa to {approx}200 kDa, especially in Triton X-100-insoluble fraction that included chromatin and the nuclear matrix. Intriguingly, in situ subnuclear fractionations revealed that Chk induced tyrosine phosphorylation of proteins that were associated with the nuclear matrix. These results suggest that various unidentified substrates of Chk, besides Src-family kinases, may be present in the nucleus. Thus, our findings indicate that the importance of the N-terminal domain to Chk-induced tyrosine phosphorylation in the nucleus, implicating that these nuclear tyrosine-phosphorylated proteins may contribute to inhibition of cell proliferation.