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Sample records for 2nd generation tyrosine

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

    PubMed Central

    Jayakar, Vishal

    2014-01-01

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

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

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

    PubMed

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

    2014-07-01

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

  4. 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.

  5. 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).

  6. 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.

  7. 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

  8. 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.

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

    PubMed

    Greene, Peter R; Medina, Antonio

    2016-10-01

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

  10. 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.

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

    PubMed Central

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

    2016-01-01

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

  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. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. 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

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

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

    PubMed

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

    2015-08-01

    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

  8. Integrated Vehicle Health Management for the 2nd Generation RLV Program

    NASA Technical Reports Server (NTRS)

    Merriam, Marshal L.

    2000-01-01

    This viewgraph presentation gives an overview of the Integrated Vehicle Health Management (IVHM) for Second Generation Reusable Launch Vehicle (RLV) program, including details on the second and third RLV programs, IVHM activity at Kennedy Space Center, the NASA X-37 IVHM flight experiment, propulsion and power IVHM, IVHM technologies at the Jet Propulsion Laboratory, structures IVHM for third generation RLVs, and IVHM systems engineering and integration.

  9. 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.

  10. 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.

  11. 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.

  12. Nonlinearly generated harmonic signals in ultra-small waveguides with magnetic films: Tunable enhancements of 2nd and 4th harmonics

    NASA Astrophysics Data System (ADS)

    Marsh, J.; Zagorodnii, V.; Celinski, Z.; Camley, R. E.

    2012-03-01

    The nonlinear generation of high harmonic signals (up to 5th harmonic) is explored in an ultra-small waveguide which contains a thin ferromagnetic film. The strength of the different harmonics is highly tunable. In particular, the power in the 2nd and 4th harmonic signals may be enhanced by over two orders of magnitude by varying the direction of a static magnetic field with respect to the long axis of the waveguide. In contrast, the 3rd and 5th harmonics are relatively insensitive to the direction of the magnetic field. The experimental results are explained by analytical and numerical calculations.

  13. 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%.

  14. 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.

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

    NASA Astrophysics Data System (ADS)

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

    2016-09-01

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

  16. 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.

  17. Second-generation inhibitors of Bruton tyrosine kinase.

    PubMed

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

    2016-01-01

    Bruton tyrosine kinase (BTK) is a critical effector molecule for B cell development and plays a major role in lymphoma genesis. Ibrutinib is the first-generation BTK inhibitor. Ibrutinib has off-target effects on EGFR, ITK, and Tec family kinases, which explains the untoward effects of ibrutinib. Resistance to ibrutinib was also reported. The C481S mutation in the BTK kinase domain was reported to be a major mechanism of resistance to ibrutinib. This review summarizes the clinical development of novel BTK inhibitors, ACP-196 (acalabrutinib), ONO/GS-4059, and BGB-3111. PMID:27590878

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

    NASA Astrophysics Data System (ADS)

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

    2011-09-01

    GM/CA-CAT at Sector 23 of the Advanced Photon Source (APS) is an NIH funded facility for crystallographic structure determination of biological macromolecules by X-ray diffraction. A second-generation Berkeley automounter is being integrated into the beamline control system at the 23BM 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.

  19. 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.

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

    NASA Astrophysics Data System (ADS)

    Fisher, J. E.; Lawrence, D. A.; Zhu, J. J.

    2002-01-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2016-10-01

    An analytical benchmark and a simple consistent Mathematica program are proposed for graphene and carbon nanotubes, that may serve to test any molecular dynamics code implemented with REBO potentials. By exploiting the benchmark, we checked results produced by LAMMPS (Large-scale Atomic/Molecular Massively Parallel Simulator) when adopting the second generation Brenner potential, we made evident that this code in its current implementation produces results which are offset from those of the benchmark by a significant amount, and provide evidence of the reason. Catalogue identifier: AFAS_v1_0 Program summary URL:http://cpc.cs.qub.ac.uk/summaries/AFAS_v1_0.html Program obtainable from: CPC Program Library, Queen's University, Belfast, N. Ireland Licensing provisions: GNU GPL v3 No. of lines in distributed program, including test data, etc.: 22854 No. of bytes in distributed program, including test data, etc.: 369171 Distribution format: tar.gz Programming language: Mathematica 9. Computer: Any PC. Operating system: Any which supports Mathematica; tested under OS Yosemite. RAM: <5 gigabytes Classification: 7.7, 16.1, 16.13. Nature of problem: Testing commercial or open-source molecular dynamics codes implementing off-the-shelf REBO potentials on an analytical benchmark. Solution method: Analytical equilibrium conditions for achiral carbon nanotubes are implemented and solved, delivering benchmark values for the corresponding natural radius and cohesive energy; material properties (Young's modulus and Poisson coefficient) are also computed. Running time: Instantaneous, or a few seconds, depending on computer hardware

  2. 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

  3. 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.

  4. 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

  5. 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.

  6. Generation Mechanism of Deferoxamine Radical by Tyrosine-Tyrosinase Reaction.

    PubMed

    Tada, Mika; Niwano, Yoshimi; Kohno, Masahiro

    2015-01-01

    Nitroxide radical formations of deferoxamine mesylate (DFX) that is used clinically to treat iron-overload patients was examined by a tyrosine-tyrosinase reaction system as models of the H-atom transfer or proton-coupled electron transfer. When DFX was exposed to the tyrosine-tyrosinase reaction, nine-line ESR spectrum (g = 2.0063, hfcc; aN = 0.78 mT, aH(2) = 0.63 mT) was detected, indicating that the oxidation of DFX leads to a nitroxide radical. The signal intensity of the DFX radical increased dependently on the concentrations of tyrosine and tyrosinase. The amounts of DMPO-OH spin adducts via the tyrosine-tyrosinase reaction declined with DFX. Furthermore, mass spectra of an extra removed from the tyrosine-tyrosinase reaction mixture showed that the enzyme reactions might not be degradations of DFX. Therefore, there might be two types of DFX reaction passways, which could be through an internal electron transfer from tyrosine and hydrogen absorptions by ·OH directly.

  7. 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

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

    PubMed

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

    2008-05-01

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

  9. 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

  10. [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

  11. Development of the 2nd Generation Redshift(z) and Early Universe Spectrometer and the Detailed Study of Far-IR Fine-Structure Lines in High-z Galaxies

    NASA Astrophysics Data System (ADS)

    Ferkinhoff, Carl; Brisbin, D.; Nikola, T.; Parshley, S.; Stacey, G. J.; Hailey-Dunsheath, S. J.; Irwin, K. D.; Cho, H.; Niemack, M.; Benford, D. J.; Staguhn, J.; Phillips, T. G.; Falgarone, E.

    2013-01-01

    The 2nd generation Redshift(z) and Early Universe Spectrometer (ZEUS-2), is a long-slit echelle grating spectrometer ( 1000) for observations at submillimeter wavelengths from 200 to 850 μm. Its design is optimized for the detection of redshifted far-infrared spectral lines from galaxies in the early universe. Combined with its exquisite sensitivity, broad wavelength coverage, and large 2.5%) instantaneous bandwidth, ZEUS-2 is uniquely suited for studying galaxies between 0.2 and 5—spanning the peaks in both the star formation rate and AGN activity in the universe. ZEUS-2 saw first light at the Caltech Submillimeter Observatory (CSO) in the spring of 2012 and was commissioned on the Atacama Pathfinder Experiment (APEX) this past November. Here we report on the instrument development and performance as well as initial scientific results from the APEX commissioning. We also discuss our ZEUS-1 (the first generation Redshift(z) and Early Universe Spectrometer) detections of the [NII] 122 μm and [OIII] 88 μm lines from starburst galaxies at redshifts between ~2.5 and 4. These are the first high-z detections of these lines and they are examples of work we plan to continue with ZEUS-2. As such, they demonstrate the potential of ZEUS-2 for increasing our understanding of galaxies and galaxy evolution over cosmic time.

  12. 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.

  13. 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…

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

    PubMed

    Bukowski, Ronald M

    2012-01-01

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

  15. Dacomitinib in lung cancer: a "lost generation" EGFR tyrosine-kinase inhibitor from a bygone era?

    PubMed

    Ou, Sai-Hong Ignatius; Soo, Ross A

    2015-01-01

    EGFR tyrosine-kinase inhibitors (TKIs) have now been firmly established as the first-line treatment for non-small-cell lung cancer (NSCLC) patients harboring activating EGFR mutations, based on seven prospective randomized Phase III trials. However, despite significantly improved overall response rate and improved median progression-free survival when compared to platinum-doublet chemotherapy, EGFR-mutant NSCLC patients treated with EGFR TKIs invariably progress due to the emergence of acquired resistances, with the gatekeeper T790M mutation accounting for up to 60% of the resistance mechanisms. Second-generation irreversible EGFR TKIs were developed in part to inhibit the T790M mutation, in addition to the common activating EGFR mutations. Dacomitinib is one such second-generation EGFR TKI designed to inhibit both the wild-type (WT) EGFR and EGFR T790M. Afatinib is another second-generation EGR TKI that has been now been approved for the first-line treatment of EGFR-mutant NSCLC patients, while dacomitinib continues to undergo clinical evaluation. We will review the clinical development of dacomitinib from Phase I to Phase III trials, including the two recently published negative large-scale randomized Phase III trials (ARCHER 1009, NCIC-BR-26). Results from another large-scale randomized trial (ARCHER 1050) comparing dacomitinib to gefitinib as first-line treatment of advanced treatment-naïve EGFR-mutant NSCLC patients will soon be available and will serve as the lynchpin trial for the potential approval of dacomitinib in NSCLC. Meanwhile, third-generation EGFR TKIs (eg, CO-1686 [rociletinib], AZ9291, HM61713, EGF816, and ASP8273) that preferentially and potently inhibit EGFR T790M but not WT EGFR are in full-scale clinical development, and some of these EGFR TKIs have received "breakthrough" designation by the US Food and Drug Administration and will likely be approved in late 2015. Given the rapid development of third-generation EGFR TKIs and the approval of

  16. Alleviation effect of arbutin on oxidative stress generated through tyrosinase reaction with l-tyrosine and l-DOPA

    PubMed Central

    2014-01-01

    Background Hydroxyl radical that has the highest reactivity among reactive oxygen species (ROS) is generated through l-tyrosine-tyrosinase reaction. Thus, the melanogenesis might induce oxidative stress in the skin. Arbutin (p-hydroxyphenyl-β-d-glucopyranoside), a well-known tyrosinase inhibitor has been widely used for the purpose of skin whitening. The aim of the present study was to examine if arbutin could suppress the hydroxyl radical generation via tyrosinase reaction with its substrates, l-tyrosine and l-DOPA. Results The hydroxyl radical, which was determined by an electron spin resonance-spin trapping technique, was generated by the addition of not only l-tyrosine but l-DOPA to tyrosinase in a concentration dependent manner. Arbutin could inhibit the hydroxyl radical generation in the both reactions. Conclusion It is presumed that arbutin could alleviate oxidative stress derived from the melanogenic pathway in the skin in addition to its function as a whitening agent in cosmetics. PMID:25297374

  17. 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

  18. 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

    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.

  19. 2nd International Planetary Probe Workshop

    NASA Technical Reports Server (NTRS)

    Venkatapathy, Ethiraj; Martinez, Ed; Arcadi, Marla

    2005-01-01

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

  20. A second-generation expression system for tyrosine sulfated proteins and its application in crop protection

    PubMed Central

    Schwessinger, Benjamin; Li, Xiang; Ellinghaus, Thomas L.; Chan, Leanne Jade G.; Wei, Tong; Joe, Anna; Thomas, Nicholas; Pruitt, Rory; Adams, Paul D.; Chern, Maw Sheng; Petzold, Christopher J.; Liu, Chang C.; Ronald, Pamela C.

    2016-01-01

    Posttranslational modification (PTM) of proteins and peptides is important for diverse biological processes in plants and animals. The paucity of heterologous expression systems for PTMs and the technical challenges associated with chemical synthesis of these modified proteins has limited detailed molecular characterization and therapeutic applications. Here we describe an optimized system for expression of tyrosine-sulfated proteins in Escherichia coli and its application in a bio-based crop protection strategy in rice. PMID:26611838

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

    PubMed

    Breccia, Massimo; Alimena, Giuliana

    2014-01-01

    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.

  2. 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

  3. 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.

  4. Results of clot waveform analysis and thrombin generation test for a plasma-derived factor VIIa and X mixture (MC710) in haemophilia patients with inhibitors--phase I trial: 2nd report.

    PubMed

    Shirahata, A; Fukutake, K; Mimaya, J; Takamatsu, J; Shima, M; Hanabusa, H; Takedani, H; Takashima, Y; Matsushita, T; Tawa, A; Higasa, S; Takata, N; Sakai, M; Kawakami, K; Ohashi, Y; Saito, H

    2013-03-01

    We reported the results of a clinical pharmacological study of MC710 (a mixture of plasma-derived FVIIa and FX) in haemophilia patients with inhibitors during a non-haemorrhagic state. This report provides the results of a clot waveform analysis (CWA) and thrombin generation test (TGT) using blood samples obtained in this study. CWA and TGT were conducted using blood samples obtained from a pharmacokinetic and pharmacodynamic study in which MC710 (five dose rates: 20, 40, 80, 100 and 120 μg kg(-1)) was compared with NovoSeven (120 μg kg(-1)) and FEIBA (two dose rates: 50 and 75 U kg(-1)) as control drugs in 11 haemophilia patients with inhibitors without haemorrhagic symptoms. CWA showed that MC710 provided significantly greater improvement than the control drugs in activated partial thromboplastin time (APTT) at 80 μg kg(-1); maximum clot velocity and maximum clot acceleration were more enhanced by MC710 than by control drugs. TGT revealed that MC710 significantly shortened the initiation time of thrombin generation in comparison to FEIBA and induced greater thrombin generation potency than NovoSeven. It was not clear whether or not MC710 caused significant dose-dependent changes in the two measurements; however, differences between MC710 and the control drugs were clarified. MC710 was confirmed to have superior coagulation activity and thrombin productivity and is expected to have superior bypassing activity. PMID:22989180

  5. 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 ...

  6. 2nd Antibiotic Halves C-Section Infection Rate

    MedlinePlus

    ... gov/news/fullstory_161230.html 2nd Antibiotic Halves C-Section Infection Rate: Study Two medications are better ... delivery, Andrews said. Overall, about 12 percent of C-sections result in an infection, according to background ...

  7. 2ND FLOOR HALLWAY LOOKING EAST, NOTE PRESSED TIN CEILING ...

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

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

  8. 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.

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

    NASA Astrophysics Data System (ADS)

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

    2015-12-01

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

  10. 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

  11. 2nd Generation RLV Airframe Structures and Materials

    NASA Technical Reports Server (NTRS)

    Johnson, Theodore F.

    2000-01-01

    The goals and objectives of the project summarized in this viewgraph presentation are the following: (1) Develop and demonstrate verified airframe and cryotank structural design and analysis technologies, including damage tolerance, safety, reliability, and residual strength technologies, robust nonlinear shell and cryotank analysis technologies, high-fidelity analysis and design technologies for local structural detail features and joints, and high-fidelity analysis technologies for sandwich structures; (2) Demonstrate low cost, robust materials and processing, including polymeric matrix composite (PMC) and metallic materials and processing, and refractory composite and metallic hot structures materials and processing; (3) Develop and demonstrate robust airframe structures and validated integrated airframe structural concepts, including low cost fabrication and joining, operations efficient designs and inspection techniques (non-destructive evaluation), scale-up and integrated thermal structure tests, and airframe structures IVHM; (4) Demonstrate low cost, robust repair techniques; and (5) Develop verified integrated airframe structural concepts, including integrated structural concepts.

  12. 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.

  13. Performance of 2nd generation CALICE/EUDET ASICs

    NASA Astrophysics Data System (ADS)

    de La Taille, C.; CALICE Collaboration; EUDET Collaboration

    2011-04-01

    The paper reviews the performance of the three ASICs : HARDROC2, SPIROC2 and SKIROC2 developed to readout the ILC calorimeter prototypes. The chips integrate 36 to 64 channels of front-end, digitization and backend electronics in SiGe 0.35 μm technology. This second version was found mature enough to be produced in several hundreds to equip large scale technological prototypes and establish the feasibility of these highly granular "imaging" calorimeters as required for particle flow algorithms at the ILC. The low noise and low power sequential readout as well as power-pulsing operation at detector level and in magnetic field are proven.

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

    PubMed

    Brunerová, Ludmila; Anděl, Michal

    2014-01-01

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

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

    PubMed

    Brunerová, Ludmila; Anděl, Michal

    2014-01-01

    The review article summarizes the principles of hedonic regulation of food intake which represents the food intake independent on the maintenance of homeostasis. The theory describing hedonic regulation, so called Incentive Salience Theory, comprises three major processes: liking (positive attribution to food stimulus), wanting (motivation to gain it) and learning (identification of these stimuli and distinguishing them from those connected with aversive reaction). Neuronal reward circuits are the anatomical and functional substrates of hedonic regulation. They react to gustatory and olfactory (or visual) stimuli associated with food intake. A food item is preferred in case its consumption is connected with a pleasant feeling thus promoting the behavioural reaction. The probability of this reaction after repetitive exposure to such a stimulus is increased (learned preference). On the contrary, learned aversion after repetitive exposure is connected with avoidance of a food item associated with a negative feeling. Main mediators of hedonic regulation are endocannabinoids, opioids and monoamines (dopamine, serotonin). Dopamine in dorsal striatum via D2 receptors generates food motivation as a key means of survival, however in ventral striatum (nucleus accumbens) is responsible for motivation to food bringing pleasure. Serotonin via its receptors 5-HT1A a T-HT2C decreases intake of palatable food. It plays a significant role in the pathogenesis of eating disorders, particularly mental anorexia. There, a food restriction represents a kind of automedication to constitutionally pathologically increased serotonin levels. Detailed understanding of processes regulating food intake is a key to new pharmacological interventions in eating disorders. PMID:24564775

  16. 2nd Quarter Transportation Report FY 2014

    SciTech Connect

    Gregory, L.

    2014-07-01

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

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

    NASA Astrophysics Data System (ADS)

    Wiberg, P.

    2004-05-01

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

  18. 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

  19. 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…

  20. 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…

  1. 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. ...

  2. TIFS/FL5 - 2nd Asheville deployment

    NASA Technical Reports Server (NTRS)

    1999-01-01

    TIFS/FL5 - 2nd Asheville deployment. People in photograph include: Charlie Peacock, Randy Bailey, Paul Deppe, Mike Reagan, Mike Norman, Rob Rivera, Paul Schifferle, Russ Parrish, Trey Auther, Lou Glaab, Dave McLuer, Mike Parrag, and Lynda Kramer.

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

    PubMed

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

    2015-07-01

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

  4. 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

  5. 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.

  6. A second-generation expression system for tyrosine-sulfated proteins and its application in crop protection.

    PubMed

    Schwessinger, Benjamin; Li, Xiang; Ellinghaus, Thomas L; Chan, Leanne Jade G; Wei, Tong; Joe, Anna; Thomas, Nicholas; Pruitt, Rory; Adams, Paul D; Chern, Maw Sheng; Petzold, Christopher J; Liu, Chang C; Ronald, Pamela C

    2016-04-18

    Posttranslational modification (PTM) of proteins and peptides is important for diverse biological processes in plants and animals. The paucity of heterologous expression systems for PTMs and the technical challenges associated with chemical synthesis of these modified proteins has limited detailed molecular characterization and therapeutic applications. Here we describe an optimized system for expression of tyrosine-sulfated proteins in Escherichia coli and its application in a bio-based crop protection strategy in rice.

  7. 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

  8. Conference report: 2nd Medicon Valley Inhalation Symposium.

    PubMed

    Lastow, Orest

    2014-02-01

    2nd Medicon Valley Inhalation Symposium 16 October 2013, Lund, Sweden The 2nd Medicon Valley Inhalation Symposium was arranged by the Medicon Valley Inhalation Consortium. It was held at the Medicon Village, which is the former AstraZeneca site in Lund, Sweden. It was a 1 day symposium focused on inhaled drug delivery and inhalation product development. 120 delegates listened to 11 speakers. The program was organized to follow the value chain of an inhalation product development. This year there was a focus on inhaled biomolecules. The inhaled delivery of insulin was covered by two presentations and a panel discussion. The future of inhaled drug delivery was discussed together with an overview of the current market situation. Two of the inhalation platforms, capsule inhalers and metered-dose inhalers, were discussed in terms of the present situation and the future opportunities. Much focus was on the regulatory and intellectual aspects of developing inhalation products. The manufacturing of a dry powder inhaler requires precision filling of powder, and the various techniques were presented. The benefits of nebulization and nasal delivery were illustrated with some case studies and examples. The eternal challenge of poor compliance was addressed from an industrial design perspective and some new approaches were introduced.

  9. 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

  10. Second-generation irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs): a better mousetrap? A review of the clinical evidence.

    PubMed

    Ou, Sai-Hong Ignatius

    2012-09-01

    The discovery of activating epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) in 2004 heralded the era of molecular targeted therapy in NSCLC. First-generation small molecule, reversible tyrosine kinase inhibitors (TKIs) of EGFR, gefitinib and erlotinib, had been approved for second- or third-line treatment of NSCLC prior to the knowledge of these mutations. However, resistance to gefitinib and erlotinib invariably develops after prolonged clinical use. Two second-generation irreversible EGFR TKIs, afatinib (BIBW 2992) and dacomitinib (PF-00299804), that can potentially overcome the majority of these resistances are in late stage clinical development. Here I will review the clinical data of EGFR TKIs and discuss the appropriate future role of afatinib and dacomitinib in NSCLC: whether as replacement of erlotinib or gefitinib or only after erlotinib or gefitinib failure and whether different subgroups would benefit from different approaches.

  11. 2nd International Conference on Health and Human Rights.

    PubMed

    Dougherty, S

    1997-01-01

    The 2nd International Conference on Health and Human Rights held in 1996 explored the issue of human rights and public health advocacy in light of the AIDS pandemic. Speakers addressed the pervasive personal and institutional racism within the United States (known as structural violence) that hinders minority health status and health care. Poverty and its relationship to women's risk of HIV infection are viewed as one of the most significant manifestations of structural violence for those in the field of HIV/AIDS. Other speakers addressed the destruction of urban habitats and the effect of this destruction on urban society and health, and how social class can affect health care delivery, access, and mortality.

  12. 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

  13. 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

  14. 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

  15. 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.

  16. 2nd Circuit vacates sanction against plantiff's attorney.

    PubMed

    1999-07-23

    The 2nd U.S. Circuit Court of Appeals vacated sanctions against attorney Lee Nuwesra whose client claimed HIV discrimination. The court ruled that U.S. District Judge Constance Baker Motley abused her judicial discretion in ruling that Nuwesra must pay $25,000 of legal costs spent by the client's employer in defending itself against litigation that the judge found frivolous. The appeals panel faulted the judge for not specifying which conduct on the part of the attorney was actionable. Plaintiff [name removed] claimed that his firing from [name removed] & [name removed], Inc., was motivated by his HIV illness and that his rights under the Americans with Disabilities Act were violated. [Name removed] failed to establish that his employer knew his HIV status. Motley sanctioned Nuwesra for not performing adequate pre-trial investigation in the case. According to Federal Rules of Civil Procedure judges can only sanction attorneys at the request of the opposing side, which was not made by the defendants in this case.

  17. [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.

  18. 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.

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

    SciTech Connect

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

    2014-02-15

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

  20. 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

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

    PubMed

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

    2015-11-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2009-03-01

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

  3. Psychiatric Diagnosis and Concomitant Medical Treatment for 1st and 2nd Grade Children

    ERIC Educational Resources Information Center

    Cornell-Swanson, La Vonne; Frankenberger, William; Ley, Katie; Bowman, Krista

    2007-01-01

    This study examined the proportion of children in 1st and 2nd grade classes who were currently prescribed medication for psychotropic disorders. The study also examined the attitudes of 1st and 2nd grade teachers toward diagnosis of psychiatric disorders and use of psychiatric medication to treat children. Results of the current study indicate…

  4. 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.

  5. 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

  6. 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…

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

    PubMed Central

    Eldeeb, Mohamed A.

    2014-01-01

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

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

    PubMed

    Eldeeb, Mohamed A; Fahlman, Richard P

    2014-05-15

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

  9. 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

  10. Clinical Features and Treatment Outcomes of 51 Patients with Chronic Myeloid Leukemia Treated with a Tyrosine Kinase Inhibitor at a Single Institution from 2002 to 2014.

    PubMed

    Kawano, Noriaki; Yoshida, Shuro; Kawano, Sayaka; Kuriyama, Takuro; Yamashita, Kiyoshi; Ochiai, Hidenobu; Shimoda, Kazuya; Ishikawa, Fumihiko; Ueda, Akira; Kikuchi, Ikuo

    2016-01-01

    Although clinical trials of first- and second-generation tyrosine kinase inhibitors (TKIs) have been shown to improve the prognosis of chronic myeloid leukemia (CML), there is still uncertainty about the clinical features, treatment outcomes, adverse effects, and other possible problems of their use in the clinical setting. We retrospectively analyzed 51 CML patients treated with TKIs at a single institution between 2002 and 2014. The patients (median age: 53.8 years) were classified as having chronic (n = 48), accelerated (n = 2), or blastic phase (n = 1) CML. Our treatments included both 1st generation TKIs (60.8%) and 2nd generation TKIs (39.2%). We found that the overall response rates of complete cytogenetic response (CCyR), major molecular response (MMR), and MR4 (molecular response 4) were 90.2%, 78.4%, and 64.7%, respectively. Second line 2nd generation TKIs had response rates equivalent to those of 1st line 1st generation TKIs. Moreover, 1st line 2nd generation TKIs tended to achieve an early response rate. Overall survival (OS) at 5 years was 93.2%. Sudden blastic crisis (BC) occurred in 2 CML patients receiving TKI with CCyR status. Hematopoietic stem cell transplantation was performed for BC (n = 1) and sudden BC (n = 2). Side effects of all grades (1-3) and grade 3 alone were 64.7% and 11.8%, respectively. Dose reduction, replacement with another TKI, or low dose TKI treatment may be useful methods to control side effects. Further reasons of TKI discontinuation were economic problems (n = 3) and pregnancy (n = 1). Consequently, our treatment strategy for CML demonstrated good response rate and OS. Currently, treatment discontinuation due to intolerance, resistance, economic problems, pregnancy, and sudden BC remains a concern in clinical practice.

  11. 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.

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

    PubMed

    Breccia, Massimo; Alimena, Giuliana

    2012-09-28

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

  13. 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

  14. 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

  15. 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

  16. 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

  17. 6. 2nd floor where stables used to be; note bottom ...

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

    6. 2nd floor where stables used to be; note bottom of truss with suspension rods for floor which results in clear span on 1st level - Diebolt Brewing Company Stable, 2695 Pittsburgh Avenue, Cleveland, Cuyahoga County, OH

  18. 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

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

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

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

  20. 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

  1. 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

  2. 12. CLOSEUP VIEW OF 2ND FLOOR WINDOW SHOWING THE WHITE ...

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

    12. CLOSE-UP VIEW OF 2ND FLOOR WINDOW SHOWING THE WHITE GLAZED TERRA COTTA DETAILS, AT FRONT ELEVATION. - Pacific Telephone & Telegraph Company Building, 1519 Franklin Street, Oakland, Alameda County, CA

  3. 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 ...

  4. 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

  5. 26. VIEW OF CUT AWAY FLOOR BUILDING 23 2ND FLOOR ...

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

    26. VIEW OF CUT AWAY FLOOR BUILDING 23 2ND FLOOR SHOWING TYPICAL MILL CONSTRUCTION (SECTION OF FLOOR CONTAMINATED WITH HAZARDOUS MATERIAL WAS REMOVED FOR DISPOSAL) - Bryant Electric Company, 1421 State Street, Bridgeport, Fairfield County, CT

  6. 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

  7. If 1st Baby's Early, 2nd Will Be Too: Study

    MedlinePlus

    ... If 1st Baby's Early, 2nd Will Be Too: Study Chances just as high for women who go ... it really is a potent factor," said senior study author Laura Jelliffe-Pawlowski. She is associate director ...

  8. 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

  9. 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.

  10. 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

  11. 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.

  12. Proceedings of the 2nd KUR symposium on hyperfine interactions

    NASA Astrophysics Data System (ADS)

    Mekata, M.; Minamisono, T.; Kawase, Y.

    1991-10-01

    Hyperfine interactions between a nuclear spin and an electronic spin discovered from hyperfine splitting in atomic optical spectra have been utilized not only for the determination of nuclear parameters in nuclear physics but also for novel experimental techniques in many fields such as solid state physics, chemistry, biology, mineralogy, and for diagnostic methods in medical science. Experimental techniques based on hyperfine interactions yield information about microscopic states of matter so that they are important in material science. Probes for material research using hyperfine interactions have been nuclei in the ground state and radioactive isotopes prepared with nuclear reactors or particle accelerators. But the use of muons generated from accelerators is growing. Such wide spread application of hyperfine interaction techniques gives rise to some difficulty in collaboration among various research fields. This report summarizes the KUR symposium in the hope that this information will help to alleviate the problem.

  13. 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.

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

    NASA Technical Reports Server (NTRS)

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

    2015-01-01

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

  15. A new analytic solution for 2nd-order Fermi acceleration

    SciTech Connect

    Mertsch, Philipp

    2011-12-01

    A new analytic solution for 2nd-order Fermi acceleration is presented. In particular, we consider time-dependent rates for stochastic acceleration, diffusive and convective escape as well as adiabatic losses. The power law index q of the turbulence spectrum is unconstrained and can therefore account for Kolmogorov (q = 5/3) and Kraichnan (q = 3/2) turbulence, Bohm diffusion (q = 1) as well as the hard-sphere approximation (q = 2). This considerably improves beyond solutions known to date and will prove a useful tool for more realistic modelling of 2nd-order Fermi acceleration in a variety of astrophysical environments.

  16. 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.

  17. Four-wave-mixing and nonlinear cavity dumping of 280 picosecond 2nd Stokes pulse at 1.3 μm from Nd:SrMoO4 self-Raman laser

    NASA Astrophysics Data System (ADS)

    Smetanin, S. N.; Jelínek, M., Jr.; Kubeček, V.; Jelínková, H.; Ivleva, L. I.; Shurygin, A. S.

    2016-01-01

    The 280 picosecond 2nd Stokes Raman pulses at 1.3 μm were generated directly from the miniature diode-pumped Nd:SrMoO4 self-Raman laser. Using the 90° phase matching insensitive to the angular mismatch, the self-Raman laser allowed for the achievement of the four-wave-mixing generation of the 2nd Stokes Raman pulse directly in the active Nd:SrMoO4 crystal at stimulated Raman scattering (SRS) self-conversion of the laser radiation. The passive Cr:YAG Q-switching and nonlinear cavity dumping was used without any phase locking device.

  18. 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

  19. 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.…

  20. 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…

  1. 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...

  2. 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)

  3. 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.

  4. 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...

  5. 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

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

    NASA Technical Reports Server (NTRS)

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

    2002-01-01

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

  7. 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…

  8. 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.

  9. 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.

  10. 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.

  11. The rotational spectrum of tyrosine.

    PubMed

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

    2015-04-23

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

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

    NASA Astrophysics Data System (ADS)

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

    2016-08-01

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

  13. 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.

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

    NASA Astrophysics Data System (ADS)

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

    2012-03-01

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

  15. 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

  16. 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.

  17. [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.

  18. [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

  19. 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

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

    NASA Astrophysics Data System (ADS)

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

    2016-10-01

    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.

  1. 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.

  2. Development of self-recognition, personal pronoun use, and pretend play during the 2nd year.

    PubMed

    Lewis, Michael; Ramsay, Douglas

    2004-01-01

    This study examined the relation of visual self-recognition to personal pronoun use and pretend play. For a longitudinal sample (N=66) at the ages when self-recognition was emerging (15, 18, and 21 months), self-recognition was related to personal pronoun use and pretend play such that children showing self-recognition used more personal pronouns and demonstrated more advanced pretend play than did children not showing self-recognition. The finding of a relation among these measures provides additional evidence that in the middle of the 2nd year of life a metarepresentation of self emerges in the human child.

  3. Modeling the influence of stromal microenvironment in the selection of ENU-induced BCR-ABL1 mutants by tyrosine kinase inhibitors

    PubMed Central

    Aggoune, Djamel; Tosca, Lucie; Sorel, Nathalie; Bonnet, Marie-Laure; Dkhissi, Fatima; Tachdjian, Gérard; Bennaceur-Griscelli, Annelise; Chomel, Jean-Claude; Turhan, Ali G

    2014-01-01

    Tyrosine kinase inhibitors (TKIs) have profoundly changed the natural history of chronic myeloid leukemia (CML). However, acquired resistance to imatinib, dasatinib or nilotinib (1st and 2nd generation TKIs), due in part to BCR-ABL1 kinase mutations, has been largely described. These drugs are ineffective on the T315I gatekeeper substitution, which remains sensitive to 3rd generation TKI ponatinib. It has recently been suggested that the hematopoietic niche could protect leukemic cells from targeted therapy. In order to investigate the role of a stromal niche in mutation-related resistance, we developed a niche-based cell mutagenesis assay. For this purpose, ENU (N-ethyl-N-nitrosourea)-exposed UT-7 cells expressing non-mutated or T315I-mutated BCR-ABL1 were cultured with or without murine MS-5 stromal cells and in the presence of imatinib, dasatinib, nilotinib, or ponatinib. In the assays relative to 1st and 2nd generation TKIs, which were performed on non-mutated BCR-ABL1 cells, our data highlighted the increasing efficacy of the latter, but did not reveal any substantial effect of the niche. In ponatinib assays performed on both non-mutated and T315I–mutated BCR-ABL1 cells, an increased number of resistant clones were observed in the presence of MS-5. Present data suggested that T315I mutants need either compound mutations (e.g. E255K/T315I) or a stromal niche to escape from ponatinib. Using array-comparative genomic hybridization experiments, we found an increased number of variations (involving some recurrent chromosome regions) in clones cultured on MS-5 feeder. Overall, our study suggests that the hematopoietic niche could play a crucial role in conferring resistance to ponatinib, by providing survival signals and favoring genetic instability. PMID:25593988

  4. Modeling the influence of stromal microenvironment in the selection of ENU-induced BCR-ABL1 mutants by tyrosine kinase inhibitors.

    PubMed

    Aggoune, Djamel; Tosca, Lucie; Sorel, Nathalie; Bonnet, Marie-Laure; Dkhissi, Fatima; Tachdjian, Gérard; Bennaceur-Griscelli, Annelise; Chomel, Jean-Claude; Turhan, Ali G

    2014-01-01

    Tyrosine kinase inhibitors (TKIs) have profoundly changed the natural history of chronic myeloid leukemia (CML). However, acquired resistance to imatinib, dasatinib or nilotinib (1(st) and 2(nd) generation TKIs), due in part to BCR-ABL1 kinase mutations, has been largely described. These drugs are ineffective on the T315I gatekeeper substitution, which remains sensitive to 3(rd) generation TKI ponatinib. It has recently been suggested that the hematopoietic niche could protect leukemic cells from targeted therapy. In order to investigate the role of a stromal niche in mutation-related resistance, we developed a niche-based cell mutagenesis assay. For this purpose, ENU (N-ethyl-N-nitrosourea)-exposed UT-7 cells expressing non-mutated or T315I-mutated BCR-ABL1 were cultured with or without murine MS-5 stromal cells and in the presence of imatinib, dasatinib, nilotinib, or ponatinib. In the assays relative to 1(st) and 2(nd) generation TKIs, which were performed on non-mutated BCR-ABL1 cells, our data highlighted the increasing efficacy of the latter, but did not reveal any substantial effect of the niche. In ponatinib assays performed on both non-mutated and T315I-mutated BCR-ABL1 cells, an increased number of resistant clones were observed in the presence of MS-5. Present data suggested that T315I mutants need either compound mutations (e.g. E255K/T315I) or a stromal niche to escape from ponatinib. Using array-comparative genomic hybridization experiments, we found an increased number of variations (involving some recurrent chromosome regions) in clones cultured on MS-5 feeder. Overall, our study suggests that the hematopoietic niche could play a crucial role in conferring resistance to ponatinib, by providing survival signals and favoring genetic instability.

  5. 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

  6. Conditional Lethal Mutants of Adenovirus 2-Simian Virus 40 Hybrids I. Host Range Mutants of Ad2+ND1

    PubMed Central

    Grodzicker, Terri; Anderson, Carl; Sharp, Phillip A.; Sambrook, Joe

    1974-01-01

    Human adenovirus type 2 (Ad2) grows poorly in monkey cells, although this defect can be overcome by co-infection with simian virus 40 (SV40). The nondefective Ad2-SV40 hybrid virus, Ad2+ND1, replicates efficiently in both human and African green monkey kidney cells, presumably due to the insertion of SV40 sequences into the Ad2 DNA. Several mutants of Ad2+ND1 have been isolated that grow and plaque poorly in monkey cells, although they retain the ability to replicate and plaque efficiently in HeLa cells. One of these mutants (H39) has been examined in detail. Studies comparing the DNA of the mutant with Ad2+ND1 either by the cleavage patterns produced by Escherichia coli R·RI restriction endonuclease digestion or by heteroduplexing reveal no differences. The pattern of protein synthesis of Ad2+ND1 and H39 in monkey cells is quite different with the mutant resembling Ad2, which is defective in the synthesis of late proteins. However, in human cells, the proteins synthesized by H39 and the parent Ad2+ND1 are very similar. The production of SV40 U antigen in H39-infected cells is different from that in Ad2+ND1-infected cells. Finally, the growth of H39 in monkey cells can be complemented by SV40. Images PMID:4364898

  7. 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

  8. 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

  9. 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.

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

    PubMed

    Yang, Wei; Xie, Yan-Ming

    2013-09-01

    Registry studies (RS) get more and more attention in recent years because it can reflect the health care situations of the real world. There are a number of large scale RS for traditional Chinese medicine (TCM). RS are observational studies that can complement randomized controlled trials (RCT). RS have an irreplaceable position in real word study (RWS), especially for small probability events. There are some different characters and qualities in RS. Registries for Evaluating Patient Outcomes: A User's Guide (2nd Edition) was published by the agency for healthcare research and quality (AHRQ) in 2010. It described the details of how to establish, maintain, and evaluate RS, and using 38 RS samples to illustrate the possible problems in undertaking such research. The User's Guide (2nd Edition) provides a reliable reference document for RS. TCM injections post-marketing safety surveillance RS is a national program involving multiple centers in China. This program can further improve RS quality their application in China and is a good illustration of how to follow this guide accurately. PMID:24471311

  11. 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

    2016-02-19

    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.

  12. 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

  13. 2nd PEGS Annual Symposium on Antibodies for Cancer Therapy: April 30-May 1, 2012, Boston, USA.

    PubMed

    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.

  14. Protein tyrosine nitration

    PubMed Central

    Chaki, Mounira; Leterrier, Marina; Barroso, Juan B

    2009-01-01

    Nitric oxide metabolism in plant cells has a relative short history. Nitration is a chemical process which consists of introducing a nitro group (-NO2) into a chemical compound. in biological systems, this process has been found in different molecules such as proteins, lipids and nucleic acids that can affect its function. This mini-review offers an overview of this process with special emphasis on protein tyrosine nitration in plants and its involvement in the process of nitrosative stress. PMID:19826215

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

    PubMed

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

    2016-01-01

    Tyrosine kinase inhibitors (TKIs) against human epidermal growth factor receptor (EGFR/HER) family have been introduced into the clinic to treat cancers, particularly non-small-cell lung cancer (NSCLC). There have been three generations of the EGFR/HER-TKIs. First-generation EGFR/HER-TKIs, binding competitively and reversibly to the ATP-binding site of the EGFR TK domain, show a significant breakthrough treatment in selected NSCLC patients with activating EGFR mutations (actEGFRm) EGFR (L858R) and EGFR (Del19), in terms of safety, efficacy, and quality of life. However, all those responders inevitably develop acquired resistance within 12 months, because of the EGFR (T790M) mutation, which prevents TKI binding to ATP-pocket of EGFR by steric hindrance. The second-generation EGFR/HER-TKIs were developed to prolong and maintain more potent response as well as overcome the resistance to the first-generation EGFR/HER-TKIs. They are different from the first-generation EGFR/HER-TKIs by covalently binding to the ATP-binding site, irreversibly blocking enzymatic activation, and targeting EGFR/HER family members, including EGFR, HER2, and HER4. Preclinically, these compounds inhibit the enzymatic activation for actEGFRm, EGFR (T790M), and wtEGFR. The second-generation EGFR/HER-TKIs improve overall survival in cancer patients with actEGFRm in a modest way. However, they are not clinically active in overcoming EGFR (T790M) resistance, mainly because of dose-limiting toxicity due to simultaneous inhibition against wtEGFR. The third-generation EGFR/HER-TKIs selectively and irreversibly target EGFR (T790M) and actEGFRm while sparing wtEGFR. They yield promising efficacy in NSCLC patients with actEGFRm as well as EGFR (T790M) resistant to the first- and second-generation EGFR-TKIs. They also appear to have a lower incidence of toxicity due to the reduced inhibitory effect on wtEGFR. Currently, the first-generation EGFR/HER-TKIs gefitinib and erlotinib and second-generation EGFR

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2015-11-17

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

  19. Microbial Protein-tyrosine Kinases*

    PubMed Central

    Chao, Joseph D.; Wong, Dennis; Av-Gay, Yossef

    2014-01-01

    Microbial ester kinases identified in the past 3 decades came as a surprise, as protein phosphorylation on Ser, Thr, and Tyr amino acids was thought to be unique to eukaryotes. Current analysis of available microbial genomes reveals that “eukaryote-like” protein kinases are prevalent in prokaryotes and can converge in the same signaling pathway with the classical microbial “two-component” systems. Most microbial tyrosine kinases lack the “eukaryotic” Hanks domain signature and are designated tyrosine kinases based upon their biochemical activity. These include the tyrosine kinases termed bacterial tyrosine kinases (BY-kinases), which are responsible for the majority of known bacterial tyrosine phosphorylation events. Although termed generally as bacterial tyrosine kinases, BY-kinases can be considered as one family belonging to the superfamily of prokaryotic protein-tyrosine kinases in bacteria. Other members of this superfamily include atypical “odd” tyrosine kinases with diverse mechanisms of protein phosphorylation and the “eukaryote-like” Hanks-type tyrosine kinases. Here, we discuss the distribution, phylogeny, and function of the various prokaryotic protein-tyrosine kinases, focusing on the recently discovered Mycobacterium tuberculosis PtkA and its relationship with other members of this diverse family of proteins. PMID:24554699

  20. 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.

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

    PubMed

    Ipson, Brett R; Fisher, Alfred L

    2016-05-01

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

  2. RTKdb: database of Receptor Tyrosine Kinase.

    PubMed

    Grassot, Julien; Mouchiroud, Guy; Perrière, Guy

    2003-01-01

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

  3. The relationship between the carrying angle and the distal extent of the 2nd and 4th fingertips.

    PubMed

    Sönmez, M; Tattemur, Y; Karacan, K; Erdal, M

    2012-08-01

    The angle towards the lateral side between the arm and forearm when the forearm is in full extension and supination is defined as the carrying angle. It is well known that the 2nd finger is longer in women whereas the 4th finger is longer in men, due to in-utero hormonal effects. In the present study, the relationship between the carrying angle and the distal extent of the 2nd and 4th fingertips is studied. The findings reveal that the carrying angle was greater both in left and right sides in women than in men. In addition, while the distal extent of the 2nd fingertips was longer in women, the 4th fingertip was longer in men. There was a moderately positive correlation between the carrying angle and the distal fingertip lengths. Therefore, it could be suggested that the morphometric factors play role on the distal extent of the fingertips other than the hormonal effects.

  4. 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 (

  5. 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

  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. 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…

  8. 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…

  9. 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...

  10. Report from the 2nd Summer School in Computational Biology organized by the Queen's University of Belfast.

    PubMed

    Emmert-Streib, Frank; Zhang, Shu-Dong; Hamilton, Peter

    2014-12-01

    In this paper, we present a meeting report for the 2nd Summer School in Computational Biology organized by the Queen's University of Belfast. We describe the organization of the summer school, its underlying concept and student feedback we received after the completion of the summer school.

  11. 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;…

  12. 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")…

  13. 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…

  14. 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…

  15. 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.

  16. First case of Fusobacterium necrophorum endocarditis to have presented after the 2nd decade of life.

    PubMed

    Moore, Curtiss; Addison, Daniel; Wilson, James M; Zeluff, Barry

    2013-01-01

    Fusobacterium necrophorum, an obligate, anaerobic, filamentous, gram-negative rod, is thought to be a normal inhabitant of the mucous membranes in human beings. Fusobacterium species have been implicated in cases of Lemierre syndrome and other pathologic conditions. Their reported association with infective endocarditis is extremely rare. We describe the case of a previously healthy 34-year-old man who emergently presented with flu-like symptoms and dyspnea on exertion. He had recently undergone a dental procedure. Empiric antibiotic therapy was initiated. Blood cultures were positive for metronidazole-resistant F. necrophorum. A transesophageal echocardiogram revealed 2 mobile vegetations on the mitral valve. Despite the antibiotic therapy, the patient's respiratory status worsened and, after 3 weeks, he died. On the basis of the organism's pathophysiology and the patient's recent dental procedure, the oral cavity was the likely source of the bacteremia. Our patient's case underscores the importance of recognizing Fusobacterium bacteremia as a possible cause of endocarditis. To our knowledge, this is the first reported case of monomicrobial F. necrophorum endocarditis to have presented in a patient after the 2nd decade of life. In addition, it is apparently only the 4th report of F. necrophorum mitral valve endocarditis with case results derived from modern culture techniques.

  17. First case of Fusobacterium necrophorum endocarditis to have presented after the 2nd decade of life.

    PubMed

    Moore, Curtiss; Addison, Daniel; Wilson, James M; Zeluff, Barry

    2013-01-01

    Fusobacterium necrophorum, an obligate, anaerobic, filamentous, gram-negative rod, is thought to be a normal inhabitant of the mucous membranes in human beings. Fusobacterium species have been implicated in cases of Lemierre syndrome and other pathologic conditions. Their reported association with infective endocarditis is extremely rare. We describe the case of a previously healthy 34-year-old man who emergently presented with flu-like symptoms and dyspnea on exertion. He had recently undergone a dental procedure. Empiric antibiotic therapy was initiated. Blood cultures were positive for metronidazole-resistant F. necrophorum. A transesophageal echocardiogram revealed 2 mobile vegetations on the mitral valve. Despite the antibiotic therapy, the patient's respiratory status worsened and, after 3 weeks, he died. On the basis of the organism's pathophysiology and the patient's recent dental procedure, the oral cavity was the likely source of the bacteremia. Our patient's case underscores the importance of recognizing Fusobacterium bacteremia as a possible cause of endocarditis. To our knowledge, this is the first reported case of monomicrobial F. necrophorum endocarditis to have presented in a patient after the 2nd decade of life. In addition, it is apparently only the 4th report of F. necrophorum mitral valve endocarditis with case results derived from modern culture techniques. PMID:24082377

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

    PubMed

    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.

  19. 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.

  20. 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.

  1. Tyrosine phosphorylation and bacterial virulence

    PubMed Central

    Whitmore, Sarah E; Lamont, Richard J

    2012-01-01

    Protein phosphorylation on tyrosine has emerged as a key device in the control of numerous cellular functions in bacteria. In this article, we review the structure and function of bacterial tyrosine kinases and phosphatases. Phosphorylation is catalyzed by autophosphorylating adenosine triphosphate-dependent enzymes (bacterial tyrosine (BY) kinases) that are characterized by the presence of Walker motifs. The reverse reaction is catalyzed by three classes of enzymes: the eukaryotic-like phosphatases (PTPs) and dual-specific phosphatases; the low molecular weight protein-tyrosine phosphatases (LMW-PTPs); and the polymerase–histidinol phosphatases (PHP). Many BY kinases and tyrosine phosphatases can utilize host cell proteins as substrates, thereby contributing to bacterial pathogenicity. Bacterial tyrosine phosphorylation/dephosphorylation is also involved in biofilm formation and community development. The Porphyromonas gingivalis tyrosine phosphatase Ltp1 is involved in a restraint pathway that regulates heterotypic community development with Streptococcus gordonii. Ltp1 is upregulated by contact with S. gordonii and Ltp1 activity controls adhesin expression and levels of the interspecies signal AI-2. PMID:22388693

  2. 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

  3. 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

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

    2013-03-13

    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 Fe(III)2-Y(•) cofactor in the NrdB subunit of the class Ia RNRs can be generated by self-assembly from Fe(II)2-NrdB, O2, and a reducing equivalent. By contrast, the structurally homologous class Ib enzymes require a Mn(III)2-Y(•) cofactor in their NrdF subunit. Mn(II)2-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 Mn(III)2-Y(•) cofactor. Here we investigate the mechanism of assembly of the Mn(III)2-Y(•) cofactor in Bacillus subtilis NrdF. Cluster assembly from Mn(II)2-NrdF, NrdI(hq), and O2 has been studied by stopped flow absorption and rapid freeze quench EPR spectroscopies. The results support a mechanism in which NrdI(hq) reduces O2 to O2(•-) (40-48 s(-1), 0.6 mM O2), the O2(•-) channels to and reacts with Mn(II)2-NrdF to form a Mn(III)Mn(IV) intermediate (2.2 ± 0.4 s(-1)), and the Mn(III)Mn(IV) 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 Mn(II)2 cluster with O2 and satisfies the requirement for an "extra" reducing equivalent in Y(•) generation.

  4. 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

  5. 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.

  6. 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

  7. 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)…

  8. Tyrosine phosphorylation of WW proteins

    PubMed Central

    Reuven, Nina; Shanzer, Matan

    2015-01-01

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

  9. Collaborative study for the establishment of the 2(nd) International Standard for Bleomycin Complex A2/B2.

    PubMed

    Jorajuria, S; Raphalen, C; Dujardin, V; Daas, A

    2015-01-01

    Organization (WHO) International Standard (IS) for bleomycin complex A2/B2. Eight laboratories from different countries participated. Potencies of the candidate material were estimated by microbiological assays with sensitive micro-organisms. To ensure continuity between consecutive batches, the 1(st) IS for bleomycin complex A2/B2 was used as a reference. Based on the results of the study, the 2(nd) IS for bleomycin complex A2/B2 was adopted at the meeting of the WHO Expert Committee for Biological Standardization (ECBS) in 2014 with an assigned potency of 12 500 International Units (IU) per vial. The 2(nd) IS for bleomycin complex A2/B2 is available from the European Directorate for the Quality of Medicines & HealthCare (EDQM).

  10. 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

  11. Targeted tyrosine iodination in a multi-tyrosine vasopressin analog.

    PubMed

    Durr, Jacques A; Blankenship, Mary; Chauhan, Satendra S; Pennington, Michael W

    2007-11-01

    Iodination of the conserved 2-tyrosine (Tyr(2)) residue in the pressin and tocin rings of arginine- or lysine-vasopressin (AVP or LVP), and oxytocin, respectively, impairs binding to their respective receptors. Synthetic antagonists that have their Tyr(2) either replaced by another amino acid or irreversibly blocked by an O-methyl or O-ethyl ether, but have, instead, an iodinatable phenol moiety outside the pressin/tocin ring, are used for radiolabeling. We explored another approach to avoid iodinating Tyr(2) by capping this residue with a reversible O-acetyl group, incorporated during peptide synthesis. The O-acetyl-Tyr(2) LVP peptide, with a free iodinatable tyrosine attached to the epsilon-amine of 8-lysine, is iodinated at a neutral pH and purified by reverse-phase high-pressure liquid chromatography (HPLC) at an acidic pH, conditions under which the O-acetyl groups are stable. Deacetylation with hydroxylamine is selective, and leaves intact the disulfide bridge. The marked shortening of the HPLC retention time after deblocking produces a chemically homogeneous label, iodinated exclusively on the free tyrosine residue attached to the epsilon-amine of LVP. Hitherto, this (125)I labeled vasopressin agonist could be obtained only in low yield, via conjugation labeling with iodinated N-t-Boc-tyrosine succinimidyl ester. This fully reversible tyrosine protection strategy does not require special equipment, and retains the conserved Tyr(2), typical of vasopressin and oxytocin agonists.

  12. 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.

  13. 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…

  14. 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

  15. Regulation of protein kinase enzymatic activity in Jurkat T cells during oxidative stress uncoupled from protein tyrosine kinases: role of oxidative changes in protein kinase activation requirements and generation of second messengers.

    PubMed

    Whisler, R L; Newhouse, Y G; Beiqing, L; Karanfilov, B K; Goyette, M A; Hackshaw, K V

    1994-12-01

    Prior studies have suggested that intracellular phosphorylation events and cellular redox mechanisms may interact in regulating a variety of cellular functions, including the transcriptional activation of gene expression. Increased activity of transcriptional factors NF kappa B and AP1 has been described in cells exposed to oxidative stress and following the direct stimulation of protein kinase C (PKC) by phorbol diesters. However, the mechanisms that may contribute to redox regulation of PKC are unknown. We studied the expression of PKC activity and several second messengers in human Jurkat T cells exposed to oxidative stress in the form of H2O2. Micromolar concentrations of H2O2 rapidly induced increased cytosolic PKC enzymatic activity in Jurkat T cells that was associated with a marked arrest of cellular proliferation. The increase in cytosolic PKC activity in cells treated with H2O2 was accompanied by elevations in intracellular free calcium ([Ca2+]i), generation of inositol phosphates, and release of arachidonic acid. Functional studies showed that H2O2 enhancement of cytosolic PKC activity required phospholipase C activity but was not primarily mediated by arachidonic acid. The response of PKC to oxidative stress displayed a lack of Ca2+ dependence and was uncoupled from the activity of protein tyrosine kinases (PTK). Furthermore, the reduced activation requirements of PKC from cells treated with H2O2 were associated with shifts in elution profiles of PKC enzymatic activity after Mono-Q chromatography. These shifts appeared to represent intrinsic changes in the conformation of PKC induced by oxidative stress because western blotting failed to reveal any PKC cleavage products or reductions in native PKC alpha or beta. These findings indicate that oxidative regulation of intracellular events can intersect phosphorylation events mediated by PKC through the release of second messengers as well as direct changes in PKC activation requirements. Moreover, redox

  16. 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.

  17. 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

  18. 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

  19. 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

  20. 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.

  1. 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…

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

    EPA Science Inventory

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

  3. 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,...

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

    SciTech Connect

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

    1999-07-01

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

  5. 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

  6. 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

  7. Improving the performance of E-beam 2nd writing in mask alignment accuracy and pattern faultless for CPL technology

    NASA Astrophysics Data System (ADS)

    Lee, Booky; Hung, Richard; Lin, Orson; Wu, Yuan-Hsun; Kozuma, Makoto; Shih, Chiang-Lin; Hsu, Michael; Hsu, Stephen D.

    2005-01-01

    The chromeless phase lithography (CPL) is a potential technology for low k1 optical image. For the CPL technology, we can control the local transmission rate to get optimized through pitch imaging performance. The CPL use zebra pattern to manipulate the pattern local transmission as a tri-tone structure in mask manufacturing. It needs the 2nd level writing to create the zebra pattern. The zebra pattern must be small enough not to be printed out and the 2nd writing overlay accuracy must keep within 40nm. The request is a challenge to E-beam 2nd writing function. The focus of this paper is in how to improve the overlay accuracy and get a precise pattern to form accurate pattern transmission. To fulfill this work several items have been done. To check the possibility of contamination in E-Beam chamber by the conductive layer coating we monitor the particle count in the E-Beam chamber before and after the coated blank load-unload. The conductivity of our conductive layer has been checked to eliminate the charging effect by optimizing film thickness. The dimension of alignment mark has also been optimized through experimentation. And finally we checked the PR remain to ensure sufficient process window in our etching process. To verify the performance of our process we check the 3D SEM picture. Also we use AIMs to prove the resolution improvement capability in CPL compared to the traditional methods-Binary mask and Half Tone mask. The achieved overlay accuracy and process can provide promising approach for NGL reticle manufacturing of CPL technology.

  8. 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

  9. 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

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

    PubMed

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

    2012-12-01

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

  11. 21 CFR 582.5920 - Tyrosine.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Tyrosine. 582.5920 Section 582.5920 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS... § 582.5920 Tyrosine. (a) Product. Tyrosine (L- and DL-forms). (b) Conditions of use. This substance...

  12. 21 CFR 582.5920 - Tyrosine.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Tyrosine. 582.5920 Section 582.5920 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS... § 582.5920 Tyrosine. (a) Product. Tyrosine (L- and DL-forms). (b) Conditions of use. This substance...

  13. 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

  14. 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 (

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

    PubMed

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

    2015-02-01

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

  16. 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.

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

    PubMed

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

    2015-02-01

    Prussian offensive operation performed by the 2nd Belorussian Front. An activity of the medical An activity of the medical service of the 65th Army during the East Prussian offensive operation performed by the 2nd Belorussian Front is a typical example of the medical support of troops during the final stages of World War II. Forms and methods of medical support management, which were developed during the war, haven't lost their importance in modern conditions. These methods include the establishment of specialized surgical and therapeutic field hospital, establishment of medical institutions in the Army, which worked on the evacuation directions and reserve of mobile hospitals and transport, timely extension of the first echelons of the hospital base front to change institutions hospital deployed the army base. A research of experience in organizing medical support of the offensive operations performed during the last year of World War II provides the material for the development of the theory of modern medical support operations and ability to provide on this basis, the continuity of the hospitals, the continuity of qualified and specialized medical care, improve the performance of diagnostic and treatment work. PMID:25920177

  18. 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

  19. 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

  20. 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

  1. 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.

  2. [G. W. Leibniz: medicine and the sciences of life: 2nd part: Leibniz as a "biologist"].

    PubMed

    Chazaud, J

    1996-01-01

    Many features of Leibniz's philosophy are a ... "naturalization" of the finding of contemporary scientists. For instance "the Monad", the fondamental element of his system, derives from Glisson's conceptions and Leeuwenhoek's observations. Among others, his ideas on generation stem from a mediation on the Dutchman's and Swammerdam's and Malpighi's works. Through them, he became a partner in the ovulists' quarrel and in the discussion about formal specification. Most of all, he expressed an amazing transformist and paleontological intuition, sensibilizing himself to comparative anatomy and to fossil imprints study. Generation and creative evolution of beings and species were logically accompanied by a reflection on death as being part of the life processes.

  3. Endocytosis of Receptor Tyrosine Kinases

    PubMed Central

    Goh, Lai Kuan

    2013-01-01

    Endocytosis is the major regulator of signaling from receptor tyrosine kinases (RTKs). The canonical model of RTK endocytosis involves rapid internalization of an RTK activated by ligand binding at the cell surface and subsequent sorting of internalized ligand-RTK complexes to lysosomes for degradation. Activation of the intrinsic tyrosine kinase activity of RTKs results in autophosphorylation, which is mechanistically coupled to the recruitment of adaptor proteins and conjugation of ubiquitin to RTKs. Ubiquitination serves to mediate interactions of RTKs with sorting machineries both at the cell surface and on endosomes. The pathways and kinetics of RTK endocytic trafficking, molecular mechanisms underlying sorting processes, and examples of deviations from the standard trafficking itinerary in the RTK family are discussed in this work. PMID:23637288

  4. 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

  5. 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

  6. 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

  7. 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.

  8. 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.

  9. 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

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

    NASA Astrophysics Data System (ADS)

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

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

  11. 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.

  12. 2nd ESMO Consensus Conference in Lung Cancer: locally advanced stage III non-small-cell lung cancer.

    PubMed

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

    2015-08-01

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

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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.

  18. A Guide to Monte Carlo Simulations in Statistical Physics - 2nd Edition

    NASA Astrophysics Data System (ADS)

    Landau, David P.; Binder, Kurt

    2005-09-01

    This new and updated edition deals with all aspects of Monte Carlo simulation of complex physical systems encountered in condensed-matter physics, statistical mechanics, and related fields. After briefly recalling essential background in statistical mechanics and probability theory, it gives a succinct overview of simple sampling methods. The concepts behind the simulation algorithms are explained comprehensively, as are the techniques for efficient evaluation of system configurations generated by simulation. It contains many applications, examples, and exercises to help the reader and provides many new references to more specialized literature. This edition includes a brief overview of other methods of computer simulation and an outlook for the use of Monte Carlo simulations in disciplines beyond physics. This is an excellent guide for graduate students and researchers who use computer simulations in their research. It can be used as a textbook for graduate courses on computer simulations in physics and related disciplines. A broad and self-contained overview of Monte Carlo simulations Contains extensive cross-referencing between simulation and relevant theory and between applications of similar algorithms in different contexts Provides many applications, examples, `recipes', and specific case studies

  19. 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.

  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. 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…

  2. 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.

  3. Tyrosine Kinase Inhibitors and Pregnancy

    PubMed Central

    Abruzzese, Elisabetta; Trawinska, Malgorzata Monika; Perrotti, Alessio Pio; De Fabritiis, Paolo

    2014-01-01

    The management of patients with chronic myeloid leukemia (CML) during pregnancy has become recently a matter of continuous debate. The introduction of the Tyrosine Kinase Inhibitors (TKIs) in clinical practice has dramatically changed the prognosis of CML patients; in fact, patients diagnosed in chronic phase can reasonably expect many years of excellent disease control and good quality of life, as well as a normal life expectancy, including the necessity to address issues relating to fertility and pregnancy. Physicians are frequently being asked for advice regarding the need for, and/or the appropriateness of, stopping treatment in order to conceive. In this report, we will review the data published in terms of fertility, conception, pregnancy, pregnancy outcome and illness control for TKI treated CML patients, as well as how to manage a planned and/or unplanned pregnancy. PMID:24804001

  4. 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.

  5. 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

  6. [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.

  7. 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

  8. Report on the 2nd International Consortium on Hallucination Research: evolving directions and top-10 "hot spots" in hallucination research.

    PubMed

    Waters, Flavie; Woods, Angela; Fernyhough, Charles

    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

  9. [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

  10. 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.

  11. 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.

  12. VizieR Online Data Catalog: 2nd Cat. of Radial Velocities with Astrometric Data (Kharchenko+, 2007)

    NASA Astrophysics Data System (ADS)

    Kharchenko, N. V.; Scholz, R.-D.; Piskunov, A. E.; Roeser, S.; Schilbach, E.

    2007-06-01

    The catalogue of radial velocities of Galactic stars with high precision astrometric data, 2nd version (CRVAD-2), is the result of a merging of star lists from the All-Sky Compiled Catalogue of 2.5 Million Stars (ASCC-2.5, Cat. I/280) with the General Catalogue of Radial Velocities (GCRV, Cat. III/213) and with other recently published radial velocity lists and catalogues. Cross identification of objects was carried out with help of coordinate, magnitude, colour and/or spectral type criteria. Data from the Catalogue of Components of Double and Multiple Stars (CCDM, Cat. I/274) were taken into account for the identification of multiple system components. Altogether 54907 stars from the ASCC-2.5 were identified with 51762 stars from the RV source catalogues, 3085 stars have secondary components and 30 stars have 3rd components in multiple systems. The CRVAD-2 includes accurate J2000 equatorial coordinates, proper motions and trigonometric parallaxes in the Hipparcos system, Johnson's BV photometric data, spectral types, radial velocities, multiplicity and variability flags. Stars are sorted in the order of increasing right ascension J2000. This catalogue supersedes the previous version numbered . (1 data file).

  13. Nitric oxide rapidly scavenges tyrosine and tryptophan radicals.

    PubMed Central

    Eiserich, J P; Butler, J; van der Vliet, A; Cross, C E; Halliwell, B

    1995-01-01

    By utilizing a pulse-radiolytic technique, we demonstrate for the first time that the rate constant for the reaction of nitric oxide (.NO) with biologically relevant tyrosine and tryptophan radicals (Tyr. and Trp. respectively) in amino acids, peptides and proteins is of the order of (1-2) x 10(9) M-1.s-1. We also show that .NO effectively interferes with electron-transfer processes between tryptophan and tyrosine residues in proteins subjected to pulse radiolysis. The near diffusion-controlled rates of these reactions, coupled with the increasingly recognized role of protein radicals in enzyme catalysis and oxidative damage, suggest that Tyr. and Trp. are likely and important targets for .NO generated in vivo. PMID:7575405

  14. 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.

  15. 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

  16. 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

  17. 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

  18. 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

  19. 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

  20. 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.

  1. 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

  2. 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

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

    PubMed

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

    2015-02-01

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

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

    PubMed

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

    2013-10-21

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

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

    NASA Astrophysics Data System (ADS)

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

    2014-12-01

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

  6. 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

  7. 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

  8. 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

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

    PubMed

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

    2015-10-01

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

  10. IRF-1 regulates alternative mRNA splicing of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) in breast epithelial cells generating an immunoreceptor tyrosine-based inhibition motif (ITIM) containing isoform

    PubMed Central

    2014-01-01

    Background Interferon regulatory factor-1 (IRF-1) is a master regulator of IFN-γ induced gene transcription. Previously we have shown that IRF-1 transcriptionally induces CEACAM1 via an ISRE (Interferon-Stimulated Response Element) in its promoter. CEACAM1 pre-mRNA undergoes extensive alternative splicing (AS) generating isoforms to produce either a short (S) cytoplasmic domain expressed primarily in epithelial cells or as an ITIM-containing long (L) isoform in immune cells. Methods The transcriptional and molecular mechanism of CEACAM1 minigenes AS containing promoter ISREs mutations in the breast epithelial, MDA-MB-468, cell line was detected using flow cytometry. In addition, transcriptome sequencing was utilized to determine whether IRF-1 could direct the AS of other genes as well. Tumor xenografts were used to evaluate CEACAM1 isoform expression on the leading edge of breast tumor cells. Results In the present study, we provide evidence that CEACAM1’s promoter and variable exon 7 cross-talk allowing IRF-1 to direct AS events. Transcriptome sequencing shows that IRF-1 can also induce the global AS of genes involved in regulation of growth and differentiation as well as genes of the cytokine family. Furthermore, MDA-MB-468 cells grown as tumor xenografts exhibit an AS switch to the L-isoform of CEACAM1, demonstrating that an in vivo inflammatory milieu is also capable of generating the AS switch, similar to that found in human breast cancers Mol Cancer 7:46, 2008. Conclusions The novel AS regulatory activities attributed to IRF-1 indicate that the IFN-γ response involves a global change in both gene transcription and AS in breast epithelial cells. PMID:24650050

  11. Src family protein tyrosine kinases induce autoactivation of Bruton's tyrosine kinase.

    PubMed Central

    Mahajan, S; Fargnoli, J; Burkhardt, A L; Kut, S A; Saouaf, S J; Bolen, J B

    1995-01-01

    Bruton's tyrosine kinase (Btk) is tyrosine phosphorylated and enzymatically activated following ligation of the B-cell antigen receptor. These events are temporally regulated, and Btk activation follows that of various members of the Src family of protein tyrosine kinases, thus raising the possibility that Src kinases participate in the Btk activation process. We have evaluated the mechanism underlying Btk enzyme activation and have explored the potential regulatory relationship between Btk and Src protein kinases. We demonstrate in COS transient-expression assays that Btk can be activated through intramolecular autophosphorylation at tyrosine 551 and that Btk autophosphorylation is required for Btk catalytic functions. Coexpression of Btk with members of the Src family of protein tyrosine kinases, but not Syk, led to Btk tyrosine phosphorylation and activation. Using a series of point mutations in Blk (a representative Src protein kinase) and Btk, we show that Src kinases activate Btk through an indirect mechanism that requires membrane association of the Src enzymes as well as functional Btk SH3 and SH2 domains. Our results are compatible with the idea that Src protein tyrosine kinases contribute to Btk activation by indirectly stimulating Btk intramolecular autophosphorylation. PMID:7565679

  12. Src family protein tyrosine kinases induce autoactivation of Bruton's tyrosine kinase.

    PubMed

    Mahajan, S; Fargnoli, J; Burkhardt, A L; Kut, S A; Saouaf, S J; Bolen, J B

    1995-10-01

    Bruton's tyrosine kinase (Btk) is tyrosine phosphorylated and enzymatically activated following ligation of the B-cell antigen receptor. These events are temporally regulated, and Btk activation follows that of various members of the Src family of protein tyrosine kinases, thus raising the possibility that Src kinases participate in the Btk activation process. We have evaluated the mechanism underlying Btk enzyme activation and have explored the potential regulatory relationship between Btk and Src protein kinases. We demonstrate in COS transient-expression assays that Btk can be activated through intramolecular autophosphorylation at tyrosine 551 and that Btk autophosphorylation is required for Btk catalytic functions. Coexpression of Btk with members of the Src family of protein tyrosine kinases, but not Syk, led to Btk tyrosine phosphorylation and activation. Using a series of point mutations in Blk (a representative Src protein kinase) and Btk, we show that Src kinases activate Btk through an indirect mechanism that requires membrane association of the Src enzymes as well as functional Btk SH3 and SH2 domains. Our results are compatible with the idea that Src protein tyrosine kinases contribute to Btk activation by indirectly stimulating Btk intramolecular autophosphorylation. PMID:7565679

  13. 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

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

    PubMed Central

    1994-01-01

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

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

    PubMed Central

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

    2016-01-01

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

  16. Two Dictyostelium tyrosine kinase–like kinases function in parallel, stress-induced STAT activation pathways

    PubMed Central

    Araki, Tsuyoshi; Vu, Linh Hai; Sasaki, Norimitsu; Kawata, Takefumi; Eichinger, Ludwig; Williams, Jeffrey G.

    2014-01-01

    When Dictyostelium cells are hyperosmotically stressed, STATc is activated by tyrosine phosphorylation. Unusually, activation is regulated by serine phosphorylation and consequent inhibition of a tyrosine phosphatase: PTP3. The identity of the cognate tyrosine kinase is unknown, and we show that two tyrosine kinase–like (TKL) enzymes, Pyk2 and Pyk3, share this function; thus, for stress-induced STATc activation, single null mutants are only marginally impaired, but the double mutant is nonactivatable. When cells are stressed, Pyk2 and Pyk3 undergo increased autocatalytic tyrosine phosphorylation. The site(s) that are generated bind the SH2 domain of STATc, and then STATc becomes the target of further kinase action. The signaling pathways that activate Pyk2 and Pyk3 are only partially overlapping, and there may be a structural basis for this difference because Pyk3 contains both a TKL domain and a pseudokinase domain. The latter functions, like the JH2 domain of metazoan JAKs, as a negative regulator of the kinase domain. The fact that two differently regulated kinases catalyze the same phosphorylation event may facilitate specific targeting because under stress, Pyk3 and Pyk2 accumulate in different parts of the cell; Pyk3 moves from the cytosol to the cortex, whereas Pyk2 accumulates in cytosolic granules that colocalize with PTP3. PMID:25143406

  17. 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.

  18. 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.

  19. 21 CFR 582.5920 - Tyrosine.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 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...

  20. 21 CFR 582.5920 - Tyrosine.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 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...

  1. 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...

  2. 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

  3. 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.

  4. 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

  5. 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

  6. 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.

  7. No effect of oral tyrosine on total tyrosine levels in breast milk: implications for dietary supplementation in early postpartum.

    PubMed

    Dowlati, Yekta; Ravindran, Arun V; Maheux, Maxim; Steiner, Meir; Stewart, Donna E; Meyer, Jeffrey H

    2014-12-01

    Postpartum depression (PPD) is the most common complication of childbearing with a 13 % prevalence rate, and there is no widespread approach for prevention. There is an appealing theoretical rationale for oral tyrosine to help prevent PPD. However, the effect of oral tyrosine on its total and free concentrations in breast milk and plasma of breastfeeding mothers is not known. Twenty-four healthy breastfeeding women were randomly assigned to 0, 2, 5, or 10 g of oral tyrosine. Free and total tyrosine in breast milk and free tyrosine in plasma were measured. Free tyrosine was also measured in 12 different infant formulas. Total tyrosine in breast milk did not rise, but there was a slight tendency towards a reduction (up to −12 %; repeated measures ANOVA (RMANOVA): p = 0.074). Maternal plasma tyrosine rose (RMANOVA: p < 0.005). In breast milk, 98 % of tyrosine was in proteins or peptides and 2 % was free. Free tyrosine levels in breast milk rose in each group (RMANOVA: p < 0.005), but levels were within the range found in common infant formulas. The negligible effect of oral tyrosine on its concentration in breast milk supports further development of oral tyrosine as part of a prevention strategy for PPD. PMID:25015680

  8. Branching ratio and angular distribution of ejected electrons from Eu 4f76p1/2nd auto-ionizing states

    NASA Astrophysics Data System (ADS)

    Wu, Xiao-Rui; Shen, Li; Zhang, Kai; Dai, Chang-Jian; Yang, Yu-Na

    2016-09-01

    The branching ratios of ions and the angular distributions of electrons ejected from the Eu 4f76p1/2nd auto-ionizing states are investigated with the velocity-map-imaging technique. To populate the above auto-ionizing states, the relevant bound Rydberg states have to be detected first. Two new bound Rydberg states are identified in the region between 41150 cm‑1 and 44580 cm‑1, from which auto-ionization spectra of the Eu 4f76p1/2nd states are observed with isolated core excitation method. With all preparations above, the branching ratios from the above auto-ionizing states to different final ionic states and the angular distributions of electrons ejected from these processes are measured systematically. Energy dependence of branching ratios and anisotropy parameters within the auto-ionization spectra are carefully analyzed, followed by a qualitative interpretation. Project supported by the National Natural Science Foundation of China (Grant No. 11174218).

  9. 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.

  10. Branching ratio and angular distribution of ejected electrons from Eu 4f76p1/2nd auto-ionizing states

    NASA Astrophysics Data System (ADS)

    Wu, Xiao-Rui; Shen, Li; Zhang, Kai; Dai, Chang-Jian; Yang, Yu-Na

    2016-09-01

    The branching ratios of ions and the angular distributions of electrons ejected from the Eu 4f76p1/2nd auto-ionizing states are investigated with the velocity-map-imaging technique. To populate the above auto-ionizing states, the relevant bound Rydberg states have to be detected first. Two new bound Rydberg states are identified in the region between 41150 cm-1 and 44580 cm-1, from which auto-ionization spectra of the Eu 4f76p1/2nd states are observed with isolated core excitation method. With all preparations above, the branching ratios from the above auto-ionizing states to different final ionic states and the angular distributions of electrons ejected from these processes are measured systematically. Energy dependence of branching ratios and anisotropy parameters within the auto-ionization spectra are carefully analyzed, followed by a qualitative interpretation. Project supported by the National Natural Science Foundation of China (Grant No. 11174218).

  11. The optical, mechanical, and thermal design and performance of the 2nd generation redshift (z) and early universe spectrometer, ZEUS-2

    NASA Astrophysics Data System (ADS)

    Parshley, Stephen C.; Ferkinhoff, Carl; Nikola, Thomas; Stacey, Gordon J.; Ade, Peter A.; Tucker, Carole E.

    2012-09-01

    We have built a new long-slit grating spectrometer (ZEUS-2) for observations in the submillimeter wavelength regime (200-650 μm). ZEUS-2 is optimized for observations of redshifted far-infrared spectral lines from galaxies in the early Universe. The spectrometer employs three transition-edge sensed bolometer arrays, allowing for simultaneous observations of multiple lines in several telluric windows. Here we will discuss the optical, mechanical, and thermal requirements of ZEUS-2 and their subsequent design and performance. The entire instrument is cooled using a pulse tube cryocooler and an adiabatic demagnetization refrigerator. The cryogen-free approach enables remote control of the cooling system and allows for deployment of ZEUS-2 to telescope sites where access is limited. The compact and lightweight design is also within the size and weight constraints of several submm telescopes, making ZEUS-2 deployable at a variety of sites. ZEUS-2 completed a successful engineering run at the CSO on Mauna Kea in May 2012, and we plan to have our science-grade array system deployed on the APEX telescope in Chile for a science run in the fall of 2012.

  12. 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

  13. 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.

  14. 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,…

  15. 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.

  16. Ultra-wideband, short-pulse electromagnetics; WRI International Conference, 2nd, Brooklyn, NY, October 8-10, 1992

    NASA Astrophysics Data System (ADS)

    Bertoni, Henry L.; Carin, Lawrence; Felsen, Leopold B.

    1993-01-01

    Major subjects discussed at this conference included the following: pulse generation and detection (electro-optical and electronic methods); broadband electronic systems and components; antennas and arrays; pulse propagation and guidance; scattering theory and computation (analytic and numerical methods); and signal processing techniques. For individual titles, see A95-90905 through A95-90962.

  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. A cytosolic activator of DNA replication is tyrosine phosphorylated in its active form.

    PubMed

    Fresa, K L; Autieri, M V; Coffman, F D; Georgoff, I; Cohen, S

    1993-04-01

    Cytosolic extracts from actively dividing lymphoid cells have been shown to induce DNA synthesis in isolated, quiescent nuclei. An initiating factor in such extracts (activator of DNA replication; ADR) is a > 90-kDa aprotinin-binding protein whose activity is inhibitable not only by aprotinin, but also by several other protease inhibitors as well. Although cytosol from non-proliferating lymphocytes is devoid of ADR activity, we have shown that these preparations can be induced to express ADR activity by brief exposure to a membrane-enriched fraction of spontaneously proliferating MOLT-4 cells via a kinase-dependent mechanism. In the present study, we examine the role of tyrosine kinases in this process. Three inhibitors of tyrosine kinases (genistein, kaempferol, and quercetin) can inhibit the in vitro generation of ADR activity. In vitro generation of ADR activity is associated with the de novo phosphorylation of several proteins, many of which are detectable using anti-phosphotyrosine monoclonal antibodies. ADR itself may be tyrosine phosphorylated in active form as immunoprecipitation using such monoclonal antibodies leads to the depletion of its activity. Moreover, immunoprecipitation results in the removal of several de novo tyrosine-phosphorylated proteins, including species at approximately 122, 105, 93, 86, 79, and 65 kDa. A subset of de novo-phosphorylated proteins, migrating at approximately 105, 93, and 70 kDa, also bound to aprotinin, suggesting that at least one of these proteins may represent ADR itself. PMID:7683270

  19. Inactivation of tyrosine hydroxylase activity by ascorbate in vitro and in rat PC12 cells.

    PubMed

    Wilgus, H; Roskoski, R

    1988-10-01

    Tyrosine hydroxylase activity is reversibly modulated by the actions of a number of protein kinases and phosphoprotein phosphatases. A previous report from this laboratory showed that low-molecular-weight substances present in striatal extracts lead to an irreversible loss of tyrosine hydroxylase activity under cyclic AMP-dependent phosphorylation conditions. We report here that ascorbate is one agent that inactivates striatal tyrosine hydroxylase activity with an EC50 of 5.9 microM under phosphorylating conditions. Much higher concentrations (100 mM) fail to inactivate the enzyme under nonphosphorylating conditions. Isoascorbate (EC50, 11 microM) and dehydroascorbate (EC50, 970 microM) also inactivated tyrosine hydroxylase under phosphorylating but not under nonphosphorylating conditions. In contrast, ascorbate sulfate was inactive under phosphorylating conditions at concentrations up to 100 mM. Since the reduced compounds generate several reactive species in the presence of oxygen, the possible protecting effects of catalase, peroxidase, and superoxide dismutase were examined. None of these three enzymes, however, afforded any protection against inactivation. We also examined the effects of ascorbate and its congeners on the activity of tyrosine hydroxylase purified to near homogeneity from a rat pheochromocytoma. This purified enzyme was also inactivated by the same agents that inactivated the impure corpus striatal enzyme. Under conditions in which ascorbate almost completely abolished enzyme activity, we found no indication for significant proteolysis of the purified enzyme as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. We also found that pretreatment of PC12 cells in culture for 4 h with 1 mM ascorbate, dehydroascorbate, or isoascorbate (but not ascorbate sulfate) also decreased tyrosine hydroxylase activity 25-50%.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2901463

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

    PubMed Central

    Parrish, Diana C.; Alston, Eric N.; Rohrer, Hermann; Nkadi, Paul; Woodward, William R.; Schütz, Günther; Habecker, Beth A.

    2010-01-01

    Myocardial infarction causes heterogeneity of noradrenergic transmission that contributes to the development of ventricular arrhythmias and sudden cardiac death. Ischemia-induced alterations in sympathetic transmission include regional variations in cardiac norepinephrine (NE) and in tyrosine hydroxylase, the rate-limiting enzyme in NE synthesis. Inflammatory cytokines that act through gp130 are elevated in the heart after myocardial infarction. These cytokines decrease expression of tyrosine hydroxylase in sympathetic neurons, and indirect evidence suggests they contribute to the local depletion of tyrosine hydroxylase in the damaged left ventricle. However, gp130 cytokines are also important for the survival of cardiac myocytes following damage to the heart. To examine the effect of cytokines on tyrosine hydroxylase and NE content in cardiac nerves we used gp130DBH-Cre/lox mice, which have a deletion of the gp130 receptor in neurons expressing dopamine beta hydroxylase. The absence of neuronal gp130 prevented the loss of tyrosine hydroxylase in cardiac sympathetic nerves innervating the left ventricle one week after ischemia-reperfusion. Surprisingly, restoring tyrosine hydroxylase in the damaged ventricle did not return neuronal NE content to normal levels. NE uptake into cardiac nerves was significantly lower in gp130 KO mice, contributing to the lack of neuronal NE stores. There were no significant differences in left ventricular peak systolic pressure, dP/dtMAX, or dP/dtMIN between the two genotypes after myocardial infarction, but ganglionic blockade revealed differences in autonomic tone between the genotypes. Stimulating the heart with dobutamine or releasing endogenous NE with tyramine generated similar responses in both genotypes. Thus, the removal of gp130 from sympathetic neurons prevents the post-infarct depletion of TH in the left ventricle, but does not alter NE content or cardiac function. PMID:19880537

  1. Mechanosensing Controlled Directly by Tyrosine Kinases.

    PubMed

    Yang, Bo; Lieu, Zi Zhao; Wolfenson, Haguy; Hameed, Feroz M; Bershadsky, Alexander D; Sheetz, Michael P

    2016-09-14

    To understand how cells form tissues, we need to understand how the tyrosine kinases are involved in controlling cell mechanics, whether they act directly as parts of mechanosensing machines or indirectly. Cells test the critical parameter of matrix rigidity by locally contracting ("pinching") matrices and measuring forces, and the depletion of contractile units causes transformation. We report here that knocking down the receptor tyrosine kinases (RTKs), AXL, and ROR2, alters rigidity sensing and increases the magnitude or duration of local contraction events, respectively. Phospho-AXL and ROR2 localize to contraction units and bind major contractile components, tropomyosin 2.1 (AXL), myosin IIA (AXL), and filamin A (ROR2). At a molecular level, phosphorylated AXL localizes to active myosin filaments and phosphorylates tropomyosin at a tyrosine critical for adhesion formation. ROR2 binding of ligand is unnecessary, but binding filamin A helps function. Thus, AXL and ROR2 alter rigidity sensing and consequently morphogenic processes by directly controlling local mechanosensory contractions without ligands. PMID:27559755

  2. 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

  3. 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.

  4. 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

  5. Tyrosine phosphorylation of dihydrolipoamide dehydrogenase as a potential cadmium target and its inhibitory role in regulating mouse sperm motility.

    PubMed

    Li, Xinhong; Wang, Lirui; Li, Yuhua; Fu, Jieli; Zhen, Linqing; Yang, Qiangzhen; Li, Sisi; Zhang, Yukun

    2016-05-16

    Cadmium (Cd) is reported to reduce sperm motility and functions. However, the molecular mechanisms of Cd-induced toxicity remain largely unknown, presenting a major knowledge gap in research on reproductive toxicology. In the present study, we identified a candidate protein, dihydrolipoamide dehydrogenase (DLD), which is a post-pyruvate metabolic enzyme, exhibiting tyrosine phosphorylation in mouse sperm exposed to Cd both in vivo and in vitro. Immunoprecipitation assay demonstrated DLD was phosphorylated in tyrosine residues without altered expression after Cd treatment, which further confirmed our identified result. However, the tyrosine phosphorylation of DLD did not participate in mouse sperm capacitation and Bovine Serum Albumin (BSA) effectively prevented the tyrosine phosphorylation of DLD. Moreover, Cd-induced tyrosine phosphorylation of DLD lowered its dehydrogenase activity and meanwhile, Nicotinamide Adenine Dinucleotide Hydrogen (NADH) content, Adenosine Triphosphate (ATP) production and sperm motility were all inhibited by Cd. Interestingly, when the tyrosine phosphorylation of DLD was blocked by BSA, the decrease of DLD activity, NADH and ATP content as well as sperm motility was also suppressed simultaneously. These results suggested that Cd-induced tyrosine phosphorylation of DLD inhibited its activity and thus suppressed the tricarboxylic acid (TCA) cycle, which resulted in the reduction of NADH and hence the ATP production generated through oxidative phosphorylation (OPHOXS). Taken together, our results revealed that Cd induced DLD tyrosine phosphorylation, in response to regulate TCA metabolic pathway, which reduced ATP levels and these negative effects led to decreased sperm motility. This study provided new understanding of the mechanisms contributing to the harmful effects of Cd on the motility and function of spermatozoa. PMID:27289041

  6. 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

  7. 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.

  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. Routine titration of foot-and-mouth disease virus suspensions by analytical ultracentrifugation 2nd communication: sedimentation equilibrium method.

    PubMed

    Strobbe, R; Lacroix, C; Charlier, G; Debecq, J

    1977-01-01

    A routine method for the determination of the virus concentration in FMD virus cultures and vaccines was developed. This method was based on sedimentation equilibrium in the analytical ultraviolet scanning ultracentrifuge. The virus suspension was first clarified. The virions were then sedimented in a preparative ultracentrifuge. The resuspended virions were diluted in a Cesium chloride solution and brought to equilibrium in the density gradient generated in the analytical ultracentrifuge. The optical density of the virus band was measured by the UV scanning system. A calculation procedure was developed to compute the density at the limits and at the maximum of the virus band. The virus concentration expressed as weight, was calculated for the original virus suspension.

  10. 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.

  11. Effects of modification of the tyrosine residues of bacteriorhodopsin with tetranitromethane.

    PubMed Central

    Campos-Cavieres, M; Moore, T A; Perham, R N

    1979-01-01

    Treatment of the purple membrane of Halobacterium halobium with tetranitromethane led to modification of tyrosine residues. Modification of more than 3-4 tyrosine residues per bacteriorhodopsin monomer caused a decrease in the light-induced proton-pumping ability of purple membrane in synthetic lipid vesicles, loss of the sharp X-ray-diffraction patterns characteristic of the crystal lattice, loss of the absorbance maximum at 560 nm, and change in the buoyant density of the membrane. No modification of lipid was detected. These changes were interpreted as a gradual denaturation of the protein component such that when 8-9 tyrosine residues are modified, no proton pumping is observed. Modification of less than 3-4 tyrosine residues with tetranitromethane caused an increse in light-induced proton pumping. It was possible to generate partly modified purple membrane which had completely lost the property of diffracting X-rays into the sharp pattern observed with native purple membrane, but which still retained the ability to pump protons in a vectorial manner. Retention of crystal lattice is not essential for proton pumping. Images Fig. 3. PMID:475758

  12. Studies of Nondefective Adenovirus 2-Simian Virus 40 Hybrid Viruses IV. Characterization of the Simian Virus 40 Ribonucleic Acid Species Induced by Wild-Type Simian Virus 40 and by the Nondefective Hybrid Virus, Ad2+ND1

    PubMed Central

    Oxman, Michael N.; Levine, Arthur S.; Crumpacker, Clyde S.; Levin, Myron J.; Henry, Patrick H.; Lewis, Andrew M.

    1971-01-01

    Ad2+ND1, a nondefective adenovirus 2 (Ad2)-simian virus 40 (SV40) hybrid virus, has been previously shown to contain a small segment of the SV40 genome covalently linked to Ad2 deoxyribonucleic acid (DNA). The SV40 portion of this hybrid virus has been characterized by relating the SV40-specific ribonucleic acid (RNA) sequences transcribed from the Ad2+ND1 DNA to those transcribed from the DNA of SV40 itself. RNA-DNA hybridization-competition studies indicate that the SV40 component of Ad2+ND1 consists of some, but not all, of that part of the SV40 genome which is transcribed early, i.e., prior to viral DNA replication, in SV40 lytic infection. PMID:4329969

  13. 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.

  14. 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.

  15. An Analysis of T-phase observed from the 2nd and 3rd underground nuclear explosions of North Korea

    NASA Astrophysics Data System (ADS)

    KIM, Seo Young; KIM, Tae Sung

    2014-05-01

    On February 12, 2013 the third underground nuclear explosion by North Korea was detected in the northeastern part of Korean Peninsula, where North Korea executed their first and second underground nuclear explosions. Through analysis on the data recorded at seismic stations of Korea Institute of Geoscience and Mineral Resources (KIGAM) we found that the T-phase generated from the second and the third underground nuclear explosions was recorded a seismic array located in an island of East Sea. The T-phase was converted from the P and S waves originated from the nuclear explosions and their group velocity in water is around 1.5km.s. A detailed study was performed with spectrogram analysis and envelops analysis applied high-pass filter (f ≥2Hz), spectrogram and progressive multi-channel correlation method (PMCC). The maximum cross correlation coefficients between two events were calculated around 0.7 and the results of the azimuth angles through PMCC were about 320-330 degree.

  16. Tyrosine metabolic enzymes from insects and mammals: a comparative perspective.

    PubMed

    Vavricka, Christopher John; Han, Qian; Mehere, Prajwalini; Ding, Haizhen; Christensen, Bruce M; Li, Jianyong

    2014-02-01

    Differences in the metabolism of tyrosine between insects and mammals present an interesting example of molecular evolution. Both insects and mammals possess fine-tuned systems of enzymes to meet their specific demands for tyrosine metabolites; however, more homologous enzymes involved in tyrosine metabolism have emerged in many insect species. Without knowledge of modern genomics, one might suppose that mammals, which are generally more complex than insects and require tyrosine as a precursor for important catecholamine neurotransmitters and for melanin, should possess more enzymes to control tyrosine metabolism. Therefore, the question of why insects actually possess more tyrosine metabolic enzymes is quite interesting. It has long been known that insects rely heavily on tyrosine metabolism for cuticle hardening and for innate immune responses, and these evolutionary constraints are likely the key answers to this question. In terms of melanogenesis, mammals also possess a high level of regulation; yet mammalian systems possess more mechanisms for detoxification whereas insects accelerate pathways like melanogenesis and therefore must bear increased oxidative pressure. Our research group has had the opportunity to characterize the structure and function of many key proteins involved in tyrosine metabolism from both insects and mammals. In this mini review we will give a brief overview of our research on tyrosine metabolic enzymes in the scope of an evolutionary perspective of mammals in comparison to insects.

  17. 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.

  18. 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

  19. 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.

  20. 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.

  1. Receptor Tyrosine Kinase and Tyrosine Kinase Inhibitors: New Hope for Success in Multiple Sclerosis Therapy.

    PubMed

    Mirshafiey, Abbas; Ghalamfarsa, Ghasem; Asghari, Babak; Azizi, Gholamreza

    2014-07-01

    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.

  2. 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.

  3. 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

  4. 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

  5. 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

  6. Targeting receptor tyrosine kinases in gastric cancer

    PubMed Central

    Morishita, Asahiro; Gong, Jian; Masaki, Tsutomu

    2014-01-01

    Molecularly targeted therapeutic agents are constantly being developed and have been shown to be effective in various clinical trials. One group of representative targeted oncogenic kinases, the receptor tyrosine kinases (RTKs), has been associated with gastric cancer development. Trastuzumab, an inhibitor of ERBB2, has been approved for the treatment of gastric cancer, although other receptor tyrosine kinases, such as epidermal growth factor receptor, vascular endothelial growth factor, platelet-derived growth factor receptor, c-Met, IGF-1R and fibroblast growth factor receptor 2, are also activated in gastric cancer. The promising results of the trastuzumab clinical trial for gastric cancer resulted in the approval of trastuzumab-based therapy as a first-line treatment for human epidermal growth factor receptor 2-positive patients. On the other hand, the trial examining bevacizumab in combination with conventional chemotherapy did not meet its primary goal of increasing the overall survival time of gastric cancer patients; however, a significantly higher response rate and a longer progression-free survival were observed in the bevacizumab arm of the trial. Other clinical trials, especially phase III trials that have tested drugs targeting RTKs, such as cetuximab, panitumumab, gefitinib, erlotinib, figitumumab, sorafenib, sunitinib and lapatinib, have shown that these drugs have modest effects against gastric cancer. This review summarizes the recent results from the clinical trials of molecularly targeted drugs and suggests that further improvements in the treatment of advanced gastric cancer can be achieved through the combination of conventional drugs with the new molecularly targeted therapies. PMID:24782606

  7. 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

  8. Computer-Generated Geometry Instruction: A Preliminary Study

    ERIC Educational Resources Information Center

    Kang, Helen W.; Zentall, Sydney S.

    2011-01-01

    This study hypothesized that increased intensity of graphic information, presented in computer-generated instruction, could be differentially beneficial for students with hyperactivity and inattention by improving their ability to sustain attention and hold information in-mind. To this purpose, 18 2nd-4th grade students, recruited from general…

  9. Fluorescence lifetimes of tyrosine residues in cytochrome c'' as local probes to study protein unfolding.

    PubMed

    Noronha, Melinda; Santos, Raquel; Paci, Emanuele; Santos, Helena; Maçanita, António L

    2009-04-01

    Time-resolved fluorescence spectroscopy was used to show that multiple tyrosine residues of a protein can serve as localized probes of structural changes during thermal unfolding. Cytochrome c'' from Methylophilus methylotrophus, which has four tyrosine residues, was chosen as a model protein. The procedure involved, first, the assignment of the experimental decay times to the tyrosine residues, followed by the interpretation of the changes in the decay times and pre-exponential coefficients with temperature. We found that the fluorescence decays of cytochrome c'' are double-exponential from 23 to 80 degrees C, with decay times much shorter than those of the parent compound N-acetyl-tyrosinamide; this quenching was ascribed to dipole-dipole energy transfer from the tyrosine residues to the heme. The tyrosine-heme distances (R) and theoretical decay times, tau(comp), were estimated for each tyrosine residue. The analysis of the simulated decay generated with tau(comp), showed that a double-exponential fit is sufficient to describe the four decay times with two pre-exponential coefficients close to values observed from the experimental decay. Therefore, the decay times at 23 degrees C could be assigned to the individual tyrosine residues as tau(1) to Tyr-10 and Tyr-23 (at 20.3 A) and tau(2) to Tyr-12 and Tyr-115 (at 12-14 A). On the basis of this assignment and MD simulations, the temperature dependence of the decay times and pre-exponential coefficients suggest that upon unfolding, Tyr-12 is displaced from the heme, with loss of the structure of alpha-helix I. Moreover, Tyr-115 remains close to the heme and the structure in this region of the protein is not altered significantly. Altogether the data support the view that the protein core, comprising the heme and the four alpha-helices II to V, is clearly more stable than the remaining region that includes alpha-helix I and the loop between residues 19-27.

  10. 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

  11. 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

  12. Tyrosine can protect against oxidative stress through ferryl hemoglobin reduction.

    PubMed

    Lu, Naihao; He, Yingjie; Chen, Chao; Tian, Rong; Xiao, Qiang; Peng, Yi-Yuan

    2014-08-01

    The toxic mechanism of hemoglobin (Hb) under oxidative stress is linked to the formations of highly cytotoxic ferryl species and subsequently heme-to-protein cross-linked derivative of Hb (Hb-X). In this study, we have examined the effects of free tyrosine and its analogues (3-chlorotyrosine, phenylalanine) on the stability of ferryl hemoglobin and the formation of Hb-X. The results showed that free tyrosine (not phenylalanine, 10-500 μM) was an efficient reducing agent of ferryl species and also effective at preventing the formation of cytotoxic Hb-X. Meanwhile, the dimeric tyrosine was formed as the oxidation product of tyrosine during Hb redox reaction. Compared with free tyrosine, 3-chlorotyrosine, an oxidation product of tyrosine and a proposed biomarker for hypochlorous acid (HOCl) in vivo, exhibited stronger antioxidant properties in Hb-induced oxidative stress, which was consistent with its more efficient ability in the reduction of ferryl species. These results showed that the presence of tyrosine and its derivative in vivo and vitro could ameliorate oxidative damage through ferryl heme reduction. The antioxidant ability, therefore, may provide new insights into the nutritional and physiological significance of free tyrosine with redox active heme proteins-related oxidative stress.

  13. Tyrosine improves working memory in a multitasking environment.

    PubMed

    Thomas, J R; Lockwood, P A; Singh, A; Deuster, P A

    1999-11-01

    Previous studies indicate that tyrosine may prove useful in promoting improved performance in situations in which performance is compromised by stress. To extend the generality of previous tyrosine findings, the present study examined the effects of tyrosine ingestion on performance during both a Multiple Task and a Simple Task battery. The multiple task battery was designed to measure working memory, arithmetic skills, and visual and auditory monitoring simultaneously, whereas the simple task battery measured only working memory and visual monitoring. Ten men and 10 women subjects underwent these batteries 1 h after ingesting 150 mg/kg of l-tyrosine or placebo. Administration of tyrosine significantly enhanced accuracy and decreased frequency of list retrieval on the working memory task during the multiple task battery compared with placebo. However, tyrosine induced no significant changes in performance on the arithmetic, visual, or auditory tasks during the Multiple Task, or modified any performance measures during the Simple Task battery. Blood levels of ACTH and cortisol were not, but heart rate and blood pressure were significantly increased during the performance tasks. The present results indicate that tyrosine may sustain working memory when competing requirements to perform other tasks simultaneously degrade performance, and that supplemental tyrosine may be appropriate for maintaining performance when mild to severe decrements are anticipated.

  14. 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...

  15. Studies of Nondefective Adenovirus 2-Simian Virus 40 Hybrid Viruses II. Relationship of Adenovirus 2 Deoxyribonucleic Acid and Simian Virus 40 Deoxyribonucleic Acid in the Ad2+ND1 Genome

    PubMed Central

    Levin, Myron J.; Crumpacker, Clyde S.; Lewis, Andrew M.; Oxman, Michael N.; Henry, Patrick H.; Rowe, Wallace P.

    1971-01-01

    A nondefective adenovirus 2 (Ad2)-simian virus 40 (SV40) hybrid virus, Ad2+ND1, has been plaque-isolated from an Ad2-SV40 hybrid population. This virus, unlike the defective Ad-SV40 hybrid populations previously described, replicates without the aid of nonhybrid adenovirus helper. Consequently, the hybrid virus deoxyribonucleic acid (DNA) can be obtained free of nonhybrid adenovirus DNA. The DNA of the Ad2+ND1 virus was shown by ribonucleic acid (RNA)-DNA hybridization to consist of nucleotide sequences complementary to Ad2- and SV40-specific RNA. Techniques of equilibrium density and rate zonal centrifugation were employed to demonstrate that these Ad2 and SV40 nucleotide sequences were linked together in the same DNA molecules by alkali-resistant bonds. Calibration curves were established relating the amount of tritium-labeled SV40-specific RNA (prepared in vitro or in vivo) bound to given amounts of SV40 DNA in a hybridization reaction, and these curves were employed to determine the equivalent amount of SV40 DNA in the Ad2+ND1 molecule. From the results obtained, it was estimated that 1% of the Ad2+ND1 DNA consists of SV40 nucleotide sequences. PMID:4323709

  16. 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…

  17. 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…

  18. An overview of second generation biofuel technologies.

    PubMed

    Sims, Ralph E H; Mabee, Warren; Saddler, Jack N; Taylor, Michael

    2010-03-01

    The recently identified limitations of 1st-generation biofuels produced from food crops (with perhaps the exception of sugarcane ethanol) have caused greater emphasis to be placed on 2nd-generation biofuels produced from ligno-cellulosic feedstocks. Although significant progress continues to be made to overcome the technical and economic challenges, 2nd-generation biofuels production will continue to face major constraints to full commercial deployment. The logistics of providing a competitive, all-year-round, supply of biomass feedstock to a commercial-scale plant is challenging, as is improving the performance of the conversion process to reduce costs. The biochemical route, being less mature, probably has a greater cost reduction potential than the thermo-chemical route, but here a wider range of synthetic fuels can be produced to better suit heavy truck, aviation and marine applications. Continued investment in research and demonstration by both public and private sectors, coupled with appropriate policy support mechanisms, are essential if full commercialisation is to be achieved within the next decade. After that, the biofuel industry will grow only at a steady rate and encompass both 1st- and 2nd-generation technologies that meet agreed environmental, sustainability and economic policy goals. PMID:19963372

  19. 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.

  20. An isotope dilution model for partitioning phenylalanine and tyrosine uptake by the mammary gland of lactating dairy cows.

    PubMed

    Crompton, L A; France, J; Reynolds, C K; Mills, J A N; Hanigan, M D; Ellis, J L; Bannink, A; Bequette, B J; Dijkstra, J

    2014-10-21

    An isotope dilution model for partitioning phenylalanine and tyrosine uptake by the mammary gland of the lactating dairy cow is constructed and solved in the steady state. The model contains four intracellular and four extracellular pools and conservation of mass principles are applied to generate the fundamental equations describing the behaviour of the system. The experimental measurements required for model solution are milk secretion and plasma flow rate across the gland in combination with phenylalanine and tyrosine concentrations and plateau isotopic enrichments in arterial and venous plasma and free and protein bound milk during a constant infusion of [1-(13)C]phenylalanine and [2,3,5,6-(2)H]tyrosine tracer. If assumptions are made, model solution enables determination of steady state flows for phenylalanine and tyrosine inflow to the gland, outflow from it and bypass, and flows representing the synthesis and degradation of constitutive protein and phenylalanine hydroxylation. The model is effective in providing information about the fates of phenylalanine and tyrosine in the mammary gland and could be used as part of a more complex system describing amino acid metabolism in the whole ruminant.

  1. Targeting FMS-related tyrosine kinase receptor 3 with the human immunoglobulin G1 monoclonal antibody IMC-EB10.

    PubMed

    Youssoufian, Hagop; Rowinsky, Eric K; Tonra, James; Li, Yiwen

    2010-02-15

    FMS-related tyrosine kinase receptor 3 (FLT3) is a class III receptor tyrosine kinase that holds considerable promise as a therapeutic target in hematologic malignancies. Current efforts directed toward the development of small-molecule tyrosine kinase inhibitors of FLT3 may be limited by off-target toxicities and the development of drug resistance. Target-specific antibodies could overcome these hurdles and provide additional mechanisms to enhance the antitumor efficacy of FLT3 inhibitors. IMC-EB10 is a novel antibody directed against FLT3. The binding of IMC-EB10 to FLT3 results in antiproliferative effects in vitro and in mouse models engrafted with human leukemia cells that harbor wild-type or constitutively activated FLT3. Future clinical trials will test these notions formally and will identify the most appropriate opportunities for this member of a new generation of antileukemic therapies.

  2. Bone fractures as indicators of intentional violence in the eastern Adriatic from the antique to the late medieval period (2nd-16th century AD).

    PubMed

    Slaus, Mario; Novak, Mario; Bedić, Zeljka; Strinović, Davor

    2012-09-01

    To test the historically documented hypothesis of a general increase in deliberate violence in the eastern Adriatic from the antique (AN; 2nd-6th c.) through the early medieval (EM; 7th-11th c.) to the late-medieval period (LM; 12th-16th c.), an analysis of the frequency and patterning of bone trauma was conducted in three skeletal series from these time periods. A total of 1,125 adult skeletons-346 from the AN, 313 from the EM, and 466 from the LM series-were analyzed. To differentiate between intentional violence and accidental injuries, data for trauma frequencies were collected for the complete skeleton, individual long bones, and the craniofacial region as well as by type of injury (perimortem vs. antemortem). The results of our analyses show a significant temporal increase in total fracture frequencies when calculated by skeleton as well as of individuals exhibiting one skeletal indicator of deliberate violence (sharp force lesions, craniofacial injuries, "parry" fractures, or perimortem trauma). No significant temporal increases were, however, noted in the frequencies of craniofacial trauma, "parry" fractures, perimortem injuries, or of individuals exhibiting multiple skeletal indicators of intentional violence. Cumulatively, these data suggest that the temporal increase in total fracture frequencies recorded in the eastern Adriatic was caused by a combination of factors that included not only an increase of intentional violence but also a significant change in lifestyle that accompanied the transition from a relatively affluent AN urban lifestyle to a more primitive rural medieval way of life.

  3. 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

  4. 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

  5. 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.

  6. 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.

  7. 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

  8. Oxidation of methanol on 2nd and 3rd row group VIII transition metals (Pt, Ir, Os, Pd, Rh, and Ru): Application to direct methanol fuel cells

    SciTech Connect

    Kua, J.; Goddard, W.A. III

    1999-12-01

    Using first principles quantum mechanics [nonlocal density functional theory (B3LYP)], the authors calculated the 13 most likely intermediate species for methanol oxidation on clusters of all 2nd and 3rd row Group VIII transition metals for all three likely binding sites (top, bridge, and cap). This comprehensive set of binding energies and structures allows a detailed analysis of possible reaction mechanisms and how they change for different metals. This illustrates the role in which modern quantum chemical methods can be used to provide data for combinatorial strategies for discovering and designing new catalysts. Methanol dehydrogenation is most facile on Pt, with the hydrogens preferentially stripped off the carbon end. However, water dehydrogenation is most facile on Ru. These results support the bifunctional mechanism for methanol oxidation on Pt-Ru alloys in direct methanol fuel cells (DMFCs). Pure Os is capable of performing both functionalities without cocatalyst. It is suggested that pure Os be examined as a potential catalyst for low overpotential, highly dispersed catalyst DMFCs. Pathways to form the second C-O bond differ between the pure metals (Pt and Os) in which (CO){sub ads} is probably activated by (OH){sub ads} and the Pt-Ru binary system in which (COH){sub ads} is probably activated by O{sub ads}. For all cases formation of (COOH){sub ads} is an important precursor to the final dehydrogenation to desorb CO{sub 2} from the surface.

  9. Pleiotrophin stimulates tyrosine phosphorylation of beta-adducin through inactivation of the transmembrane receptor protein tyrosine phosphatase beta/zeta.

    PubMed

    Pariser, Harold; Perez-Pinera, Pablo; Ezquerra, Laura; Herradon, Gonzalo; Deuel, Thomas F

    2005-09-16

    Pleiotrophin (PTN the protein, Ptn the gene) signals through a unique mechanism; it inactivates the tyrosine phosphatase activity of its receptor, the transmembrane receptor protein tyrosine phosphatase (RPTP)beta/zeta, and increases tyrosine phosphorylation of the substrates of RPTPbeta/zeta through the continued activity of a yet to be described protein tyrosine kinase(s) in PTN-stimulated cells. We have now found that the cytoskeletal protein beta-adducin interacts with the intracellular domain of RPTPbeta/zeta in a yeast two-hybrid system, that beta-adducin is a substrate of RPTPbeta/zeta, that beta-adducin is phosphorylated in tyrosine in cells not stimulated by PTN, and that tyrosine phosphorylation of beta-adducin is sharply increased in PTN-stimulated cells, suggesting that beta-adducin is a downstream target of and regulated by the PTN/RPTPbeta/zeta signaling pathway. beta-Catenin was the first downstream target of the PTN/RPTPbeta/zeta signaling pathway to be identified; these data thus also suggest that PTN coordinately regulates steady state levels of tyrosine phosphorylation of the important cytoskeletal proteins beta-adducin and beta-catenin and, through PTN-stimulated tyrosine phosphorylation, beta-adducin may contribute to the disruption of cytoskeletal structure, increased plasticity, and loss of homophilic cell-cell adhesion that are the consequences of PTN stimulation of cells and a characteristic feature of different malignant cells with mutations that activate constitutive expression of the endogenous Ptn gene.

  10. Mutation of tyrosine-141 inhibits insulin-promoted tyrosine phosphorylation and increased responsiveness of the human beta 2-adrenergic receptor.

    PubMed Central

    Valiquette, M; Parent, S; Loisel, T P; Bouvier, M

    1995-01-01

    The ability of insulin to promote phosphorylation of the human beta 2-adrenergic receptor (beta 2AR) was assessed in Chinese hamster fibroblasts transfected with beta 2AR cDNA. Phosphotyrosine residues were detected in purified beta 2AR using a polyclonal anti-phosphotyrosine antibody and by phosphoamino acid analysis following metabolic labelling with inorganic 32P. Treatment of the cells with insulin induced a 2.4-fold increase in the phosphotyrosine content of the receptor. The insulin-promoted phosphorylation of the beta 2AR was accompanied by an increase in the beta-adrenergic-stimulated adenyl cyclase activity. Substitution of a phenylalanine residue for tyrosine-141 completely prevented both the increased tyrosine phosphorylation and the enhanced responsiveness of the beta 2AR promoted by insulin treatment. Mutation of three other tyrosines located in the cytoplasmic domain of the receptor, tyrosine-366, tyrosine-350 and tyrosine-354, did not abolish the insulin-promoted tyrosine phosphorylation. Taken together, these results suggest that insulin promotes phosphorylation of the beta 2AR on tyrosine-141 and that such phosphorylation leads to a supersensitization of the receptor. Images PMID:8521811

  11. 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

  12. 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.

  13. 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.

  14. Particle Physics, 2nd Edition

    NASA Astrophysics Data System (ADS)

    Martin, B. R.; Shaw, G.

    1998-01-01

    Particle Physics, Second Edition is a concise and lucid account of the fundamental constituents of matter. The standard model of particle physics is developed carefully and systematically, without heavy mathematical formalism, to make this stimulating subject accessible to undergraduate students. Throughout, the emphasis is on the interpretation of experimental data in terms of the basic properties of quarks and leptons, and extensive use is made of symmetry principles and Feynman diagrams, which are introduced early in the book. The Second Edition brings the book fully up to date, including the discovery of the top quark and the search for the Higgs boson. A final short chapter is devoted to the continuing search for new physics beyond the standard model. Particle Physics, Second Edition features: * A carefully structured and written text to help students understand this exciting and demanding subject. * Many worked examples and problems to aid student learning. Hints for solving the problems are given in an Appendix. * Optional "starred" sections and appendices, containing more specialised and advanced material for the more ambitious reader.

  15. Statistical Physics, 2nd Edition

    NASA Astrophysics Data System (ADS)

    Mandl, F.

    1989-01-01

    The Manchester Physics Series General Editors: D. J. Sandiford; F. Mandl; A. C. Phillips Department of Physics and Astronomy, University of Manchester Properties of Matter B. H. Flowers and E. Mendoza Optics Second Edition F. G. Smith and J. H. Thomson Statistical Physics Second Edition E. Mandl Electromagnetism Second Edition I. S. Grant and W. R. Phillips Statistics R. J. Barlow Solid State Physics Second Edition J. R. Hook and H. E. Hall Quantum Mechanics F. Mandl Particle Physics Second Edition B. R. Martin and G. Shaw The Physics of Stars Second Edition A. C. Phillips Computing for Scientists R. J. Barlow and A. R. Barnett Statistical Physics, Second Edition develops a unified treatment of statistical mechanics and thermodynamics, which emphasises the statistical nature of the laws of thermodynamics and the atomic nature of matter. Prominence is given to the Gibbs distribution, leading to a simple treatment of quantum statistics and of chemical reactions. Undergraduate students of physics and related sciences will find this a stimulating account of the basic physics and its applications. Only an elementary knowledge of kinetic theory and atomic physics, as well as the rudiments of quantum theory, are presupposed for an understanding of this book. Statistical Physics, Second Edition features: A fully integrated treatment of thermodynamics and statistical mechanics. A flow diagram allowing topics to be studied in different orders or omitted altogether. Optional "starred" and highlighted sections containing more advanced and specialised material for the more ambitious reader. Sets of problems at the end of each chapter to help student understanding. Hints for solving the problems are given in an Appendix.

  16. Abdominal ultrasonography, 2nd Ed

    SciTech Connect

    Goldberg, B.B.

    1984-01-01

    This volume is a new and updated edition of an extensively illustrated text and reference on the capabilities and imaging of gray scale ultrasonography for each major abdominal organ. Each major organ system is treated separately, including liver, gallbladder and bile ducts, pancreas, kidney, retroperitoneum, abdominal vasculature, and more. There are over 500 illustrations and ten pages of full color plates for cross sectional anatomy.

  17. Sedimentary petrology. 2nd edition

    SciTech Connect

    Blatt, H.

    1992-01-01

    The second edition of Sedimentary Petrology is extensively revised and updated; much effort has been expended to strengthen the weaknesses of the earlier edition, and much of this effort has been successful. It consists of sixteen chapters. Following two introductory chapters (occurrence of sedimentary rocks; weathering and soils), eleven chapters cover the various sedimentary rock types. Coverage is allocated in proportion to their relative abundance and relative ease of study -- three chapters on conglomerates and sandstones (textures and structures, composition, and diagenesis); one on mud rocks; three on carbonates (limestone textures, structures, and environments; limestone mineralogy and diagenesis; and dolostones); and one each on evaporites, cherts, iron-rich rocks, and phosphorites. A novel and useful chapter on paleogeothermometry rounds out the discussion of rocks, followed by chapters on The Development of a Research Project'' and common laboratory methods.

  18. Modern Physics, 2nd Edition

    NASA Astrophysics Data System (ADS)

    Krane, Kenneth S.

    1995-08-01

    Bring Modern Physics to Life with a Realistic Software Simulation! Enhance the thorough coverage of Krane's Modern Physics 2e with hands-on, real-world experience! Modern Physics Simulations, developed by the Consortium for Upper-Level Physics Software (CUPS), offers complex, realistic calculations of models of various physical systems. Like all of the CUPS simulations, it is remarkably easy to use, yet sophisticated enough for explorations of new ideas. Important Features Include: * Powerful simulations covering Historic Experiments in Electron Diffraction, Laser Cavities & Dynamics, Classical Scattering, Nuclear Properties & Decays, Special Relativity, Quantum Mechanics, and the Hydrogen Atom & the H2+ Molecule. * Pascal source code for all programs and a number of exercises suggesting specific ways the programs can be modified. * Graphical (often animated) displays in most simulations. The entire CUPS simulation series consists of nine books/software simulations which cover Astrophysics, Electricity and Magnetism, Classical Mechanics, Modern Physics, Quantum Mechanics, Nuclear and Particle Physics, Solid State Physics, Thermal and Statistical Physics, and Waves and Optics.

  19. 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

  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.

  1. 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

  2. High-sensitivity determination of tyrosine-phosphorylated peptides by on-line enzyme reactor and electrospray ionization mass spectrometry.

    PubMed Central

    Amankwa, L. N.; Harder, K.; Jirik, F.; Aebersold, R.

    1995-01-01

    We describe a simple, fast, sensitive, and nonisotopic bioanalytical technique for the detection of tyrosine-phosphorylated peptides and the determination of sites of protein tyrosine phosphorylation. The technique employs a protein tyrosine phosphatase micro enzyme reactor coupled on-line to either capillary electrophoresis or liquid chromatography and electrospray ionization mass spectrometry instruments. The micro enzyme reactor was constructed by immobilizing genetically engineered, metabolically biotinylated human protein tyrosine phosphatase beta onto the inner surface of a small piece of a 50-microns inner diameter, 360-microns outer diameter fused silica capillary or by immobilization of the phosphatase onto 40-90-microns avidin-activated resins. By coupling these reactors directly to either a capillary electrophoresis column or a liquid chromatography column, we were able to rapidly perform enzymatic dephosphorylation and separation of the reaction products. Detection and identification of the components of the reaction mixture exiting these reactors were done by mass analysis with an on-line electrospray ionization mass spectrometer. Tyrosine-phosphorylated peptides, even if present in a complex peptide mixture, were identified by subtractive analysis of peptide patterns generated with or without phosphatase treatment. Two criteria, namely a phosphatase-induced change in hydropathy and charge, respectively, and a change in molecular mass by 80 Da, were used jointly to identify phosphopeptides. We demonstrate that, with this technique, low picomole amounts of a tyrosine-phosphorylated peptide can be detected in a complex peptide mixture generated by proteolysis of a protein and that even higher sensitivities can be realized if more sensitive detection systems are applied. PMID:7539661

  3. Tyrosine promotes oxidative stress in cerebral cortex of young rats.

    PubMed

    Sgaravatti, Angela M; Vargas, Bethânia A; Zandoná, Bernardo R; Deckmann, Kátia B; Rockenbach, Francieli J; Moraes, Tarsila B; Monserrat, José M; Sgarbi, Mirian B; Pederzolli, Carolina D; Wyse, Angela T S; Wannmacher, Clóvis M D; Wajner, Moacir; Dutra-Filho, Carlos Severo

    2008-10-01

    Tyrosine accumulates in inborn errors of tyrosine catabolism, especially in tyrosinemia type II, where tyrosine levels are highly elevated in tissues and physiological fluids of affected patients. In tyrosinemia type II, high levels of tyrosine are correlated with eyes, skin and central nervous system disturbances. Considering that the mechanisms of brain damage in these disorders are poorly known, in the present study, we investigated whether oxidative stress is elicited by l-tyrosine in cerebral cortex homogenates of 14-day-old Wistar rats. The in vitro effect of 0.1-4.0mM l-tyrosine was studied on the following oxidative stress parameters: total radical-trapping antioxidant potential (TRAP), total antioxidant reactivity (TAR), ascorbic acid content, reduced glutathione (GSH) content, spontaneous chemiluminescence, thiobarbituric acid-reactive substances (TBA-RS), thiol-disulfide redox state (SH/SS ratio), protein carbonyl content, formation of DNA-protein cross-links, and the activities of the enzymes superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glucose-6-phosphate dehydrogenase (G6PDH). TRAP, TAR, ascorbic acid content, SH/SS ratio and CAT activity were significantly diminished, while formation of DNA-protein cross-link was significantly enhanced by l-tyrosine in vitro. In contrast, l-tyrosine did not affect the other parameters of oxidative stress evaluated. These results indicate that l-tyrosine decreases enzymatic and non-enzymatic antioxidant defenses, changes the redox state and stimulates DNA damage in cerebral cortex of young rats in vitro. This suggests that oxidative stress may represent a pathophysiological mechanism in tyrosinemic patients, in which this amino acid accumulates.

  4. 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.

  5. 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

  6. The truncated Newton using 1st and 2nd order adjoint-state method: a new approach for traveltime tomography without rays

    NASA Astrophysics Data System (ADS)

    Bretaudeau, F.; Metivier, L.; Brossier, R.; Virieux, J.

    2013-12-01

    named as the truncated Newton (TCN) (Métivier et al. 2012) with a more accurate estimation of the impact of the Hessian. We propose an efficient implementation for first-arrival traveltime tomography. In TCN, the model update Δm is obtained through the iterative resolution of the Newton linear system H Δm = - g. Based on a matrix-free conjugate gradient resolution, the iterative solver requires only the computation of the gradient and of Hessian-vector products. We propose a generalization of the computation of the gradient using the adjoint-state method that allows to consider receivers located anywhere. Then the Hessian-vector products are computed using an original formulation based on a 2nd-order adjoint-state method, at the cost of an additional forward modeling. The TCN algorithm is composed of two nested loops: an internal loop to compute Δm, and an external loop where a line search is performed to update the subsurface parameters. TCN thus considers locally the inversion of the traveltime data using an estimation of the full Hessian (both 1st and 2nd order terms) at an acceptable cost. Tomography with TCN is an improvement over the simple gradient-based adjoint-state tomography due to its good convergence property, to the better consideration of illumination, and is a promising tool for multi-parameter inversion as rescaling is given by the Hessian.

  7. Microstructure and Mechanical Properties of Friction Stir-Welded Mg-2Nd-0.3Zn-0.4Zr Magnesium Alloy

    NASA Astrophysics Data System (ADS)

    Zhao, Yong; Wang, Qingzhao; He, Xudan; Huang, Jian; Yan, Keng; Dong, Jie

    2014-11-01

    A 2 mm thick Mg-2Nd-0.3Zn-0.4Zr (NZ20K) and AZ31 plates were friction stir welded. The microstructures of joint were compared and the tensile properties at room temperature and 200 °C were measured. The fracture features and the microhardness of joints were investigated. The effect of the strengthening phases in NZ20K joint was discussed compared with AZ31 joint. The results indicate that NZ20K shows better property especially at high-temperature environment. The grain of NZ20K in the nugget zone (NZ) is refined obviously with uniform distribution of strengthening phase particles and it shows clear boundary between NZ and thermo-mechanically affected zone (TMAZ). The grains of TMAZ are elongated because of the stir action of tool pin. The heat-affected zone is narrow with coarse grains. Mg12Nd is the main strengthening phase in NZ20K joint through XRD analysis. The ultimate tensile strength of NZ20K joint decreases a little from room temperature to 200 °C for its main strengthening phase particle-Mg12Nd being stable when the temperature goes up. On the contrast, the ultimate tensile strength of AZ31 joint decreases a lot at 200 °C for its strengthening phase soften or dissolve at high temperature. The hardness of NZ20K joint is higher than AZ31 joint and the lowest hardness of both joints is achieved on the advancing side where the fracture occurred.

  8. 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

  9. 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

  10. Desferrioxamine Inhibits Protein Tyrosine Nitration: Mechanisms and Implications

    PubMed Central

    Adgent, Margaret A.; Squadrito, Giuseppe L.; Ballinger, Carol A.; Krzywanski, David M.; Lancaster, Jack R.; Postlethwait, Edward M.

    2012-01-01

    Tissues are exposed to exogenous and endogenous nitrogen dioxide (•NO2), which is the terminal agent in protein tyrosine nitration. Besides iron chelation, the hydroxamic acid (HA) desferrioxamine (DFO) shows multiple functionalities including nitration inhibition. To investigate mechanisms whereby DFO affects 3-nitrotyrosine (3-NT) formation, we utilized gas phase •NO2 exposures, to limit introduction of other reactive species, and a lung surface model wherein red cell membranes (RCM) were immobilized under a defined aqueous film. When RCM were exposed to •NO2 covered by +/− DFO: (i) DFO inhibited 3-NT formation more effectively than other HA and non-HA chelators; (ii) 3-NT inhibition occurred at very low [DFO] for prolonged times; and (iii) 3-NT formation was iron independent but inhibition required DFO present. DFO poorly reacted with •NO2 compared to ascorbate, assessed via •NO2 reactive absorption and aqueous phase oxidation rates, yet limited 3-NT formation at far lower concentrations. DFO also inhibited nitration under aqueous bulk phase conditions, and inhibited 3-NT generated by active myeloperoxidase “bound” to RCM. Per the above and kinetic analyses suggesting preferential DFO versus •NO2 reaction within membranes, we conclude that DFO inhibits 3-NT formation predominantly by facile repair of the tyrosyl radical intermediate, which prevents •NO2 addition, and thus nitration, and potentially influences biochemical functionalities. PMID:22705369

  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. Treatment of non-small cell lung cancer, advanced disease, with erlotinib in 2(nd) and 3(rd) lines. Two cases report.

    PubMed

    Teixeira, Encarnação; Sotto-Mayor, Renato; Macedo, Rita; Todo-Bom, Filipa; de Almeida, A Bugalho

    2008-10-01

    Agents that inhibit the activity of cell membrane receptor tyrosine kinases, such as the human epidermal growth factor receptor (EGFR) have been an attractive target because EGFR is expressed by 80% of NSCLC. Erlotinib as monotherapy in the treatment of NSCLC after failure of at least one prior chemotherapy regimen, prolonged survival and improved quality of life, although modest response rate. Women, Asiens, patients with Adenocarcinoma and never smokers, were more likely than other patients to have a response to erlotinib. This is the group of patients that most commonly have an EGFR mutation. The authors describe two cases, with important control of symptoms and increased time to progression, independently o response rate (stable disease or partial response). Rev Port Pneumol 2008; XIV (Supl 3): S53-S60. PMID:25967688

  13. Treatment of non-small cell lung cancer, advanced disease, with erlotinib in 2(nd) and 3(rd) lines. Two cases report.

    PubMed

    Teixeira, Encarnação; Sotto-Mayor, Renato; Macedo, Rita; Todo-Bom, Filipa; de Almeida, A Bugalho

    2008-10-01

    Agents that inhibit the activity of cell membrane receptor tyrosine kinases, such as the human epidermal growth factor receptor (EGFR) have been an attractive target because EGFR is expressed by 80% of NSCLC. Erlotinib as monotherapy in the treatment of NSCLC after failure of at least one prior chemotherapy regimen, prolonged survival and improved quality of life, although modest response rate. Women, Asiens, patients with Adenocarcinoma and never smokers, were more likely than other patients to have a response to erlotinib. This is the group of patients that most commonly have an EGFR mutation. The authors describe two cases, with important control of symptoms and increased time to progression, independently o response rate (stable disease or partial response). Rev Port Pneumol 2008; XIV (Supl 3): S53-S60.

  14. Weak oligomerization of low-molecular-weight protein tyrosine phosphatase is conserved from mammals to bacteria.

    PubMed

    Blobel, Jascha; Bernadó, Pau; Xu, Huimin; Jin, Changwen; Pons, Miquel

    2009-08-01

    The well-characterized self-association of a mammalian low-molecular-weight protein tyrosine phosphatase (lmwPTP) produces inactive oligomers that are in equilibrium with active monomers. A role of the inactive oligomers as supramolecular proenzymes has been suggested. The oligomerization equilibrium of YwlE, a lmwPTP from Bacillus subtilis, was studied by NMR. Chemical shift data and NMR relaxation confirm that dimerization takes place through the enzyme's active site, and is fully equivalent to the dimerization previously characterized in a eukaryotic low-molecular-weight phosphatase, with similarly large dissociation constants. The similarity between the oligomerization of prokaryotic and eukaryotic phosphatases extends beyond the dimer and involves higher order oligomers detected by NMR relaxation analysis at high protein concentrations. The conservation across different kingdoms of life suggests a physiological role for lmwPTP oligomerization in spite of the weak association observed in vitro. Structural data suggest that substrate modulation of the oligomerization equilibrium could be a regulatory mechanism leading to the generation of signaling pulses. The presence of a phenylalanine residue in the dimerization site of YwlE, replacing a tyrosine residue conserved in all eukaryotic lmwPTPs, demonstrates that lmwPTP regulation by oligomerization can be independent from tyrosine phosphorylation.

  15. Defining the Protein-Protein Interaction Network of the Human Protein Tyrosine Phosphatase Family.

    PubMed

    Li, Xu; Tran, Kim My; Aziz, Kathryn E; Sorokin, Alexey V; Chen, Junjie; Wang, Wenqi

    2016-09-01

    Protein tyrosine phosphorylation, which plays a vital role in a variety of human cellular processes, is coordinated by protein tyrosine kinases and protein tyrosine phosphatases (PTPs). Genomic studies provide compelling evidence that PTPs are frequently mutated in various human cancers, suggesting that they have important roles in tumor suppression. However, the cellular functions and regulatory machineries of most PTPs are still largely unknown. To gain a comprehensive understanding of the protein-protein interaction network of the human PTP family, we performed a global proteomic study. Using a Minkowski distance-based unified scoring environment (MUSE) for the data analysis, we identified 940 high confidence candidate-interacting proteins that comprise the interaction landscape of the human PTP family. Through a gene ontology analysis and functional validations, we connected the PTP family with several key signaling pathways or cellular functions whose associations were previously unclear, such as the RAS-RAF-MEK pathway, the Hippo-YAP pathway, and cytokinesis. Our study provides the first glimpse of a protein interaction network for the human PTP family, linking it to a number of crucial signaling events, and generating a useful resource for future studies of PTPs.

  16. 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.

  17. Rational, combinatorial, and genomic approaches for engineering L-tyrosine production in Escherichia coli

    PubMed Central

    Santos, Christine Nicole S.; Xiao, Wenhai; Stephanopoulos, Gregory

    2012-01-01

    Although microbial metabolic engineering has traditionally relied on rational and knowledge-driven techniques, significant improvements in strain performance can be further obtained through the use of combinatorial approaches exploiting phenotypic diversification and screening. Here, we demonstrate the combined use of global transcriptional machinery engineering and a high-throughput L-tyrosine screen towards improving L-tyrosine production in Escherichia coli. This methodology succeeded in generating three strains from two separate mutagenesis libraries (rpoA and rpoD) exhibiting up to a 114% increase in L-tyrosine titer over a rationally engineered parental strain with an already high capacity for production. Subsequent strain characterization through transcriptional analysis and whole genome sequencing allowed complete phenotype reconstruction from well-defined mutations and point to important roles for both the acid stress resistance pathway and the stringent response of E. coli in imparting this phenotype. As such, this study presents one of the first examples in which cell-wide measurements have helped to elucidate the genetic and biochemical underpinnings of an engineered cellular property, leading to the total restoration of metabolite overproduction from specific chromosomal mutations. PMID:22869698

  18. The transcription factor RUNX2 regulates receptor tyrosine kinase expression in melanoma

    PubMed Central

    Boregowda, Rajeev K.; Medina, Daniel J.; Markert, Elke; Bryan, Michael A.; Chen, Wenjin; Chen, Suzie; Rabkin, Anna; Vido, Michael J.; Gunderson, Samuel I.; Chekmareva, Marina; Foran, David J.; Lasfar, Ahmed; Goydos, James S.; Cohen-Solal, Karine A.

    2016-01-01

    Receptor tyrosine kinases-based autocrine loops largely contribute to activate the MAPK and PI3K/AKT pathways in melanoma. However, the molecular mechanisms involved in generating these autocrine loops are still largely unknown. In the present study, we examine the role of the transcription factor RUNX2 in the regulation of receptor tyrosine kinase (RTK) expression in melanoma. We have demonstrated that RUNX2-deficient melanoma cells display a significant decrease in three receptor tyrosine kinases, EGFR, IGF-1R and PDGFRβ. In addition, we found co-expression of RUNX2 and another RTK, AXL, in both melanoma cells and melanoma patient samples. We observed a decrease in phosphoAKT2 (S474) and phosphoAKT (T308) levels when RUNX2 knock down resulted in significant RTK down regulation. Finally, we showed a dramatic up regulation of RUNX2 expression with concomitant up-regulation of EGFR, IGF-1R and AXL in melanoma cells resistant to the BRAF V600E inhibitor PLX4720. Taken together, our results strongly suggest that RUNX2 might be a key player in RTK-based autocrine loops and a mediator of resistance to BRAF V600E inhibitors involving RTK up regulation in melanoma. PMID:27102439

  19. No obvious abnormality in mice deficient in receptor protein tyrosine phosphatase beta.

    PubMed

    Harroch, S; Palmeri, M; Rosenbluth, J; Custer, A; Okigaki, M; Shrager, P; Blum, M; Buxbaum, J D; Schlessinger, J

    2000-10-01

    The development of neurons and glia is governed by a multitude of extracellular signals that control protein tyrosine phosphorylation, a process regulated by the action of protein tyrosine kinases and protein tyrosine phosphatases (PTPs). Receptor PTPbeta (RPTPbeta; also known as PTPzeta) is expressed predominantly in the nervous system and exhibits structural features common to cell adhesion proteins, suggesting that this phosphatase participates in cell-cell communication. It has been proposed that the three isoforms of RPTPbeta play a role in regulation of neuronal migration, neurite outgrowth, and gliogenesis. To investigate the biological functions of this PTP, we have generated mice deficient in RPTPbeta. RPTPbeta-deficient mice are viable, are fertile, and showed no gross anatomical alterations in the nervous system or other organs. In contrast to results of in vitro experiments, our study demonstrates that RPTPbeta is not essential for neurite outgrowth and node formation in mice. The ultrastructure of nerves of the central nervous system in RPTPbeta-deficient mice suggests a fragility of myelin. However, conduction velocity was not altered in RPTPbeta-deficient mice. The normal development of neurons and glia in RPTPbeta-deficient mice demonstrates that RPTPbeta function is not necessary for these processes in vivo or that loss of RPTPbeta can be compensated for by other PTPs expressed in the nervous system. PMID:11003666

  20. Studying Protein-Tyrosine Phosphatases in Zebrafish.

    PubMed

    Hale, Alexander James; den Hertog, Jeroen

    2016-01-01

    Protein-tyrosine phosphatases (PTPs) are a large family of signal transduction regulators that have an essential role in normal development and physiology. Aberrant activation or inactivation of PTPs is at the basis of many human diseases. The zebrafish, Danio rerio, is being used extensively to model major aspects of development and disease as well as the mechanism of regeneration of limbs and vital organs, and most classical PTPs have been identified in zebrafish. Zebrafish is an excellent model system for biomedical research because the genome is sequenced, zebrafish produce a large number of offspring, the eggs develop outside the mother and are transparent, facilitating intravital imaging, and transgenesis and (site-directed) mutagenesis are feasible. Together, these traits make zebrafish amenable for the analysis of gene and protein function. In this chapter we cover three manipulations of zebrafish embryos that we have used to study the effects of PTPs in development, regeneration, and biochemistry. Microinjection at the one-cell stage is at the basis of many zebrafish experiments and is described first. This is followed by a description for measuring regeneration of the embryonic caudal fin, a powerful and robust physiological assay. Finally, the considerable but manageable troubleshooting of several complications associated with preparing zebrafish embryos for immunoblotting is explained. Overall, this chapter provides detailed protocols for manipulating zebrafish embryo samples with a compilation of tips collected through extensive experience from the zebrafish research community. PMID:27514815

  1. 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

  2. Transcriptional regulation through glutamate receptors: Involvement of tyrosine kinases.

    PubMed

    López-Bayghen, Esther; Aguirre, Adán; Ortega, Arturo

    2003-12-01

    Glutamate receptors play a key role in neuronal plasticity, learning and memory, and in several neuropathologies. Short-term and long-term changes in synaptic efficacy are triggered by glutamate. Although an enhanced glutamate-dependent tyrosine phosphorylation has been described in several systems, its role in membrane-to-nuclei signaling is unclear. Taking advantage of the fact that the gene encoding the chick kainate-binding protein undergoes a glutamate-dependent transcriptional regulation via an activator protein-1 (AP-1) site, we evaluated the involvement of tyrosine kinases in this process. We describe here the participation of receptor and non-receptor tyrosine kinases in the signaling cascade triggered by glutamate. Our results suggest that in Bergmann glia cells, glutamate receptors transactivate receptor tyrosine kinases, favoring the idea of a complex network of signals activated by this excitatory neurotransmitter that results in regulation of gene expression.

  3. Tyrosine kinase signaling and the emergence of multicellularity.

    PubMed

    Miller, W Todd

    2012-06-01

    Tyrosine phosphorylation is an essential element of signal transduction in multicellular animals. Although tyrosine kinases were originally regarded as specific to the metazoan lineage, it is now clear that they evolved prior to the split between unicellular and multicellular eukaryotes (≈600million years ago). Genome analyses of choanoflagellates and other protists show an abundance of tyrosine kinases that rivals the most complex animals. Some of these kinases are orthologs of metazoan enzymes (e.g., Src), but others display unique domain compositions not seen in any metazoan. Biochemical experiments have highlighted similarities and differences between the unicellular and multicellular tyrosine kinases. In particular, it appears that the complex systems of kinase autoregulation may have evolved later in the metazoan lineage. PMID:22480439

  4. Skin problems and EGFR-tyrosine kinase inhibitor.

    PubMed

    Kozuki, Toshiyuki

    2016-04-01

    Epidermal growth factor receptor inhibition is a good target for the treatment of lung, colon, pancreatic and head and neck cancers. Epidermal growth factor receptor-tyrosine kinase inhibitor was first approved for the treatment of advanced lung cancer in 2002. Epidermal growth factor receptor-tyrosine kinase inhibitor plays an essential role in the treatment of cancer, especially for patients harbouring epidermal growth factor receptor activating mutation. Hence, skin toxicity is the most concerning issue for the epidermal growth factor receptor-tyrosine kinase inhibitor treatment. Skin toxicity is bothersome and sometimes affects the quality of life and treatment compliance. Thus, it is important for physicians to understand the background and how to manage epidermal growth factor receptor-tyrosine kinase inhibitor-associated skin toxicity. Here, the author reviewed the mechanism and upfront preventive and reactive treatments for epidermal growth factor receptor inhibitor-associated skin toxicities.

  5. A bacterial tyrosine phosphatase inhibits plant pattern recognition receptor activation.

    PubMed

    Macho, Alberto P; Schwessinger, Benjamin; Ntoukakis, Vardis; Brutus, Alexandre; Segonzac, Cécile; Roy, Sonali; Kadota, Yasuhiro; Oh, Man-Ho; Sklenar, Jan; Derbyshire, Paul; Lozano-Durán, Rosa; Malinovsky, Frederikke Gro; Monaghan, Jacqueline; Menke, Frank L; Huber, Steven C; He, Sheng Yang; Zipfel, Cyril

    2014-03-28

    Innate immunity relies on the perception of pathogen-associated molecular patterns (PAMPs) by pattern-recognition receptors (PRRs) located on the host cell's surface. Many plant PRRs are kinases. Here, we report that the Arabidopsis receptor kinase EF-TU RECEPTOR (EFR), which perceives the elf18 peptide derived from bacterial elongation factor Tu, is activated upon ligand binding by phosphorylation on its tyrosine residues. Phosphorylation of a single tyrosine residue, Y836, is required for activation of EFR and downstream immunity to the phytopathogenic bacterium Pseudomonas syringae. A tyrosine phosphatase, HopAO1, secreted by P. syringae, reduces EFR phosphorylation and prevents subsequent immune responses. Thus, host and pathogen compete to take control of PRR tyrosine phosphorylation used to initiate antibacterial immunity.

  6. Tyrosine kinase signaling and the emergence of multicellularity.

    PubMed

    Miller, W Todd

    2012-06-01

    Tyrosine phosphorylation is an essential element of signal transduction in multicellular animals. Although tyrosine kinases were originally regarded as specific to the metazoan lineage, it is now clear that they evolved prior to the split between unicellular and multicellular eukaryotes (≈600million years ago). Genome analyses of choanoflagellates and other protists show an abundance of tyrosine kinases that rivals the most complex animals. Some of these kinases are orthologs of metazoan enzymes (e.g., Src), but others display unique domain compositions not seen in any metazoan. Biochemical experiments have highlighted similarities and differences between the unicellular and multicellular tyrosine kinases. In particular, it appears that the complex systems of kinase autoregulation may have evolved later in the metazoan lineage.

  7. Targeting Tyrosine Kinases and Autophagy in Prostate Cancer

    PubMed Central

    2010-01-01

    Tyrosine kinases play significant roles in tumor progression and therapy resistance. Inhibitors of tyrosine kinases are on the forefront of targeted therapy. For prostate cancer, tyrosine kinases play an additional role in the development of castration-resistant disease state, the most troubling aspect of prostate cancinogenesis which presently defies any effective treatment. Among the 30 or so tyrosine kinases expressed in a typical prostate cancer cell, nearly one third of them have been implicated in prostate carcinogenesis. Interestingly, most of them channel signals through a trio of non-receptor tyrosine kinases, Src/Etk/FAK, referred here as Src tyrosine kinase complex. This complex has been shown to play a significant role in the aberrant activation of androgen receptor (AR) mediated by growth factors (e.g., epidermal growth factor (EGF)), cytokines (interleukin (IL)-6), chemokines (IL-8), and neurokines (gastrin-releasing peptide). These factors are induced and released from the prostate cancer to the stromal cells upon androgen withdrawal. The Src kinase complex has the ability to phosphorylate androgen receptor, resulting in the nuclear translocation and stabilization of un-liganded androgen receptor. Indeed, tyrosine kinase inhibitors targeting Src can inhibit androgen-independent growth of prostate cancer cells in vitro and in preclinical xenograft model. While effective in inducing growth arrest and inhibiting metastasis of castration-resistant tumors, Src inhibitors rarely induce a significant level of apoptosis. This is also reflected by the general ineffectiveness of tyrosine kinase inhibitors as monotherapy in clinical trials. One of the underlying causes of apoptosis resistance is “autophagy,” which is induced by tyrosine kinase inhibitors and by androgen withdrawal. Autophagy is a self-digesting process to regenerate energy by removal of long-lived proteins and retired organelles to provide a survival mechanism to cells encountering stresses

  8. 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.

  9. 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.

  10. 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.

  11. 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

  12. Beta 2 integrin-dependent protein tyrosine phosphorylation and activation of the FGR protein tyrosine kinase in human neutrophils

    PubMed Central

    1994-01-01

    Stimulation of adherent human neutrophils (PMN) with tumor necrosis factor (TNF) triggers protein tyrosine phosphorylation (Fuortes, M., W. W. Jin, and C. Nathan. 1993. J. Cell Biol. 120:777-784). We investigated the dependence of this response on beta 2 integrins by using PMN isolated from a leukocyte adhesion deficiency (LAD) patient, which do not express beta 2 integrins, and by plating PMN on surface bound anti-beta 2 (CD18) antibodies. Protein tyrosine phosphorylation increased in PMN plated on fibrinogen and this phosphorylation was enhanced by TNF. Triggering of protein tyrosine phosphorylation did not occur in LAD PMN plated on fibrinogen either in the absence or the presence of TNF. Surface bound anti-CD18, but not isotype-matched anti- Class I major histocompatibility complex (MHC) antigens, antibodies triggered tyrosine phosphorylation in normal, but not in LAD PMN. As the major tyrosine phosphorylated proteins we found in our assay conditions migrated with an apparent molecular mass of 56-60 kD, we investigated whether beta 2 integrins are implicated in activation of members of the src family of intracellular protein-tyrosine kinases. We found that the fgr protein-tyrosine kinase (p58fgr) activity, and its extent of phosphorylation in tyrosine, in PMN adherent to fibrinogen, was enhanced by TNF. Activation of p58fgr in response to TNF was evident within 10 min of treatment and increased with times up to 30 min. Also other activators of beta 2 integrins such as phorbol-12- myristate 13-acetate (PMA), and formyl methionyl-leucyl-phenylalanine (FMLP), induced activation of p58fgr kinase activity. Activation of p58fgr kinase activity, and phosphorylation in tyrosine, did not occur in PMN of a LAD patient in response to TNF. Soluble anti-CD18, but not anti-Class I MHC antigens, antibodies inhibited activation of p58fgr kinase activity in PMN adherent to fibrinogen in response to TNF, PMA, and FMLP. These findings demonstrate that, in PMN, beta 2 integrins

  13. SHP1 tyrosine phosphatase negatively regulates NPM-ALK tyrosine kinase signaling.

    PubMed

    Honorat, Jean-François; Ragab, Ashraf; Lamant, Laurence; Delsol, Georges; Ragab-Thomas, Jeannie

    2006-05-15

    Anaplastic large-cell lymphoma (ALCL) is frequently associated with the 2;5 translocation and expresses the NPM-ALK fusion protein, which possesses a constitutive tyrosine kinase activity. We analyzed SHP1 tyrosine phosphatase expression and activity in 3 ALK-positive ALCL cell lines (Karpas 299, Cost, and SU-DHL1) and in lymph node biopsies (n = 40). We found an inverse correlation between the level of NPM-ALK phosphorylation and SHP1 phosphatase activity. Pull-down and coimmunoprecipitation experiments demonstrated a SHP1/NPM-ALK association. Furthermore, confocal microscopy performed on ALCL cell lines and biopsy specimens showed the colocalization of the 2 proteins in cytoplasmic bodies containing Y664-phosphorylated NPM-ALK. Dephosphorylation of NPM-ALK by SHP1 demonstrated that NPM-ALK was a SHP1 substrate. Downregulation of SHP1 expression by RNAi in Karpas cells led to hyperphosphorylation of NPM-ALK, STAT3 activation, and increase in cell proliferation. Furthermore, SHP1 overexpression in 3T3 fibroblasts stably expressing NPM-ALK led to the decrease of NPM-ALK phosphorylation, lower cell proliferation, and tumor progression in nude mice. These findings show that SHP1 is a negative regulator of NPM-ALK signaling. The use of tissue microarrays revealed that 50% of ALK-positive ALCLs were positive for SHP1. Our results suggest that SHP1 could be a critical enzyme in ALCL biology and a potential therapeutic target.

  14. Awareness and health consciousness regarding the national health plan "Health Japan 21" (2nd edition) among the Japanese population in 2013 and 2014.

    PubMed

    Sugiyama, Kemmyo; Tomata, Yasutake; Takemi, Yukari; Tsushita, Kazuyo; Nakamura, Masakazu; Hashimoto, Shuji; Miyachi, Motohiko; Yamagata, Zentaro; Yokoyama, Tetsuji; Tsuji, Ichiro

    2016-01-01

    Objectives To examine the prevalence of health consciousness regarding "Health Japan 21" (2nd edition) among the Japanese population, we conducted a telephone survey of a sample extracted randomly from the whole nation in 2013 and 2014.Methods We extracted 1800 men and women with 150 persons for each gender and 10-year age group (6 age groups ranging from 20 years to 70 years and older) using Random Digital Dialing sampling. Each participant was asked about 1) recognition of the following items: "Health Japan 21," "healthy life expectancy," "metabolic syndrome (MetS)," "chronic obstructive pulmonary disease (COPD)," "locomotive syndrome," "Active Guide," "WHO Framework Convention on Tobacco Control," and "Smart Life Project" and 2) health consciousness toward the following: "health examination taken within the past one year," "smoking status," and "the amount of vegetables considered desirable to consume per day for health." We performed simple tabulation of the collected answers and cross-tabulation by sex and age groups, respectively. For each question about recognition, we categorized "I know the name and meaning" and "I know the name but not the meaning" as "awareness." We compared data between 2013 and 2014, sexes, and age groups, using chi-squared test.Results In 2013, the top 5 items with high awareness were "MetS" (96.2%), "COPD" (51.1%), "healthy life expectancy" (34.2%), "locomotive syndrome" (30.2%), and "WHO Framework Convention on Tobacco Control" (28.0%). Moreover, awareness of "healthy life expectancy," "locomotive syndrome," and "Active Guide" were significantly higher in 2014 than in 2013. Meanwhile, the proportion of participants who correctly chose "350 grams" as "the desirable amount of vegetables to consume per day" was 41.6% in 2013 and became significantly higher at 50.1% in 2014. In 2013, awareness of "healthy life expectancy," "COPD," and "locomotive syndrome" and the proportion of correct answers for "the desirable amount of

  15. Awareness and health consciousness regarding the national health plan "Health Japan 21" (2nd edition) among the Japanese population in 2013 and 2014.

    PubMed

    Sugiyama, Kemmyo; Tomata, Yasutake; Takemi, Yukari; Tsushita, Kazuyo; Nakamura, Masakazu; Hashimoto, Shuji; Miyachi, Motohiko; Yamagata, Zentaro; Yokoyama, Tetsuji; Tsuji, Ichiro

    2016-01-01

    Objectives To examine the prevalence of health consciousness regarding "Health Japan 21" (2nd edition) among the Japanese population, we conducted a telephone survey of a sample extracted randomly from the whole nation in 2013 and 2014.Methods We extracted 1800 men and women with 150 persons for each gender and 10-year age group (6 age groups ranging from 20 years to 70 years and older) using Random Digital Dialing sampling. Each participant was asked about 1) recognition of the following items: "Health Japan 21," "healthy life expectancy," "metabolic syndrome (MetS)," "chronic obstructive pulmonary disease (COPD)," "locomotive syndrome," "Active Guide," "WHO Framework Convention on Tobacco Control," and "Smart Life Project" and 2) health consciousness toward the following: "health examination taken within the past one year," "smoking status," and "the amount of vegetables considered desirable to consume per day for health." We performed simple tabulation of the collected answers and cross-tabulation by sex and age groups, respectively. For each question about recognition, we categorized "I know the name and meaning" and "I know the name but not the meaning" as "awareness." We compared data between 2013 and 2014, sexes, and age groups, using chi-squared test.Results In 2013, the top 5 items with high awareness were "MetS" (96.2%), "COPD" (51.1%), "healthy life expectancy" (34.2%), "locomotive syndrome" (30.2%), and "WHO Framework Convention on Tobacco Control" (28.0%). Moreover, awareness of "healthy life expectancy," "locomotive syndrome," and "Active Guide" were significantly higher in 2014 than in 2013. Meanwhile, the proportion of participants who correctly chose "350 grams" as "the desirable amount of vegetables to consume per day" was 41.6% in 2013 and became significantly higher at 50.1% in 2014. In 2013, awareness of "healthy life expectancy," "COPD," and "locomotive syndrome" and the proportion of correct answers for "the desirable amount of

  16. Are striatal tyrosine hydroxylase interneurons dopaminergic?

    PubMed

    Xenias, Harry S; Ibáñez-Sandoval, Osvaldo; Koós, Tibor; Tepper, James M

    2015-04-22

    Striatal GABAergic interneurons that express the gene for tyrosine hydroxylase (TH) have been identified previously by several methods. Although generally assumed to be dopaminergic, possibly serving as a compensatory source of dopamine (DA) in Parkinson's disease, this assumption has never been tested directly. In TH-Cre mice whose nigrostriatal pathway had been eliminated unilaterally with 6-hydroxydopamine, we injected a Cre-dependent virus coding for channelrhodopsin-2 and enhanced yellow fluorescent protein unilaterally into the unlesioned midbrain or bilaterally into the striatum. Fast-scan cyclic voltammetry in striatal slices revealed that both optical and electrical stimulation readily elicited DA release in control striata but not from contralateral striata when nigrostriatal neurons were transduced. In contrast, neither optical nor electrical stimulation could elicit striatal DA release in either the control or lesioned striata when the virus was injected directly into the striatum transducing only striatal TH interneurons. This demonstrates that striatal TH interneurons do not release DA. Fluorescence immunocytochemistry in enhanced green fluorescent protein (EGFP)-TH mice revealed colocalization of DA, l-amino acid decarboxylase, the DA transporter, and vesicular monoamine transporter-2 with EGFP in midbrain dopaminergic neurons but not in any of the striatal EGFP-TH interneurons. Optogenetic activation of striatal EGFP-TH interneurons produced strong GABAergic inhibition in all spiny neurons tested. These results indicate that striatal TH interneurons are not dopaminergic but rather are a type of GABAergic interneuron that expresses TH but none of the other enzymes or transporters necessary to operate as dopaminergic neurons and exert widespread GABAergic inhibition onto direct and indirect spiny neurons. PMID:25904808

  17. Are striatal tyrosine hydroxylase interneurons dopaminergic?

    PubMed

    Xenias, Harry S; Ibáñez-Sandoval, Osvaldo; Koós, Tibor; Tepper, James M

    2015-04-22

    Striatal GABAergic interneurons that express the gene for tyrosine hydroxylase (TH) have been identified previously by several methods. Although generally assumed to be dopaminergic, possibly serving as a compensatory source of dopamine (DA) in Parkinson's disease, this assumption has never been tested directly. In TH-Cre mice whose nigrostriatal pathway had been eliminated unilaterally with 6-hydroxydopamine, we injected a Cre-dependent virus coding for channelrhodopsin-2 and enhanced yellow fluorescent protein unilaterally into the unlesioned midbrain or bilaterally into the striatum. Fast-scan cyclic voltammetry in striatal slices revealed that both optical and electrical stimulation readily elicited DA release in control striata but not from contralateral striata when nigrostriatal neurons were transduced. In contrast, neither optical nor electrical stimulation could elicit striatal DA release in either the control or lesioned striata when the virus was injected directly into the striatum transducing only striatal TH interneurons. This demonstrates that striatal TH interneurons do not release DA. Fluorescence immunocytochemistry in enhanced green fluorescent protein (EGFP)-TH mice revealed colocalization of DA, l-amino acid decarboxylase, the DA transporter, and vesicular monoamine transporter-2 with EGFP in midbrain dopaminergic neurons but not in any of the striatal EGFP-TH interneurons. Optogenetic activation of striatal EGFP-TH interneurons produced strong GABAergic inhibition in all spiny neurons tested. These results indicate that striatal TH interneurons are not dopaminergic but rather are a type of GABAergic interneuron that expresses TH but none of the other enzymes or transporters necessary to operate as dopaminergic neurons and exert widespread GABAergic inhibition onto direct and indirect spiny neurons.

  18. Anticipating and blocking HIV-1 escape by second generation antiviral shRNAs

    PubMed Central

    2010-01-01

    Background RNA interference (RNAi) is an evolutionary conserved gene silencing mechanism that mediates the sequence-specific breakdown of target mRNAs. RNAi can be used to inhibit HIV-1 replication by targeting the viral RNA genome. However, the error-prone replication machinery of HIV-1 can generate RNAi-resistant variants with specific mutations in the target sequence. For durable inhibition of HIV-1 replication the emergence of such escape viruses must be controlled. Here we present a strategy that anticipates HIV-1 escape by designing 2nd generation short hairpin RNAs (shRNAs) that form a complete match with the viral escape sequences. Results To block the two favorite viral escape routes observed when the HIV-1 integrase gene sequence is targeted, the original shRNA inhibitor was combined with two 2nd generation shRNAs in a single lentiviral expression vector. We demonstrate in long-term viral challenge experiments that the two dominant viral escape routes were effectively blocked. Eventually, virus breakthrough did however occur, but HIV-1 evolution was skewed and forced to use new escape routes. Conclusion These results demonstrate the power of the 2nd generation RNAi concept. Popular viral escape routes are blocked by the 2nd generation RNAi strategy. As a consequence viral evolution was skewed leading to new escape routes. These results are of importance for a deeper understanding of HIV-1 evolution under RNAi pressure. PMID:20529316

  19. Divergent Approach to a Family of Tyrosine-Derived Ru-Alkylidene Olefin Metathesis Catalysts.

    PubMed

    Gleeson, Ellen C; Wang, Zhen J; Jackson, W Roy; Robinson, Andrea J

    2015-07-17

    A simple and generic approach to access a new family of Ru-alkylidene olefin metathesis catalysts with specialized properties is reported. This strategy utilizes a late stage, utilitarian Hoveyda-type ligand derived from tyrosine, which can be accessed via a multigram-scale synthesis. Further functionalization allows the catalyst properties to be tuned, giving access to modified second-generation Hoveyda-Grubbs-type catalysts. This divergent synthetic approach can be used to access solid-supported catalysts and catalysts that function under solvent-free and aqueous conditions. PMID:26100533

  20. Divergent Approach to a Family of Tyrosine-Derived Ru-Alkylidene Olefin Metathesis Catalysts.

    PubMed

    Gleeson, Ellen C; Wang, Zhen J; Jackson, W Roy; Robinson, Andrea J

    2015-07-17

    A simple and generic approach to access a new family of Ru-alkylidene olefin metathesis catalysts with specialized properties is reported. This strategy utilizes a late stage, utilitarian Hoveyda-type ligand derived from tyrosine, which can be accessed via a multigram-scale synthesis. Further functionalization allows the catalyst properties to be tuned, giving access to modified second-generation Hoveyda-Grubbs-type catalysts. This divergent synthetic approach can be used to access solid-supported catalysts and catalysts that function under solvent-free and aqueous conditions.

  1. Relationship between apoptosis and the cell cycle in lymphocytes: roles of protein kinase C, tyrosine phosphorylation, and AP1.

    PubMed

    Walker, P R; Kwast-Welfeld, J; Gourdeau, H; Leblanc, J; Neugebauer, W; Sikorska, M

    1993-07-01

    The mechanism of switching between the cell cycle and active cell death (apoptosis) was investigated in cytokine-dependent CTLL cells. These cells proliferate in the presence of interleukin 2 (IL2), but accumulate in early G1 and undergo apoptosis in its absence. In the absence of IL2 the cells also become sensitive to glucocorticoid-induced apoptosis. Using specific inhibitors of protein kinase C and tyrosine kinases we established that two signals are required to fully repress cell death and stimulate G1 progression. One of these signals activates protein kinase C (PKC) which represses cell death and the other activates a tyrosine kinase which confers glucocorticoid resistance and permits cell cycle progression. Thus, phorbol esters can activate PKC and maintain cell viability in the absence of IL2, but the cells cannot proliferate. Moreover, the cells remain sensitive to glucocorticoid-induced apoptosis unless the tyrosine kinase-mediated signal is also given. There is a correlation between the presence of AP1 DNA-binding activity and the repression of the cell death pathway. The c-jun gene is expressed constitutively and both IL2 and phorbol esters induce the expression of c-fos to generate a functional AP1 capable of repressing cell death. However, only interleukin 2 can initiate the tyrosine kinase-mediated modification that confers dexamethasone resistance and permits G1 progression. In the absence of IL2 glucocorticoids stimulate AP1 degradation and induce apoptosis.

  2. p-Hydroxyphenylacetaldehyde is the major product of L-tyrosine oxidation by activated human phagocytes. A chloride-dependent mechanism for the conversion of free amino acids into reactive aldehydes by myeloperoxidase.

    PubMed

    Hazen, S L; Hsu, F F; Heinecke, J W

    1996-01-26

    Reactive aldehydes generated during lipid peroxidation have been implicated in the pathogenesis of atherosclerosis as well as other inflammatory diseases. A potential catalyst for such reactions is myeloperoxidase, a hemeprotein secreted by activated phagocytes. We now report that activated neutrophils utilize the myeloperoxidase-H2O2-chloride system to convert L-tyrosine to p-hydroxyphenylacetaldehyde. Production of p-hydroxyphenylacetaldehyde was nearly quantitative at physiological concentrations of L-tyrosine and chloride. Aldehyde generation required myeloperoxidase, H2O2, L-tyrosine, and chloride ion; it was inhibited by the H2O2 scavenger catalase and by the heme poisons azide and cyanide. Phorbol ester- and calcium ionophore-stimulated human neutrophils likewise generated p-hydroxyphenylacetaldehyde from L-tyrosine by a pathway inhibited by azide, cyanide, and catalase. Aldehyde production accounted for 75% of H2O2 generated by optimally stimulated neutrophils at plasma concentrations of L-tyrosine and chloride. Collectively, these results indicate that activated phagocytes, under physiological conditions, utilize myeloperoxidase to execute the chloride-dependent conversion of L-tyrosine to the lipid-soluble aldehyde, p-hydroxyphenylacetaldehyde, in near quantitative yield. Moreover, like aldehydes derived from lipid peroxidation, amino acid-derived aldehydes may exert potent biological effects in vascular lesions and other sites of inflammation.

  3. An Overview of Phenylalanine and Tyrosine Kinetics in Humans12

    PubMed Central

    Matthews, Dwight E.

    2008-01-01

    The initial use of a tracer of phenylalanine was by Moss and Schoenheimer in rats in 1940 to determine that phenylalanine was hydroxylated to tyrosine, defining for the first time the primacy of this pathway. Phenylalanine and tyrosine kinetics were not measured in humans until the 1970–80s. The first application was for determination of the degree of blockage of phenylalanine hydroxylation in patients with hyperphenylalanemia and phenylketonuria, but this approach was expanded to determination of phenylalanine hydroxylation in normal subjects. Far more uses have been demonstrated for measuring rates of phenylalanine disposal and tyrosine production in relatively normal subjects than in patients with in-born errors of metabolism. Key to use of tracers to determine phenylalanine and tyrosine metabolic rates has been development of appropriate tracer models. Most applications have used relatively simple models ignoring the intracellular hydroxylation rate component. Because the liver is the primary site of hydroxylation in the body, the intracellular enrichment at the site of hydroxylation can be assessed from the tracer enrichments at isotopic steady state in rapid-turnover plasma proteins, such as Apo-B, made and secreted by the liver. Although there are potential problems with use of deuterated tracers of phenylalanine, suitable tracers are available and have been demonstrated for general measurement of phenylalanine and tyrosine kinetics in humans. PMID:17513423

  4. Tyrosine phosphorylation of WASP promotes calpain-mediated podosome disassembly

    PubMed Central

    Macpherson, Lee; Monypenny, James; Blundell, Michael P.; Cory, Giles O.; Tomé-García, Jessica; Thrasher, Adrian J.; Jones, Gareth E.; Calle, Yolanda

    2012-01-01

    Podosomes are actin-based adhesions involved in migration of cells that have to cross tissue boundaries such as myeloid cells. The Wiskott Aldrich Syndrome Protein regulates de novo actin polymerization during podosome formation and it is cleaved by the protease calpain during podosome disassembly. The mechanisms that may induce the Wiskott Aldrich Syndrome Protein cleavage by calpain remain undetermined. We now report that in myeloid cells, tyrosine phosphorylation of the Wiskott Aldrich Syndrome Protein-tyrosine291 (Human)/tyrosine293 (mouse) not only enhances Wiskott Aldrich Syndrome Protein-mediated actin polymerization but also promotes its calpain-dependent degradation during podosome disassembly. We also show that activation of the Wiskott Aldrich Syndrome Protein leading to podosome formation occurs independently of tyrosine phosphorylation in spleen-derived dendritic cells. We conclude that tyrosine phosphorylation of the Wiskott Aldrich Syndrome Protein integrates dynamics of actin and cell adhesion proteins during podosome disassembly required for mobilization of myeloid cells during the immune response. PMID:22133775

  5. 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

  6. Regulation of mouse gamete interaction by a sperm tyrosine kinase.

    PubMed

    Leyton, L; LeGuen, P; Bunch, D; Saling, P M

    1992-12-15

    A 95-kDa mouse sperm protein has been previously identified as a putative receptor involved in the sperm-egg interactions that lead to fertilization. The ligand for this receptor is the zona pellucida glycoprotein ZP3. This constituent of the oocyte-specific extracellular matrix mediates not only sperm binding to the zona but also triggers acrosomal exocytosis. The latter, also termed the acrosome reaction, is a key regulatory event upon which fertilization is absolutely dependent. Previously, we showed that the 95-kDa protein that binds ZP3 is a substrate for tyrosine kinase, and its phosphotyrosine content increases after sperm-zona pellucida binding. Here, we show the presence of protein tyrosine kinase activity in sperm plasma membranes and in electroeluted 95-kDa protein. The tyrosine kinase activity of the isolated protein is stimulated by solubilized zona pellucida and inhibited by tyrphostin RG-50864, a membrane-permeable tyrosine kinase inhibitor. Furthermore, tyrphostin inhibits zona-triggered acrosomal exocytosis in a dose-dependent manner. These findings indicate that the 95-kDa protein participates in a critical regulatory event of gamete interaction; moreover, our experiments suggest that sperm protein tyrosine kinase may be an excellent target for the control of fertility.

  7. Bacterial tyrosine kinases: evolution, biological function and structural insights

    PubMed Central

    Grangeasse, Christophe; Nessler, Sylvie; Mijakovic, Ivan

    2012-01-01

    Reversible protein phosphorylation is a major mechanism in the regulation of fundamental signalling events in all living organisms. Bacteria have been shown to possess a versatile repertoire of protein kinases, including histidine and aspartic acid kinases, serine/threonine kinases, and more recently tyrosine and arginine kinases. Tyrosine phosphorylation is today recognized as a key regulatory device of bacterial physiology, linked to exopolysaccharide production, virulence, stress response and DNA metabolism. However, bacteria have evolved tyrosine kinases that share no resemblance with their eukaryotic counterparts and are unique in exploiting the ATP/GTP-binding Walker motif to catalyse autophosphorylation and substrate phosphorylation on tyrosine. These enzymes, named BY-kinases (for Bacterial tYrosine kinases), have been identified in a majority of sequenced bacterial genomes, and to date no orthologues have been found in Eukarya. The aim of this review was to present the most recent knowledge about BY-kinases by focusing primarily on their evolutionary origin, structural and functional aspects, and emerging regulatory potential based on recent bacterial phosphoproteomic studies. PMID:22889913

  8. Tyrosine aminotransferase contributes to benzylisoquinoline alkaloid biosynthesis in opium poppy.

    PubMed

    Lee, Eun-Jeong; Facchini, Peter J

    2011-11-01

    Tyrosine aminotransferase (TyrAT) catalyzes the transamination of L-Tyr and α-ketoglutarate, yielding 4-hydroxyphenylpyruvic acid and L-glutamate. The decarboxylation product of 4-hydroxyphenylpyruvic acid, 4-hydroxyphenylacetaldehyde, is a precursor to a large and diverse group of natural products known collectively as benzylisoquinoline alkaloids (BIAs). We have isolated and characterized a TyrAT cDNA from opium poppy (Papaver somniferum), which remains the only commercial source for several pharmaceutical BIAs, including codeine, morphine, and noscapine. TyrAT belongs to group I pyridoxal 5'-phosphate (PLP)-dependent enzymes wherein Schiff base formation occurs between PLP and a specific Lys residue. The amino acid sequence of TyrAT showed considerable homology to other putative plant TyrATs, although few of these have been functionally characterized. Purified, recombinant TyrAT displayed a molecular mass of approximately 46 kD and a substrate preference for L-Tyr and α-ketoglutarate, with apparent K(m) values of 1.82 and 0.35 mm, respectively. No specific requirement for PLP was detected in vitro. Liquid chromatography-tandem mass spectrometry confirmed the conversion of L-Tyr to 4-hydroxyphenylpyruvate. TyrAT gene transcripts were most abundant in roots and stems of mature opium poppy plants. Virus-induced gene silencing was used to evaluate the contribution of TyrAT to BIA metabolism in opium poppy. TyrAT transcript levels were reduced by at least 80% in silenced plants compared with controls and showed a moderate reduction in total alkaloid content. The modest correlation between transcript levels and BIA accumulation in opium poppy supports a role for TyrAT in the generation of alkaloid precursors, but it also suggests the occurrence of other sources for 4-hydroxyphenylacetaldehyde.

  9. Mechanism of fluorescence quenching of tyrosine derivatives by amide group

    NASA Astrophysics Data System (ADS)

    Wiczk, Wiesław; Rzeska, Alicja; Łukomska, Joanna; Stachowiak, Krystyna; Karolczak, Jerzy; Malicka, Joanna; Łankiewicz, Leszek

    2001-06-01

    The difference between fluorescence lifetimes of the following amino acids: phenylalanine (Phe), tyrosine (Tyr), ( O-methyl)tyrosine (Tyr(Me)), (3-hydroxy)tyrosine (Dopa), (3,4-dimethoxy)phenylalanine (Dopa(Me) 2) and their amides was used to testify the mechanism of fluorescence quenching of aromatic amino acids by the amide group. On the basis of the Marcus theory of photoinduced electron transfer parabolic relationships between ln kET and ionization potentials reduced by energy of excitation ( IP-E ∗0,0) for the above-mentioned amino acids were obtained. This finding indicates the occurrence of photoinduced electron transfer from the excited chromophore group to the amide group.

  10. Tyrosine aminotransferase activity in the benzene intoxicated rat

    SciTech Connect

    Bong, M.; Michalska, A.; Laskowska-Klita, T.; Szymczyk, T.

    1985-01-01

    The toxic effect of hydrocarbon solvents on hepatic metabolism manifests itself by changes in the enzymatic pattern of blood serum. Changes in the activity of phosphatases as well as leucine aminopeptidase, glutamine aminotransferase, sorbitol dehydrogenase and ..gamma..-glutamyltransferase were observed in rats intoxicated with different fractions of benzene. Therefore it seemed reasonable to investigate the effect of benzene fraction of petroleum on cellular metabolism. The results of the present work concern the activity of tyrosine aminotransferase, the enzyme involved in catabolism of aromatic amino acid which is known to be under both hormonal and stress dependent control. Changes in tyrosine aminotransferase activity effect the level of tyrosine oxidation as well as the metabolic conversion of this amino acid into tyramine, tyroxin, adrenaline and noradrenaline.

  11. 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.

  12. Phosphorylation of two regulatory tyrosine residues in the activation of Bruton’s tyrosine kinase via alternative receptors

    PubMed Central

    Wahl, Matthew I.; Fluckiger, Anne-Catherine; Kato, Roberta M.; Park, Hyunsun; Witte, Owen N.; Rawlings, David J.

    1997-01-01

    Mutation of Bruton’s tyrosine kinase (Btk) impairs B cell maturation and function and results in a clinical phenotype of X-linked agammaglobulinemia. Activation of Btk correlates with an increase in the phosphorylation of two regulatory Btk tyrosine residues. Y551 (site 1) within the Src homology type 1 (SH1) domain is transphosphorylated by the Src family tyrosine kinases. Y223 (site 2) is an autophosphorylation site within the Btk SH3 domain. Polyclonal, phosphopeptide-specific antibodies were developed to evaluate the phosphorylation of Btk sites 1 and 2. Crosslinking of the B cell antigen receptor (BCR) or the mast cell Fcɛ receptor, or interleukin 5 receptor stimulation each induced rapid phosphorylation at Btk sites 1 and 2 in a tightly coupled manner. Btk molecules were singly and doubly tyrosine-phosphorylated. Phosphorylated Btk comprised only a small fraction (≤5%) of the total pool of Btk molecules in the BCR-activated B cells. Increased dosage of Lyn in B cells augmented BCR-induced phosphorylation at both sites. Kinetic analysis supports a sequential activation mechanism in which individual Btk molecules undergo serial transphosphorylation (site 1) then autophosphorylation (site 2), followed by successive dephosphorylation of site 1 then site 2. The phosphorylation of conserved tyrosine residues within structurally related Tec family kinases is likely to regulate their activation. PMID:9326643

  13. Fluorination of (E)-{beta}-(fluoromethylene)-m-tyrosine: Regioslective synthesis of 4-fluoro-(E)-{beta}-(fluoromethylene)-m-tyrosine

    SciTech Connect

    Lacan, G.; Satyamurthy, N.; Barrio, J.R.

    1995-01-13

    Fluorination of (R)- and (S)-(E)-{beta}-(fluoromethylene)-m-tyrosine (1) by acetyl hypofluorite yielded a mixture of the corresponding 2-fluoro- (2a), 6-fluoro- (2b), 4-fluoro- (2c), and 2,6-difluoro- (2d) derivatives along with a pair of diastereomeric products of addition across the vinylic double bond. A regioselective synthesis of 4-fluoro-(E)-{beta}-(fluoromethylene)-m-tyrosine has also been developed based on a fluorodestannylation reaction with elemental fluorine followed by acid hydrolysis. This reaction sequence yielded minor byproducts, namely, 4-fluoro-(Z)-{beta}(fluoromethylene)-m-tyrosine (11), 4,6-difluoro- and 2,4-difluoro-(E)-{beta}-(fluoromethylene)-m-tyrosines (12a and 12b). All these products were completely separated by semipreparative HPLC and fully characterized by NMR and mass spectroscopy. Single crystal X-ray crystallographic analyses of 2-fluoro-, 4-fluoro-, and 6-fluoro-(E)-{beta}-(fluoromethylene)-m-tyrosines unequivocally established the structures of these amino acids. 1 fig., 3 tabs.

  14. Tryptophan prenyltransferases showing higher catalytic activities for Friedel-Crafts alkylation of o- and m-tyrosines than tyrosine prenyltransferases.

    PubMed

    Fan, Aili; Xie, Xiulan; Li, Shu-Ming

    2015-07-21

    Tryptophan prenyltransferases FgaPT2, 5-DMATS, 6-DMATSSv and 7-DMATS catalyse regiospecific C-prenylations on the indole ring, while tyrosine prenyltransferases SirD and TyrPT catalyse the O-prenylation of the phenolic hydroxyl group. In this study, we report the Friedel-Crafts alkylation of L-o-tyrosine by these enzymes. Surprisingly, no conversion was detected with SirD and three tryptophan prenyltransferases showed significantly higher activity than another tyrosine prenyltransferase TyrPT. C5-prenylated L-o-tyrosine was identified as a unique product of these enzymes. Using L-m-tyrosine as the prenylation substrate, product formation was only observed with the tryptophan prenyltransferases FgaPT2 and 7-DMATS. C4- and C6-prenylated derivatives were identified in the reaction mixture of FgaPT2. These results provided additional evidence for the similarities and differences between these two subgroups within the DMATS superfamily in their catalytic behaviours.

  15. Tryptophan prenyltransferases showing higher catalytic activities for Friedel-Crafts alkylation of o- and m-tyrosines than tyrosine prenyltransferases.

    PubMed

    Fan, Aili; Xie, Xiulan; Li, Shu-Ming

    2015-07-21

    Tryptophan prenyltransferases FgaPT2, 5-DMATS, 6-DMATSSv and 7-DMATS catalyse regiospecific C-prenylations on the indole ring, while tyrosine prenyltransferases SirD and TyrPT catalyse the O-prenylation of the phenolic hydroxyl group. In this study, we report the Friedel-Crafts alkylation of L-o-tyrosine by these enzymes. Surprisingly, no conversion was detected with SirD and three tryptophan prenyltransferases showed significantly higher activity than another tyrosine prenyltransferase TyrPT. C5-prenylated L-o-tyrosine was identified as a unique product of these enzymes. Using L-m-tyrosine as the prenylation substrate, product formation was only observed with the tryptophan prenyltransferases FgaPT2 and 7-DMATS. C4- and C6-prenylated derivatives were identified in the reaction mixture of FgaPT2. These results provided additional evidence for the similarities and differences between these two subgroups within the DMATS superfamily in their catalytic behaviours. PMID:26077893

  16. 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

  17. Metal-catalyzed protein tyrosine nitration in biological systems.

    PubMed

    Campolo, Nicolás; Bartesaghi, Silvina; Radi, Rafael

    2014-11-01

    Protein tyrosine nitration is an oxidative postranslational modification that can affect protein structure and function. It is mediated in vivo by the production of nitric oxide-derived reactive nitrogen species (RNS), including peroxynitrite (ONOO(-)) and nitrogen dioxide ((•)NO₂). Redox-active transition metals such as iron (Fe), copper (Cu), and manganese (Mn) can actively participate in the processes of tyrosine nitration in biological systems, as they catalyze the production of both reactive oxygen species and RNS, enhance nitration yields and provide site-specificity to this process. Early after the discovery that protein tyrosine nitration can occur under biologically relevant conditions, it was shown that some low molecular weight transition-metal centers and metalloproteins could promote peroxynitrite-dependent nitration. Later studies showed that nitration could be achieved by peroxynitrite-independent routes as well, depending on the transition metal-catalyzed oxidation of nitrite (NO₂(-)) to (•)NO₂ in the presence of hydrogen peroxide. Processes like these can be achieved either by hemeperoxidase-dependent reactions or by ferrous and cuprous ions through Fenton-type chemistry. Besides the in vitro evidence, there are now several in vivo studies that support the close relationship between transition metal levels and protein tyrosine nitration. So, the contribution of transition metals to the levels of tyrosine nitrated proteins observed under basal conditions and, specially, in disease states related with high levels of these metal ions, seems to be quite clear. Altogether, current evidence unambiguously supports a central role of transition metals in determining the extent and selectivity of protein tyrosine nitration mediated both by peroxynitrite-dependent and independent mechanisms.

  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.

  19. The tyrosine phosphatase Shp2 interacts with NPM-ALK and regulates anaplastic lymphoma cell growth and migration.

    PubMed

    Voena, Claudia; Conte, Chiara; Ambrogio, Chiara; Boeri Erba, Elisabetta; Boccalatte, Francesco; Mohammed, Shabaz; Jensen, Ole N; Palestro, Giorgio; Inghirami, Giorgio; Chiarle, Roberto

    2007-05-01

    Anaplastic large cell lymphomas (ALCL) are mainly characterized by the reciprocal translocation t(2;5)(p23;q35) that involves the anaplastic lymphoma kinase (ALK) gene and generates the fusion protein NPM-ALK with intrinsic tyrosine kinase activity. NPM-ALK triggers several signaling cascades, leading to increased cell growth, resistance to apoptosis, and changes in morphology and migration of transformed cells. To search for new NPM-ALK interacting molecules, we developed a mass spectrometry-based proteomic approach in HEK293 cells expressing an inducible NPM-ALK and identified the tyrosine phosphatase Shp2 as a candidate substrate. We found that NPM-ALK was able to bind Shp2 in coprecipitation experiments and to induce its phosphorylation in the tyrosine residues Y542 and Y580 both in HEK293 cells and ALCL cell lines. In primary lymphomas, antibodies against the phosphorylated tyrosine Y542 of Shp2 mainly stained ALK-positive cells. In ALCL cell lines, Shp2-constitutive phosphorylation was dependent on NPM-ALK, as it significantly decreased after short hairpin RNA (shRNA)-mediated NPM-ALK knock down. In addition, only the constitutively active NPM-ALK, but not the kinase dead NPM-ALK(K210R), formed a complex with Shp2, Gab2, and growth factor receptor binding protein 2 (Grb2), where Grb2 bound to the phosphorylated Shp2 through its SH2 domain. Shp2 knock down by specific shRNA decreased the phosphorylation of extracellular signal-regulated kinase 1/2 and of the tyrosine residue Y416 in the activation loop of Src, resulting in impaired ALCL cell proliferation and growth disadvantage. Finally, migration of ALCL cells was reduced by Shp2 shRNA. These findings show a direct involvement of Shp2 in NPM-ALK lymphomagenesis, highlighting its critical role in lymphoma cell proliferation and migration.

  20. Palmitoylation of protease-activated receptor-1 regulates adaptor protein complex-2 and -3 interaction with tyrosine-based motifs and endocytic sorting.

    PubMed

    Canto, Isabel; Trejo, JoAnn

    2013-05-31

    Protease-activated receptor-1 (PAR1) is a G protein-coupled receptor for the coagulant protease thrombin. Thrombin binds to and cleaves the N terminus of PAR1, generating a new N terminus that functions as a tethered ligand that cannot diffuse away. In addition to rapid desensitization, PAR1 trafficking is critical for the regulation of cellular responses. PAR1 displays constitutive and agonist-induced internalization. Constitutive internalization of unactivated PAR1 is mediated by the clathrin adaptor protein complex-2 (AP-2), which binds to a distal tyrosine-based motif localized within the C-terminal tail (C-tail) domain. Once internalized, PAR1 is sorted from endosomes to lysosomes via AP-3 interaction with a second C-tail tyrosine motif proximal to the transmembrane domain. However, the regulatory processes that control adaptor protein recognition of PAR1 C-tail tyrosine-based motifs are not known. Here, we report that palmitoylation of PAR1 is critical for regulating proper utilization of tyrosine-based motifs and endocytic sorting. We show that PAR1 is basally palmitoylated at highly conserved C-tail cysteines. A palmitoylation-deficient PAR1 mutant is competent to signal and exhibits a marked increase in constitutive internalization and lysosomal degradation compared with wild type receptor. Intriguingly, enhanced constitutive internalization of PAR1 is mediated by AP-2 and requires the proximal tyrosine-based motif rather than the distal tyrosine motif used by wild type receptor. Moreover, palmitoylation-deficient PAR1 displays increased degradation that is mediated by AP-3. These findings suggest that palmitoylation of PAR1 regulates appropriate utilization of tyrosine-based motifs by adaptor proteins and endocytic trafficking, processes that are critical for maintaining appropriate expression of PAR1 at the cell surface. PMID:23580642

  1. Palmitoylation of protease-activated receptor-1 regulates adaptor protein complex-2 and -3 interaction with tyrosine-based motifs and endocytic sorting.

    PubMed

    Canto, Isabel; Trejo, JoAnn

    2013-05-31

    Protease-activated receptor-1 (PAR1) is a G protein-coupled receptor for the coagulant protease thrombin. Thrombin binds to and cleaves the N terminus of PAR1, generating a new N terminus that functions as a tethered ligand that cannot diffuse away. In addition to rapid desensitization, PAR1 trafficking is critical for the regulation of cellular responses. PAR1 displays constitutive and agonist-induced internalization. Constitutive internalization of unactivated PAR1 is mediated by the clathrin adaptor protein complex-2 (AP-2), which binds to a distal tyrosine-based motif localized within the C-terminal tail (C-tail) domain. Once internalized, PAR1 is sorted from endosomes to lysosomes via AP-3 interaction with a second C-tail tyrosine motif proximal to the transmembrane domain. However, the regulatory processes that control adaptor protein recognition of PAR1 C-tail tyrosine-based motifs are not known. Here, we report that palmitoylation of PAR1 is critical for regulating proper utilization of tyrosine-based motifs and endocytic sorting. We show that PAR1 is basally palmitoylated at highly conserved C-tail cysteines. A palmitoylation-deficient PAR1 mutant is competent to signal and exhibits a marked increase in constitutive internalization and lysosomal degradation compared with wild type receptor. Intriguingly, enhanced constitutive internalization of PAR1 is mediated by AP-2 and requires the proximal tyrosine-based motif rather than the distal tyrosine motif used by wild type receptor. Moreover, palmitoylation-deficient PAR1 displays increased degradation that is mediated by AP-3. These findings suggest that palmitoylation of PAR1 regulates appropriate utilization of tyrosine-based motifs by adaptor proteins and endocytic trafficking, processes that are critical for maintaining appropriate expression of PAR1 at the cell surface.

  2. 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

  3. 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

  4. Interference of peptone and tyrosine with the lignin peroxidase assay.

    PubMed Central

    ten Have, R; Hartmans, S; Field, J A

    1997-01-01

    The N-unregulated white rot fungus Bjerkandera sp. strain BOS55 was cultured in 1 liter of peptone-yeast extract medium to produce lignin peroxidase (LiP). During the LiP assay, the oxidation of veratryl alcohol to veratraldehyde was inhibited due to tyrosine present in the peptone and the yeast extract. PMID:9251220

  5. 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....

  6. 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....

  7. 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....

  8. Prokaryotic expression cloning of a novel human tyrosine kinase

    SciTech Connect

    Beeler, J.F.; LaRochelle, W.J.; Chedid, M.

    1994-02-01

    Screening of a human embryonic lung fibroblast cDNA expression library with antiphosphotyrosine antibodies led to isolation of a novel protein kinase. A clone, designated A6, contained a 3-kb cDNA insert with a predicted open reading frame of 350 amino acids. DNA sequence analysis failed to reveal any detectable similarity with previously known genes, and the predicted A6 protein lacked any of the motifs commonly conserved in the catalytic domains of protein kinases. However, the bacterially expressed {beta}-galactosidase-A6 fusion protein demonstrated both tyrosine and serine phosphorylation in an in vitro kinase assay and phosphorylated exogenous substrates including myelin basic protein specifically on tyrosine residues. The enzyme also displayed biochemical properties analogous to those of other protein tyrosine kinases. The A6 gene was found to be expressed widely at the transcript level in normal tissues and was evolutionarily conserved. Thus, A6 represents a novel tyrosine kinase which is highly divergent from previously described members of this important class of regulatory molecules. 29 refs., 8 figs., 1 tab.

  9. Enhanced photoluminescence by tyrosine-containing bolaamphiphile self-assembly.

    PubMed

    Kwak, Jinyoung; Lee, Sang-Yup

    2013-04-01

    Photoluminescent spherical nanostructures were prepared through the self-assembly of a tyrosine-containing bolaamphiphilic molecule, and their antenna effect was examined. The photoluminescent spherical nanostructures were simply prepared by self-assembly of bolaamphiphile molecules in an aqueous solution in which water-soluble photosensitizers and lanthanide ions were dissolved. The photosensitizers and lanthanide cations were incorporated with the phenol group and the carboxyl end of the tyrosine moiety, respectively. Through fluorescence microscopy and photoluminescence spectroscopy analyses, the various combinations of two lanthanide ions (Eu and Tb) and four photosensitizers were screened for synergetic photoluminescence with bolaamphiphile self-assembly. The bolaamphiphile assembly enhanced the photoluminescence intensity by a factor of around 2 when it was associated with Tb and salicylic acid. This enhancement is driven by the phosphorescence enhancement of the photosensitizer induced by the π-π interactions with the phenol group in tyrosine. These results indicate that the tyrosine-containing bolaamphiphile is a promising molecule that can easily produce a soft nanoscaled host matrix with an antenna effect for photoluminescence.

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

    PubMed

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

    2016-01-01

    Gastrointestinal cancer treatment is based more on molecular biology that has provided increasing knowledge about cancer pathogenesis on which targeted therapy is being developed. Precisely, targeted therapy is defined as a "type of treatment that uses drugs, such as monoclonal antibodies or tyrosine kinase inhibitors, to identify and attack specific cancer cells". Nowadays, the United States Food and Drug Administration has approved many targeted therapies for gastrointestinal cancer treatment, as many are in various phases of development as well. In a previous review we discussed the main monoclonal antibodies used and studied in gastrointestinal cancer. In addition to monoclonal antibodies, tyrosine kinase inhibitors represent another class of targeted therapy and following the approval of imatinib for gastrointestinal stromal tumours, other tyrosine kinase inhibitors have been approved for gastrointestinal cancers treatment such as sunitinib, regoragenib, sorafenib and erlotinib. Moving forward, the purpose of this review is to focus on the efficacy data of main tyrosine kinase inhibitors commonly used in the personalized treatment of each gastrointestinal tumour and to provide a comprehensive overview about experimental targeted therapies ongoing in this setting.

  11. Specific dephosphorylation of Janus Kinase 2 by protein tyrosine phosphatases.

    PubMed

    Li, Jianzhuo; Liu, Xidong; Chu, Huiying; Fu, Xueqi; Li, Tianbao; Hu, Lianghai; Xing, Shu; Li, Guohui; Gu, Jingkai; Zhao, Zhizhuang Joe

    2015-01-01

    Many protein kinases are activated through phosphorylation of an activation loop thereby turning on downstream signaling pathways. Activation of JAK2, a nonreceptor tyrosine kinase with an important role in growth factor and cytokine signaling, requires phosphorylation of the 1007 and 1008 tyrosyl residues. Dephosphorylation of these two sites by phosphatases presumably inactivates the enzyme, but the underlying mechanism is not known. In this study, we employed MALDI-TOF/TOF and triple quadrupole mass spectrometers to analyze qualitatively and quantitatively the dephosphorylation process by using synthetic peptides derived from the tandem autophosphorylation sites (Y1007 and Y1008) of human JAK2. We found that tyrosine phosphatases catalyzed the dephosphorylation reaction sequentially, but different enzymes exhibited different selectivity. Protein tyrosine phosphatase 1B caused rapid dephosphorylation of Y1008 followed by Y1007, while SHP1 and SHP2 selectively dephosphorylated Y1008 only, and yet HePTP randomly removed a single phosphate from either Y1007 or Y1008, leaving behind mono-phosphorylated peptides. The specificity of dephosphorylation was further confirmed by molecular modeling. The data reveal multiple modes of JAK2 regulation by tyrosine phosphatases, reflecting a complex, and intricate interplay between protein phosphorylation and dephosphorylation.

  12. 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....

  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. 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.

  15. 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.

  16. 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.

  17. Inhibition of the Fc receptor-mediated oxidative burst in macrophages by the Yersinia pseudotuberculosis tyrosine phosphatase.

    PubMed Central

    Bliska, J B; Black, D S

    1995-01-01

    Suppression of host-cell-mediated immunity is a hallmark feature of Yersinia pseudotuberculosis infection. To better understand this process, the interaction of Y. pseudotuberculosis with macrophages and the effect of the virulence plasmid-encoded Yersinia tyrosine phosphatase (YopH) on the oxidative burst was analyzed in a chemiluminescence assay. An oxidative burst was generated upon infection of macrophages with a plasmid-cured strain of Y. pseudotuberculosis opsonized with immunoglobulin G antibody. Infection with plasmid-containing Y. pseudotuberculosis inhibited the oxidative burst triggered by secondary infection with opsonized bacteria. The tyrosine phosphatase activity of YopH was necessary for this inhibition. These results indicate that YopH inhibits Fc receptor-mediated signal transduction in macrophages in a global fashion. In addition, bacterial protein synthesis was not required for macrophage inhibition, suggesting that YopH export and translocation are controlled at the posttranslational level. PMID:7822039

  18. Protein (tyrosine)-chromophore (protonated Schiff base) coupling in bacteriorhodopsin

    SciTech Connect

    Hanamoto, J.H.; Dupuis, P.; El-Sayed, M.A.

    1984-11-01

    The kinetics of formation of both the tyrosinate ion (from its absorption at 296 nm) and the deprotonated Schiff base (M/sub 412/) (from its absorption at 404 nm) are studied simultaneously at different pH values (7-11) and temperatures (5-25/sup 0/C). Two formation rates are observed for M/sub 412/ in agreement with previous observations. The slow one is dominant under physiological conditions and is found to be slightly faster than that for the tyrosinate formation. This is in disagreement with the proposal that the tyrosinate formation is a prerequisite to the deprotonation of the Schiff base (M/sub 412/). The ratio of the amplitudes of the fast and slow components is found to be sensitive to pH and, at any pH, it can be used to calculate an amino acid pK/sub a/ value of 9.6. This is explained by proposing the existence of two sites for the protonated Schiff base within the protein. In one site, the Schiff base is near the neutral form of an amino acid residue with a pK/sub a/ value of 9.6 (giving rise to the slow component), while in the other, it is near its conjugate base. The formation of the tyrosinate ion as well as the formation of the slow and fast components of M/sub 412/ all have activation energies that are comparable to H-bond energies. A model is suggested to account for this and the comparable deprotonation rates of tyrosine and the slow component of the protonated Schiff base. It involves the reduction of their pK/sub a/ by their exposure to a positively charged species. 43 references, 2 figures, 2 tables.

  19. Biochemistry of primary headaches: role of tyrosine and tryptophan metabolism.

    PubMed

    D'Andrea, G; Cevoli, S; Colavito, D; Leon, A

    2015-05-01

    The pathogenesis of migraine as well as cluster headache (CH) is yet a debated question. In this review, we discuss the possible role of the of tyrosine and tryptophan metabolism in the pathogenesis of these primary headaches. These include the abnormalities in the synthesis of neurotransmitters: high level of DA, low level of NE and very elevated levels of octopamine and synephrine (neuromodulators) in plasma of episodic migraine without aura and CH patients. We hypothesize that the imbalance between the levels of neurotransmitters and elusive amines synthesis is due to a metabolic shift directing tyrosine toward an increased decarboxylase and reduced hydroxylase enzyme activities. The metabolic shift of the tyrosine is favored by a state of neuronal hyperexcitability and a reduced mitochondrial activity present in migraine. In addition we present biochemical studies performed in chronic migraine and chronic tension-type headache patients to verify if the same anomalies of the tyrosine and tryptophan metabolism are present in these primary headaches and, if so, their possible role in the chronicity process of CM and CTTH. The results show that important abnormalities of tyrosine metabolism are present only in CM patients (very high plasma levels of DA, NE and tryptamine). Tryptamine plasma levels were found significantly lower in both CM and CTTH patients. In view of this, we propose that migraine and, possibly, CH attacks derive from neurotransmitter and neuromodulator metabolic abnormalities in a hyperexcitable and hypoenergetic brain that spread from the frontal lobe, downstream, resulting in abnormally activated nuclei of the pain matrix. The low tryptamine plasma levels found in CM and CTTH patients suggest that these two primary chronic headaches are characterized by a common insufficient serotoninergic control of the pain threshold.

  20. Protein tyrosine phosphatase regulation of endothelial cell apoptosis and differentiation.

    PubMed

    Yang, C; Chang, J; Gorospe, M; Passaniti, A

    1996-02-01

    Apoptosis, or programmed cell death, occurs during development and may also be an important factor in many diseases. However, little is known about the signal transduction pathways regulating apoptosis. In these studies, loss of endothelial cell-substrate attachment and apoptosis after removal of growth factors was associated with dephosphorylation of tyrosine residues at the cell periphery. Dephosphorylation of total cellular proteins accompanied apoptosis and was reduced by orthovanadate, an inhibitor of protein tyrosine phosphatases. Orthovanadate blocked the fragmentation of nuclear DNA, inhibited DNA laddering, and suppressed the expression of TRPM-2, an apoptosis-associated gene. The tyrosine phosphorylation levels of FAK125, erk1 (mitogen-activated kinase kinase), and cdc-2 were reduced during apoptosis. FAK125 dephosphorylation was inhibited by orthovanadate, but premature activation (tyrosine dephosphorylation) of cdc-2 was not. Orthovanadate was as effective as basic fibroblast growth factor in activating erk1 without increasing cell proliferation and in preventing the apoptosis of endothelial cells after treatment with tumor necrosis factor alpha. Endothelial cell differentiation on extracellular matrix (Matrigel) was also stimulated by orthovanadate in the absence of basic fibroblast growth factor without affecting growth arrest and inhibition of DNA synthesis. Expression of the cyclin-dependent kinase inhibitor p21 (Waf1/Cip1/Sdi1) was down-regulated during the early stages of differentiation, remained low for at least 6 hours as differentiation proceeded, and increased upon completion of differentiation. Cells that failed to down-regulate p21 mRNA on Matrigel in the absence of angiogenic factors underwent apoptosis. These results suggest that protein tyrosine phosphatases are actively involved in signal transduction during apoptosis and may regulate p21 expression to inhibit endothelial cell differentiation.

  1. 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

  2. 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.

  3. Interaction between cAMP-dependent and insulin-dependent signal pathways in tyrosine phosphorylation in primary cultures of rat hepatocytes.

    PubMed Central

    Ito, Y; Uchijima, Y; Ariga, M; Seki, T; Takenaka, A; Hakuno, F; Takahashi, S I; Ariga, T; Noguchi, T

    1997-01-01

    The present studies were undertaken to determine whether the interaction between cAMP-dependent and insulin-dependent pathways in primary cultures of rat hepatocytes affects biological functions and tyrosine phosphorylation. Quiescent hepatocytes were pretreated with dibutyryl cAMP or cAMP-generating agents such as glucagon, and then treated or not with insulin. Preincubation for 6 h with dibutyryl cAMP or glucagon enhanced the effect of insulin on DNA synthesis, but not the effect of insulin on amino acid transport or glycogen and protein synthesis. Tyrosine phosphorylation of intracellular proteins was determined by immunoblot analysis using an anti-phosphotyrosine antibody. Maximum tyrosine phosphorylation of a 195 kDa protein, which may be a substrate of insulin receptor kinase, of 175-180 kDa proteins, including insulin receptor substrate (IRS)-1, and of 90-95 kDa proteins, including the insulin receptor beta-subunit, was reached within 30 s of incubation with insulin. Pretreatment for about 3 h with dibutyryl cAMP or cAMP-generating agents clearly increased insulin-dependent tyrosine phosphorylation of the 195 kDa protein, but not IRS-1, IRS-2 or the insulin receptor beta-subunit. Because dibutyryl cAMP and cAMP-generating agents did not increase insulin receptor number or its kinase activity, the effect of cAMP on this potentiation of tyrosine phosphorylation is assumed to be exerted at a step distal to insulin receptor kinase activation. The potentiation by cAMP pretreatment of insulin-stimulated tyrosine phosphorylation may in part be secondary to inhibition of phosphotyrosine phosphatase activity, because cAMP pretreatment blunted the effect of Na3VO4 on the net tyrosine phosphorylation of the 195 kDa protein as compared with cells pretreated with no additive. In summary, the interactions between cAMP-dependent and insulin-dependent pathways that lead to augmentation of DNA synthesis appear to parallel the changes in tyrosine phosphorylation. Further

  4. Novel bone-targeted Src tyrosine kinase inhibitor drug discovery.

    PubMed

    Shakespeare, William C; Metcalf, Chester A; Wang, Yihan; Sundaramoorthi, Raji; Keenan, Terence; Weigele, Manfred; Bohacek, Regine S; Dalgarno, David C; Sawyer, Tomi K

    2003-09-01

    Bone-targeted Src tyrosine kinase (STK) inhibitors have recently been developed for the treatment of osteoporosis and cancer-related bone diseases. The concept of bone targeting derives from bisphosphonates, and from the evolution of such molecules in terms of therapeutic efficacy for the treatment of bone disorders. Interestingly, some of the earliest bisphosphonates were recognized for their ability to inhibit calcium carbonate precipitation (scaling) by virtue of their affinity to chelate calcium. This chelating property was subsequently exploited in the development of bisphosphonate analogs as inhibitors of the bone-resorbing cells known as osteoclasts, giving rise to breakthrough medicines, such as Fosamax (for the treatment of osteoporosis) and Zometa (for the treatment of osteoporosis and bone metastases). Relative to these milestone achievements, there is a tremendous opportunity to explore beyond the limited chemical space (functional group diversity) of such bisphosphonates to design novel bone-targeting moieties, which may be used to develop other classes of promising small-molecule drugs affecting different biological pathways. Here, we review studies focused on bone-targeted inhibitors of STK, a key enzyme in osteoclast-dependent bone resorption. Two strategies are described relative to bone-targeted STK inhibitor drug discovery: (i) the development of novel Src homology (SH)-2 inhibitors incorporating non-hydrolyzable phosphotyrosine mimics and exhibiting molecular recognition and bone-targeting properties, leading to the in vivo-effective lead compound AP-22408; and (ii) the development of novel ATP-based Src kinase inhibitors incorporating bone-targeting moieties, leading to the in vivo-effective lead compound AP-23236. In summary, AP-22408 and AP-23236, which differ mechanistically by virtue of blocking Src-dependent non-catalytic or catalytic activities in osteoclasts, exemplify ARIAD Pharmaceuticals' structure-based design of novel bone

  5. 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…

  6. 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

  7. 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

  8. Roles of cysteine 161 and tyrosine 154 in the lecithin-retinol acyltransferase mechanism.

    PubMed

    Xue, Linlong; Rando, Robert R

    2004-05-25

    Lecithin-retinol acyltransferase (LRAT) catalyzes the transfer of an acyl moiety from the sn-1 position of lecithin to vitamin A, generating all-trans-retinyl esters. LRAT is a unique enzyme and is the founder member of an expanding group of proteins of largely unknown function. In an effort to understand the mechanism of LRAT action, it was of interest to assign the amino acid residues responsible for the two pK(a) values of 8.22 and 9.95 observed in the pH vs rate profile. Titrating C161 of LRAT with a specific affinity labeling agent at varying pH values shows that this residue has a pK(a) = 8.03. Coupled with previous studies, this titration reveals the catalytically essential C161 as the residue responsible for the ascending limb of the pH vs rate profile. Site-specific mutagenic experiments on the lysine and tyrosine residues of LRAT reveal that only the highly conserved tyrosine 154 is essential for catalytic activity. This residue is likely to be responsible for the pK(a) = 9.95 found in the pH vs rate profile. Thus, LRAT has three essential residues (C161, Y154, and H60), all of which are conserved in the LRAT family of enzymes.

  9. Hypertrophy and dietary tyrosine ameliorate the phenotypes of a mouse model of severe nemaline myopathy.

    PubMed

    Nguyen, Mai-Anh T; Joya, Josephine E; Kee, Anthony J; Domazetovska, Ana; Yang, Nan; Hook, Jeff W; Lemckert, Frances A; Kettle, Emma; Valova, Valentina A; Robinson, Philip J; North, Kathryn N; Gunning, Peter W; Mitchell, Christina A; Hardeman, Edna C

    2011-12-01

    Nemaline myopathy, the most common congenital myopathy, is caused by mutations in genes encoding thin filament and thin filament-associated proteins in skeletal muscles. Severely affected patients fail to survive beyond the first year of life due to severe muscle weakness. There are no specific therapies to combat this muscle weakness. We have generated the first knock-in mouse model for severe nemaline myopathy by replacing a normal allele of the α-skeletal actin gene with a mutated form (H40Y), which causes severe nemaline myopathy in humans. The Acta1(H40Y) mouse has severe muscle weakness manifested as shortened lifespan, significant forearm and isolated muscle weakness and decreased mobility. Muscle pathologies present in the human patients (e.g. nemaline rods, fibre atrophy and increase in slow fibres) were detected in the Acta1(H40Y) mouse, indicating that it is an excellent model for severe nemaline myopathy. Mating of the Acta1(H40Y) mouse with hypertrophic four and a half LIM domains protein 1 and insulin-like growth factor-1 transgenic mice models increased forearm strength and mobility, and decreased nemaline pathologies. Dietary L-tyrosine supplements also alleviated the mobility deficit and decreased the chronic repair and nemaline rod pathologies. These results suggest that L-tyrosine may be an effective treatment for muscle weakness and immobility in nemaline myopathy. PMID:22067542

  10. Regulation and function of syk tyrosine kinase in mast cell signaling and beyond.

    PubMed

    de Castro, Rodrigo Orlandini

    2011-01-01

    The protein tyrosine kinase Syk plays a critical role in FcεRI signaling in mast cells. Binding of Syk to phosphorylated immunoreceptor tyrosine-based activation motifs (p-ITAM) of the receptor subunits results in conformational changes and tyrosine phosphorylation at multiple sites that leads to activation of Syk. The phosphorylated tyrosines throughout the molecule play an important role in the regulation of Syk-mediated signaling. Reconstitution of receptor-mediated signaling in Syk(-/-) cells by wild-type Syk or mutants which have substitution of these tyrosines with phenylalanine together with in vitro assays has been useful strategies to understand the regulation and function of Syk.

  11. Structures IVHM for 3rd Generation RLVs

    NASA Technical Reports Server (NTRS)

    Rogowski, Robert S.

    2000-01-01

    The primary goal of a Structures Integrated Vehicle Health Management (IVHM) system for 3rd generation Reusable Launch Vehicles (RLV) is to provide near 100% structural sensing coverage and thus eliminate both routine, and especially unplanned, inspections which are costly and time consuming. To meet this goal, significant advances in sensing and measurement system technology, data systems architectures, and structures based analysis methodology will be required to enable the needed large numbers of sensors with little weight penalty. This program will leverage X-33, 2nd Gen RLV, Shuttle, and Aviation Safety SIVHM system development experience to address this goal.

  12. 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

  13. Unexpected differences between D- and L- tyrosine lead to chiral enhancement in racemic mixtures.

    PubMed

    Shinitzky, Meir; Nudelman, Fabio; Barda, Yaniv; Haimovitz, Rachel; Chen, Effie; Deamer, David W

    2002-08-01

    We report here an unexpected difference in the solubilities of D- and L-tyrosine in water, which could be discerned by their rate of crystallization and the resulting concentrations of their saturated solutions. A supersaturated solution of 10 mM L-tyrosine at 20 degrees C crystallized much more slowly than that of D-tyrosine under the same conditions, and the saturated solution of L-tyrosine was more concentrated than that of D-tyrosine. Supersaturated solutions of 10 mM DL-tyrosine in water formed precipitates of predominantly D-tyrosine and DL-tyrosine, resulting in an excess of L-tyrosine in the saturated solution. The experimental setups were monitored independently by UV-absorption, radioactivity tracing, optical rotation and X-ray diffraction. The process of nucleation and crystallization of D- and L-tyrosine is characterized by an exceptionally high cooperativity. It is possible that minute energy differences between D- and L-tyrosine, originating from parity violation or other non-conservative chiral discriminatory rules, could account for the observations. The physical process that initiated chiral selection in biological systems remains a challenging problem in understanding the origin of life, and it is possible that chiral compounds were concentrated from supersaturated racemic mixtures by preferential crystallization.

  14. Behavioral and cognitive effects of tyrosine intake in healthy human adults.

    PubMed

    Hase, Adrian; Jung, Sophie E; aan het Rot, Marije

    2015-06-01

    The amino acid tyrosine is the precursor to the catecholamine neurotransmitters dopamine and norepinephrine. Increasing tyrosine uptake may positively influence catecholamine-related psychological functioning. We conducted a systematic review to examine the effects of tyrosine on behavior and cognition. Fifteen studies were reviewed. All studies except one involved tyrosine loading during a single test session. In most behavioral studies, there were no significant effects of tyrosine on exercise performance. In contrast, cognitive studies employing neuropsychological measures found that tyrosine loading acutely counteracts decrements in working memory and information processing that are induced by demanding situational conditions such as extreme weather or cognitive load. The buffering effects of tyrosine on cognition may be explained by tyrosine's ability to neutralize depleted brain catecholamine levels. There is evidence that tyrosine may benefit healthy individuals exposed to demanding situational conditions. For future research we recommend moving from studying the acute effects of a single tyrosine load in small samples to studying the behavioral and cognitive effects of tyrosine in larger groups over multiple weeks.

  15. 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…

  16. meta-Tyrosine in Festuca rubra ssp. commutata (Chewings fescue) is synthesized by hydroxylation of phenylalanine.

    PubMed

    Huang, Tengfang; Rehak, Ludmila; Jander, Georg

    2012-03-01

    m-Tyrosine is a non-protein amino acid that is structurally similar to the common protein amino acids p-tyrosine and phenylalanine. Copious amounts of m-tyrosine can be found in root exudates of the fine fescue cultivar, Festuca rubra L. ssp. commutata (Chewings fescue). The phytotoxicity of m-tyrosine may contribute to the allelopathic potential of F. rubra. m-Tyrosine in Euphorbia myrsinites (donkey-tail spurge), was previously shown to be synthesized via transamination of m-hydroxyphenylpyruvate. Here we show that m-tyrosine biosynthesis in F. rubra occurs through direct hydroxylation of phenylalanine in the root tips, perhaps through the activity of a cytochrome P450 enzyme. Hence, E. myrsinites and F. rubra, the only two plant species known to produce m-tyrosine, use distinct biosynthetic pathways that likely arose independently in evolutionary history.

  17. Purification and characterization of tyrosine phenol lyase from Citrobacter freundii.

    PubMed

    Chandel, Meenakshi; Azmi, Wamik

    2013-12-01

    The purification and characterization of intracellular tyrosine phenol lyase from Citrobacter freundii has been carried out. The enzyme was purified 35-fold to homogeneity by ammonium sulphate precipitation and hydrophobic interaction chromatography. Its subunit molecular weight was found to be 52 kDa on sodium dodecyl sulphate polyacrylamide gel electrophoresis. The purified tyrosine phenol lyase showed maximum activity in borate buffer (0.05 M at pH 8.5) at 45 °C after 20 min of incubation. The Km and Vmax values of purified enzyme were found to be 0.446 mm and 0.342 mM/min/mg. This enzyme exhibits t1/2 of 10, 52 and 130 min at 55, 45 and 35 °C, respectively. The N-terminal amino acid sequence was determined as MET-ASN-TYR-PRO-ALA-GLU-PRO-PHE-ARG-ILETRP- TRP-VAL-GLY.

  18. 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

  19. 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.

  20. Glucose-mediated tyrosine nitration in adipocytes: Targets and consequences

    PubMed Central

    Koeck, Thomas; Willard, Belinda; Crabb, John W.; Kinter, Mike; Stuehr, Dennis J.; Aulak, Kulwant S.

    2010-01-01

    Hyperglycemia, a key factor in insulin resistance and diabetic pathology, is associated with cellular oxidative stress that promotes oxidative protein modifications. We report that protein nitration is responsive to changes in glucose concentrations in 3T3-L1 adipocytes. Alterations in the extent of tyrosine nitration as well as the cellular nitroproteome profile correlated tightly with changing glucose concentrations. The target proteins we identified are involved in fatty acid binding, cell signaling, protein folding, energy metabolism, antioxidant capacity, and membrane permeability. The nitration of adipocyte fatty acid binding protein (FABP4) at Tyr19 decreases, similar to phosphorylation, the binding of palmitic acid to the fatty acid-free protein. This potentially alters intracellular fatty acid transport, nuclear translocation of FABP4, and agonism of PPAR gamma. Our results suggest that protein tyrosine nitration may be a factor in obesity, insulin resistance, and the pathogenesis of diabetes. PMID:19135148

  1. 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.

  2. 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

  3. Reaction of tyrosine oxidation products with proteins of the lens

    PubMed Central

    Pirie, Antoinette

    1968-01-01

    Oxidation of tyrosine in the presence of bovine lens proteins leads to the formation of brown or black melanoproteins. Both tyrosinase and the oxidizing system of ferrous sulphate–ascorbic acid–EDTA are effective. The fluorescence of the lens proteins is both altered and enhanced by the tyrosine-oxidizing systems. Their fluorescence spectra resemble those of urea-insoluble proteins of human cataractous lens and of 1,2-naphthaquinone–proteins of naphthalene cataract. The lens proteins lose their thiol groups and, in acid hydrolysates of treated β-and γ-crystallins, a substance has been detected chromatographically that behaves similarly to a compound formed when 3,4-dihydroxyphenylalanine (dopa) is oxidized by tyrosinase in the presence of cysteine. Analysis and behaviour of this substance from hydrolysates of lens proteins suggest that it is a compound of cysteine and dopa. PMID:4971287

  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. Characterization of a PRL protein tyrosine phosphatase from Plasmodium falciparum.

    PubMed

    Pendyala, Prakash Rao; Ayong, Lawrence; Eatrides, Jennifer; Schreiber, Melissa; Pham, Connie; Chakrabarti, Ratna; Fidock, David A; Allen, Charles M; Chakrabarti, Debopam

    2008-03-01

    Isoprenylated proteins have important functions in cell growth and differentiation of eukaryotic cells. Inhibitors of protein prenylation in malaria have recently shown strong promise as effective antimalarials. In studying protein prenylation in the malaria protozoan parasite Plasmodium falciparum, we have shown earlier that the incubation of P. falciparum cells with (3)H-prenol precursors resulted in various size classes of labeled proteins. To understand the physiological function of prenylated proteins of malaria parasites, that are targets of prenyltransferase inhibitors, we searched the PlasmoDB database for proteins containing the C-terminus prenylation motif. We have identified, among other potentially prenylated proteins, an orthologue of a PRL (protein of regenerating liver) subgroup protein tyrosine phosphatases, termed PfPRL. Here, we show that PfPRL is expressed in the parasite's intraerythrocytic stages, where it partially associates with endoplasmic reticulum and within a subcompartment of the food vacuole. Additionally, PfPRL targeting parallels that of apical membrane antigen-1 in developing merozoites. Recombinant PfPRL shows phosphatase activity that is preferentially inhibited by a tyrosine phosphatase inhibitor suggesting that PfPRL functions as a tyrosine phosphatase. Recombinant PfPRL can also be farnesylated in vitro. Inhibition of malarial farnesyltransferase activity can be achieved with the heptapetide RKCHFM, which corresponds to the C-terminus of PfPRL. This study provides the first evidence for expression of enzymatically active PRL-related protein tyrosine phosphatases in malarial parasites, and demonstrates the potential of peptides derived from Plasmodium prenylated proteins as malarial farnesyltransferase inhibitors.

  8. Perspective: Dynamics of receptor tyrosine kinase signaling complexes.

    PubMed

    Mayer, Bruce J

    2012-08-14

    Textbook descriptions of signal transduction complexes provide a static snapshot view of highly dynamic events. Despite enormous strides in identifying the key components of signaling complexes and the underlying mechanisms of signal transduction, our understanding of the dynamic behavior of these complexes has lagged behind. Using the example of receptor tyrosine kinases, this perspective takes a fresh look at the dynamics of the system and their potential impact on signal processing. PMID:22584051

  9. Temporal patterns of tyrosine nitration in embryo heart development

    PubMed Central

    Viera, Liliana; Radmilovich, Milka; Vargas, Marcelo R.; Dennys, Cassandra N.; Wilson, Landon; Barnes, Stephen; Franco, Maria Clara; Beckman, Joseph S.; Estévez, Alvaro G.

    2012-01-01

    Tyrosine nitration is a biomarker for the production of peroxynitrite and other reactive nitrogen species. Nitrotyrosine immunoreactivity is present in many pathological conditions including several cardiac diseases. Because the events observed during heart failure may recapitulate some aspects of development, we tested whether nitrotyrosine is present during normal development of the rat embryo heart and its potential relationship in cardiac remodeling through apoptosis. Nitric oxide (NO) production is highly dynamic during development, but whether peroxynitrite and nitrotyrosine are formed during normal embryonic development has received little attention. Rat embryo hearts exhibited strong nitrotyrosine immunoreactivity in endocardial and myocardial cells of the atria and ventricles from E12 to E18. After E18, nitrotyrosine staining faded and disappeared entirely by birth. Tyrosine nitration in the myocardial tissue coincided with elevated protein expression of nitric oxide synthases (eNOS and iNOS). The immunoreactivity for these NOS isoforms remained elevated even after nitrotyrosine had disappeared. Tyrosine nitration did not correlate with cell death or proliferation of cardiac cells. Analysis of tryptic peptides by MALDI-TOF shows that nitration occurs in actin, myosin, and the mitochondrial ATP synthase alpha chain. These results suggest that reactive nitrogen species are not restricted to pathological conditions but may play a role during normal embryonic development. PMID:23195686

  10. 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

  11. 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

  12. 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.

  13. Protein Tyrosine Phosphatases in Hypothalamic Insulin and Leptin Signaling.

    PubMed

    Zhang, Zhong-Yin; Dodd, Garron T; Tiganis, Tony

    2015-10-01

    The hypothalamus is critical to the coordination of energy balance and glucose homeostasis. It responds to peripheral factors, such as insulin and leptin, that convey to the brain the degree of adiposity and the metabolic status of the organism. The development of leptin and insulin resistance in hypothalamic neurons appears to have a key role in the exacerbation of diet-induced obesity. In rodents, this has been attributed partly to the increased expression of the tyrosine phosphatases Protein Tyrosine Phosphatase 1B (PTP1B) and T cell protein tyrosine phosphatase (TCPTP), which attenuate leptin and insulin signaling. Deficiencies in PTP1B and TCPTP in the brain, or specific neurons, promote insulin and leptin signaling and prevent diet-induced obesity, type 2 diabetes mellitus (T2DM), and fatty liver disease. Although targeting phosphatases and hypothalamic circuits remains challenging, recent advances indicate that such hurdles might be overcome. Here, we focus on the roles of PTP1B and TCPTP in insulin and leptin signaling and explore their potential as therapeutic targets.

  14. 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.

  15. Tyrosine kinase blockers: new hope for successful cancer therapy.

    PubMed

    Pytel, Dariusz; Sliwinski, Tomasz; Poplawski, Tomasz; Ferriola, Deborah; Majsterek, Ireneusz

    2009-01-01

    Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of kinase blockers is Imatinib (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others kinase inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic kinase, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor kinase, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT kinase. The following TK blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment.

  16. Regulation of receptor protein-tyrosine phosphatase dimerization.

    PubMed

    van der Wijk, Thea; Blanchetot, Christophe; den Hertog, Jeroen

    2005-01-01

    Receptor protein-tyrosine phosphatases (RPTPs) are single membrane spanning proteins belonging to the family of PTPs that, together with the antagonistically acting protein-tyrosine kinases (PTKs), regulate the protein phosphotyrosine levels in cells. Protein-tyrosine phosphorylation is an important post-translational modification that has a major role in cell signaling by affecting protein-protein interactions and enzymatic activities. Increasing evidence indicates that RPTPs, like RPTKs, are regulated by dimerization. For RPTPalpha, we have shown that rotational coupling of the constitutive dimers in the cell membrane determines enzyme activity. Furthermore, oxidative stress, identified as an important second messenger during the past decade, is a regulator of rotational coupling of RPTPalpha dimers. In this review, we discuss the biochemical and cell biological techniques that we use to study the regulation of RPTPs by dimerization. These techniques include (co-) immunoprecipitation, RPTP activity assays, chemical and genetic cross-linking, detection of cell surface proteins by biotinylation, and analysis of RPTPalpha dimers, using conformation-sensitive antibody binding.

  17. Tyrosine, phenylalanine, and tryptophan in gastroesophageal malignancy: a systematic review.

    PubMed

    Wiggins, Tom; Kumar, Sacheen; Markar, Sheraz R; Antonowicz, Stefan; Hanna, George B

    2015-01-01

    Gastroesophageal cancer has a rapidly increasing incidence worldwide and reliable biomarkers are urgently required to facilitate earlier diagnosis and improve survival. The aromatic amino acids tyrosine, phenylalanine, and tryptophan represent potential biomarkers and their relation to gastroesophageal cancer will be evaluated in this review. An electronic literature search was performed to identify all published research relating to the measurement of tyrosine, phenylalanine, or tryptophan in the biofluids or tissues of patients with gastroesophageal cancer. Sixteen studies were included in this systematic review. Six studies investigated serum concentrations, which all found decreased concentrations of these aromatic amino acids, except one study that found increased phenylalanine. Five studies reported increased concentrations within gastric content of these patients and two reported increased urinary concentrations. Tissue concentrations of these aromatic amino acids were increased in three studies. Tyrosine, phenylalanine, and tryptophan represent potential biomarkers of gastroesophageal cancer, and further research is necessary to definitively establish the mechanism responsible for altered concentrations of these compounds in patients with gastroesophageal cancer.

  18. 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

  19. The Croonian Lecture 1997. The phosphorylation of proteins on tyrosine: its role in cell growth and disease.

    PubMed Central

    Hunter, T

    1998-01-01

    The reversible phosphorylation of tyrosines in proteins plays a key role in regulating many different processes in eukaryotic organisms, such as growth control, cell cycle control, differentiation cell shape and movement, gene transcription, synaptic transmission, and insulin action. Phosphorylation of proteins is brought about by enzymes called protein-tyrosine kinases that add phosphate to specific tyrosines in target proteins; phosphate is removed from phosphorylated tyrosines by enzymes called protein-tyrosine phosphatases. Phosphorylated tyrosines are recognized by specialized binding domains on other proteins, and such interactions are used to initiate intracellular signaling pathways. Currently, more than 95 protein-tyrosine kinases and more than 55 protein-tyrosine phosphatase genes are known in Homo sapiens. Aberrant tyrosine phosphorylation is a hallmark of many types of cancer and other human diseases. Drugs are being developed that antagonize the responsible protein-tyrosine kinases and phosphatases in order to combat these diseases. PMID:9602534

  20. Biosynthetic substitution of tyrosine in green fluorescent protein with its surrogate fluorotyrosine in Escherichia coli.

    PubMed

    Ayyadurai, Niraikulam; Prabhu, Nadarajan Saravanan; Deepankumar, Kanagavel; Kim, Aran; Lee, Sun-Gu; Yun, Hyungdon

    2011-11-01

    Introduction of a fluorine moiety into green fluorescent protein offers an interesting novel spectral variant. The calculated binding energy of fluorotyrosine (F-Tyr) (-8.42 kcal/mol) for tyrosyl tRNA synthetase was moderately higher than that of tyrosine (Tyr) (-8.36 kcal/mol). This result directly correlated with the expression level of F-Tyr containing GFP (38 mg/l), which was comparably higher than that of the parent GFP expression level (34 mg/l). Finally, we generated a model structure for GFP to assess possible interaction in the chromophore of the protein structure, which plays an important role in determining the spectral and folding behaviors of the F-Tyr incorporated GFP variant.