WorldWideScience

Sample records for gelina target development

  1. Development of a Secondary Neutron Fluence Standard at GELINA

    International Nuclear Information System (INIS)

    Heyse, Jan; Eykens, Roger; Moens, Andre; Plompen, Arjan J.M.; Schillebeeckx, Peter; Wynants, Ruud; Anastasiou, Maria

    2013-06-01

    The MetroFission project, a Joint Research Project within the European Metrology Research Program, aims at addressing a number of metrological problems involved in the design of proposed Generation IV nuclear reactors. One of the objectives of this multidisciplinary project is the improvement of neutron cross section measurement techniques in order to arrive at uncertainties as required for the design and safety assessment of new generation power plants and fuel cycles. This objective is in line with the 'Uncertainty and target accuracy assessment for innovative systems using recent covariance data evaluations' published by a working party of the OECD Nuclear Energy Agency in 2008. These requests are often very challenging, being at or beyond the state-of-the-art in neutron measurements, which is set by self-normalizing methods and the neutron data standards used at laboratories where the data are measured. A secondary neutron fluence standard has been developed and calibrated at the neutron time-of-flight facility GELINA of the JRC's Institute for Reference Materials and Measurements (IRMM). It consists of a flux monitor, a reference ionization chamber containing a 10 B layer and a 235 U layer, and a parallel plate ionization chamber with 8 well characterized 235 U deposits. These devices are used to determine the neutron fluence, based on the well-known neutron induced fission reaction on 235 U. All deposits have been prepared and characterized at the IRMM target preparation lab. The secondary fluence standard at the GELINA facility can be used for reliable determination of the efficiency of fluence measurement devices used in neutron data measurements at IRMM and elsewhere. It is an essential tool to reliably calibrate fluence normalization devices used in neutron time-of-flight cross section measurements. (authors)

  2. Manufacturing and supply of a mercury cooled rotary uranium target for the GELINA accelerator facility of IRMM

    International Nuclear Information System (INIS)

    Febvre, M.

    2009-01-01

    AREVA CERCA is a manufacturer of Uranium fuel elements for Research Reactors, Mechanical Components for nuclear industry and Radioactive Reference Sources for nuclear industry and medicine. The GELINA high-resolution neutron time-of-flight measurements facility of IRMM (Institute for Reference Materials and Measurements) operates with a very special Uranium target. There is no other neutron production target in the world that has the same or even similar characteristics. Over more than two decades, AREVA CERCA developed and manufactured the rotary Uranium targets for the GELINA facility of IRMM. The use of Uranium and the induced activation during operation in GELINA ask for extremely reliable equipment, responding to very high safety demands. For the fabrication of the target, the very high quality control standards applicable for the fabrication of nuclear equipment must be applied. The material of the Uranium-molybdenum disk must fulfill very restrictive conditions. The target core of the target is cooled by a stream of Mercury, pumped by an electromagnetic pump manufactured by AREVA CERCA. Temperatures in the Uranium disk must be measured with thermocouples distributed inside the Uranium core, at the Uranium/cladding interface and at the inlet and outlet of the Mercury. The target has to rotate between an upper and a lower neutron moderator with very severe geometrical tolerances. The very small gap between the Uranium and the cladding must be filled with Helium before sealing. Preparation and installation of the Target at the GELINA linear Accelerator is presented. Performances and reliability of the targets are reported combined with major experiences and results gained by IRMM. (author)

  3. Neutron transmission measurements at the IRMM pulsed neutron facility GELINA

    CERN Document Server

    Brusegan, A

    2002-01-01

    Measurements of neutron transmission are performed at the pulsed neutron source GELINA (Geel Linear Accelerator) of the JRC Institute of Reference Materials and Measurements in Belgium. This white neutron possibility is one of the world best as it posses an excellent energy resolution and good intensity, which offer the possibility of obtaining high quality neutron data. In the lecture are given typical characteristics of the time-of-flight (TOF) measurements performed here. The neutron transmission through a sample is connected directly with the total neutron cross section of the isotope. The precision of the experimental data is important for the exact determination of the neutron resonance parameters, which are relevant in applications like astrophysics and nuclear reactor design. The knowledge of the average nuclear properties, like the strength function, is desirable in nuclear reaction theory for comparison with predictions of different optical models. High quality of the transmission data is assured by...

  4. Neutron transmission measurements at the IRMM pulsed neutron facility GELINA

    International Nuclear Information System (INIS)

    Brusegan, A.

    2002-01-01

    Measurements of neutron transmission are performed at the pulsed neutron source GELINA (Geel Linear Accelerator) of the JRC Institute of Reference Materials and Measurements in Belgium. This white neutron possibility is one of the world best as it posses an excellent energy resolution and good intensity, which offer the possibility of obtaining high quality neutron data. In the lecture are given typical characteristics of the time-of-flight (TOF) measurements performed here. The neutron transmission through a sample is connected directly with the total neutron cross section of the isotope. The precision of the experimental data is important for the exact determination of the neutron resonance parameters, which are relevant in applications like astrophysics and nuclear reactor design. The knowledge of the average nuclear properties, like the strength function, is desirable in nuclear reaction theory for comparison with predictions of different optical models. High quality of the transmission data is assured by precise measurements and data analysis. The latter is done carefully by using sophisticated computer codes. The resolution function of the neutron source and the resonance Doppler broadening are objects of special attention. In the lecture are presented typical examples of the neutron transmission measurements at CELINA, the main direction of data applications and an overview of the future investigations in the field

  5. LA CONFIGURACIÓN DEL SIGLO XXI EN LA POÉTICA DE DANA GELINAS

    Directory of Open Access Journals (Sweden)

    GLORIA VERGARA

    2013-05-01

    Full Text Available In this article we will study the poetry of Dana Gelinas, highlighting the strategies to representing the contemporary world. This Mexican poetess sees humans as entranced in front of windows or powerlessin the social struggle. Dana Gelinas’ poetry is naked and strong like the desert. Her verse come without much of preamble to define the image of the 21st century.

  6. Development of distributed target

    CERN Document Server

    Yu Hai Jun; Li Qin; Zhou Fu Xin; Shi Jin Shui; Ma Bing; Chen Nan; Jing Xiao Bing

    2002-01-01

    Linear introduction accelerator is expected to generate small diameter X-ray spots with high intensity. The interaction of the electron beam with plasmas generated at the X-ray converter will make the spot on target increase with time and debase the X-ray dose and the imaging resolving power. A distributed target is developed which has about 24 pieces of thin 0.05 mm tantalum films distributed over 1 cm. due to the structure adoption, the distributed target material over a large volume decreases the energy deposition per unit volume and hence reduces the temperature of target surface, then reduces the initial plasma formalizing and its expansion velocity. The comparison and analysis with two kinds of target structures are presented using numerical calculation and experiments, the results show the X-ray dose and normalized angle distribution of the two is basically the same, while the surface of the distributed target is not destroyed like the previous block target

  7. Investigations for the use of the fast digitizers with C6D6 detectors for radiative capture measurements at GELINA

    International Nuclear Information System (INIS)

    Mihailescu, L.C.; Borella, A.; Massimi, C.; Schillebeeckx, P.

    2009-01-01

    The relatively long dead time in conventional data acquisition systems that provide simultaneously the pulse height and the time information for the detected events hinders cross-section measurements with high count rates. This is the case for capture cross-section measurements at the time-of-flight facility GELINA using high radioactive samples or thick samples of materials having strong resonances. Either the high average count rate (e.g. due to the radioactivity of the sample) or the high instantaneous count rate for strong resonances results in a large dead time correction. One solution to reduce the impact of the dead time is the use of a data acquisition system based on fast digitizers. The performances of two commercial digitizers (CAEN N172B and Acqiris DC282), coupled to a C 6 D 6 scintillator, have been tested in terms of pulse height linearity and resolution, dead time and time resolution. The signal processing was done on-line obtaining simultaneously the pulse height and time information for each detected event. With both digitizers a comparable pulse height linearity and resolution has been obtained as with a conventional system. The total dead time of both digital systems is at least a factor 5 shorter than the one for the conventional system. The main difference in performance between the two digitizers is the time resolution. For a relatively large scintillator, a time resolution of about 2 ns has been achieved with the DC282 module and the conventional system while the time resolution was limited to 15 ns with the CAEN N1728B module. For most nuclei a 15 ns time resolution is sufficient to perform resonance shape analysis. Therefore, the CAEN N1728B module can be used for the majority of capture cross-section measurements at GELINA. However, for nuclei with low level density, for which the resolved resonance region extends to the keV-region, a better time resolution is required and the Acqiris DC282 module has to be used.

  8. Development of targeted radiotherapy systems

    International Nuclear Information System (INIS)

    Ferro, Guillermina; Villarreal, Jose E.; Garcia, Laura; Tendilla, Jose I.; Paredes, Lydia; Murphy, Consuelo A.; Pedraza, Martha

    2001-01-01

    Conventional or external beam radiotherapy, has been a viable alternative for cancer treatment. Although this technique is effective, its use is limited if the patient has multiple malignant lesions (metastases). An alternative approach is based on the design of radiopharmaceuticals that, to be administered in the patient, are directed specifically toward the target cell producing a selective radiation delivery. This treatment is known as targeted radiotherapy. We have summarized and discussed some results related to our investigations on the development of targeted radiotherapy systems, including aspects of internal dosimetry

  9. Nuclear target making and development

    International Nuclear Information System (INIS)

    Klimczak, G.W.; Thomas, G.E.

    1985-01-01

    The Physics Division operates a facility which produces and coordinates production of thin targets for charged-particle induced experiments, primarily at the Tandem-Linac and Dynamitron accelerators. In addition, these thin films are occasionally prepared for other scientific purposes. The services of the nuclear target-making facility are available to the Physics Division, other divisions of the Laboratory, and other scientific institutions. In addition to the typical production requirements, research work is performed in this facility to develop new techniques, as well as to implement and advance new state-of-the-art techniques developed at other institutions. Several new facilities and items of equipment are described

  10. Cytomegalovirus protease targeted prodrug development.

    Science.gov (United States)

    Sabit, Hairat; Dahan, Arik; Sun, Jing; Provoda, Chester J; Lee, Kyung-Dall; Hilfinger, John H; Amidon, Gordon L

    2013-04-01

    Human cytomegalovirus (HCMV) is a prevalent virus that infects up to 90% of the population. The goal of this research is to determine if small molecular prodrug substrates can be developed for a specific HCMV encoded protease and thus achieve site-specific activation. HCMV encodes a 256 amino acid serine protease that is responsible for capsid assembly, an essential process for herpes virus production. The esterase activity of the more stable HCMV A143T/A144T protease mutant was evaluated with model p-nitrophenol (ONp) esters, Boc-Xaa-ONp (Ala, Leu, Ile, Val, Gln, Phe at the Xaa position). We demonstrate that the A143T/A144T mutant has esterase activity toward specific small ester compounds, e.g., Boc-L-Ala-ONp. Mono amino acid and dipeptide prodrugs of ganciclovir (GCV) were also synthesized and evaluated for hydrolysis by the A143T/A144T protease mutant in solution. Hydrolysis of these prodrugs was also evaluated in Caco-2 cell homogenates, human liver microsomes (HLMs), and rat and human plasma. For the selectivity potential of the prodrugs, the hydrolysis ratio was evaluated as a percentage of prodrug hydrolyzed by the HCMV protease over the percentages of prodrug hydrolyses by Caco-2 cell homogenates, HLMs, and human/rat plasma. A dipeptide prodrug of ganciclovir, Ac-l-Gln-l-Ala-GCV, emerged as a potential selective prodrug candidate. The results of this research demonstrate that targeting prodrugs for activation by a specific protease encoded by the infectious HCMV pathogen may be achievable.

  11. Targets development at Sandia National Laboratories

    International Nuclear Information System (INIS)

    Smith, M.L.; Hebron, D.; Derzon, M.; Olson, R.; Alberts, T.

    1997-01-01

    For many years, Sandia National Laboratories under contract to the Department of Energy has produced targets designed to understand complex ion beam and z-pinch plasma physics. This poster focuses on the features of target designs that make them suitable for Z-pinch plasma physics applications. Precision diagnostic targets will prove critical in understanding the plasma physics model needed for future ion beam and z-pinch design. Targets are designed to meet specific physics needs; in this case the authors have fabricated targets to maximize information about the end-on versus side-on x-ray emission and z-pinch hohlraum development. In this poster, they describe the fabrication and characterization techniques. They include discussion of current targets under development as well as target fabrication capabilities. Advanced target designs are fabricated by Sandia National Laboratories in cooperation with General Atomics of San Diego, CA and W.J. Schafer Associates, Inc. of Livermore, CA

  12. Contraceptive development: targets, approaches and challenges.

    Science.gov (United States)

    Kopf, G S

    2007-01-01

    The control of fertility constitutes a global health issue, since overpopulation and unintended pregnancy have both major personal and societal impact. Although some regions of the world are seeing neutral or negative population growth, many developing countries are seeing explosive growth of their populations and these population changes will affect the entire globe. It is estimated that in a decade, the largest cohort of young women worldwide in human history will reach adolescence thus necessitating the need for a wide range of contraceptive options that can be used by both females and males. The contraceptive revolution that occurred in the 1960s with the development of the hormonal-based oral contraceptive for women has subsequently made a significant impact on societal dynamics in several cultures, yet there has been virtually no innovation in this field since that time. This lack of innovation contrasts dramatically with the vast enhancement of our knowledge base of the basic processes of reproduction. The genomic and proteomic revolutions have provided new tools and new targets for contraceptive development, and the results of such approaches have identified gene products that play critical roles in female and male reproduction, thus expanding the array of targets for novel and innovative female- and male-based contraceptives. This normally would herald a renaissance in contraceptive development, yet the commitment of industry to this endeavor is limited to a few firms due to the economics of contraceptive development. This chapter will consider the types of targets being considered in the development of new generations of contraceptives and will also focus on the challenges that industry has in meeting these goals.

  13. Target and accelerator developments at CTI

    Science.gov (United States)

    Alvord, C. W.; Mendez, A. J.; Wittner, D. E.

    2001-07-01

    The accelerator products marketed by CTI have exclusively focused on proton-only, low energy (11 MeV) designs. This choice best suited the research customer, interested in producing several doses a day of a variety of positron emitting compounds. The PET cyclotron market has evolved into a high output, cost driven, competitive radiotracer production environment. A thoughtful analysis of the choices of energy and particle reveals that an 11 MeV proton accelerator outfitted with target changers and automated target loading and unloading equipment is still the best choice for FDG distribution. However technological innovations are required to face the challenges of the rapidly growing PET radiotracer business. Modifications to the CTI line of accelerators developed to face this evolving need will be presented.

  14. Targeting TLR2 for Vaccine Development

    Directory of Open Access Journals (Sweden)

    Afonso P. Basto

    2014-01-01

    Full Text Available Novel and more effective immunization strategies against many animal diseases may profit from the current knowledge on the modulation of specific immunity through stimulation of innate immune receptors. Toll-like receptor (TLR2-targeting formulations, such as synthetic lipopeptides and antigens expressed in fusion with lipoproteins, have been shown to have built-in adjuvant properties and to be effective at inducing cellular and humoral immune mechanisms in different animal species. However, contradictory data has arisen concerning the profile of the immune response elicited. The benefits of targeting TLR2 for vaccine development are thus still debatable and more studies are needed to rationally explore its characteristics. Here, we resume the main features of TLR2 and TLR2-induced immune responses, focusing on what has been reported for veterinary animals.

  15. Development strategy and targets of CGNPG

    International Nuclear Information System (INIS)

    Zan Yunlong

    2002-01-01

    The development of nuclear power industry in Guangdong results from the steady implementation of a catch-up strategy aimed at the advanced world level in the nuclear power industry. China Guangdong Nuclear Power (Holding) Co., Ltd. (CGNPC) started from Daya Bay Nuclear Power Station (GNPS). In the form of joint venture, GNPS has obtained sophisticated technology, management expertise and human resources both at home and abroad, and has successfully completed the learning curve from importing, digesting, absorbing to innovating and self-improving. Under the principle of maintaining continuous nuclear power development by reinvesting the returns on the operating nuclear power stations, the second nuclear power project, Ling Ao Nuclear Power Station (LNPS) is progressing well and preparation for the third nuclear power project is now in full swing. With a rolling-on development mechanism being established, Daya Bay has become the cradle for nuclear power development in Guangdong. In the 21 st century, CGNPC is facing new challenges and opportunity. CGNPC will uphold the principle of maintaining continuous nuclear power development by reinvesting the returns on the operating nuclear power stations, brace itself for the market competition and explore sustained development of nuclear power in China by pursuing constant innovation in technology, management, system and concept. The strategy framework for future development of CGNPC is defined as follows: - to establish three-dimension strategic targets; - to pursue two-step development with the year 2015 as the dividing point; - to promote concerted development of nuclear power, associated industries and supporting services

  16. Antibiotics in development targeting protein synthesis.

    Science.gov (United States)

    Sutcliffe, Joyce A

    2011-12-01

    The resolution of antibiotic-ribosomal subunit complexes and antibacterial-protein complexes at the atomic level has provided new insights into modifications of clinically relevant antimicrobials and provided new classes that target the protein cellular apparatus. New chemistry platforms that use fragment-based drug design or allow novel modifications in known structural classes are being used to design new antibiotics that overcome known resistance mechanisms and extend spectrum and potency by circumventing ubiquitous efflux pumps. This review provides details on seven antibiotics in development for treatment of moderate-to-severe community-acquired bacterial pneumonia and/or acute bacterial skin and skin structure infections: solithromycin, cethromycin, omadacycline, CEM-102, GSK1322322, radezolid, and tedizolid. Two antibiotics of the oxazolidinone class, PF-02341272 and AZD5847, are being developed as antituberculosis agents. Only three antibiotics that target the protein cellular machinery, TP-434, GSK2251052, and plazomicin, have a spectrum that encompasses multidrug-resistant Gram-negative pathogens. These compounds provide hope for treating key pathogens that cause serious disease in both the community and the hospital. © 2011 New York Academy of Sciences.

  17. Development of Helios target insertion mechanism

    International Nuclear Information System (INIS)

    Day, R.D.; Cummings, C.E.; Tucker, H.E.

    1979-01-01

    A system for precisely positioning a DT-filled target in the Helios target vacuum chamber is described. The target insertion mechanism (TIM), which is designed to insert either a target or a surrogate sphere into the vacuum chamber through an airlock to prevent loss of vacuum, is discussed in detail and its performance is evaluated

  18. Polarized few-nucleon targets: new developments

    International Nuclear Information System (INIS)

    Haeusser, O.

    1992-09-01

    We discuss recent improvements in producing polarized few-nucleon targets for nuclear and particle physics experiments. The emphasis is on progress with polarized gas targets intended for experiments at electron and proton storage rings. (author) 54 refs., 1 tab

  19. Intermittent claudication: new targets for drug development.

    Science.gov (United States)

    Brass, Eric P

    2013-07-01

    Peripheral artery disease (PAD) is the result of extensive atherosclerosis in the arterial supply to the lower extremities. PAD is associated with increased systemic cardiovascular morbidity and mortality as well as substantial disability due to walking impairment. Claudication is the classic symptom of leg pain with walking that is relieved by rest, but patients with PAD without typical claudication also have a walking limitation. Treatment of the patient with PAD is directed towards reducing cardiovascular risk and improving exercise capacity. The pathophysiology of the physical impairment is complex as changes in the muscle distal to the arterial stenoses contribute to the limitations. Current treatment options to improve exercise performance have limitations emphasizing the need for new pharmacotherapies for this highly prevalent condition. The multifactorial contributors to the exercise impairment in PAD suggest potential targets for novel drug therapies. Advances in understanding angiogenesis make pharmacologic revascularization possible. However, ensuring that new blood vessels develop in a distribution relevant to the clinical impairment remains a challenge. Skeletal muscle metabolism and its regulation are altered in patients with PAD and strategies to improve the efficient oxidation of fuel substrates may improve muscle function. PAD is associated with increased oxidative stress which may result in injury to the muscle microvasculature and myocyte. Minimizing this oxidative stress by enhancing cellular defense mechanisms, administration of anti-inflammatory agents or by providing antioxidants, could prevent oxidative injury. Given the central role of atherosclerosis in the flow limitation, therapies to induce regression of atherosclerotic lesions could result in improved blood flow and oxygen delivery. Drugs targeting the distribution of blood flow in the microcirculatory environment of the muscle have the potential to better match oxygen delivery with

  20. Development of an autonomous target tracking system

    Science.gov (United States)

    Gidda, Venkata Ramaiah

    In recent years, surveillance and border patrol have become one of the key research areas in UAV research. Increase in the computational capability of the computers and embedded electronics, coupled with compatibility of various commercial vision algorithms and commercial off the shelf (COTS) embedded electronics, and has further fuelled the research. The basic task in these applications is perception of environment through the available visual sensors like camera. Visual tracking, as the name implies, is tracking of objects using a camera. The process of autonomous target tracking starts with the selection of the target in a sequence of video frames transmitted from the on-board camera. We use an improved fast dynamic template matching algorithm coupled with Kalman Filter to track the selected target in consecutive video frames. The selected target is saved as a reference template. On the ground station computer, the reference template is overlaid on the live streaming video from the on-board system, starting from the upper left corner of the video frame. The template is slid pixel by pixel over the entire source image. A comparison of the pixels is performed between the template and source image. A confidence value R of the match is calculated at each pixel. Based on the method used to perform the template matching, the best match pixel location is found according to the highest or lowest confidence value R. The best match pixel location is communicated to the on-board gimbal controller over the wireless Xbee network. The software on the controller actuates the pan-tilt servos to continuously to hold the selected target at the center of the video frame. The complete system is a portable control system assembled from commercial off the shelf parts. The tracking system is tested on a target having several motion patterns.

  1. Early clinical development of targeted anticancer agents

    NARCIS (Netherlands)

    van Brummelen, E.M.J.

    2017-01-01

    Van Brummelen studied the safety and preliminary signs of efficacy of several novel targeted anticancer agents in phase I trials. In her thesis, she reports the results of trials with the immunotherapies pembrolizumab and cergutuzumab-amunaleukin, and with combinations of inhibitors of the MEK and

  2. Meeting the millennium development goals' targets: Proposed UN ...

    African Journals Online (AJOL)

    Drawing on existing literature on governance and MDGs, the paper seeks to illuminate the dismal progress towards meeting the Millennium Development Goals' (MDGs) targets, with almost two-thirds of the target period gone by, since the targets were set by 189 member states of the UN in 2000. The urge to meet the ...

  3. Graphic Communication for Development in Africa: Target Audience ...

    African Journals Online (AJOL)

    Achieving desired response from target audience is the overall goal for graphic communication in support of development initiatives. However, in Africa, responses to development messages, which are largely determined by target audience perception, are predominantly far from being desired. Therefore, this paper focuses ...

  4. Continuing professional development and ICT: target practice.

    Science.gov (United States)

    Eaton, K A; Reynolds, P A

    2008-07-26

    Ever-increasing needs and demands by dentists and all other members of the dental team for education and training at all levels - undergraduate, postgraduate and continuing - are straining the resources of existing providers of such education. At the same time, there are ever-increasing opportunities to develop online delivery and the use of a range of information and communication technology (ICT) systems and services further, in all aspects of dental education. This paper reviews recent developments that have led to an increased demand for dental postgraduate programmes and continuing professional development (CPD) courses in the United Kingdom and then discusses how ICT has and will impact on teaching practice. Examples include the use of teaching and learning resources in a virtual learning environment (VLE) and the increasing use of blended learning. The paper then explores the need for both teachers and students to adapt to the new environment to ensure they can benefit to the maximum and that teaching and learning practices are changed accordingly.

  5. Spallation neutron source target station design, development, and commissioning

    International Nuclear Information System (INIS)

    Haines, J.R.; McManamy, T.J.; Gabriel, T.A.; Battle, R.E.; Chipley, K.K.; Crabtree, J.A.; Jacobs, L.L.; Lousteau, D.C.; Rennich, M.J.; Riemer, B.W.

    2014-01-01

    The spallation neutron source target station is designed to safely, reliably, and efficiently convert a 1 GeV beam of protons to a high flux of about 1 meV neutrons that are available at 24 neutron scattering instrument beam lines. Research and development findings, design requirements, design description, initial checkout testing, and results from early operation with beam are discussed for each of the primary target subsystems, including the mercury target, neutron moderators and reflector, surrounding vessels and shielding, utilities, remote handling equipment, and instrumentation and controls. Future plans for the mercury target development program are also briefly discussed

  6. Low enrichment Mo-99 target development program at ANSTO

    International Nuclear Information System (INIS)

    Donlevy, Therese M.; Anderson, Peter J.; Beattie, David; Braddock, Ben; Fulton, Scott; Godfrey, Robert; Law, Russell; McNiven, Scott; Sirkka, Pertti; Storr, Greg; Wassink, David; Wong, Alan; Yeoh, Guan

    2002-01-01

    The Australian Nuclear Science and Technology Organisation (ANSTO, formerly AAEC) has been producing fission product Mo-99 in HIFAR, from the irradiation of Low Enrichment Uranium (LEU) UO 2 targets, for nearly thirty years. Over this period, the U-235 enrichment has been increased in stages, from natural to 1.8% to 2.2%. The decision to provide Australia with a replacement research reactor (RRR) for HIFAR has created an ideal opportunity to review and improve the current Mo-99 production process from target design through to chemical processing and waste management options. ANSTO has entered into a collaboration with Argonne National Laboratory (RERTR) to develop a target using uranium metal foil with U-235 enrichment of less than 20% The initial focus has been to demonstrate use of LEU foil targets in HIFAR, using existing irradiation methodology. The current effort focussed on designing a target assembly with optimised thermohydraulic characteristics to accommodate larger LEU foils to meet Mo-99 production needs. The ultimate goal is to produce an LEU target suitable for use in the Replacement Research Reactor when it is commissioned in 2005. This paper reports our activities on: - The regulatory approval processes required in order to undertake irradiation of this new target; -Supporting calculations (neutronics, computational fluid dynamics) for safety submission; - Design challenges and changes to prototype irradiation; - Trial irradiation of LEU foil target in HIFAR; - Future target and rig development program at ANSTO. (author)

  7. Developing conservation targets in social-ecological systems

    Directory of Open Access Journals (Sweden)

    Phillip S. Levin

    2015-12-01

    Full Text Available The development of targets is foundational in conservation. Although progress has been made in setting targets, the diverse linkages among ecological and social components make target setting for coupled social-ecological systems extremely challenging. Developing integrated social-ecological targets is difficult because it forces policy makers to consider how management actions propagate throughout social-ecological systems, and because ultimately it is society, not scientists, that defines targets. We developed an interdisciplinary approach for identifying management targets and illustrate this approach using an example motivated by Puget Sound, USA. Our approach blends ecological modeling with empirical social science to articulate trade-offs and reveal societal preferences for different social-ecological states. The framework aims to place information in the hands of decision makers and promote discussion in the appropriate forums. Our ultimate objective is to encourage the informed participation of citizens in the development of social-ecological targets that reflect their values while also protecting key ecosystem attributes.

  8. Overview of Target Development for Next Generation Radioactive Beam Experiments

    Science.gov (United States)

    Nolen, Jerry

    2014-09-01

    With the increased intensities of radioactive ion beams at present and future facilities a wide variety of target technologies are being brought to bear for the experimental studies undertaken with these beams. For astrophysical reaction studies, classical thin foil targets are still going to be extensively used, mainly as hydrogen- or deuterium-rich plastics (or metals). But more complex target systems such as windowless gas jets, liquid or cryogenic solid targets are being developed. Cryogenic gas cells have also been employed though one must contend with issues relating to the windows used. Active targets usually integrated with time projection chambers are being used with rare beams for their high detection efficiency and also for low energy processes. In an active target, the gas acts as both a target and detector and allows for investigations of nuclear structure and transfer reactions with very high efficiency and at high resolution due to the thickness of the target. Polarized targets, in the form of gas-phase, foil, and crystal targets, are being used and further developed for use at rare isotope facilities. And finally, in heavy-element research, more exotic beams even at moderate intensities can be used with the standard 208Pb as well as exotic actinide targets to perhaps open previously unanticipated reaction channels for the production, chemistry, and spectroscopic studies of isotopes of the heaviest elements. For use with high quality secondary beams, very small samples of rare actinide isotopes in conjunction with high efficiency gamma ray detectors can be used for such research. This talk will be an overview to introduce the topics to be covered in detail in the contributions to this mini-symposium. Prepared in collaboration with John P. Greene, Physics Division, ANL. With the increased intensities of radioactive ion beams at present and future facilities a wide variety of target technologies are being brought to bear for the experimental studies

  9. Development of ion beam sputtering techniques for actinide target preparation

    International Nuclear Information System (INIS)

    Aaron, W.S.; Zevenbergen, L.A.; Adair, H.L.

    1985-01-01

    Ion beam sputtering is a routine method for the preparation of thin films used as targets because it allows the use of minimum quantity of starting material, and losses are much lower than most other vacuum deposition techniques. Work is underway in the Isotope Research Materials Laboratory (IRML) at ORNL to develop the techniques that will make the preparation of actinide targets up to 100 μg/cm 2 by ion beam sputtering a routinely available service from IRML. The preparation of the actinide material in a form suitable for sputtering is a key to this technique, as is designing a sputtering system that allows the flexibility required for custom-ordered target production. At present, development work is being conducted on low-activity in a bench-top system. The system will then be installed in a hood or glove box approved for radioactive materials handling where processing of radium, actinium, and plutonium isotopes among others will be performed. (orig.)

  10. Experimental methods in radioactive ion-beam target/ion source development and characterization

    International Nuclear Information System (INIS)

    Welton, R.F.; Alton, G.D.; Cui, B.; Murray, S.N.

    1998-01-01

    We have developed off-line experimental techniques and apparatuses that permit direct measurement of effusive-flow delay times and ionization efficiencies for nearly any chemically reactive element in high-temperature target/ion sources (TIS) commonly used for on-line radioactive ion-beam (RIB) generation. The apparatuses include a hot Ta valve for effusive-flow delay-time measurements, a cooled molecular injection system for determination of ionization efficiencies, and a gas flow measurement/control system for introducing very low, well-defined molecular flows into the TIS. Measurements are performed on a test stand using molecular feed compounds containing stable complements of the radioactive nuclei of interest delivered to the TIS at flow rates commensurate with on-line RIB generation. In this article, the general techniques are described and effusive-flow delay times and ionization efficiency measurements are reported for fluorine in an electron-beam plasma target/ion source developed for RIB generation and operated in both positive- and negative-ion extraction modes. copyright 1998 American Institute of Physics

  11. Formulation and development of colon-targeted mucopenetrating ...

    African Journals Online (AJOL)

    Purpose: To formulation and develop colon-targeted mucopenetrating metronidazole nanoparticles. Methods: Metronidazole-loaded chitosan nanoparticles with a pH-sensitive polymer, hydroxyl propyl methyl cellulose phthalate (HPMCP), were prepared by ionic gelation technique and then coated with Eudragit S100 by ...

  12. Development of Antibacterials Targeting the MEP Pathway of Select Agents

    Science.gov (United States)

    2015-03-01

    Yersinia pestis will serve as effective antibiotics by blocking isoprene biosynthesis . In strong support of this hypothesis, we have demonstrated the dose... antibiotic resistant strains and the ease by which antibiotic resistance can be engineered into bacteria further highlights the need for continued...development of novel antibiotics against new bacterial targets. This research project directly addresses this need through the development of a broad spectrum

  13. Developing targets for public health initiatives to improve palliative care

    Directory of Open Access Journals (Sweden)

    Klindtworth Katharina

    2010-04-01

    Full Text Available Abstract Background Palliative Care is an approach that improves quality of life for patients and their families facing the problems associated with incurable life-threatening illness. In many countries, due to the rapidly ageing population, increasingly more people are suffering from serious chronic disease towards the end of life, making further development in palliative care a major public health challenge. The aim of this study was to develop the first targets for public health initiatives to improve palliative care in Germany. Methods Based on the findings from pilot studies (qualitative interviews and surveys with different stakeholders in the health care system, we conducted a modified Delphi study with two rounds of questionnaires with experts in public health and palliative care. In the first round, the experts commented on the findings from the pilot studies. The answers were evaluated descriptively and with qualitative content analysis, resulting in the formulation of 25 targets. These were presented to the experts in the second Delphi round to assess each of them separately with regard to its importance and current implementation (7-point answer scales and in relation to the other targets (defining the five most important of the 25 targets. Results Six most relevant targets for public health initiatives to improve palliative care in Germany were worked out: Supporting palliative care as a basic attitude for the care of people in the last phase of life; coordinating healthcare for people in the last phase of life; establishing cooperation among health professions and disciplines; establishing education in palliative care for all professional groups with contact to people in the last phase of life; reviewing the evidence of palliative care measures; offering support to family members who are caring for someone in the last phase of life. Conclusions To systematically develop palliative care, it makes sense to define fields of action

  14. Developing targets for public health initiatives to improve palliative care.

    Science.gov (United States)

    Schneider, Nils; Lueckmann, Sara L; Kuehne, Franziska; Klindtworth, Katharina; Behmann, Mareike

    2010-04-29

    Palliative Care is an approach that improves quality of life for patients and their families facing the problems associated with incurable life-threatening illness. In many countries, due to the rapidly ageing population, increasingly more people are suffering from serious chronic disease towards the end of life, making further development in palliative care a major public health challenge. The aim of this study was to develop the first targets for public health initiatives to improve palliative care in Germany. Based on the findings from pilot studies (qualitative interviews and surveys with different stakeholders in the health care system), we conducted a modified Delphi study with two rounds of questionnaires with experts in public health and palliative care. In the first round, the experts commented on the findings from the pilot studies. The answers were evaluated descriptively and with qualitative content analysis, resulting in the formulation of 25 targets. These were presented to the experts in the second Delphi round to assess each of them separately with regard to its importance and current implementation (7-point answer scales) and in relation to the other targets (defining the five most important of the 25 targets). Six most relevant targets for public health initiatives to improve palliative care in Germany were worked out: Supporting palliative care as a basic attitude for the care of people in the last phase of life; coordinating healthcare for people in the last phase of life; establishing cooperation among health professions and disciplines; establishing education in palliative care for all professional groups with contact to people in the last phase of life; reviewing the evidence of palliative care measures; offering support to family members who are caring for someone in the last phase of life. To systematically develop palliative care, it makes sense to define fields of action with individual targets. For Germany, it can be recommended to give

  15. Nonstructural Proteins of Alphavirus—Potential Targets for Drug Development

    Directory of Open Access Journals (Sweden)

    Farhana Abu Bakar

    2018-02-01

    Full Text Available Alphaviruses are enveloped, positive single-stranded RNA viruses, typically transmitted by arthropods. They often cause arthralgia or encephalitic diseases in infected humans and there is currently no targeted antiviral treatment available. The re-emergence of alphaviruses in Asia, Europe, and the Americas over the last decade, including chikungunya and o’nyong’nyong viruses, have intensified the search for selective inhibitors. In this review, we highlight key molecular determinants within the alphavirus replication complex that have been identified as viral targets, focusing on their structure and functionality in viral dissemination. We also summarize recent structural data of these viral targets and discuss how these could serve as templates to facilitate structure-based drug design and development of small molecule inhibitors.

  16. Inertial Confinement Fusion Target Component Fabrication and Technology Development report

    International Nuclear Information System (INIS)

    Steinman, D.

    1994-03-01

    On December 30, 1990, the US Department of Energy entered into a contract with General Atomics (GA) to be the Inertial Confinement Fusion Target Component Fabrication and Technology Development Support contractor. This report documents the technical activities which took place under this contract during the period of October 1, 1992 through September 30, 1993. During this period, GA was assigned 18 tasks in support of the Inertial Confinement Fusion program and its laboratories. These tasks included ''Capabilities Activation'' and ''Capabilities Demonstration'' to enable us to begin production of glass and composite polymer capsules. Capsule delivery tasks included ''Small Glass Shell Deliveries'' and ''Composite Polymer Capsules'' for Lawrence Livermore National Laboratory (LLNL) and Los Alamos National Laboratory (LANL). We also were asked to provide direct ''Onsite Support'' at LLNL and LANL. We continued planning for the transfer of ''Micromachining Equipment from Rocky Flats'' and established ''Target Component Micromachining and Electroplating Facilities'' at GA. We fabricated over 1100 films and filters of 11 types for Sandia National Laboratory and provided full-time onsite engineering support for target fabrication and characterization. We initiated development of methods to make targets for the Naval Research Laboratory. We investigated spherical interferometry, built an automated capsule sorter, and developed an apparatus for calorimetric measurement of fuel fill for LLNL. We assisted LANL in the ''Characterization of Opaque b-Layered Targets.'' We developed deuterated and UV-opaque polymers for use by the University of Rochester's Laboratory for Laser Energetics (UR/LLE) and devised a triple-orifice droplet generator to demonstrate the controlled-mass nature of the microencapsulation process

  17. Recent advances in developing small molecules targeting RNA.

    Science.gov (United States)

    Guan, Lirui; Disney, Matthew D

    2012-01-20

    RNAs are underexploited targets for small molecule drugs or chemical probes of function. This may be due, in part, to a fundamental lack of understanding of the types of small molecules that bind RNA specifically and the types of RNA motifs that specifically bind small molecules. In this review, we describe recent advances in the development and design of small molecules that bind to RNA and modulate function that aim to fill this void.

  18. Targets downstream of Cdk8 in Dictyostelium development

    Directory of Open Access Journals (Sweden)

    Skelton Jason

    2011-01-01

    Full Text Available Abstract Background Cdk8 is a component of the mediator complex which facilitates transcription by RNA polymerase II and has been shown to play an important role in development of Dictyostelium discoideum. This eukaryote feeds as single cells but starvation triggers the formation of a multicellular organism in response to extracellular pulses of cAMP and the eventual generation of spores. Strains in which the gene encoding Cdk8 have been disrupted fail to form multicellular aggregates unless supplied with exogenous pulses of cAMP and later in development, cdk8- cells show a defect in spore production. Results Microarray analysis revealed that the cdk8- strain previously described (cdk8-HL contained genome duplications. Regeneration of the strain in a background lacking detectable gene duplication generated strains (cdk8-2 with identical defects in growth and early development, but a milder defect in spore generation, suggesting that the severity of this defect depends on the genetic background. The failure of cdk8- cells to aggregate unless rescued by exogenous pulses of cAMP is consistent with a failure to express the catalytic subunit of protein kinase A. However, overexpression of the gene encoding this protein was not sufficient to rescue the defect, suggesting that this is not the only important target for Cdk8 at this stage of development. Proteomic analysis revealed two potential targets for Cdk8 regulation, one regulated post-transcriptionally (4-hydroxyphenylpyruvate dioxygenase (HPD and one transcriptionally (short chain dehydrogenase/reductase (SDR1. Conclusions This analysis has confirmed the importance of Cdk8 at multiple stages of Dictyostelium development, although the severity of the defect in spore production depends on the genetic background. Potential targets of Cdk8-mediated gene regulation have been identified in Dictyostelium which will allow the mechanism of Cdk8 action and its role in development to be determined.

  19. Monitoring Water Targets in the Post-2015 Development Goals

    Science.gov (United States)

    Lawford, R. G.

    2015-12-01

    The Water Sustainable Development Goal (SDG) provides a comprehensive approach to developing water services in a way that ensures social equity, health, well-being and sustainability for all. In particular, the water goal includes targets related to sanitation, wastewater, water quality, water efficiency, integrated water management and ecosystems (details to be finalized in September 2015). As part of its implementation, methods to monitor target indicators must be developed. National governments will be responsible for reporting on progress toward these targets using national data sets and possibly information from global data sets that applies to their countries. Oversight of this process through the use of global data sets is desirable for encouraging the use of standardized information for comparison purposes. Disparities in monitoring due to very sparse data networks in some countries can be addressed by using geospatially consistent data products from space-based remote sensing. However, to fully exploit these data, capabilities will be needed to downscale information, to interpolate and assimilate data both in time and space, and to integrate these data with socio-economic data sets, model outputs and survey data in a geographical information system framework. Citizen data and other non-standard data types may also supplement national data systems. A comprehensive and integrated analysis and dissemination system is needed to enable the important contributions that satellites could make to achieving Water SDG targets. This presentation will outline the progress made in assessing the needs for information to track progress on the Water SDG, options for meeting these needs using existing data infrastructure, and pathways for expanding the role of Earth observations in SDG monitoring. It will also discuss the potential roles of Future Earth's Sustainable Water Futures Programme (SWFP) and the Group on Earth Observations (GEO) in coordinating these efforts.

  20. Ovarian and oocyte targets for development of female contraceptives.

    Science.gov (United States)

    Gupta, Satish Kumar; Malik, Ankita; Arukha, Ananta Prasad

    2015-01-01

    Steroid hormone-based contraceptives have been used by women for long time since their introduction. Efforts have been made to make steroidal contraceptives cost-effective, safe and improve their users' compliance. In addition, attempts have been made to develop nonsteroidal contraceptives. Contraceptive vaccines have been investigated as an alternate strategy for contraception. The currently used steroidal contraceptives are reviewed. In addition, status of emerging nonsteroidal contraceptives that inhibit folliculogenesis, oocyte maturation, ovulation and endometrium receptivity targeting phosphodiesterase 3, angiopoietins, gonadotropin-releasing hormone, COX-2, progesterone/estrogen receptor and follicle-stimulating hormone receptor are presented. Various approaches to develop contraceptive vaccines aiming to inhibit ovarian follicle development, ovulation, fertilization and implantation including their current applications and limitations are discussed. Development of new nonsteroidal contraceptives, in addition to long-acting steroidal contraceptives, is pertinent for offering wider choice to women. It is imperative that basic research to discover new targets in the ovaries must be undertaken to facilitate development of novel contraceptives. Further, efforts on studying the feasibility and safety of contraceptive vaccines may be continued to bring these within the realm of application as contraceptives for humans.

  1. Development of ion beam sputtering techniques for actinide target preparation

    Science.gov (United States)

    Aaron, W. S.; Zevenbergen, L. A.; Adair, H. L.

    1985-06-01

    Ion beam sputtering is a routine method for the preparation of thin films used as targets because it allows the use of a minimum quantity of starting material, and losses are much lower than most other vacuum deposition techniques. Work is underway in the Isotope Research Materials Laboratory (IRML) at ORNL to develop the techniques that will make the preparation of actinide targets up to 100 μg/cm 2 by ion beam sputtering a routinely available service from IRML. The preparation of the actinide material in a form suitable for sputtering is a key to this technique, as is designing a sputtering system that allows the flexibility required for custom-ordered target production. At present, development work is being conducted on low-activity actinides in a bench-top system. The system will then be installed in a hood or glove box approved for radioactive materials handling where processing of radium, actinium, and plutonium isotopes among others will be performed.

  2. Chinas carbon-intensity target: climate actors and policy developments

    Energy Technology Data Exchange (ETDEWEB)

    Stensdal, Iselin

    2012-11-01

    China has become the largest GHG emitting country, and announced in 2009 its first policy objective measured in carbon emissions. The carbon-intensity target is to reduce the carbon intensity by 40-45 % by 2020 compared to 200 levels. Since then there has been further policy developments in order to attain the reduction carbon intensity and steer China towards a low-carbon development. The 12th 5-year plan (2011-2015) is strong on incentives for reducing China's carbon intensity such as energy conservation measures and the establishment of new market-based mechanisms. While the central government forms the policies, the implementation is dependent on a range of actors. In addition to the climate change bureaucracy, the positive forces and actors on GHG mitigation is presented. All in all, there are promising developments in China for the years to come.(auth)

  3. Development of risperidone liposomes for brain targeting through intranasal route.

    Science.gov (United States)

    Narayan, Reema; Singh, Mohan; Ranjan, OmPrakash; Nayak, Yogendra; Garg, Sanjay; Shavi, Gopal V; Nayak, Usha Y

    2016-10-15

    The present paper is aimed at development of functionalized risperidone liposomes for brain targeting through nasal route for effective therapeutic management of schizophrenia. The risperidone liposomes were prepared by thin film hydration method. Various parameters such as lipid ratio and lipid to drug ratio were optimized by using Design-Expert(®) Software to obtain high entrapment with minimum vesicle size. The surface of the optimized liposomes was modified by coating stearylamine and MPEG-DSPE for enhanced penetration to the brain. The formulations were evaluated for vesicle size, zeta potential, and entrapment efficiency. The morphology was studied by Transmission Electron Microscopy (TEM). In vivo efficacy was assessed by performing pharmacokinetic study in Wistar albino rats following intranasal administration of the formulations in comparison to intravenous bolus administration of pure drug. The mean vesicle size of optimized liposomes ranged from 90 to 100nm with low polydispersity index (risperidone into the brain than plasma. High brain targeting efficiency index for LP-16 indicating preferential transport of the drug to brain. The study demonstrated successful formulation of surface modified risperidone liposomes for nasal delivery with brain targeting potential. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. Dihydroorotate dehydrogenase: A drug target for the development of antimalarials.

    Science.gov (United States)

    Singh, Anju; Maqbool, Mudasir; Mobashir, Mohammad; Hoda, Nasimul

    2017-01-05

    Malaria is a critical human disease with extensive exploration yet unestablished due to occurrence of frequent drug resistance. This aspect of malaria pharmacology calls for the introduction of new antimalarial. The drugs reported till date targeted different stages of the parasites in order to stop their growth and proliferation. Beside this, various drugs that could inhibit the imperative enzymes of the parasite have also been reported. Amid them, dihydroorotate dehydrogenase (DHODH) has a key worth. DHODH is involved in the de novo pyrimidine biosynthesis of the malarial parasite which acts as a primary source of energy for its survival. Since life of the parasite utterly depends on pyrimidine biosynthesis, so it can be used as an apt drug target for malaria eradication. In addition to this, DHODH is also present in human and their active sites have significant structural dissimilarities, so the development of selective inhibitors may prove to be a milestone in search of new antimalarials. Inhibitors of human DHODH have been used to treat autoimmune diseases such as, rheumatoid arthritis or multiple sclerosis and have been investigated in the treatment of cancer, viral diseases, as well as in plant pathology. Here, we have reviewed the important role of DHODH as a viable drug target against malaria, its importance for the survival of the parasite, and DHODH inhibitors reported so far. The rate of success of the reported DHODH inhibitors and further required improvements have also been accounted. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  5. Development of a cluster-jet target for PANDA

    International Nuclear Information System (INIS)

    Gruber, A.; Marton, J.; Widmann, E.; Zmeskal, J.; PANDA Cluster Jet Target Group

    2006-01-01

    Full text: The Stefan Meyer Institute (SMI) is part of the international PANDA collaboration. The universal detector will be constructed for the future high-energy antiproton storage ring HESR at FAIR (Facility for Antiproton and Ion Research, GSI/Darmstadt). PANDA will use antiproton beams (1.5 to 15 GeV/c) for hadron physics in the charmonium region. The physics program of PANDA will comprehend charmonium spectroscopy below and above open charm threshold, search for exotics (glueballs, hybrids), lambda and double-lambda hypernuclei studies and the investigation of in-medium modifications of charmed mesons - an experimentally unexplored field. SMI contributes to major parts of the PANDA detector like the hydrogen cluster-jet target and the antiproton - cluster jet interaction zone: in order to reach the desired target density, an optimization of the nozzle and the skimmer arrangement is essential. A density-profile monitor for the cluster-jet was designed and built at SMI. Several nozzle types have been studied using different gases, temperatures and inlet pressures. To ensure low background the residual gas load in the interaction zone has to be minimized. The installation of NEG (non-evaporative-getter) coated beam pipes is planned. A prototype of the interaction zone has been set up at SMI. The pumping capacity of NEG and the reactivation cycles were tested. The status of the development of the cluster-jet target and studies of the interaction region will be presented (author)

  6. Development and preparation of thin, supported targets and stripper foils

    International Nuclear Information System (INIS)

    Aaron, W.S.; Petek, M.; Zevenbergen, L.A.; Gibson, J.R.

    1989-01-01

    Usually, it is desirable to prepare thin films that are self-supporting so that any extraneous support materials will not interfere with experimental measurements. However, films with very low areal densities, films other than metals or films covering large areas may require the use of a backing or support. Two classes of supported thin films are being developed by the Isotope Research Materials Laboratory (IRML). Electrodeposition of oxide thin films is a fairly common target preparation technique that is usually performed on backings such as thin metal foils or low atomic number materials like Be and to a lesser extent, C foils. Techniques have been developed by IRML that result in electrodeposition of oxide films up to 500 μg/cm 2 on carbon foils or aluminized mylar. Electrodeposition is a very attractive target fabrication method since it is very efficient in the usage of rare and/or valuable isotopes. The ability to prepare these films on carbon or mylar foils provides a target that has, in most applications, far less interference resulting from the backing. Thin films of carbon, aluminum, boron and titanium are being used as stripper foils in the generation of neutral (H - →H 0 ) particle beams with energies of 50 MeV or greater. Neutralizer foils as large as 25 cm x 25 cm have been prepared from Al and C in thicknesses ranging from 5 to 12 μg/cm 2 that are mounted on thin nickel grids with a transmittance of approximately 90%. Significantly larger foils are currently under development. (orig.)

  7. Hedgehog pathway as a drug target: Smoothened inhibitors in development

    Directory of Open Access Journals (Sweden)

    Lin TL

    2012-03-01

    Full Text Available Tara L Lin1, William Matsui21Division of Hematology/Oncology, Department of Internal Medicine, University of Kansas, Kansas City, MO, USA; 2Division of Hematologic Malignancies, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USAAbstract: Emerging laboratory and clinical investigations demonstrate that Hedgehog signaling (Hh represents a novel therapeutic target in various human cancers. This conserved signaling pathway precisely regulates self-renewal and terminal differentiation in embryonic development, but is typically silenced in adult tissues, with reactivation usually only during tissue repair. Aberrant Hh pathway signaling has been implicated in the pathogenesis, self-renewal, and chemotherapy resistance of a growing number of solid and hematologic malignancies. Major components of the Hh pathway include the Hh ligands (Sonic, Desert, and Indian, the transmembrane receptor Patched, the signal transducer Smoothened (Smo, and transcription factors Gli1–3 which regulate the transcription of Hh target genes. Mutations in Hh pathway genes, increased Hh signaling in tumor stroma, and Hh overexpression in self-renewing cells (cancer stem cells have been described, and these different modes of Hh signaling have implications for the design of Hh pathway inhibitors and their integration into conventional treatment regimens. Discovery of a naturally-occurring Smo inhibitor, cyclopamine, and the identification of Hh pathway mutations and over expression in cancer cells prompted the development of several cyclopamine derivatives. Encouraging laboratory and in vivo data has resulted in Phase I and II clinical trials of Smo inhibitors. In this review, we will discuss the current understanding of Hh pathway signaling in malignancy and Smo antagonists in development. Recent data with these agents shows that they are well-tolerated and may be effective for subsets of patients. Challenges remain

  8. Hedgehog pathway as a drug target: Smoothened inhibitors in development.

    Science.gov (United States)

    Lin, Tara L; Matsui, William

    2012-01-01

    Emerging laboratory and clinical investigations demonstrate that Hedgehog signaling (Hh) represents a novel therapeutic target in various human cancers. This conserved signaling pathway precisely regulates self-renewal and terminal differentiation in embryonic development, but is typically silenced in adult tissues, with reactivation usually only during tissue repair. Aberrant Hh pathway signaling has been implicated in the pathogenesis, self-renewal, and chemotherapy resistance of a growing number of solid and hematologic malignancies. Major components of the Hh pathway include the Hh ligands (Sonic, Desert, and Indian), the transmembrane receptor Patched, the signal transducer Smoothened (Smo), and transcription factors Gli1-3 which regulate the transcription of Hh target genes. Mutations in Hh pathway genes, increased Hh signaling in tumor stroma, and Hh overexpression in self-renewing cells (cancer stem cells) have been described, and these different modes of Hh signaling have implications for the design of Hh pathway inhibitors and their integration into conventional treatment regimens. Discovery of a naturally-occurring Smo inhibitor, cyclopamine, and the identification of Hh pathway mutations and over expression in cancer cells prompted the development of several cyclopamine derivatives. Encouraging laboratory and in vivo data has resulted in Phase I and II clinical trials of Smo inhibitors. In this review, we will discuss the current understanding of Hh pathway signaling in malignancy and Smo antagonists in development. Recent data with these agents shows that they are well-tolerated and may be effective for subsets of patients. Challenges remain for appropriate patient selection and the optimal combination and sequence of these targeted therapies into current treatment paradigms.

  9. IAP proteins as targets for drug development in oncology

    Directory of Open Access Journals (Sweden)

    Dubrez L

    2013-09-01

    Full Text Available Laurence Dubrez,1,2 Jean Berthelet,1,2 Valérie Glorian,1,21Institut National de la Santé et de la Recherche Médicale (Inserm, Dijon, France; 2Université de Bourgogne, Dijon, FranceAbstract: The inhibitors of apoptosis (IAPs constitute a family of proteins involved in the regulation of various cellular processes, including cell death, immune and inflammatory responses, cell proliferation, cell differentiation, and cell motility. There is accumulating evidence supporting IAP-targeting in tumors: IAPs regulate various cellular processes that contribute to tumor development, such as cell death, cell proliferation, and cell migration; their expression is increased in a number of human tumor samples, and IAP overexpression has been correlated with tumor growth, and poor prognosis or low response to treatment; and IAP expression can be rapidly induced in response to chemotherapy or radiotherapy because of the presence of an internal ribosome entry site (IRES-dependent mechanism of translation initiation, which could contribute to resistance to antitumor therapy. The development of IAP antagonists is an important challenge and was subject to intense research over the past decade. Six molecules are currently in clinical trials. This review focuses on the role of IAPs in tumors and the development of IAP-targeting molecules for anticancer therapy.Keywords: Smac mimetics, apoptosis, antitumor therapy

  10. Peptide deformylase as an antibacterial drug target: target validation and resistance development.

    Science.gov (United States)

    Apfel, C M; Locher, H; Evers, S; Takács, B; Hubschwerlen, C; Pirson, W; Page, M G; Keck, W

    2001-04-01

    New inhibitors of peptide deformylase (PDF) which are very potent against the isolated enzyme and show a certain degree of antibacterial activity have recently been synthesized by our group. Several lines of experimental evidence indicate that these inhibitors indeed interfere with the target enzyme in the bacterial cell. (i) The inhibition of Escherichia coli growth could be counteracted by overexpression of PDF from different organisms, including E. coli, Streptococcus pneumoniae, and Haemophilus influenzae. Conversely, reduced expression of PDF in S. pneumoniae resulted in an increased susceptibility to the inhibitors. (ii) Proteome analysis on two-dimensional gels revealed a shift for many proteins towards lower pI in the presence of PDF inhibitors, as would be expected if the proteins still carry their N-formyl-Met terminus. (iii) PDF inhibitors show no antimicrobial activity against E. coli under conditions that make growth independent of formylation and deformylation. The antibacterial activity in E. coli was characterized as bacteriostatic. Furthermore, the development of resistance in E. coli was observed to occur with high frequency (10(-7)). Resistant mutants show a reduced growth rate, and DNA sequence analysis revealed mutations in their formyl transferase gene. Taking all these aspects into account, we conclude that PDF may not be an optimal target for broad-spectrum antibacterial agents.

  11. Developments in numerical simulation of IFE target and chamber physics

    International Nuclear Information System (INIS)

    Velarde, G.; Minguez, E.; Alonso, E.; Gil, J.M.; Malerba, L.; Marian, J.; Martel, P.; Martinez-Val, J.M.; Munoz, R.; Ogando, F.; Perlado, J.M.; Piera, M.; Reyes, S.; Rubiano, J.G.; Sanz, J.; Sauvan, P.; Velarde, M.; Velarde, P.

    2000-01-01

    The work presented outlines the global frame given at the Institute of Nuclear Fusion (DENIM) for having an integral perspective of the different research areas with the development of Inertial Fusion for energy generation. The coupling of a new radiation transport (RT) solver with an existing multi-material fluid dynamics code using Adaptive Mesh Refinement (ARM) is presented in Section 2, including improvements and additional information about the solver precision. In Section 3, new developments in the atomic physics codes under target conditions, to determine populations, opacity data and emissivities have been performed. Exotic and innovative ideas about Inertial Fusion Energy (IFE), as catalytic fuels and Z-pinches have been explored, and they are explained in Section 4. Numerical simulations demonstrate important reductions in the tritium inventory. Section 5 is devoted to safety and environment of the IFE. Uncertainties analysis in activation calculations have been included in the ACAB activation code, and also calculations on pulse activation in IFE reactors and on the activation of target debris in NIF are presented. A comparison of the accidental releases of tritium from some IFE reactors computed using MACCS2 code is explained. Finally, Section 6 contains the research on the basic mechanisms of neutron damage in SiC (low-activation material) and FeCu alloy using the DENIM/LLNL molecular dynamics code MDCASK. (authors)

  12. Targeting Villages for Rural Development Using Satellite Image Analysis.

    Science.gov (United States)

    Varshney, Kush R; Chen, George H; Abelson, Brian; Nowocin, Kendall; Sakhrani, Vivek; Xu, Ling; Spatocco, Brian L

    2015-03-01

    Satellite imagery is a form of big data that can be harnessed for many social good applications, especially those focusing on rural areas. In this article, we describe the common problem of selecting sites for and planning rural development activities as informed by remote sensing and satellite image analysis. Effective planning in poor rural areas benefits from information that is not available and is difficult to obtain at any appreciable scale by any means other than algorithms for estimation and inference from remotely sensed images. We discuss two cases in depth: the targeting of unconditional cash transfers to extremely poor villages in sub-Saharan Africa and the siting and planning of solar-powered microgrids in remote villages in India. From these cases, we draw out some common lessons broadly applicable to informed rural development.

  13. Development of target-tracking algorithms using neural network

    Energy Technology Data Exchange (ETDEWEB)

    Park, Dong Sun; Lee, Joon Whaoan; Yoon, Sook; Baek, Seong Hyun; Lee, Myung Jae [Chonbuk National University, Chonjoo (Korea)

    1998-04-01

    The utilization of remote-control robot system in atomic power plants or nuclear-related facilities grows rapidly, to protect workers form high radiation environments. Such applications require complete stability of the robot system, so that precisely tracking the robot is essential for the whole system. This research is to accomplish the goal by developing appropriate algorithms for remote-control robot systems. A neural network tracking system is designed and experimented to trace a robot Endpoint. This model is aimed to utilized the excellent capabilities of neural networks; nonlinear mapping between inputs and outputs, learning capability, and generalization capability. The neural tracker consists of two networks for position detection and prediction. Tracking algorithms are developed and experimented for the two models. Results of the experiments show that both models are promising as real-time target-tracking systems for remote-control robot systems. (author). 10 refs., 47 figs.

  14. PCSK9: Regulation and Target for Drug Development for Dyslipidemia.

    Science.gov (United States)

    Burke, Amy C; Dron, Jacqueline S; Hegele, Robert A; Huff, Murray W

    2017-01-06

    Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a secreted zymogen expressed primarily in the liver. PCSK9 circulates in plasma, binds to cell surface low-density lipoprotein (LDL) receptors, is internalized, and then targets the receptors to lysosomal degradation. Studies of naturally occurring PCSK9 gene variants that caused extreme plasma LDL cholesterol (LDL-C) deviations and altered atherosclerosis risk unleashed a torrent of biological and pharmacological research. Rapid progress in understanding the physiological regulation of PCSK9 was soon translated into commercially available biological inhibitors of PCSK9 that reduced LDL-C levels and likely also cardiovascular outcomes. Here we review the swift evolution of PCSK9 from novel gene to drug target, to animal and human testing, and finally to outcome trials and clinical applications. In addition, we explore how the genetics-guided path to PCSK9 inhibitor development exemplifies a new paradigm in pharmacology. Finally, we consider some potential challenges as PCSK9 inhibition becomes established in the clinic.

  15. Cdc7 kinase - a new target for drug development.

    Science.gov (United States)

    Swords, Ronan; Mahalingam, Devalingam; O'Dwyer, Michael; Santocanale, Corrado; Kelly, Kevin; Carew, Jennifer; Giles, Francis

    2010-01-01

    The cell division cycle 7 (Cdc7) is a serine threonine kinase that is of critical importance in the regulation of normal cell cycle progression. Cdc7 kinase is highly conserved during evolution and much has been learned about its biological roles in humans through the study of lower eukaryotes, particularly yeasts. Two important regulator proteins, Dbf4 and Drf1, bind to and modulate the kinase activity of human Cdc7 which phosphorylates several sites on Mcm2 (minichromosome maintenance protein 2), one of the six subunits of the replicative DNA helicase needed for duplication of the genome. Through regulation of both DNA synthesis and DNA damage response, both key functions in the survival of tumour cells, Cdc7 becomes an attractive target for pharmacological inhibition. There are much data available on the pre-clinical anti-cancer effects of Cdc7 depletion and although there are no available Cdc7 inhibitors in clinical trials as yet, several lead compounds are being optimised for this purpose. In this review, we will address the current status of Cdc7 as an important target for new drug development.

  16. The Pim kinases: new targets for drug development.

    Science.gov (United States)

    Swords, Ronan; Kelly, Kevin; Carew, Jennifer; Nawrocki, Stefan; Mahalingam, Devalingam; Sarantopoulos, John; Bearss, David; Giles, Francis

    2011-12-01

    The three Pim kinases are a small family of serine/threonine kinases regulating several signaling pathways that are fundamental to cancer development and progression. They were first recognized as pro-viral integration sites for the Moloney Murine Leukemia virus. Unlike other kinases, they possess a hinge region which creates a unique binding pocket for ATP. Absence of a regulatory domain means that these proteins are constitutively active once transcribed. Pim kinases are critical downstream effectors of the ABL (ableson), JAK2 (janus kinase 2), and Flt-3 (FMS related tyrosine kinase 1) oncogenes and are required by them to drive tumorigenesis. Recent investigations have established that the Pim kinases function as effective inhibitors of apoptosis and when overexpressed, produce resistance to the mTOR (mammalian target of rapamycin) inhibitor, rapamycin . Overexpression of the PIM kinases has been reported in several hematological and solid tumors (PIM 1), myeloma, lymphoma, leukemia (PIM 2) and adenocarcinomas (PIM 3). As such, the Pim kinases are a very attractive target for pharmacological inhibition in cancer therapy. Novel small molecule inhibitors of the human Pim kinases have been designed and are currently undergoing preclinical evaluation.

  17. Autophagy as a target for cancer therapy: new developments

    International Nuclear Information System (INIS)

    Carew, Jennifer S; Kelly, Kevin R; Nawrocki, Steffan T

    2012-01-01

    Autophagy is an evolutionarily conserved lysosomal degradation pathway that eliminates cytosolic proteins, macromolecules, organelles, and protein aggregates. Activation of autophagy may function as a tumor suppressor by degrading defective organelles and other cellular components. However, this pathway may also be exploited by cancer cells to generate nutrients and energy during periods of starvation, hypoxia, and stress induced by chemotherapy. Therefore, induction of autophagy has emerged as a drug resistance mechanism that promotes cancer cell survival via self-digestion. Numerous preclinical studies have demonstrated that inhibition of autophagy enhances the activity of a broad array of anticancer agents. Thus, targeting autophagy may be a global anticancer strategy that may improve the efficacy of many standard of care agents. These results have led to multiple clinical trials to evaluate autophagy inhibition in combination with conventional chemotherapy. In this review, we summarize the anticancer agents that have been reported to modulate autophagy and discuss new developments in autophagy inhibition as an anticancer strategy

  18. Targeted p120-catenin ablation disrupts dental enamel development.

    Directory of Open Access Journals (Sweden)

    John D Bartlett

    2010-09-01

    Full Text Available Dental enamel development occurs in stages. The ameloblast cell layer is adjacent to, and is responsible for, enamel formation. When rodent pre-ameloblasts become tall columnar secretory-stage ameloblasts, they secrete enamel matrix proteins, and the ameloblasts start moving in rows that slide by one another. This movement is necessary to form the characteristic decussating enamel prism pattern. Thus, a dynamic system of intercellular interactions is required for proper enamel development. Cadherins are components of the adherens junction (AJ, and they span the cell membrane to mediate attachment to adjacent cells. p120 stabilizes cadherins by preventing their internalization and degradation. So, we asked if p120-mediated cadherin stability is important for dental enamel formation. Targeted p120 ablation in the mouse enamel organ had a striking effect. Secretory stage ameloblasts detached from surrounding tissues, lost polarity, flattened, and ameloblast E- and N-cadherin expression became undetectable by immunostaining. The enamel itself was poorly mineralized and appeared to be composed of a thin layer of merged spheres that abraded from the tooth. Significantly, p120 mosaic mouse teeth were capable of forming normal enamel demonstrating that the enamel defects were not a secondary effect of p120 ablation. Surprisingly, blood-filled sinusoids developed in random locations around the developing teeth. This has not been observed in other p120-ablated tissues and may be due to altered p120-mediated cell signaling. These data reveal a critical role for p120 in tooth and dental enamel development and are consistent with p120 directing the attachment and detachment of the secretory stage ameloblasts as they move in rows.

  19. Development of annular targets for 99MO production-1999

    International Nuclear Information System (INIS)

    Conner, C.; Lewandowski, E. F.; Snelgrove, J. L.; Liberatore, M. W.; Walker, D. E.; Wiencek, T. C.; McGann, D. J.; Hofman, G. L.; Vandegrift, G. F.

    1999-01-01

    The new annular target performed well during irradiation. The target is inexpensive and provides good heat transfer during irradiation. Based on these and previous tests, we conclude that targets with zirconium tubes and either nickel-plated or zinc-plated foils work well. We proved that we could use aluminum target tubes, which are much cheaper and easier to work with than the zirconium tubes. In aluminum target tubes nickel-plated fission-recoil barriers work well and prevent bonding of the foil to the new target tubes during irradiation. Also, zinc-plated and aluminum-foil barriers appear promising in anodized aluminum tubes. Additional tests are anticipated to address such issues as fission-recoil barrier thickness and uranium foil composition. Overall, however, the target was successful and will provide an inexpensive, efficient way to irradiate LEU metal foil for the production of 99 Mo

  20. Prospects for developing new antibacterials targeting bacterial type IIA topoisomerases.

    Science.gov (United States)

    Tomašić, Tihomir; Mašič, Lucija Peterlin

    2014-01-01

    The modulation of DNA topology by DNA gyrase and topoisomerase IV, both of which are type IIA topoisomerases and found in most bacteria, is a function vital to DNA replication, repair and decatenation. Despite the potential for resistance development, DNA gyrase and/or topoisomerase IV have been proven to be and remain highly attractive targets in antibacterial drug discovery due to their potential for dual targeting. The search for new GyrA and/or ParC inhibitors that can overcome the increasing spread of multidrug-resistant bacteria has been successfully focused in the last decades on the modification of the known fluoroquinolone scaffold as primarily guided by ligand-based design via classical structure-activity relationship studies and the optimisation of physicochemical properties. This focus has resulted in several novel fluoroquinolones that have been introduced into clinical practice since 2000, and several of these new compounds are currently in different phases of clinical trials. Due to increasing resistance to fluoroquinolones, a significant part of DNA gyrase research has shifted to the discovery of new GyrB and/or ParE inhibitors, which are commonly identified through fragment-based design as well as virtual screening techniques and structure-based hit optimisation programs. This research often results in lead compounds with potent inhibitory activity and promising antibacterial activity profiles. Nevertheless, it is important to understand how different physicochemical properties (e.g., logD and total polar surface area) and different structural motifs influence the compounds' permeability to ensure the efficient discovery of potent, small-molecule antibacterials particularly against Gram-negative strains.

  1. Development of a cryogenic target system for the FOREST experiments

    International Nuclear Information System (INIS)

    Hashimoto, R.; Fujimura, H.; Ishikawa, T.; Kasagi, J.; Kuwasaki, S.; Sato, M.; Yamazaki, H.; Shimizu, H.; Kanda, H.

    2009-01-01

    A new cryogenic target production system for a 4π γ-ray detector FOREST has been installed in the GeV-γ experimental hall. The achieving temperature at the target is 4.5 K. It can maintain solid or liquid H 2 /D 2 . The target system enables us to make up solid or liquid hydrogen in a short time ∼2 hours after 3 hour-precooling. (author)

  2. Targeting DNA repair systems in antitubercular drug development.

    Science.gov (United States)

    Minias, Alina; Brzostek, Anna; Dziadek, Jaroslaw

    2018-01-28

    Infections with Mycobacterium tuberculosis, the causative agent of tuberculosis, are difficult to treat using currently available chemotherapeutics. Clinicians agree on the urgent need for novel drugs to treat tuberculosis. In this mini review, we summarize data that prompts the consideration of DNA repair-associated proteins as targets for the development of new antitubercular compounds. We discuss data, including gene expression data, that highlight the importance of DNA repair genes during the pathogenic cycle as well as after exposure to antimicrobials currently in use. Specifically, we report experiments on determining the essentiality of DNA repair-related genes. We report the availability of protein crystal structures and summarize discovered protein inhibitors. Further, we describe phenotypes of available gene mutants of M. tuberculosis and model organisms Mycobacterium bovis and Mycobacterium smegmatis. We summarize experiments regarding the role of DNA repair-related proteins in pathogenesis and virulence performed both in vitro and in vivo during the infection of macrophages and animals. We detail the role of DNA repair genes in acquiring mutations, which influence the rate of drug resistance acquisition. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  3. 100-B/C Target Analyte List Development for Soil

    Energy Technology Data Exchange (ETDEWEB)

    R.W. Ovink

    2010-03-18

    This report documents the process used to identify source area target analytes in support of the 100-B/C remedial investigation/feasibility study addendum to DOE/RL-2008-46. This report also establishes the analyte exclusion criteria applicable for 100-B/C use and the analytical methods needed to analyze the target analytes.

  4. International Nuclear Target Development Society workshop 1983: proceedings

    Energy Technology Data Exchange (ETDEWEB)

    Thomas, G. (ed.)

    1983-01-01

    Separate abstracts were prepared for 11 of the 19 papers presented. Eight papers were previously included in the data base. Discussion group session papers on carbon stripper foils, problems in producing heavy-ion targets, and problems in producing general type targets are included. (WHK)

  5. International Nuclear Target Development Society workshop 1983: proceedings

    International Nuclear Information System (INIS)

    Thomas, G.

    1983-01-01

    Separate abstracts were prepared for 11 of the 19 papers presented. Eight papers were previously included in the data base. Discussion group session papers on carbon stripper foils, problems in producing heavy-ion targets, and problems in producing general type targets are included

  6. Future technological developments to fulfill AG2020 targets

    DEFF Research Database (Denmark)

    Markussen, Mads Ville; Østergård, Hanne; Borch, Kristian

    2010-01-01

    . Based on the technological narratives and imperatives, we select a set of present available technologies that are able to support the society in reaching the targets set up by AG2020. For each of these technologies, we evaluate the strengths and weaknesses of the technology to reach the target as well...

  7. Research and development on materials for the SPES target

    Science.gov (United States)

    Corradetti, Stefano; Andrighetto, Alberto; Manzolaro, Mattia; Scarpa, Daniele; Vasquez, Jesus; Rossignoli, Massimo; Monetti, Alberto; Calderolla, Michele; Prete, Gianfranco

    2014-03-01

    The SPES project at INFN-LNL (Istituto Nazionale di Fisica Nucleare - Laboratori Nazionali di Legnaro) is focused on the production of radioactive ion beams. The core of the SPES facility is constituted by the target, which will be irradiated with a 40 MeV, 200 µA proton beam in order to produce radioactive species. In order to efficiently produce and release isotopes, the material constituting the target should be able to work under extreme conditions (high vacuum and temperatures up to 2000 °C). Both neutron-rich and proton-rich isotopes will be produced; in the first case, carbon dispersed uranium carbide (UCx) will be used as a target, whereas to produce p-rich isotopes, several types of targets will have to be irradiated. The synthesis and characterization of different types of material will be reported. Moreover, the results of irradiation and isotopes release tests on different uranium carbide target prototypes will be discussed.

  8. Development of a higher power cooling system for lithium targets.

    Science.gov (United States)

    Phoenix, B; Green, S; Scott, M C; Bennett, J R J; Edgecock, T R

    2015-12-01

    The accelerator based Boron Neutron Capture Therapy beam at the University of Birmingham is based around a solid thick lithium target cooled by heavy water. Significant upgrades to Birmingham's Dynamitron accelerator are planned prior to commencing a clinical trial. These upgrades will result in an increase in maximum achievable beam current to at least 3 mA. Various upgrades to the target cooling system to cope with this increased power have been investigated. Tests of a phase change coolant known as "binary ice" have been carried out using an induction heater to provide a comparable power input to the Dynamitron beam. The experimental data shows no improvement over chilled water in the submerged jet system, with both systems exhibiting the same heat input to target temperature relation for a given flow rate. The relationship between the cooling circuit pumping rate and the target temperature in the submerged jet system has also been tested. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. Development and evaluation of vinpocetine inclusion complex for brain targeting

    OpenAIRE

    Jiaojiao Ding; Jinfeng Li; Shirui Mao

    2015-01-01

    The objective of this paper is to prepare vinpocetine (VIN) inclusion complex and evaluate its brain targeting effect after intranasal administration. In the present study, VIN inclusion complex was prepared in order to increase its solubility. Stability constant (Kc) was used for host selection. Factors influencing properties of the inclusion complex was investigated. Formation of the inclusion complex was identified by solubility study and DSC analysis. The brain targeting effect of the com...

  10. Research and development on materials for the SPES target

    Directory of Open Access Journals (Sweden)

    Corradetti Stefano

    2014-03-01

    Full Text Available The SPES project at INFN-LNL (Istituto Nazionale di Fisica Nucleare - Laboratori Nazionali di Legnaro is focused on the production of radioactive ion beams. The core of the SPES facility is constituted by the target, which will be irradiated with a 40 MeV, 200 µA proton beam in order to produce radioactive species. In order to efficiently produce and release isotopes, the material constituting the target should be able to work under extreme conditions (high vacuum and temperatures up to 2000 °C. Both neutron-rich and proton-rich isotopes will be produced; in the first case, carbon dispersed uranium carbide (UCx will be used as a target, whereas to produce p-rich isotopes, several types of targets will have to be irradiated. The synthesis and characterization of different types of material will be reported. Moreover, the results of irradiation and isotopes release tests on different uranium carbide target prototypes will be discussed.

  11. A Holistic In silico Approach to Develop Novel Inhibitors Targeting ...

    African Journals Online (AJOL)

    Purpose: To design a dual inhibitor of natural origin capable of targeting ErbB1 and ErbB2 kinases for the treatment of lung cancer. Method: Advanced In silico drug designing techniques were explored in this study. Sequence and structure analysis of ErbB1 and ErbB2 was followed by three dimensional (3D) ...

  12. Meeting the Kyoto Targets : the importance of developing country participation

    NARCIS (Netherlands)

    Zhang, Zhong Xiang

    2000-01-01

    This paper investigates the implications of progressively broadening the scope of the market of tradable permits from no emissions trading to full global trading. We start with the no emissions trading case where each Annex I country must individually meet its Kyoto targets. Next, we consider a case

  13. Efficient Fourier based Algorithm Development for Airborne Moving Target Indication

    NARCIS (Netherlands)

    Lidicky, L.; Hoogeboom, P.

    2009-01-01

    This paper shows how the signal model that is commonly used as a starting point in multi-channel Space Time Adaptive Processing (STAP) for airborne Moving Target Indication (MTI) formally corresponds to a model that can be derived from a bi-static Synthetic Aperture Radar (SAR) model extended for

  14. 100-K Target Analyte List Development for Soil

    Energy Technology Data Exchange (ETDEWEB)

    Ovink, R.

    2012-09-18

    This report documents the process used to identify source area target analytes in support of the 100-K Area remedial investigation/feasibility study (RI/FS) addendum to the Integrated 100 Area Remedial Investigation/Feasibility Study Work Plan (DOE/RL-2008-46, Rev. 0).

  15. 100-F Target Analyte List Development for Soil

    Energy Technology Data Exchange (ETDEWEB)

    Ovink, R.

    2012-09-18

    This report documents the process used to identify source area target analytes in support of the 100-F Area remedial investigation/feasibility study (RI/FS) addendum to the Integrated 100 Area Remedial Investigation/Feasibility Study Work Plan (DOE/RL-2008-46, Rev. 0).

  16. Identifying the Right Disease Targets to Develop Better Drugs, Faster | NIH MedlinePlus the Magazine

    Science.gov (United States)

    ... this page please turn JavaScript on. Identifying the Right Disease Targets to Develop Better Drugs, Faster Past ... reason is that we're not selecting the right biological changes to target from the start. How ...

  17. Modeling to Support the Development of Habitat Targets for Piping Plovers on the Missouri River

    Energy Technology Data Exchange (ETDEWEB)

    Buenau, Kate E. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States)

    2015-05-05

    Report on modeling and analyses done in support of developing quantative sandbar habitat targets for piping plovers, including assessment of reference, historical, dams present but not operated, and habitat construction calibrated to meet population viability targets.

  18. Developing Targeted Hybrid Imaging Probes by Chelator Scaffolding.

    Science.gov (United States)

    Summer, Dominik; Grossrubatscher, Leo; Petrik, Milos; Michalcikova, Tereza; Novy, Zbynek; Rangger, Christine; Klingler, Maximilian; Haas, Hubertus; Kaeopookum, Piriya; von Guggenberg, Elisabeth; Haubner, Roland; Decristoforo, Clemens

    2017-06-21

    Positron emission tomography (PET) as well as optical imaging (OI) with peptide receptor targeting probes have proven their value for oncological applications but also show restrictions depending on the clinical field of interest. Therefore, the combination of both methods, particularly in a single molecule, could improve versatility in clinical routine. This proof of principle study aims to show that a chelator, Fusarinine C (FSC), can be utilized as scaffold for novel dimeric dual-modality imaging agents. Two targeting vectors (a minigastrin analogue (MG11) targeting cholecystokinin-2 receptor overexpression (CCK2R) or integrin α V β 3 targeting cyclic pentapeptides (RGD)) and a near-infrared fluorophore (Sulfo-Cyanine7) were conjugated to FSC. The probes were efficiently labeled with gallium-68 and in vitro experiments including determination of logD, stability, protein binding, cell binding, internalization, and biodistribution studies as well as in vivo micro-PET/CT and optical imaging in U-87MG α V β 3 - and A431-CCK2R expressing tumor xenografted mice were carried out. Novel bioconjugates showed high receptor affinity and highly specific targeting properties at both receptors. Ex vivo biodistribution and micro-PET/CT imaging studies revealed specific tumor uptake accompanied by slow blood clearance and retention in nontargeted tissues (spleen, liver, and kidneys) leading to visualization of tumors at early (30 to 120 min p.i.). Excellent contrast in corresponding optical imaging studies was achieved especially at delayed time points (24 to 72 h p.i.). Our findings show the proof of principle of chelator scaffolding for hybrid imaging agents and demonstrate FSC being a suitable bifunctional chelator for this approach. Improvements to fine-tune pharmacokinetics are needed to translate this into a clinical setting.

  19. Development of a cluster-jet target for PANDA

    International Nuclear Information System (INIS)

    Gruber, A.; Marton, J.; Widmann, E.; Zmeskal, J.; Orth, H.; Luehning, J.

    2008-01-01

    Full text: The Stefan Meyer Institut (SMI) is part of the international PANDA collaboration. The universal detector will be constructed at the future high-energy antiproton storage ring HESR at FAIR (Facility for Antiproton and Ion Research, GSI/Darmstadt). PANDA will use antiproton beams (1.5 to 15 GeV/c) for hadron physics in the charmonium region. The physics program of PANDA will encompass charmonium spectroscopy below and above open charm threshold, search for exotics (glueballs, hybrids), lambda and double-lambda hypernuclei studies and the investigation of in-medium modifications of charmed mesons - an experimentally unexplored field. SMI contributes to major parts of the PANDA detector like the hydrogen cluster-jet target and the vacuum system of the antiproton - target interaction zone. In order to reach the desired target density, an optimization of the cold head, the nozzle and the skimmer arrangement is essential. A density-profile monitor for the cluster-jet was designed and built at SMI. Several nozzle types will be studied using different gases, temperatures and inlet pressures. Additionally we, together with the cluster-jet target group at GSI, are carrying out R and D for improving the jet-density. The Genova/Fermilab cluster-jet target used for these measurements has been in use at Fermilab for the experiments E760 and E835 and has been transferred to GSI for this purpose. The setup of the density-profile monitor at SMI and several measurements at GSI will be presented. (author)

  20. Development of AN Active 238UF6 Gas Target

    Science.gov (United States)

    Eckardt, C.; Enders, J.; Freudenberger, M.; Göök, A.; von Neumann-Cosel, P.; Oberstedt, A.; Oberstedt, S.

    2014-09-01

    Detailed studies of the fission process, e.g., the search for parity nonconservation (PNC) effects, the energy dependence of fission modes or the population of fission isomers, depend on high quality data, therefore requiring high luminosities. An active gas target containing uranium may overcome the deterioration of energy and angular resolution caused by large solid target thicknesses. A single Frisch-grid ionization chamber has been built to test a mixture of standard counting gases (e.g., argon) with depleted uranium hexafluoride (238UF6), utilizing a triple alpha source to evaluate signal quality and drift velocity. For mass fractions of up to 4 percent of 238U the drift velocity increases with rising UF6 content, while a good signal quality and energy resolution is preserved.

  1. Changes of acoustic target strength during juvenile perch development

    Czech Academy of Sciences Publication Activity Database

    Frouzová, Jaroslava; Kubečka, Jan

    2004-01-01

    Roč. 66, 2-3 (2004), s. 355-361 ISSN 0165-7836 R&D Projects: GA AV ČR(CZ) KSK6005114; GA AV ČR(CZ) KSK3046108; GA AV ČR(CZ) IAA6017901; GA AV ČR(CZ) IAA6017801 Keywords : perch * larvae * target strength Subject RIV: BI - Acoustics Impact factor: 0.932, year: 2004

  2. Development of optical-pumping polarized deuteron target

    International Nuclear Information System (INIS)

    Tamae, Tadaaki; Yokokawa, Tamio; Nishikawa, Itaru; Abe, Kazuhiro; Konno, Osamu; Nakagawa, Itaru; Sugawara, Masumi; Tanaka, Eiji; Yamaguchi, Nobuo; Yamazaki, Hirohito; Miyase, Haruhisa; Tsubota, Hiroaki

    1998-01-01

    An optical-pumping system of rubidium atoms for a laser-driven polarized deuteron target was constructed. The density and polarization of the rubidium atoms were measured using Faraday rotation. The rotation angle was determined within an error of 0.01 deg. Our preliminary result showed a polarization of 0.4 at a gas thickness of 4x10 13 atoms/cm 2

  3. Hedgehog pathway as a drug target: Smoothened inhibitors in development

    OpenAIRE

    Lin, Tara; Matsui,William

    2012-01-01

    Tara L Lin1, William Matsui21Division of Hematology/Oncology, Department of Internal Medicine, University of Kansas, Kansas City, MO, USA; 2Division of Hematologic Malignancies, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USAAbstract: Emerging laboratory and clinical investigations demonstrate that Hedgehog signaling (Hh) represents a novel therapeutic target in various human cancers. This conserved signaling pathway precisely reg...

  4. Targeting autophagy in cancer management – strategies and developments

    International Nuclear Information System (INIS)

    Ozpolat, Bulent; Benbrook, Doris M

    2015-01-01

    Autophagy is a highly regulated catabolic process involving lysosomal degradation of intracellular components, damaged organelles, misfolded proteins, and toxic aggregates, reducing oxidative stress and protecting cells from damage. The process is also induced in response to various conditions, including nutrient deprivation, metabolic stress, hypoxia, anticancer therapeutics, and radiation therapy to adapt cellular conditions for survival. Autophagy can function as a tumor suppressor mechanism in normal cells and dysregulation of this process (ie, monoallelic Beclin-1 deletion) may lead to malignant transformation and carcinogenesis. In tumors, autophagy is thought to promote tumor growth and progression by helping cells to adapt and survive in metabolically-challenged and harsh tumor microenvironments (ie, hypoxia and acidity). Recent in vitro and in vivo studies in preclinical models suggested that modulation of autophagy can be used as a therapeutic modality to enhance the efficacy of conventional therapies, including chemo and radiation therapy. Currently, more than 30 clinical trials are investigating the effects of autophagy inhibition in combination with cytotoxic chemotherapies and targeted agents in various cancers. In this review, we will discuss the role, molecular mechanism, and regulation of autophagy, while targeting this process as a novel therapeutic modality, in various cancers

  5. Exploiting mitochondria as targets for the development of new antifungals.

    Science.gov (United States)

    Li, Dongmei; Calderone, Richard

    2017-02-17

    Mitochondria are essential for cell growth and survival of most fungal pathogens. Energy (ATP) produced during oxidation/reduction reactions of the electron transport chain (ETC) Complexes I, III and IV (CI, CIII, CIV) fuel cell synthesis. The mitochondria of fungal pathogens are understudied even though more recent published data suggest critical functional assignments to fungal-specific proteins. Proteins of mammalian mitochondria are grouped into 16 functional categories. In this review, we focus upon 11 proteins from 5 of these categories in fungal pathogens, OXPHOS, protein import, stress response, carbon source metabolism, and fission/fusion morphology. As these proteins also are fungal-specific, we hypothesize that they may be exploited as targets in antifungal drug discovery. We also discuss published transcriptional profiling data of mitochondrial CI subunit protein mutants, in which we advance a novel concept those CI subunit proteins have both shared as well as specific responsibilities for providing ATP to cell processes.

  6. Optimizing target selection and development strategy in cancer treatment: the next wave.

    Science.gov (United States)

    Sausville, Edward A

    2004-09-01

    Successful cancer treatments of the future are being developed with a focus on the molecular targets underlying the pathophysiology of neoplasia. Prominent targets which have emerged are those which are mutated in the course of a cancer's development, and mediate activation or release from suppression of pathways mediating proliferation or apoptosis. These arguably are "pathogenic" targets. However, equally important are targets which can be defined on the basis of "large scale" analysis techniques of gene or protein expression in tumors which define targets expressed as a result of a tumor's differentiation state or tissue of origin ("ontogenic" targets); targets mediating drug uptake or metabolism ("pharmacologic" targets), and "microenvironmental" targets mediating the alteration of tumor stromal elements. Irrespective of the nature of the molecular target which is the focus of new therapeutic efforts, target definition in susceptible tumors or patients ideally would be part of the development plan. In addition, an understanding of the therapeutic index which might be achieved in host vs tumor tissues using a surrogate or actual marker of drug effect ideally would be available from animal models and inform the development strategy in humans.

  7. The Cellular Targets of Estrogen in Mammary Ductal Development

    National Research Council Canada - National Science Library

    Kushner, Peter

    2002-01-01

    ...) or with alternative response elements, especially AP-i and CRE elements, mediate proliferation. We have been successful in developing transgenic mice with expression of wild type and AP-1/CRE superactive human ER alpha (K206A...

  8. A drug target that stimulates development of healthy stem cells

    Science.gov (United States)

    Scientists have overcome a major impediment to the development of effective stem cell therapies by studying mice that lack CD47, a protein found on the surface of both healthy and cancer cells. They discovered that cells obtained from the lungs of CD47-de

  9. Molecular target in oncology. Opportunity for radiopharmaceuticals development

    International Nuclear Information System (INIS)

    Navarro Marques, Fabio Luiz

    2016-01-01

    Cancer is a cellular multifactorial disease, regulated by changes in phenotype characteristics, such as adhesion, invasion, migration, and tumorigenesis; genotypic status of commonly altered genes (KRAS and p53); microenvironmental conditions, such pH, oxygen and nutrient supply. All these features provide opportunities for radiopharmaceuticals development, both for diagnostic and therapy. For both applications, radiopharmaceuticals molecules can be divided in small synthetic molecules, small peptides (natural or modified), large molecules such as antibody or nanoparticles. The characteristics of those molecules and use will guide the choice of the radionuclide to be used for labeling it. In the presentation, data from literature and research ongoing in the Faculty of Medicine of the University of São Paulo/Brazil will be used for demonstrate the potential for radiopharmaceuticals development. (author)

  10. Trees, poverty and targets: Forests and the Millennium Development Goals

    Energy Technology Data Exchange (ETDEWEB)

    Myers, James

    2007-04-15

    Where are the forests in the MDGs? When players in the forestry world get together they are good at setting goals. They are a good match for the political leaders that gave us the Millennium Development Goals (MDGs). Since the 1980s there has been a proliferation of international dialogues dealing with forests and, a bit like the football World Cup, every four years or so they come up with a feast of goals. If forestry goals were all we needed to make progress, then sustainable and pro-poor forestry would have long since become a worldwide reality. Of course, implementation still lags well behind aspiration, but at least there is now a considerable body of international knowledge and agreement on how forests can contribute to development.

  11. Advancing cancer drug discovery towards more agile development of targeted combination therapies.

    Science.gov (United States)

    Carragher, Neil O; Unciti-Broceta, Asier; Cameron, David A

    2012-01-01

    Current drug-discovery strategies are typically 'target-centric' and are based upon high-throughput screening of large chemical libraries against nominated targets and a selection of lead compounds with optimized 'on-target' potency and selectivity profiles. However, high attrition of targeted agents in clinical development suggest that combinations of targeted agents will be most effective in treating solid tumors if the biological networks that permit cancer cells to subvert monotherapies are identified and retargeted. Conventional drug-discovery and development strategies are suboptimal for the rational design and development of novel drug combinations. In this article, we highlight a series of emerging technologies supporting a less reductionist, more agile, drug-discovery and development approach for the rational design, validation, prioritization and clinical development of novel drug combinations.

  12. Pengendalian Malaria dalam Upaya Percepatan Pencapaian Target Millennium Development Goals

    Directory of Open Access Journals (Sweden)

    Tri Rini Puji Lestari

    2012-08-01

    health official Malaria Center, and community leaders who observe malaria. Retrieval of data time is 10 – 16 April 2011 by in-depth interviews. It was found that malaria control programs have been implemented by the Departement of Health North Maluku Province, but have not been able to effectively reduce malaria morbidity. This is because malaria control is performed is not comprehensive. Handling is more directed to break the chain transmission to human, their habitats have not been touched up. Key words: Control of malaria, millennium development goals, malaria morbidity

  13. Development of radioactively labelled cancer seeking biomolecules for targeted radiotherapy

    International Nuclear Information System (INIS)

    Varvarigou, A.D.; Archimandritis, S.C.

    2000-01-01

    Within the framework of the above project we are studying the labelling of biomolecules, peptides and antibodies, with radionuclides emitting β - and γ radiation. More specifically, for the time being, we have investigated the labelling of peptides with Re-188 and of antibodies with Sm-153 and Re-188. The radiolabelled derivatives are further evaluated in vivo for possible application in Oncology. For these radiobiological studies we are trying to apply ectopic and orthotopic tumour animal models and to develop, in collaboration with other national and foreign institutes, proper imaging devices for small animal imaging

  14. Gene therapy of cancer and development of therapeutic target gene

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Chang Min; Kwon, Hee Chung

    1998-04-01

    We applied HSV-tk/GCV strategy to orthotopic rat hepatoma model and showed anticancer effects of hepatoma. The increased expression of Lac Z gene after adenovirus-mediated gene delivery throughout hepatic artery was thought that is increased the possibility of gene therapy for curing hepatoma. With the construction of kGLP-laboratory, it is possible to produce a good quantity and quality of adenovirus in lage-scale production and purification of adenovirus vector. Also, the analysis of hepatoma related genes by PCR-LOH could be used for the diagnosis of patients and the development of therapeutic gene.

  15. Development of radioactively labelled cancer seeking biomolecules for targeted therapy

    International Nuclear Information System (INIS)

    Pillai, M.R.A.

    2000-01-01

    The work done towards the development of bifunctional chelating agents, modified peptide and their radiolabelling studies with 90 Y and 188 Re are reported. Bifunctional chelating agents DOTA, TETA and DAHPES were synthesised. DOTA-Lanreotide (Mauritius) was synthesised from lanreotide. 90 Y and 188 Re used in the studies were obtained from 90 Sr- 90 Y and 188 W- 188 Re generators. Complexation studies of DOTA and Mauritius with 90 Y and that of DAHPES and EC with 188 Re were carried out. Cell labelling of 90 Y-DOTA-Lanreotide with a cell line expressing somatostatin receptors was also carried out

  16. Gene therapy of cancer and development of therapeutic target gene

    International Nuclear Information System (INIS)

    Kim, Chang Min; Kwon, Hee Chung

    1998-04-01

    We applied HSV-tk/GCV strategy to orthotopic rat hepatoma model and showed anticancer effects of hepatoma. The increased expression of Lac Z gene after adenovirus-mediated gene delivery throughout hepatic artery was thought that is increased the possibility of gene therapy for curing hepatoma. With the construction of kGLP-laboratory, it is possible to produce a good quantity and quality of adenovirus in lage-scale production and purification of adenovirus vector. Also, the analysis of hepatoma related genes by PCR-LOH could be used for the diagnosis of patients and the development of therapeutic gene

  17. Psoriasis pathogenesis and the development of novel targeted immune therapies.

    Science.gov (United States)

    Hawkes, Jason E; Chan, Tom C; Krueger, James G

    2017-09-01

    Psoriasis is caused by a complex interplay between the immune system, psoriasis-associated susceptibility loci, autoantigens, and multiple environmental factors. Over the last 2 decades, research has unequivocally shown that psoriasis represents a bona fide T cell-mediated disease primarily driven by pathogenic T cells that produce high levels of IL-17 in response to IL-23. The discovery of the central role for the IL-23/type 17 T-cell axis in the development of psoriasis has led to a major paradigm shift in the pathogenic model for this condition. The activation and upregulation of IL-17 in prepsoriatic skin produces a "feed forward" inflammatory response in keratinocytes that is self-amplifying and drives the development of mature psoriatic plaques by inducing epidermal hyperplasia, epidermal cell proliferation, and recruitment of leukocyte subsets into the skin. Clinical trial data for mAbs against IL-17 signaling (secukinumab, ixekizumab, and brodalumab) and newer IL-23p19 antagonists (tildrakizumab, guselkumab, and risankizumab) underscore the central role of these cytokines as predominant drivers of psoriatic disease. Currently, we are witnessing a translational revolution in the treatment and management of psoriasis. Emerging bispecific antibodies offer the potential for even better disease control, whereas small-molecule drugs offer future alternatives to the use of biologics and less costly long-term disease management. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  18. Multi-target drugs: the trend of drug research and development.

    Science.gov (United States)

    Lu, Jin-Jian; Pan, Wei; Hu, Yuan-Jia; Wang, Yi-Tao

    2012-01-01

    Summarizing the status of drugs in the market and examining the trend of drug research and development is important in drug discovery. In this study, we compared the drug targets and the market sales of the new molecular entities approved by the U.S. Food and Drug Administration from January 2000 to December 2009. Two networks, namely, the target-target and drug-drug networks, have been set up using the network analysis tools. The multi-target drugs have much more potential, as shown by the network visualization and the market trends. We discussed the possible reasons and proposed the rational strategies for drug research and development in the future.

  19. Development of a Pamphlet Targeting Computer Workstation Ergonomics

    Science.gov (United States)

    Faraci, Jennifer S.

    1997-01-01

    With the increased use of computers throughout Goddard Space Flight Center, the Industrial Hygiene Office (IHO) has observed a growing trend in the number of health complaints attributed to poor computer workstation setup. A majority of the complaints has centered around musculoskeletal symptoms, including numbness, pain, and tingling in the upper extremities, shoulders, and neck. Eye strain and headaches have also been reported. In some cases, these symptoms can lead to chronic conditions such as repetitive strain injuries (RSI's). In an effort to prevent or minimize the frequency of these symptoms among the GSFC population, the IHO conducts individual ergonomic workstation evaluations and ergonomics training classes upon request. Because of the extensive number of computer workstations at GSFC, and the limited amount of manpower which the Industrial Hygiene staff could reasonably allocate to conduct workstation evaluations and employee training, a pamphlet was developed with a two-fold purpose: (1) to educate the GSFC population about the importance of ergonomically-correct computer workstation setup and the potential effects of a poorly configured workstation; and (2) to enable employees to perform a general assessment of their own workstations and make any necessary modifications for proper setup.

  20. Development of the systems for uniform target irradiation

    International Nuclear Information System (INIS)

    Voronin, A.Yu.; Garanin, S.G.; Derkach, V.N.; Zhidkov, N.V.; Kravchenko, A.G.; Petrazhitskaya, N.A.; Starodubtsev, K.V.; Sukharev, S.A.; Shnyagin, R.A.

    2010-01-01

    Complete text of publication follows. The new devices have been developed for laser beams homogenizing in the focal spot - multi-component lens raster and raster with the edges smoothing phase mask. The envelope non-uniformity of -4 radians. Investigation into the temporary-spatial smoothing with the use of low-density foams with the density less than the critical one is still in progress. Experiments on the foams with the density of 1-2.3 mg/cm 3 , thickness of 100-200 μm, and the cells' sizes up to the tens of micrometers were carried out with the radiation wavelength of 0.657 μm. The RMS non-uniformity < 5% has been found for the beam passed through the foam. The non-uniformity is evenly distributed over the spatial frequency spectrum. The induced divergence of radiation is measured to be 0.35 radian. The frequency of the rearranged speckled field of about 2 THz was obtained. The beam smoothing was recorded from the start of pulse of radiation, had the duration up to 1 ns, and the width of the radiation spectrum was about 30 A. The work was performed in part under the sponsorship of the RFFI (grants No. 09-02-12157-ofi-m and No. 09-02-97095-r-povolzh'ye-a) and grant of the President of the RF to leading scientific schools No. 65192.2010.2.

  1. Development of production of {sup 99}Mo from LEU target

    Energy Technology Data Exchange (ETDEWEB)

    Adang, H.G.; Mutalib, A.; Lubis, H. [Radioisotope Production Centre, National Atomic Energy Agency, Kawasan Puspiptek, Serpong (Indonesia)] [and others

    1998-10-01

    {sup 99}TC, the most popular radioisotope in nuclear medicine, is daughter of {sup 99}Mo. {sup 99}Mo is produced in research reactor by irradiating of high enriched uranium (HEU). However, in recent year, strict regulation that has been implemented by USA DOE and NPT has led to the difficulty in getting HEU. Therefore, BATAN has tried to develop the production of {sup 99}Mo by using low enriched uranium (LEU). The research involves the use of LEU in the production of {sup 99}Mo. This research was started in 1994 by joint-research between BATAN and Argonne National Laboratory USA. This program is divided into three research groups. The first group emphasizes its research on fabrication of LEU foil that is going to be irradiated. The second group studies the irradiation`s aspects and physical characteristic of irradiated LEU foils. The third group studies the radiochemical separation process of fission product {sup 99}Mo from solution of irradiated LEU foils. There are five steps that are carried out in studying of radiochemical separation of {sup 99}Mo from irradiated LEU. First is designing a dissolver that is going to be used in dissolving of LEU foil and testing its reliability. Second is dissolving LEU in the new design dissolver. Third is evaluation the modified of Cintichem`s radiochemical separation process of {sup 99}Mo from LEU. Forth is modifying the Cintichem`s radiochemical separation process of {sup 99}Mo from the solution of irradiated LEU. And fifth is using the modified of Cintichem`s radiochemical separation process for separation {sup 99}Mo from solution of irradiated LEU. The first through the forth steps of experiments were already carried out and will be reported in this workshop, whereas the fifth step of experiment is going to be conducted in February 1998. (author)

  2. Development of a Ne gas target for {sup 22}Na production by proton irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Mandal, Bidhan Ch., E-mail: mechbidhan@gmail.com; Pal, Gautam [Mechanical Engineering Group, Variable Energy Cyclotron Centre, Kolkata 700 064 (India); Barua, Luna; Das, Sujata Saha [Radiopharmaceuticals Laboratory, Board of Radiation and Isotope Technology, Variable Energy Cyclotron Centre, Kolkata 700 064 (India)

    2016-03-15

    The article presents the design and development of a neon gas target for the production of {sup 22}Na using a proton beam from the room temperature cyclotron in Variable Energy Cyclotron Centre, Kolkata. The target design is made to handle a beam power of 85 W (17 MeV, 5 μA). The design is based on simulation using the computer code FLUKA for the beam dump and CFD-CFX for target cooling. The target has been successfully used for the production of {sup 22}Na in a 6 day long 17 MeV, 5 μA proton irradiation run.

  3. A target development program for beamhole spallation neutron sources in the megawatt range

    Energy Technology Data Exchange (ETDEWEB)

    Bauer, G.S.; Atchison, F. [Rutherford Appleton Laboratory, Oxon (United Kingdom)] [and others

    1995-10-01

    Spallation sources as an alternative to fission neutron sources have been operating successfully up to 160 kW of beam power. With the next generation of these facilities aiming at the medium power range between 0.5 and 5 MW, loads on the targets will be high enough to make present experience of little relevance. With the 0.6 MW continuous facility SINQ under construction, and a 5 MW pulsed facility (ESS) under study in Europe, a research and development program is about to be started which aimes at assessing the limits of stationary and moving solid targets and the feasibility and potential benefits of flowing liquid metal targets. Apart from theoretical work and examination of existing irradiated material, including used targets from ISIS, it is intended to take advantage of the SINQ solid rod target design to improve the relevant data base by building the target in such a way that individual rods can be equipped as irradiation capsules.

  4. The Bacterial Type III Secretion System as a Target for Developing New Antibiotics

    OpenAIRE

    McShan, Andrew C.; De Guzman, Roberto N.

    2015-01-01

    Antibiotic resistance in pathogens requires new targets for developing novel antibacterials. The bacterial type III secretion system (T3SS) is an attractive target for developing antibacterials as it is essential in the pathogenesis of many Gram-negative bacteria. The T3SS consists of structural proteins, effectors and chaperones. Over 20 different structural proteins assemble into a complex nanoinjector that punctures a hole on the eukaryotic cell membrane to allow the delivery of effectors ...

  5. PROBLEMS OF FINANCING OF TARGET PROGRAMS OF DEVELOPMENT OF REGION (EXPERIENCE OF KHABAROVSK TERRITORY

    Directory of Open Access Journals (Sweden)

    A.Z. Shljahovoj

    2009-03-01

    Full Text Available In article considers variants of financing of target programs of development of the region, providing joint participation state and commercial structures. Parameters of conformity of conditions of target programs and terms of financing of programs are specified by the credit organization. The three-level scheme of financing of regional programs by the regional banks, being a component of bank strategy of development, is offered.

  6. Functional foam coatings inside tubing and custom developed diamond ignition targets

    International Nuclear Information System (INIS)

    Dawedeit, Christoph

    2014-01-01

    The development of inertial confinement fusion targets requires new efficient ablator materials and characteristic temperature measurements during confinement. Here, an aerogel coating process is developed to coat inside spheres and cylinders. The characteristic emission spectrum of doped aerogel inside diamond targets is used as temperature gauge during confinement. Coatings inside metal cylinders confirmed the generality of the coating procedure. In addition artificial diamond is characterized which represents an interesting ablator material.

  7. Development of new target concepts for proton beams at CERN/ISOLDE

    CERN Document Server

    Delonca, Melanie; Montavon, Ghislain; Peyraut, Francois

    More and more, the power of primary beam sent onto targets increases until reaching several kiloWatts of magnitude, inducing new problematic and challenges. Consequently, the need of new target design arises and leads to new conceptual design proposal. Amongst them, a concept of Lead Bismuth Eutectic (LBE) loop target making use of an heat exchanger (HEX) and a pump has been proposed during the European project EURISOL Design Study. This concept proposed an improvement in terms of release efficiency of short-lived species by transforming the irradiated liquid into droplets shape. This thesis presents the development of this target design proposal. A prototype target has been developed and will be tested under proton beam at ISOLDE at Cern, Geneva. Several analytical tools for the study of this kind of targets are proposed, taking into account different design parameters. These tools can be applied for other high power target concept and allow an easy dimensioning of this kind of targets. As well, an innovativ...

  8. Biofuels development in China: Technology options and policies needed to meet the 2020 target

    International Nuclear Information System (INIS)

    Chang, Shiyan; Zhao, Lili; Timilsina, Govinda R.; Zhang, Xiliang

    2012-01-01

    China promulgated the Medium and Long-Term Development Plan for Renewable Energy in 2007, which included sub-targets of 2010 and 2020 for various renewable energy technologies. Almost all the 2010 sub-targets have been met and even surpassed except non-grain fuel ethanol. There is debate surrounding the questions of whether and how the country will be able to meet the 2020 biofuels target. This paper provides the assessment of potential technology pathways to achieve the 2020 target regarding their respective resource potential and supply cost. Barriers and policy options are identified based on broad literatures review. And an overview of biofuels projections is presented to provide insight into the comparison of various policy scenarios. The study shows that China can potentially satisfy non-grain fuel ethanol target by 2020 from technology perspective. But she will probably fall far short of this target if current situations continue. Additional policy efforts are needed. Meanwhile, the target of biodiesel production has high probability to be achieved. However, if given support policies, it will develop better. - Highlights: ► I. Non-grain feedstocks such as cassava, sweet sorghum and sweet potato grown in low productive arable lands or unutilized lands have enough potential to meet ethanol targets in 2020. ► II. If current situations continue, China will fall far short of the 2020 target. ► III. The target of biodiesel production has high probability to be achieved, while, if given support policies, it will develop better. ► IV. Supply cost is one of the major barriers faced by all biofuels pathways. ► V. Various policy measures would be necessary to overcome the costs barriers to biofuels in China.

  9. The LEU target development and conversion program for the MAPLE reactors and new processing facility

    International Nuclear Information System (INIS)

    Malkoske, G.R.

    2002-01-01

    Historically, the production of molybdenum-99 in the NRU research reactors at Chalk River, Canada has been extracted from reactor targets employing highly enriched uranium (HEU). A reliable supply of HEU metal from the United States used in the manufacture of targets for the NRU research reactor has been a key factor to enable MDS Nordion to develop a secure supply of medical isotopes for the international nuclear medicine community. The molybdenum extraction process from HEU targets provides predictable, consistent yields for our high-volume molybdenum production process. Each link of the isotope supply chain, from isotope production to ultimate use by the physician, has been established using this proven and established method of HEU target irradiation and processing to extract molybdenum-99. To ensure a continued reliable and timely supply of medical isotopes, MDS Nordion is completing the construction of two MAPLE reactors and a New Processing Facility. The design of the MAPLE facilities was based on an established process developed by Atomic Energy of Canada Ltd. (AECL) - extraction of isotopes from HEU target material. However, in concert with the global trend to utilize low enriched uranium (LEU) in research reactors, MDS Nordion has launched a three phase LEU Target Development and Conversion Program for the MAPLE facilities. Phase 1, the Initial Feasibility Study, which identified the technical issues to convert the MAPLE reactor targets from HEU to LEU for large scale commercial production was reported on at the RERTR- 2000 conference. The second phase of the LEU Target Development and Conversion Program was developed with extensive consultation and involvement of experts knowledgeable in target development, process system design, enriched uranium conversion chemistry and commercial scale reactor operations and molybdenum production. This paper will provide an overview of the Phase 2 Conversion Development Program, report on progress to date, and further

  10. Guidelines for target costing adoption in the development of products for the residential real estate market

    Directory of Open Access Journals (Sweden)

    Reymard Savio Sampaio de Melo

    Full Text Available Abstract This study focuses on the problems associated with the traditional practice of reducing costs in construction and the need to increase business competitiveness in the residential real estate sector. In this context, target costing is a promising approach to improve the competitiveness of companies by ensuring that the products launched on the market do not jeopardize the company's results and value delivery to customers. However, far too little attention is paid to target costing implementation by companies that develop residential real state products for sale and face strong market competition. Thus, this paper seeks to investigate whether the standard framework of target costing in the literature applies - with or without adjustments - to real estate developers. Case study was the research strategy adopted. Guidelines are proposed for the introduction of target costing in the development process of residential real estate products. The proposed guidelines are related to the three main sections of the target costing process: market-driven costing, product-level target costing and component-level target costing.

  11. The Individual Practice Development Theory: an individually focused practice development theory that helps target practice development resources.

    Science.gov (United States)

    Melton, Jane; Forsyth, Kirsty; Freeth, Della

    2012-06-01

    Research indicates that multifaceted practice development (PD) interventions are more effective than single strategies. However, models of education in health care need to consider cost-effectiveness. This paper presents a research-based, PD theory called the Individual Practice Development Theory. It argues that programmes that use the Individual Practice Development Theory to tailor PD support to the learning needs of practitioners will result in more engagement in PD and will target PD resources efficiently. The in-depth qualitative, multi-method realistic evaluation was of a multifaceted, organization-wide PD programme in one National Health Service Mental Health and Learning Disabilities Trust. Semi-structured interviews, practice observation and documentation audit were used to gather data from occupational therapists. Results indicated that environmental contexts, particularly the support of the immediate team, and the participant's personal circumstances affected PD behaviour change. Six mechanisms acted as catalysts. These were: Building Confidence, Finding Flow, Accumulating Reward, Conferring with Others, Constructing Knowledge Know-how and Channelling Time. Four stages of PD characterized as: 'In the Hangar', 'On the Runway', 'Take-off' and 'In the Air' were identified. The research also illustrated the interconnectivity between outcome levels, contextual circumstances and activating mechanisms. The findings suggested that PD interventions need to be more individually tailored to achieve optimum learning outcomes. The identification of four discernable stages permits rapid understanding of PD support needs in order to focus PD support. With a systematic and individualized approach to PD in health care, more target PD supports can be put in place. © 2011 Blackwell Publishing Ltd.

  12. Novel and viable acetylcholinesterase target site for developing effective and environmentally safe insecticides.

    Science.gov (United States)

    Pang, Yuan-Ping; Brimijoin, Stephen; Ragsdale, David W; Zhu, Kun Yan; Suranyi, Robert

    2012-04-01

    Insect pests are responsible for human suffering and financial losses worldwide. New and environmentally safe insecticides are urgently needed to cope with these serious problems. Resistance to current insecticides has resulted in a resurgence of insect pests, and growing concerns about insecticide toxicity to humans discourage the use of insecticides for pest control. The small market for insecticides has hampered insecticide development; however, advances in genomics and structural genomics offer new opportunities to develop insecticides that are less dependent on the insecticide market. This review summarizes the literature data that support the hypothesis that an insect-specific cysteine residue located at the opening of the acetylcholinesterase active site is a promising target site for developing new insecticides with reduced off-target toxicity and low propensity for insect resistance. These data are used to discuss the differences between targeting the insect-specific cysteine residue and targeting the ubiquitous catalytic serine residue of acetylcholinesterase from the perspective of reducing off-target toxicity and insect resistance. Also discussed is the prospect of developing cysteine-targeting anticholinesterases as effective and environmentally safe insecticides for control of disease vectors, crop damage, and residential insect pests within the financial confines of the present insecticide market.

  13. Novel and Viable Acetylcholinesterase Target Site for Developing Effective and Environmentally Safe Insecticides

    Science.gov (United States)

    Pang, Yuan-Ping; Brimijoin, Stephen; Ragsdale, David W; Zhu, Kun Yan; Suranyi, Robert

    2012-01-01

    Insect pests are responsible for human suffering and financial losses worldwide. New and environmentally safe insecticides are urgently needed to cope with these serious problems. Resistance to current insecticides has resulted in a resurgence of insect pests, and growing concerns about insecticide toxicity to humans discourage the use of insecticides for pest control. The small market for insecticides has hampered insecticide development; however, advances in genomics and structural genomics offer new opportunities to develop insecticides that are less dependent on the insecticide market. This review summarizes the literature data that support the hypothesis that an insect-specific cysteine residue located at the opening of the acetylcholinesterase active site is a promising target site for developing new insecticides with reduced off-target toxicity and low propensity for insect resistance. These data are used to discuss the differences between targeting the insect-specific cysteine residue and targeting the ubiquitous catalytic serine residue of acetylcholinesterase from the perspective of reducing off-target toxicity and insect resistance. Also discussed is the prospect of developing cysteine-targeting anticholinesterases as effective and environmentally safe insecticides for control of disease vectors, crop damage, and residential insect pests within the financial confines of the present insecticide market. PMID:22280344

  14. A conversion development program to LEU targets for medical isotope production in the MAPLE Facilities

    International Nuclear Information System (INIS)

    Malkoske, G.R.

    2000-01-01

    Historically, the production of molybdenum-99 in the NRU research reactors at Chalk River, Canada has been extracted from reactor targets employing highly enriched uranium (HEU). The molybdenum extraction process from the HEU targets provided predictable, consistent yields for our high-volume molybdenum production process. A reliable supply of HEU for the NRU research reactor targets has enabled MDS Nordion to develop a secure chain of medical isotope supply for the international nuclear medicine community. Each link of the isotope supply chain, from isotope production to patient application, has been established on a proven method of HEU target irradiation and processing. To ensure a continued reliable and timely supply of medical isotopes, the design of the MAPLE facilities was based on our established process - extraction of isotopes from HEU target material. However, in concert with the global trend to utilize low enriched uranium (LEU) in research reactors, MDS Nordion has launched a program to convert the MAPLE facilities to LEU targets. An initial feasibility study was initiated to identify the technical issues to convert the MAPLE targets from HEU to LEU. This paper will present the results of the feasibility study. It will also describe future challenges and opportunities in converting the MAPLE facilities to LEU targets for large scale, commercial medical isotope production. (author)

  15. Development of dissolution process for metal foil target containing low enriched uranium

    International Nuclear Information System (INIS)

    Srinivasan, B.; Hutter, J.C.; Johnson, G.K.; Vandegrift, G.F.

    1994-01-01

    About six times more low enriched uranium (LEU) metal is needed to produce the same quantity of 99 Mo as from a high enriched uranium (HEU) oxide target, under similar conditions of neutron irradiation. In view of this, the post-irradiation processing procedures of the LEU target are likely to be different from the Cintichem process procedures now in use for the HEU target. The authors have begun a systematic study to develop modified procedures for LEU target dissolution and 99 Mo separation. The dissolution studies include determination of the dissolution rate, chemical state of uranium in the solution, and the heat evolved in the dissolution reaction. From these results the authors conclude that a mixture of nitric and sulfuric acid is a suitable dissolver solution, albeit at higher concentration of nitric acid than in use for the HEU targets. Also, the dissolver vessel now in use for HEU targets is inadequate for the LEU target, since higher temperature and higher pressure will be encountered in the dissolution of LEU targets. The desire is to keep the modifications to the Cintichem process to a minimum, so that the switch from HEU to LEU can be achieved easily

  16. Developed Countries 2020 Pledges Fall Short of IPCC Target What can we do

    International Nuclear Information System (INIS)

    Guerin, E.; Colombier, M.

    2009-01-01

    With the recent announcement by President Obama of the US emission reduction target, the map of developed countries pledges is now full. The US will come to Copenhagen with a -17% target in 2020 compared to 2005 levels that translates into a -4% compared to 1990 levels (together with a -42% target in 2030 that translates into a -33% compared to 1990. Some countries have put forward multiple pledges. They will only commit to the highest pledge if the Copenhagen agreement is deemed satisfactory. For example, the European Union (EU) stated it would move from -20% (the lower pledge) to -30% (the higher pledge) in 2020 compared to 1990 levels if developed countries undertake comparable emission cuts and if major developing countries undertake adequate mitigation actions. Countries also choose different base years in quantifying their pledges. These mitigation pledges by developed countries result in aggregate emissions of -14 to -19% in 2020 compared to 1990 levels, which fall well below the range established by the IPCC (Intergovernmental Panel of Climate Change). According to the IPCC, developed countries need to reduce their emissions by -25 to -40% in 2020 compared to 1990 levels to have approximately a 50% chance to limit the temperature increase to 2 deg. C above pre-industrial levels. It should be noted that some targets presented here (such as EU and US pledges) account for international offsets. To be consistent with IPCC figures, this fraction of expected reductions should not be accounted for. Only the domestic component should be considered. But as specified now, certain pledges are expected to fall further below target. For example, the EU's -20% target translates into -15%, with offsets excluded. This is quite problematic. First, from a climate point of view: developed countries are not making the emission reduction commitments necessary for stabilizing global temperatures at a level that averts dangerous climate change. Second, from a negotiation point of

  17. Development of a cryogenic target delivery system for HiPER

    Energy Technology Data Exchange (ETDEWEB)

    Perin, J.P. [CEA, DRFMC, Serv Basses Temp, F-38054 Grenoble, (France); Perlado, M. [Univ Politecn Madrid, Inst Fus Nucl DENIM, ETSII, Madrid, (Spain); Tolley, M. [Rutherford Appleton Lab, Cent Laser Facil, Rutherford, NJ (United States)

    2009-07-01

    For the future, we have to develop new sources of energy. These new sources may be based on nuclear fusion with magnetic confinement (as with the ITER experiment) or with a new concept based on inertial confinement. The European community plans to build a facility (HiPER project) which is dedicated to reaching high gain with cryogenic targets, and to test the concepts of target mass production and rep rate shots. The cryogenic system for the first phase experiments in HiPER is based on the cryogenic system developed for the French facility Laser MegaJoule (LMJ). The latter must be modified and upgraded for direct drive targets. In particular the target must be protected from the radiation flux from the vacuum vessel by a thermal shroud In addition, the LMJ system must be equipped with a thermal system to allow layering of the fusion fuel to take place. (authors)

  18. Present status of spallation target development. JAERI/KEK Joint Project

    International Nuclear Information System (INIS)

    Hino, R.; Kaminaga, M.; Haga, K.

    2001-01-01

    The Japan Atomic Energy Research Institute (JAERI) and the High Energy Accelerator Research Organization (KEK) are promoting a plan to construct a neutron scattering facility under the JAERI/KEK Joint Project. Design and R and D works are being carried out vigorously for realizing the mercury target system consisting of the mercury target, moderators and reflectors working as a spallation neutron source, as well as a remote handling system for exchanging such components which will be highly irradiated. This report introduces an outline of the present status of design and development activities on the spallation target system. (author)

  19. Proceedings of the sixth annual conference of the International Nuclear Target Development Society

    Energy Technology Data Exchange (ETDEWEB)

    Steers, G. (comp.)

    1978-08-01

    The Sixth Annual Conference of the International Nuclear Target Development Society was held at the Lawrence Berkeley Laboratory, University of California, Berkeley, California, on October 19--21, 1977. The discussion covered nuclear target preparation by evaporation, reduction of oxides, electrodeposition, reactive sputtering, rolling, gas jets, and related techniques. Abstracts were prepared for eighteen of the papers presented at the conference and are included in the data base. (GHT)

  20. Developing, Implementing, and Evaluating a Condom Promotion Program Targeting Sexually Active Adolescents.

    Science.gov (United States)

    Alstead, Mark; Campsmith, Michael; Halley, Carolyn Swope; Hartfield, Karen; Goldblum, Gary; Wood, Robert W.

    1999-01-01

    Describes the development, implementation, and evaluation of an HIV prevention program promoting condom use among sexually active adolescents. It mobilized target communities to guide program development and implementation; created a mass media campaign to promote correct condom use; and recruited public agencies and organizations to distribute…

  1. Development of highly heat-resistant target elements for fusion reactors; Entwicklung hochwaermebestaendiger Targetelemente fuer Fusionsreaktoren

    Energy Technology Data Exchange (ETDEWEB)

    Boscary, Jean; Stadler, R.; Greuner, H.; Smirnow, M.; Drescher, N.; Boeswirth, B.; Tretter, J.; Mendelevitch, B.

    2016-06-15

    The following topics are dealt with: Scientific and technical results for divertor components (''target elements'') of the Wendelstein 7-X facility, development of nondestructive test procedures at the cooling structures, development of an automatized procedure for the visual inspection, the ''scraper''-element. (HSI)

  2. Targeted Programs and Career Pathways within Workforce Development Policies. ECS Education Policy Analysis

    Science.gov (United States)

    Anderson, Lexi

    2015-01-01

    States are introducing and enacting an increasing number of bills targeted toward workforce development and career and technical education. The increase in legislation illustrates a shift toward creating collaborations between higher education institutions and employers in the state as one strategy to enhance workforce development and…

  3. MET targeted therapy for lung cancer: clinical development and future directions

    Directory of Open Access Journals (Sweden)

    Feng Y

    2012-08-01

    Full Text Available Yan Feng,1,2 Patrick C Ma1–31Translational Hematology and Oncology Research, 2Solid Tumor Oncology, 3Aerodigestive Oncology Translational Research, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USAAbstract: MET, the receptor for hepatocyte growth factor, has been identified as a novel promising target in various human malignancies, including lung cancer. Research studies have demonstrated that MET signaling plays important physiologic roles in embryogenesis and early development, whereas its deregulation from an otherwise quiescent signaling state in mature adult tissues can lead to upregulated cell proliferation, survival, scattering, motility and migration, angiogenesis, invasion, and metastasis in tumorigenesis and tumor progression. The MET pathway can be activated through ligand (hepatocyte growth factor, HGF or MET receptor overexpression, genomic amplification, MET mutations, and alternative splicing. A number of novel therapeutic agents that target the MET/hepatocyte growth factor pathway have been tested in early-phase clinical studies with promising results. Phase III studies of MET targeting agents have recently been initiated. This paper will review the MET signaling pathway and biology in lung cancer, and the recent clinical development and advances of MET/hepatocyte growth factor targeting agents. Emphasis will be placed on discussing various unanswered issues and key strategies needed to optimize further clinical development of MET targeting personalized lung cancer therapy.Keywords: MET, HGF, lung cancer, targeted therapy

  4. Influence networks based on coexpression improve drug target discovery for the development of novel cancer therapeutics

    Science.gov (United States)

    2014-01-01

    Background The demand for novel molecularly targeted drugs will continue to rise as we move forward toward the goal of personalizing cancer treatment to the molecular signature of individual tumors. However, the identification of targets and combinations of targets that can be safely and effectively modulated is one of the greatest challenges facing the drug discovery process. A promising approach is to use biological networks to prioritize targets based on their relative positions to one another, a property that affects their ability to maintain network integrity and propagate information-flow. Here, we introduce influence networks and demonstrate how they can be used to generate influence scores as a network-based metric to rank genes as potential drug targets. Results We use this approach to prioritize genes as drug target candidates in a set of ER + breast tumor samples collected during the course of neoadjuvant treatment with the aromatase inhibitor letrozole. We show that influential genes, those with high influence scores, tend to be essential and include a higher proportion of essential genes than those prioritized based on their position (i.e. hubs or bottlenecks) within the same network. Additionally, we show that influential genes represent novel biologically relevant drug targets for the treatment of ER + breast cancers. Moreover, we demonstrate that gene influence differs between untreated tumors and residual tumors that have adapted to drug treatment. In this way, influence scores capture the context-dependent functions of genes and present the opportunity to design combination treatment strategies that take advantage of the tumor adaptation process. Conclusions Influence networks efficiently find essential genes as promising drug targets and combinations of targets to inform the development of molecularly targeted drugs and their use. PMID:24495353

  5. Development of a software for quantitative evaluation radiotherapy target and organ-at-risk segmentation comparison.

    Science.gov (United States)

    Kalpathy-Cramer, Jayashree; Awan, Musaddiq; Bedrick, Steven; Rasch, Coen R N; Rosenthal, David I; Fuller, Clifton D

    2014-02-01

    Modern radiotherapy requires accurate region of interest (ROI) inputs for plan optimization and delivery. Target delineation, however, remains operator-dependent and potentially serves as a major source of treatment delivery error. In order to optimize this critical, yet observer-driven process, a flexible web-based platform for individual and cooperative target delineation analysis and instruction was developed in order to meet the following unmet needs: (1) an open-source/open-access platform for automated/semiautomated quantitative interobserver and intraobserver ROI analysis and comparison, (2) a real-time interface for radiation oncology trainee online self-education in ROI definition, and (3) a source for pilot data to develop and validate quality metrics for institutional and cooperative group quality assurance efforts. The resultant software, Target Contour Testing/Instructional Computer Software (TaCTICS), developed using Ruby on Rails, has since been implemented and proven flexible, feasible, and useful in several distinct analytical and research applications.

  6. Basic/Translational Development of Forthcoming Opioid- and Nonopioid-Targeted Pain Therapeutics.

    Science.gov (United States)

    Knezevic, Nebojsa Nick; Yekkirala, Ajay; Yaksh, Tony L

    2017-11-01

    Opioids represent an efficacious therapeutic modality for some, but not all pain states. Singular reliance on opioid therapy for pain management has limitations, and abuse potential has deleterious consequences for patient and society. Our understanding of pain biology has yielded insights and opportunities for alternatives to conventional opioid agonists. The aim is to have efficacious therapies, with acceptable side effect profiles and minimal abuse potential, which is to say an absence of reinforcing activity in the absence of a pain state. The present work provides a nonexclusive overview of current drug targets and potential future directions of research and development. We discuss channel activators and blockers, including sodium channel blockers, potassium channel activators, and calcium channel blockers; glutamate receptor-targeted agents, including N-methyl-D-aspartate, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, and metabotropic receptors. Furthermore, we discuss therapeutics targeted at γ-aminobutyric acid, α2-adrenergic, and opioid receptors. We also considered antagonists of angiotensin 2 and Toll receptors and agonists/antagonists of adenosine, purine receptors, and cannabinoids. Novel targets considered are those focusing on lipid mediators and anti-inflammatory cytokines. Of interest is development of novel targeting strategies, which produce long-term alterations in pain signaling, including viral transfection and toxins. We consider issues in the development of druggable molecules, including preclinical screening. While there are examples of successful translation, mechanistically promising preclinical candidates may unexpectedly fail during clinical trials because the preclinical models may not recapitulate the particular human pain condition being addressed. Molecular target characterization can diminish the disconnect between preclinical and humans' targets, which should assist in developing nonaddictive analgesics.

  7. Mechanical design and development of a high power target system for the SLC Positron Source

    International Nuclear Information System (INIS)

    Reuter, E.; Mansour, D.; Porter, T.; Sax, W.; Szumillo, A.

    1991-12-01

    In order to bring the SLC Positron Source luminosity up to design specifications, the previous (stationary) positron target had to be replaced with a version which could reliably dissipate the higher power levels and cyclic pulsed thermal stresses of the high intensity 33GeV electron beam. In addition to this basic requirement, the new target system had to meet SLAC's specifications for Ultra High Vacuum, be remotely controllable, ''radiation hard,'' and designed in such a way that it could be removed and replaced quickly and easily with minimum personnel exposure to radiation. It was also desirable to integrate the target and collection components into a compact, easily manufacturable, and easily maintainable module. This paper briefly summarize the mechanical design and development of the new modular target system, its associated controls and software, alignment, and the quick removal system. Operational experience gained with the new system over the first running cycle is also summarized

  8. Perspective on the pipeline of drugs being developed with modulation of DNA damage as a target.

    Science.gov (United States)

    Plummer, Ruth

    2010-09-15

    Inhibitors of various elements of the DNA repair pathways have entered clinical development or are in late preclinical stages of drug development. It was initially considered that agents targeting DNA repair would act to overcome tumor resistance to chemotherapy and radiotherapy. More recent data have shown that targeting DNA repair pathways can be effective in selected tumors via a synthetically lethal route, with single agent activity having been shown with poly-ADP ribose polymerase (PARP) inhibitors. An increased understanding of the biology and interaction of the DNA repair pathways also means that rational combination of DNA repair inhibitors may also give great benefit in the clinic. ©2010 AACR.

  9. Development of a target-site based regional frequency model using historical information

    Science.gov (United States)

    Hamdi, Yasser; Bardet, Lise; Duluc, Claire-Marie; Rebour, Vincent

    2016-04-01

    Nuclear power facilities in France were designed to withstand extreme environmental conditions with a very low probability of failure. Nevertheless, some exceptional surges considered as outliers are not properly addressed by classical frequency analysis models. If available data at the site of interest (target-site) is sufficiently complete on a long period and not characterized by the presence of an outlier, at-site frequency analysis can be used to estimate quantiles with acceptable uncertainties. Otherwise, regional and historical information (HI) may be used to mitigate the lack of data and the influence of the outlier by increasing its representativeness in the sample. several models have been proposed over the last years for regional extreme surges frequency analysis in France to take into account these outliers in the frequency analysis. However, these models do not give a specific weight to the target site and cannot take into account HI. The objective of the present work is to develop a regional frequency model (RFM) centered on a target-site and using HI. The neighborhood between sites is measured by a degree of physical and statistical dependence between observations (with a prior confidence level). Unlike existing models, the obtained region around the target site (and constituting the neighboring sites) is sliding from a target-site to another. In other words, the developed model assigns a region for each target site. The idea behind the construction of a frequency model favoring target sites and the principle of moving regions around these target-sites is the original key point of the developed model. A related issue regards the estimation of missed and/or ungauged surges at target-sites from those of gauged potential neighboring sites, a multiple linear regression (MLR) is used and it can be extended to other reconstitutions models. MLR analysis can be considered conclusive only if available observations at neighboring sites are informative enough

  10. The LEU target development and conversion program for the MAPLE reactors and new processing facility

    International Nuclear Information System (INIS)

    Malkoske, G.R.

    2003-01-01

    The availability of isotope grade, Highly Enriched Uranium (HEU), from the United States for use in the manufacture of targets for molybdenum-99 production in AECL's NRU research reactor has been a key factor to enable MDS Nordion to develop a reliable, secure supply of medical isotopes for the international nuclear medicine community. The molybdenum extraction process from HEU targets is a proven and established method that has reliably produced medical isotopes for several decades. The HEU process provides predictable, consistent yields for our high-volume, molybdenum-99 production. Other medical isotopes such as I-131 and Xe-133, which play an important role in nuclear medicine applications, are also produced from irradiated HEU targets as a by-product of the molybdenum-99 process. To ensure a continued reliable and timely supply of medical isotopes, MDS Nordion is completing the commissioning of two MAPLE reactors and an associated isotope processing facility (the New Processing Facility). The new MAPLE facilities, which will be dedicated exclusively to medical isotope production, will provide an essential contribution to a secure, robust global healthcare system. Design and construction of these facilities has been based on a life cycle management philosophy for the isotope production process. This includes target irradiation, isotope extraction and waste management. The MAPLE reactors will operate with Low Enriched Uranium (LEU) fuel, a significant contribution to the objectives of the RERTR program. The design of the isotope production process in the MAPLE facilities is based on an established process - extraction of isotopes from HEU target material. This is a proven technology that has been demonstrated over more than three decades of operation. However, in support of the RERTR program and in compliance with U.S. legislation, MDS Nordion has undertaken a LEU Target Development and Conversion Program for the MAPLE facilities. This paper will provide an

  11. Development of a polarized deuterium target to measure T/sub 20/ in electron storage rings

    Energy Technology Data Exchange (ETDEWEB)

    Young, L.; Coulter, K.; Gilman, R.A.; Holt, R.J.; Kinney, E.R.; Kowalczyk, R.S.; Napolitano, J.; Potterveld, D.; Lasarenko, B.A.; Mishnev, S.I.

    1989-01-01

    The development of a polarized deuterium target to measure the analyzing power in electron scattering from the deuteron at the highest possible momentum transfer is described. Two areas of research have been simultaneously pursued: the development of a storage cell for polarized atoms (ANL and INP) and the development of a high-flux laser-driven source of polarized deuterium (ANL). The successful combination of these two technological developments will produce a polarized target having a figure of merit of np/sub zz//sup 2/ approx. np/sub z//sup 2/ approx. 10/sup 14/ cm/sup /minus/2/. The progress to date, including, feasibility tests of the storage cell concept, design of a high-density storage cell ad the development of the laser-driven source will be described. 14 refs., 7 figs.

  12. Target fabrication and development in the Centre d'Etudes de Limeil

    International Nuclear Information System (INIS)

    Clement, X.; Coudeville, A.; Eyharts, P.; Perrine, J.P.; Rouillard, R.

    1983-10-01

    The present state of research in Limeil laboratory for the production of inertial confinement fusion targets is described in this communication. A summary of typical areas, previously investigated, including new developments, is as follows: - production of hollow glass microspheres, having wide outside diameter range and aspect-ratio, using dried-alcogels, - preparation and fabrication of low density foams having plane or hemispherical shape, - deposition of a wide range of conductive materials as well as silicon and organic polymers, - development of laser and spark erosion machining which are useful tools for producing minute parts of complex targets, - characterization and analysis of plastic or coal metal coated targets, are done by using interferometry techniques and X-ray image analysis as well as X-ray absorption measurements

  13. Frizzled3 controls axonal polarity and intermediate target entry during striatal pathway development

    NARCIS (Netherlands)

    Morello, Francesca; Prasad, Asheeta A.; Rehberg, Kati; Baptista Vieira de Sá, Renata; Antón-Bolaños, Noelia; Leyva-Diaz, Eduardo; Adolfs, Youri; Tissir, Fadel; López-Bendito, Guillermina; Pasterkamp, R. Jeroen

    2015-01-01

    The striatum is a large brain nucleus with an important role in the control of movement and emotions.Mediumspiny neurons (MSNs) are striatal output neurons forming prominent descending axon tracts that target different brain nuclei. However, how MSN axon tracts in the forebrain develop remains

  14. Learning Communities Faculty Scholars: An Online, Targeted Faculty Development Course to Promote Scholarly Teaching

    Science.gov (United States)

    Steiner, Hillary H.

    2016-01-01

    Many learning communities instructors seek professional development opportunities that foster their growth as teacher-scholars. Learning communities programs, therefore, have an opportunity to provide targeted, "just in time" training that allows for the immediate application of knowledge to a learning community setting, maximizing…

  15. Mechanical activation of mammalian target of rapamycin pathway is required for cartilage development

    OpenAIRE

    Guan, Yingjie; Yang, Xu; Yang, Wentian; Charbonneau, Cherie; Chen, Qian

    2014-01-01

    Mechanical stress regulates development by modulating cell signaling and gene expression. However, the cytoplasmic components mediating mechanotransduction remain unclear. In this study, elimination of muscle contraction during chicken embryonic development resulted in a reduction in the activity of mammalian target of rapamycin (mTOR) in the cartilaginous growth plate. Inhibition of mTOR activity led to significant inhibition of chondrocyte proliferation, cartilage tissue growth, and express...

  16. Identification of miRNAs and their target genes in developing soybean seeds by deep sequencing

    Directory of Open Access Journals (Sweden)

    Chen Shou-Yi

    2011-01-01

    Full Text Available Abstract Background MicroRNAs (miRNAs regulate gene expression by mediating gene silencing at transcriptional and post-transcriptional levels in higher plants. miRNAs and related target genes have been widely studied in model plants such as Arabidopsis and rice; however, the number of identified miRNAs in soybean (Glycine max is limited, and global identification of the related miRNA targets has not been reported in previous research. Results In our study, a small RNA library and a degradome library were constructed from developing soybean seeds for deep sequencing. We identified 26 new miRNAs in soybean by bioinformatic analysis and further confirmed their expression by stem-loop RT-PCR. The miRNA star sequences of 38 known miRNAs and 8 new miRNAs were also discovered, providing additional evidence for the existence of miRNAs. Through degradome sequencing, 145 and 25 genes were identified as targets of annotated miRNAs and new miRNAs, respectively. GO analysis indicated that many of the identified miRNA targets may function in soybean seed development. Additionally, a soybean homolog of Arabidopsis SUPPRESSOR OF GENE SLIENCING 3 (AtSGS3 was detected as a target of the newly identified miRNA Soy_25, suggesting the presence of feedback control of miRNA biogenesis. Conclusions We have identified large numbers of miRNAs and their related target genes through deep sequencing of a small RNA library and a degradome library. Our study provides more information about the regulatory network of miRNAs in soybean and advances our understanding of miRNA functions during seed development.

  17. Target Laboratory

    Data.gov (United States)

    Federal Laboratory Consortium — [Part of the ATLAS user facility.] The Physics Division operates a target development laboratory that produces targets and foils of various thickness and substrates,...

  18. In silico tools used for compound selection during target-based drug discovery and development.

    Science.gov (United States)

    Caldwell, Gary W

    2015-01-01

    The target-based drug discovery process, including target selection, screening, hit-to-lead (H2L) and lead optimization stage gates, is the most common approach used in drug development. The full integration of in vitro and/or in vivo data with in silico tools across the entire process would be beneficial to R&D productivity by developing effective selection criteria and drug-design optimization strategies. This review focuses on understanding the impact and extent in the past 5 years of in silico tools on the various stage gates of the target-based drug discovery approach. There are a large number of in silico tools available for establishing selection criteria and drug-design optimization strategies in the target-based approach. However, the inconsistent use of in vitro and/or in vivo data integrated with predictive in silico multiparameter models throughout the process is contributing to R&D productivity issues. In particular, the lack of reliable in silico tools at the H2L stage gate is contributing to the suboptimal selection of viable lead compounds. It is suggested that further development of in silico multiparameter models and organizing biologists, medicinal and computational chemists into one team with a single accountable objective to expand the utilization of in silico tools in all phases of drug discovery would improve R&D productivity.

  19. Feasible climate targets. The roles of economic growth, coalition development and expectations

    International Nuclear Information System (INIS)

    Blanford, Geoffrey J.; Richels, Richard G.; Rutherford, Thomas F.

    2009-01-01

    The analysis presented here follows the design specified by the Energy Modeling Forum (EMF) Transition Scenarios study on achieving climate stabilization goals with delayed participation by developing countries. We use the MERGE model to evaluate the core EMF scenarios for both the international and the US-specific studies. Our results indicate that a radiative forcing target equivalent to 450 ppmv CO 2 -e cannot be met even allowing for full participation and overshoot during the entire 21st century. With delayed participation of developing countries, a target of 550 ppmv CO 2 -e is only attainable with pessimistic assumptions about economic growth, and even then only at very high cost. A target of 650 ppmv CO 2 -e can be met with delayed participation for a more affordable cost. We highlight sensitivities to the core scenarios in two key dimensions: (1) the effect of the unfolding global financial crisis on the rate of economic growth and (2) the willingness of initially non-participating countries to agree at the beginning of the next commitment period (i.e. 2012) to join the coalition at a pre-specified date in the future. We find that while the recession does not fundamentally change the crucial role of developing country involvement, advance agreement on their part to future targets could substantially reduce costs for all countries. (author)

  20. Recent developments of target and ion sources to produce ISOL beams

    CERN Document Server

    Stora, Thierry

    2013-01-01

    In this review on target and ion sources for ISOL (Isotope Separation OnLine) beams, important develop- ments from the past five years are highlighted. While at precedent EMIS conferences, a particular focus was given to a single topics, for instance specifically on ion sources or on chemical purification tech- niques, here each of the important elements present in an ISOL production unit is discussed. Fast diffus- ing nanomaterials, uranium-based targets, high power targets for next generation facilities, purification by selective adsorption, new ion sources are all part of this review. For each of these selected topics, the reported results lead to significant gains in intensity, purity, or quality of the delivered beam, or in the production of new isotope beams. Often the outcome resulted from the combination of original ideas with state-of-the-art investigations; this was carried out using very different scientific disciplines, lead- ing to understanding of the underlying chemical or physical mechanisms a...

  1. Yeast-based assay identifies novel Shh/Gli target genes in vertebrate development

    Directory of Open Access Journals (Sweden)

    Milla Luis A

    2012-01-01

    Full Text Available Abstract Background The increasing number of developmental events and molecular mechanisms associated with the Hedgehog (Hh pathway from Drosophila to vertebrates, suggest that gene regulation is crucial for diverse cellular responses, including target genes not yet described. Although several high-throughput, genome-wide approaches have yielded information at the genomic, transcriptional and proteomic levels, the specificity of Gli binding sites related to direct target gene activation still remain elusive. This study aims to identify novel putative targets of Gli transcription factors through a protein-DNA binding assay using yeast, and validating a subset of targets both in-vitro and in-vivo. Testing in different Hh/Gli gain- and loss-of-function scenarios we here identified known (e.g., ptc1 and novel Hh-regulated genes in zebrafish embryos. Results The combined yeast-based screening and MEME/MAST analysis were able to predict Gli transcription factor binding sites, and position mapping of these sequences upstream or in the first intron of promoters served to identify new putative target genes of Gli regulation. These candidates were validated by qPCR in combination with either the pharmacological Hh/Gli antagonist cyc or the agonist pur in Hh-responsive C3H10T1/2 cells. We also used small-hairpin RNAs against Gli proteins to evaluate targets and confirm specific Gli regulation their expression. Taking advantage of mutants that have been identified affecting different components of the Hh/Gli signaling system in the zebrafish model, we further analyzed specific novel candidates. Studying Hh function with pharmacological inhibition or activation complemented these genetic loss-of-function approaches. We provide evidence that in zebrafish embryos, Hh signaling regulates sfrp2, neo1, and c-myc expression in-vivo. Conclusion A recently described yeast-based screening allowed us to identify new Hh/Gli target genes, functionally important in

  2. EURISOL-DS Multi-MW Target: Cost Analysis for a Proposed Development Phase

    CERN Document Server

    Karel, Samec; Kadi, Yacine; Noah, Etam; Lettry, Jacques; Wagner, Werner; Thomsen, Knud; Patorski, Jacek; Dementevjs, Sergej; Zik, Anatoli; Platacis, Erik

    The EURISOL Design Study has reached final completion and the three institutes, CERN, IPUL and PSI, participating in the development of the Multi-Megawatt target station have met the objective of a reliable, affordable and credible design. The costs involved in the full development of such a target are forecast to reach 200 million €, approximately 15% of the total costs of the EURISOL facility.A breakdown of the costs is presented as well as an outline of future possible R&D efforts aimed at improving reliability and safety of the facility. Another important goal of the proposed R&D is to minimise development risk by focusing resources, early on in the project, on areas identified as presenting a particular risk. An example clearly identified in the study would be the conditioning of the contaminated Mercury, both during the lifetime of the facility and after decommissioning.

  3. Overcoming Chemical, Biological, and Computational Challenges in the Development of Inhibitors Targeting Protein-Protein Interactions

    Science.gov (United States)

    Laraia, Luca; McKenzie, Grahame; Spring, David R.; Venkitaraman, Ashok R.; Huggins, David J.

    2015-01-01

    Protein-protein interactions (PPIs) underlie the majority of biological processes, signaling, and disease. Approaches to modulate PPIs with small molecules have therefore attracted increasing interest over the past decade. However, there are a number of challenges inherent in developing small-molecule PPI inhibitors that have prevented these approaches from reaching their full potential. From target validation to small-molecule screening and lead optimization, identifying therapeutically relevant PPIs that can be successfully modulated by small molecules is not a simple task. Following the recent review by Arkin et al., which summarized the lessons learnt from prior successes, we focus in this article on the specific challenges of developing PPI inhibitors and detail the recent advances in chemistry, biology, and computation that facilitate overcoming them. We conclude by providing a perspective on the field and outlining four innovations that we see as key enabling steps for successful development of small-molecule inhibitors targeting PPIs. PMID:26091166

  4. Developing Internet interventions to target the individual impact of stigma in health conditions

    Directory of Open Access Journals (Sweden)

    Neil Thomas

    2015-09-01

    Full Text Available A number of health problems are associated with significant stigma, a social phenomenon in which individuals become the object of negative stereotypes. In addition to experiencing negative reactions from others, stigmatised individuals and groups can experience harmful consequences when they internalise these negative prevailing attitudes. The objective of this paper was to consider the potential to develop Internet-based health-related interventions explicitly targeting the effects of stigma on the individual. A review of the literature was conducted to synthesise current conceptualisations of stigma and self-stigma across a number of groups, and to identify current intervention developments. Self-stigma reduction strategies developed for in-person services include cognitive reframing, myth busting, contact with other members of the stigmatised group, and disclosure promotion. The development and provision of interventions targeting self-stigma within an online environment is in its infancy. Our review considers there to be particular potential of online interventions for this target, associated with the capacity of the Internet to promote having contact with peers within one’s stigmatised group, and for user interaction and empowerment. We conclude that self-stigma is a domain in which there is significant potential for innovation with health-related interventions, and provide a number of recommendations for online intervention development.

  5. Oligodendrocyte Development in the Absence of Their Target Axons In Vivo.

    Directory of Open Access Journals (Sweden)

    Rafael Almeida

    Full Text Available Oligodendrocytes form myelin around axons of the central nervous system, enabling saltatory conduction. Recent work has established that axons can regulate certain aspects of oligodendrocyte development and myelination, yet remarkably oligodendrocytes in culture retain the ability to differentiate in the absence of axons and elaborate myelin sheaths around synthetic axon-like substrates. It remains unclear the extent to which the life-course of oligodendrocytes requires the presence of, or signals derived from axons in vivo. In particular, it is unclear whether the specific axons fated for myelination regulate the oligodendrocyte population in a living organism, and if so, which precise steps of oligodendrocyte-cell lineage progression are regulated by target axons. Here, we use live-imaging of zebrafish larvae carrying transgenic reporters that label oligodendrocyte-lineage cells to investigate which aspects of oligodendrocyte development, from specification to differentiation, are affected when we manipulate the target axonal environment. To drastically reduce the number of axons targeted for myelination, we use a previously identified kinesin-binding protein (kbp mutant, in which the first myelinated axons in the spinal cord, reticulospinal axons, do not fully grow in length, creating a region in the posterior spinal cord where most initial targets for myelination are absent. We find that a 73% reduction of reticulospinal axon surface in the posterior spinal cord of kbp mutants results in a 27% reduction in the number of oligodendrocytes. By time-lapse analysis of transgenic OPC reporters, we find that the reduction in oligodendrocyte number is explained by a reduction in OPC proliferation and survival. Interestingly, OPC specification and migration are unaltered in the near absence of normal axonal targets. Finally, we find that timely differentiation of OPCs into oligodendrocytes does not depend at all on the presence of target axons

  6. Assessing the universal health coverage target in the Sustainable Development Goals from a human rights perspective.

    Science.gov (United States)

    Chapman, Audrey R

    2016-12-15

    The UN's Sustainable Development Goals (SDGs), adopted in September 2015, include a comprehensive health goal, "to ensure healthy lives and promote well-being at all ages." The health goal (SDG 3) has nine substantive targets and four additional targets which are identified as a means of implementation. One of these commitments, to achieve universal health coverage (UHC), has been acknowledged as central to the achievement of all of the other health targets. As defined in the SDGs, UHC includes financial risk protection, access to quality essential health-care services, and access to safe, effective, quality and affordable essential medicines and vaccines for all. This article evaluates the extent to which the UHC target in the SDGs conforms with the requirements of the right to health enumerated in the International Covenant on Economic, Social and Cultural Rights, the Convention on the Rights of the Child, and other international human rights instruments and interpreted by international human rights bodies. It does so as a means to identify strengths and weaknesses in the framing of the UHC target that are likely to affect its implementation. While UHC as defined in the SDGs overlaps with human rights standards, there are important human rights omissions that will likely weaken the implementation and reduce the potential benefits of the UHC target. The most important of these is the failure to confer priority to providing access to health services to poor and disadvantaged communities in the process of expanding health coverage and in determining which health services to provide. Unless the furthest behind are given priority and strategies adopted to secure their participation in the development of national health plans, the SDGs, like the MDGs, are likely to leave the most disadvantaged and vulnerable communities behind.

  7. Axonal wiring in neural development: Target-independent mechanisms help to establish precision and complexity.

    Science.gov (United States)

    Petrovic, Milan; Schmucker, Dietmar

    2015-09-01

    The connectivity patterns of many neural circuits are highly ordered and often impressively complex. The intricate order and complexity of neuronal wiring remain not only a challenge for questions related to circuit functions but also for our understanding of how they develop with such an apparent precision. The chemotropic guidance of the growing axon by target-derived cues represents a central paradigm for how neurons get connected with the correct target cells. However, many studies reveal a remarkable variety of important target-independent wiring mechanisms. These mechanisms include axonal sorting, axonal tiling, growth cone polarization, as well as cell-intrinsic mechanisms underlying growth cone sprouting, and neurite branching. Our review focuses on target independent wiring mechanisms and in particular on recent progress emerging from studies on three different sensory systems: olfactory, visual, and somatosensory. We discuss molecular mechanisms that operate during axon-axon interactions or constitute axon-intrinsic functions and outline how they complement the well-known target-dependent wiring mechanisms. © 2015 WILEY Periodicals, Inc.

  8. New developments in cryo-targets for the external COSY experiments

    CERN Document Server

    Abdel-Samad, S; Kilian, K

    2002-01-01

    For cooling the liquid hydrogen/deuterium target from room temperature to the operating temperature (15 K/19 K) until recently a long solid copper heat conductor and a short heat pipe was used between cooling machine and the target cell. Recently, a new target version with metallic heat conductor of minimal length and a long gravity-assisted heat pipe section was constructed. The target material is used as a heat transport medium and high heat transfer is achieved by liquid-gas circulation. This design drastically reduces the weight of the system to less than 10 g in the 32 cm long standard geometry as compared with the previous copper heat conductors of 600 g. Uncontrollable secondary interactions are thus avoided. The cycle time of cooling down or heating up is reduced. The characteristics at steady-state operating conditions of the new 32 cm heat pipe-target system have been measured for hydrogen, deuterium, nitrogen and methane as the working fluids. Also successful was the development of a 2 m long heat ...

  9. Recent Developments in the VISRAD 3-D Target Design and Radiation Simulation Code

    Science.gov (United States)

    Macfarlane, Joseph; Golovkin, Igor; Sebald, James

    2017-10-01

    The 3-D view factor code VISRAD is widely used in designing HEDP experiments at major laser and pulsed-power facilities, including NIF, OMEGA, OMEGA-EP, ORION, Z, and LMJ. It simulates target designs by generating a 3-D grid of surface elements, utilizing a variety of 3-D primitives and surface removal algorithms, and can be used to compute the radiation flux throughout the surface element grid by computing element-to-element view factors and solving power balance equations. Target set-up and beam pointing are facilitated by allowing users to specify positions and angular orientations using a variety of coordinates systems (e.g., that of any laser beam, target component, or diagnostic port). Analytic modeling for laser beam spatial profiles for OMEGA DPPs and NIF CPPs is used to compute laser intensity profiles throughout the grid of surface elements. VISRAD includes a variety of user-friendly graphics for setting up targets and displaying results, can readily display views from any point in space, and can be used to generate image sequences for animations. We will discuss recent improvements to conveniently assess beam capture on target and beam clearance of diagnostic components, as well as plans for future developments.

  10. Development of antibody-based c-Met inhibitors for targeted cancer therapy

    Directory of Open Access Journals (Sweden)

    Lee D

    2015-02-01

    Full Text Available Dongheon Lee, Eun-Sil Sung, Jin-Hyung Ahn, Sungwon An, Jiwon Huh, Weon-Kyoo You Hanwha Chemical R&D Center, Biologics Business Unit, Daejeon, Republic of Korea Abstract: Signaling pathways mediated by receptor tyrosine kinases (RTKs and their ligands play important roles in the development and progression of human cancers, which makes RTK-mediated signaling pathways promising therapeutic targets in the treatment of cancer. Compared with small-molecule compounds, antibody-based therapeutics can more specifically recognize and bind to ligands and RTKs. Several antibody inhibitors of RTK-mediated signaling pathways, such as human epidermal growth factor receptor 2, vascular endothelial growth factor, epidermal growth factor receptor or vascular endothelial growth factor receptor 2, have been developed and are widely used to treat cancer patients. However, since the therapeutic options are still limited in terms of therapeutic efficacy and types of cancers that can be treated, efforts are being made to identify and evaluate novel RTK-mediated signaling pathways as targets for more efficacious cancer treatment. The hepatocyte growth factor/c-Met signaling pathway has come into the spotlight as a promising target for development of potent cancer therapeutic agents. Multiple antibody-based therapeutics targeting hepatocyte growth factor or c-Met are currently in preclinical or clinical development. This review focuses on the development of inhibitors of the hepatocyte growth factor/c-Met signaling pathway for cancer treatment, including critical issues in clinical development and future perspectives for antibody-based therapeutics. Keywords: hepatocyte growth factor, ligands, receptor tyrosine kinase, signaling pathway, therapeutic agent

  11. Status of SINQ, the only MW spallation neutron source-highlighting target development and industrial applications

    International Nuclear Information System (INIS)

    Wagner, Werner; Dai, Yong; Glasbrenner, Heike; Grosse, Mirco; Lehmann, Eberhard

    2006-01-01

    SINQ is a continuous spallation neutron source, driven by PSI's 590 MeV proton accelerator. Receiving a stable proton current of 1.3 mA, SINQ is the presently most powerful accelerator-driven facility worldwide. Besides the primary designation of SINQ to serve as user facility for neutron scattering and neutron imaging, PSI seeks to play a leading role in the development of the facility, focusing on spallation targets and materials research for high-dose radiation environments. Accompanying these activities, SINQ has established several projects serving a more general, profound development towards high-power spallation targets: the most prominent ones being SINQ Target Irradiation Program (STIP) and megawatt pilot experiment for a liquid metal target (MEGAPIE), complemented by LiSoR and VIMOS. Within the user program, SINQ is aspiring to attract an appropriate contingent of industrial applications. The paper highlights the potential for industrial applications by means of selected examples from strain mapping and neutron imaging

  12. The Bacterial Type III Secretion System as a Target for Developing New Antibiotics

    Science.gov (United States)

    McShan, Andrew C.; De Guzman, Roberto N.

    2017-01-01

    Antibiotic resistance in pathogens requires new targets for developing novel antibacterials. The bacterial type III secretion system (T3SS) is an attractive target for developing antibacterials as it is essential in the pathogenesis of many Gram-negative bacteria. The T3SS consists of structural proteins, effectors and chaperones. Over 20 different structural proteins assemble into a complex nanoinjector that punctures a hole on the eukaryotic cell membrane to allow the delivery of effectors directly into the host cell cytoplasm. Defects in the assembly and function of the T3SS render bacteria non-infective. Two major classes of small molecules, salicylidene acylhydrazides and thiazolidinones, have been shown to inhibit multiple genera of bacteria through the T3SS. Many additional chemically and structurally diverse classes of small molecule inhibitors of the T3SS have been identified as well. While specific targets within the T3SS of a few inhibitors have been suggested, the vast majority of specific protein targets within the T3SS remain to be identified or characterized. Other T3SS inhibitors include polymers, proteins and polypeptides mimics. In addition, T3SS activity is regulated by its interaction with biologically relevant molecules, such as bile salts and sterols, which could serve as scaffolds for drug design. PMID:25521643

  13. Development of Industrial-Scale Fission 99Mo Production Process Using Low Enriched Uranium Target

    Directory of Open Access Journals (Sweden)

    Seung-Kon Lee

    2016-06-01

    Full Text Available Molybdenum-99 (99Mo is the most important isotope because its daughter isotope, technetium-99m (99mTc, has been the most widely used medical radioisotope for more than 50 years, accounting for > 80% of total nuclear diagnostics worldwide. In this review, radiochemical routes for the production of 99Mo, and the aspects for selecting a suitable process strategy are discussed from the historical viewpoint of 99Mo technology developments. Most of the industrial-scale 99Mo processes have been based on the fission of 235U. Recently, important issues have been raised for the conversion of fission 99Mo targets from highly enriched uranium to low enriched uranium (LEU. The development of new LEU targets with higher density was requested to compensate for the loss of 99Mo yield, caused by a significant reduction of 235U enrichment, from the conversion. As the dramatic increment of intermediate level liquid waste is also expected from the conversion, an effective strategy to reduce the waste generation from the fission 99Mo production is required. The mitigation of radioxenon emission from medical radioisotope production facilities is discussed in relation with the monitoring of nuclear explosions and comprehensive nuclear test ban. Lastly, the 99Mo production process paired with the Korea Atomic Energy Research Institute's own LEU target is proposed as one of the most suitable processes for the LEU target.

  14. An update on anticancer drug development and delivery targeting carbonic anhydrase IX

    Directory of Open Access Journals (Sweden)

    Justina Kazokaitė

    2017-11-01

    Full Text Available The expression of carbonic anhydrase (CA IX is up-regulated in many types of solid tumors in humans under hypoxic and acidic microenvironment. Inhibition of CA IX enzymatic activity with selective inhibitors, antibodies or labeled probes has been shown to reverse the acidic environment of solid tumors and reduce the tumor growth establishing the significant role of CA IX in tumorigenesis. Thus, the development of potent antitumor drugs targeting CA IX with minimal toxic effects is important for the target-specific tumor therapy. Recently, several promising antitumor agents against CA IX have been developed to treat certain types of cancers in combination with radiation and chemotherapy. Here we review the inhibition of CA IX by small molecule compounds and monoclonal antibodies. The methods of enzymatic assays, biophysical methods, animal models including zebrafish and Xenopus oocytes, and techniques of diagnostic imaging to detect hypoxic tumors using CA IX-targeted conjugates are discussed with the aim to overview the recent progress related to novel therapeutic agents that target CA IX in hypoxic tumors.

  15. Enhancement of the efficiency of magnetic targeting for drug delivery: Development and evaluation of magnet system

    International Nuclear Information System (INIS)

    Cao Quanliang; Han Xiaotao; Li Liang

    2011-01-01

    Deep magnetic capture and clinical application are the current trends for magnetic targeted drug delivery system. More promising and possible strategies are needed to overcome the current limitations and further improve the magnetic targeting technique. Recent advances in the development of targeting magnet system show promise in progressing this technology from the laboratory to the clinic. Starting from well-known basic concepts, current limitations of magnetic targeted drug delivery system are analyzed. Meanwhile, the design concepts and evaluations of some effective improvements in magnet system are discussed and reviewed with reference to (i) reasonable design of magnet system; (ii) control modes of magnet system used to generate dynamical magnetic fields; and (iii) magnetic field driving types. - Research Highlights: → The current limitations of MTDDS for deep capture and clinical application are analyzed. → The development of magnet system shows promise in progressing MTDDS to clinical application. → The design concepts and evaluations of improvements in magnet system are reviewed and discussed. → The key to improve magnet system lies in controllable magnets and different excitations.

  16. Development of industrial-scale fission {sup 99}Mo production process using low enriched uranium target

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Seung Kon; Lee, Jun Sig [Radioisotope Research Division, Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of); Beyer, Gerd J. [Grunicke Strasse 15, Leipzig (Germany)

    2016-06-15

    Molybdenum-99 ({sup 99}Mo) is the most important isotope because its daughter isotope, technetium-99m ({sup 99}mTc), has been the most widely used medical radioisotope for more than 50 years, accounting for > 80% of total nuclear diagnostics worldwide. In this review, radiochemical routes for the production of {sup 99}Mo, and the aspects for selecting a suitable process strategy are discussed from the historical viewpoint of {sup 99}Mo technology developments. Most of the industrial-scale {sup 99}Mo processes have been based on the fission of {sup 235}U. Recently, important issues have been raised for the conversion of fission {sup 99}Mo targets from highly enriched uranium to low enriched uranium (LEU). The development of new LEU targets with higher density was requested to compensate for the loss of {sup 99}Mo yield, caused by a significant reduction of {sup 235}U enrichment, from the conversion. As the dramatic increment of intermediate level liquid waste is also expected from the conversion, an effective strategy to reduce the waste generation from the fission {sup 99}Mo production is required. The mitigation of radioxenon emission from medical radioisotope production facilities is discussed in relation with the monitoring of nuclear explosions and comprehensive nuclear test ban. Lastly, the {sup 99}Mo production process paired with the Korea Atomic Energy Research Institute's own LEU target is proposed as one of the most suitable processes for the LEU target.

  17. Development of Targeted, Enzyme-Activated Nano-Conjugates for Hepatic Cancer Therapy

    Science.gov (United States)

    Kuruvilla, Sibu Philip

    Hepatocellular carcinoma (HCC) is the 5th most commonly-occurring cancer worldwide and the 2nd highest cause for cancer-related deaths globally. The current treatment strategy is the direct injection of a chemotherapeutic agent (e.g. doxorubicin; DOX) into the hepatic artery, through a process called hepatic arterial infusion (HAI). Unfortunately, HAI is severely hindered by limited therapeutic efficacy against the tumor and high systemic toxicity to surrounding organs (e.g. cardiotoxicity). This thesis focuses on the development of a targeted, nanoparticle-based drug delivery system aimed to improve the clinical treatment of HCC. In particular, we employ generation 5 (G5) poly(amido amine) (PAMAM) dendrimers targeted to hepatic cancer cells via N-acetylgalactosamine (NAcGal) ligands attached to the surface through a poly(ethylene glycol) (PEG) brush. DOX is attached to the G5 surface through two different enzyme-sensitive linkages, L3 or L4, to achieve controllable release of the drug inside hepatic cancer cells. The combination of NAcGal-PEG targeting branches with either L3- or L4-DOX linkages led to the development of P1 and P2 particles, respectively. In Part 1, we discuss the development of these particles and measure their ability to target and kill hepatic cancer cells in vitro. In Part 2, we investigate the antitumor activity of P1 and P2 particles in tumor-bearing mice in comparison to the free drug, and we measure the cardiac function of mice undergoing treatment to assess differences in DOX-induced cardiotoxicity. Finally, in Part 3, we explore multi-valent targeting of G5 dendrimers in pursuit of further improving their specificity to hepatic cancer cells. Ultimately, this thesis provides insight into the utility of nanoparticle-based drug delivery systems that can potentially be translated to the clinic to improve cancer therapy.

  18. Axonal cleaved caspase-3 regulates axon targeting and morphogenesis in the developing auditory brainstem

    Directory of Open Access Journals (Sweden)

    Sarah E Rotschafer

    2016-10-01

    Full Text Available Caspase-3 is a cysteine protease that is most commonly associated with cell death. Recent studies have shown additional roles in mediating cell differentiation, cell proliferation, and development of cell morphology. We investigated the role of caspase-3 in the development of chick auditory brainstem nuclei during embryogenesis. Immunofluorescence from embryonic days E6-13 revealed that the temporal expression of cleaved caspase-3 follows the ascending anatomical pathway. Expression is first seen in the auditory portion of VIIIth nerve including central axonal regions projecting to nucleus magnocellularis (NM, then later in NM axons projecting to nucleus laminaris (NL, and subsequently in NL dendrites. To examine the function of cleaved caspase-3 in chick auditory brainstem development, we blocked caspase-3 cleavage in developing chick embryos with the caspase-3 inhibitor Z-DEVD-FMK from E6 to E9, then examined NM and NL morphology and NM axonal targeting on E10. NL lamination in treated embryos was disorganized and the neuropil around NL contained a significant number of glial cells normally excluded from this region. Additionally, NM axons projected into inappropriate portions of NL in Z-DEVD-FMK treated embyros. We found that the presence of misrouted axons was associated with more severe NL disorganization. The effects of axonal caspase-3 inhibition on both NL morphogenesis and NM axon targeting suggest that these developmental processes are coordinated, likely through communication between axons and their targets.

  19. Exploiting the proteomics revolution in biotechnology: from disease and antibody targets to optimizing bioprocess development.

    Science.gov (United States)

    Heffner, Kelley M; Hizal, Deniz Baycin; Kumar, Amit; Shiloach, Joseph; Zhu, Jie; Bowen, Michael A; Betenbaugh, Michael J

    2014-12-01

    Recent advancements in proteomics have enabled the generation of high-quality data sets useful for applications ranging from target and monoclonal antibody (mAB) discovery to bioprocess optimization. Comparative proteomics approaches have recently been used to identify novel disease targets in oncology and other disease conditions. Proteomics has also been applied as a new avenue for mAb discovery. Finally, CHO and Escherichia coli cells represent the dominant production hosts for biopharmaceutical development, yet the physiology of these cells types has yet to be fully established. Proteomics approaches can provide new insights into these cell types, aiding in recombinant protein production, cell growth regulation, and medium formulation. Optimization of sample preparations and protein database developments are enhancing the quantity and accuracy of proteomic results. In these ways, innovations in proteomics are enriching biotechnology and bioprocessing research across a wide spectrum of applications. Copyright © 2014 Elsevier Ltd. All rights reserved.

  20. The development of uranium foil farication technology utilizing twin roll method for Mo-99 irradiation target

    CERN Document Server

    Kim, C K; Park, H D

    2002-01-01

    MDS Nordion in Canada, occupying about 75% of global supply of Mo-99 isotope, has provided the irradiation target of Mo-99 using the rod-type UAl sub x alloys with HEU(High Enrichment Uranium). ANL (Argonne National Laboratory) through co-operation with BATAN in Indonesia, leading RERTR (Reduced Enrichment for Research and Test Reactors) program substantially for nuclear non-proliferation, has designed and fabricated the annular cylinder of uranium targets, and successfully performed irradiation test, in order to develop the fabrication technology of fission Mo-99 using LEU(Low Enrichment Uranium). As the uranium foils could be fabricated in laboratory scale, not in commercialized scale by hot rolling method due to significant problems in foil quality, productivity and economic efficiency, attention has shifted to the development of new technology. Under these circumstances, the invention of uranium foil fabrication technology utilizing twin-roll casting method in KAERI is found to be able to fabricate LEU or...

  1. ANL progress in developing an LEU target and process for Mo-99 production: Cooperation with CNEA

    International Nuclear Information System (INIS)

    Gelis, A.V.; Vandegrift, G.F.; Aase, S.B.; Bakel, A.J.; Falkenberg, J.R.; Regalbuto, M.C.; Quigley, K.J.

    2003-01-01

    The primary mission of the Reduced Enrichment in Research and Test Reactors (RERTR) Program is to facilitate the conversion of research and test-reactor fuel and targets from high-enriched uranium (HEU) to low-enriched uranium (LEU). One of the current goals at Argonne National Laboratory (ANL) is to assist the Argentine Comision Nacional de Energia Atomica (CNEA) in developing an LEU foil target and a process for 99 Mo production. Specifically addressed in this paper is ANL R and D related to this conversion: (1) designing a prototype production vessel for digesting irradiated LEU foils in alkaline solutions and (2) developing a new digestion method to address all issues related to HEU to LEU conversion. (author)

  2. Development of Lipid-Based Nanoparticles for In Vivo Targeted Delivery of Imaging Agents into Breast Cancer Cells

    Science.gov (United States)

    2009-10-01

    targeted therapy. Targeted delivery of a combined imaging and therapy agent to cancer cells is an avenue to develop a new generation of effective and...ligands for targeting HER-2/neu on breast cancer cells . In near future we will test these nanoparticles with SK-BR-3 (HER-2/neu+) and MDA-MD-468 (HER-2/neu-) breast cancer cell lines.

  3. Multiple functions of CREB-binding protein during postembryonic development: identification of target genes.

    Science.gov (United States)

    Roy, Amit; George, Smitha; Palli, Subba Reddy

    2017-12-29

    Juvenile hormones (JH) and ecdysteroids control postembryonic development in insects. They serve as valuable targets for pest management. Hence, understanding the molecular mechanisms of their action is of crucial importance. CREB-binding protein (CBP) is a universal transcriptional co-regulator. It controls the expression of several genes including those from hormone signaling pathways through co-activation of many transcription factors. However, the role of CBP during postembryonic development in insects is not well understood. Therefore, we have studied the role of CBP in postembryonic development in Tribolium, a model coleopteran insect. CBP is ubiquitously expressed in the red flour beetle, Tribolium castaneum. RNA interference (RNAi) mediated knockdown of CBP resulted in a decrease in JH induction of Kr-h1 gene expression in Tribolium larvae and led to a block in their development. Moreover, the injection of CBP double-stranded RNA (dsRNA) showed lethal phenotypes within 8 days of injection. RNA-seq and subsequent differential gene expression analysis identified CBP target genes in Tribolium. Knockdown of CBP caused a decrease in the expression of 1306 genes coding for transcription factors and other proteins associated with growth and development. Depletion of CBP impaired the expression of several JH response genes (e.g., Kr-h1, Hairy, early trypsin) and ecdysone response genes (EcR, E74, E75, and broad complex). Further, GO enrichment analyses of the downregulated genes showed enrichment in different functions including developmental processes, pigmentation, anatomical structure development, regulation of biological and cellular processes, etc. These data suggest diverse but crucial roles for CBP during postembryonic development in the coleopteran model insect, Tribolium. It can serve as a target for RNAi mediated pest management of this stored product pest.

  4. Targeted therapies in development for non-small cell lung cancer

    Directory of Open Access Journals (Sweden)

    Thanyanan Reungwetwattana

    2013-01-01

    Full Text Available The iterative discovery in various malignancies during the past decades that a number of aberrant tumorigenic processes and signal transduction pathways are mediated by "druggable" protein kinases has led to a revolutionary change in drug development. In non-small cell lung cancer (NSCLC, the ErbB family of receptors (e.g., EGFR [epidermal growth factor receptor], HER2 [human epidermal growth factor receptor 2], RAS (rat sarcoma gene, BRAF (v-raf murine sarcoma viral oncogene homolog B1, MAPK (mitogen-activated protein kinase c-MET (c-mesenchymal-epithelial transition, FGFR (fibroblast growth factor receptor, DDR2 (discoidin domain receptor 2, PIK3CA (phosphatidylinositol-4,5-bisphosphate3-kinase, catalytic subunit alpha, PTEN (phosphatase and tensin homolog, AKT (protein kinase B, ALK (anaplastic lym phoma kinase, RET (rearranged during transfection, ROS1 (reactive oxygen species 1 and EPH (erythropoietin-producing hepatoma are key targets of various agents currently in clinical development. These oncogenic targets exert their selective growth advantage through various intercommunicating pathways, such as through RAS/RAF/MEK, phosphoinositide 3-kinase/AKT/mammalian target of rapamycin and SRC-signal transduction and transcription signaling. The recent clinical studies, EGFR tyrosine kinase inhibitors and crizotinib were considered as strongly effective targeted therapies in metastatic NSCLC. Currently, five molecular targeted agents were approved for treatment of advanced NSCLC: Gefitinib, erlotinib and afatinib for positive EGFR mutation, crizotinib for positive echinoderm microtubule-associated protein-like 4 (EML4-ALK translocation and bevacizumab. Moreover, oncogenic mutant proteins are subject to regulation by protein trafficking pathways, specifically through the heat shock protein 90 system. Drug combinations affecting various nodes in these signaling and intracellular processes are predicted and demonstrated to be synergistic and

  5. Targeted therapies in development for non-small cell lung cancer.

    Science.gov (United States)

    Reungwetwattana, Thanyanan; Dy, Grace Kho

    2013-01-01

    The iterative discovery in various malignancies during the past decades that a number of aberrant tumorigenic processes and signal transduction pathways are mediated by "druggable" protein kinases has led to a revolutionary change in drug development. In non-small cell lung cancer (NSCLC), the ErbB family of receptors (e.g., EGFR [epidermal growth factor receptor], HER2 [human epidermal growth factor receptor 2]), RAS (rat sarcoma gene), BRAF (v-raf murine sarcoma viral oncogene homolog B1), MAPK (mitogen-activated protein kinase) c-MET (c-mesenchymal-epithelial transition), FGFR (fibroblast growth factor receptor), DDR2 (discoidin domain receptor 2), PIK3CA (phosphatidylinositol-4,5-bisphosphate3-kinase, catalytic subunit alpha)), PTEN (phosphatase and tensin homolog), AKT (protein kinase B), ALK (anaplastic lym phoma kinase), RET (rearranged during transfection), ROS1 (reactive oxygen species 1) and EPH (erythropoietin-producing hepatoma) are key targets of various agents currently in clinical development. These oncogenic targets exert their selective growth advantage through various intercommunicating pathways, such as through RAS/RAF/MEK, phosphoinositide 3-kinase/AKT/mammalian target of rapamycin and SRC-signal transduction and transcription signaling. The recent clinical studies, EGFR tyrosine kinase inhibitors and crizotinib were considered as strongly effective targeted therapies in metastatic NSCLC. Currently, five molecular targeted agents were approved for treatment of advanced NSCLC: Gefitinib, erlotinib and afatinib for positive EGFR mutation, crizotinib for positive echinoderm microtubule-associated protein-like 4 (EML4)-ALK translocation and bevacizumab. Moreover, oncogenic mutant proteins are subject to regulation by protein trafficking pathways, specifically through the heat shock protein 90 system. Drug combinations affecting various nodes in these signaling and intracellular processes are predicted and demonstrated to be synergistic and

  6. DISC1 pathway in brain development: exploring therapeutic targets for major psychiatric disorders

    Directory of Open Access Journals (Sweden)

    Atsushi eKamiya

    2012-03-01

    Full Text Available Genetic risk factors for major psychiatric disorders play key roles in neurodevelopment. Thus, exploring the molecular pathways of risk genes is important not only for understanding the molecular mechanisms underlying brain development, but also to decipher how genetic disturbances affect brain maturation and functioning relevant to major mental illnesses. During the last decade, there has been significant progress in determining the mechanisms whereby risk genes impact brain development. Nonetheless, given that the majority of psychiatric disorders have etiological complexities encompassing multiple risk genes and environmental factors, the biological mechanisms of these diseases remain poorly understood. How can we move forward in our research for discovery of the biological markers and novel therapeutic targets for major mental disorders? Here we review recent progress in the neurobiology of Disrupted in schizophrenia 1 (DISC1, a major risk gene for major mental disorders, with a particular focus on its roles in cerebral cortex development. Convergent findings implicate DISC1 as part of a large, multi-step pathway implicated in various cellular processes and signal transduction. We discuss links between the DISC1 pathway and environmental factors, such as immune/inflammatory responses, which may suggest novel therapeutic targets. Existing treatments for major mental disorders are hampered by a limited number of pharmacological targets. Consequently, elucidation of the DISC1 pathway, and its association with neuropsychiatric disorders, may offer hope for novel treatment interventions.

  7. Development of colloids for cell and tissue targeting: bisphosphonate-functionalized gold nanoparticles for the investigation of bone targeting

    OpenAIRE

    Zayed, Gamal

    2010-01-01

    Gold nanoparticles (GNPs) possess a great potential as model systems for the investigation of nanoparticulate drug delivery due to their ease of production, low toxicity and also the high stability of the noble metal in biological fluids. Due to their unique surface chemistry, they can be used as building platform for stable self assembled monolayers of thioalkylated poly(ethylene glycol)s with different surface functionalities, allowing the investigation of different drug targeting principle...

  8. Developing Culturally Targeted Diabetes Educational Materials for Older Russian-Speaking Immigrants.

    Science.gov (United States)

    Van Son, Catherine R

    2014-07-01

    Older adults who immigrate late in life face many challenges adapting to a new country. Immigrants bring their cultural beliefs and behaviors with them, which can influence their ability to make dietary changes required when they have type 2 diabetes. Culturally targeted patient education materials are needed to improve immigrants' health literacy and abilities to self-manage diabetes. Currently, there is a scarcity of diabetes patient education materials to meet the educational needs of the Russian-speaking immigrant group. The purpose of this article is to describe a project in which culturally targeted diabetes education materials for older Russian-speaking immigrants were designed and developed. Culturally targeted patient education materials are essential if they are to be accepted and used by clients from different ethnic minority populations. The creation of culturally relevant materials requires a team effort and community stakeholder input. The availability of materials on the internet facilitates access and use by health care providers. Culturally targeted education materials are an important component in addressing health literacy in ethnic minority populations. Next steps require that these materials be evaluated to test their impact on diabetes self-management behaviors and clinical outcomes such as adherence, amount of physical activity, and blood glucose levels. © 2014 The Author(s).

  9. Recent progress in the development of a polarized proton target for reactions with radioactive ion beams

    International Nuclear Information System (INIS)

    Urrego-Blanco, J.P.; Bingham, C.R.; Brandt, B. van den; Galindo-Uribarri, A.; Gomez del Campo, J.; Hautle, P.; Konter, J.A.; Padilla-Rodal, E.; Schmelzbach, P.A.

    2007-01-01

    Polarization observables in nuclear reactions with stable beams have provided important information concerning structural properties of nuclei and reaction mechanisms and hold great promise in the context of exotic nuclei. We report on the development of a polarized target based on plastic foils of 20-200 μm thickness to be used with radioactive ion beams. The operation of such a target requires a moderately high magnetic field and very low temperatures. The plastic foil is placed inside a chamber attached to the mixing chamber of a 3 He- 4 He dilution refrigerator. Cooling of the foil is achieved via a superfluid film of 4 He that can be supplied through two capillaries. The chamber has two thin, highly uniform silicon nitride windows. An NMR coil is attached to the target to monitor the polarization. Results of a first test to characterize the target system, using the elastic scattering of 38 MeV 12 C by protons in inverse kinematics are presented

  10. Meeting targets or saving lives: maternal health policy and Millennium Development Goal 5 in Nicaragua.

    Science.gov (United States)

    Kvernflaten, Birgit

    2013-11-01

    In support of maternal health, disease-specific and target-oriented global policy initiatives, such as in Millennium Development Goal 5, have led to a prioritisation of narrow indicators at the expense of more comprehensive approaches. In line with global policy, Nicaragua has made skilled attendants and institutionalised delivery central to its efforts to achieving MDG5 on maternal health. Drawing on ethnographic fieldwork in Nicaragua, involving participant observation and interviews with hospital and community health workers, and women and their families, this paper critically discusses how target-oriented maternal health strategies were manifested in local realities. It shows that Nicaragua's brigadistas (community health workers) and parteras (traditional birth attendants) have been driven to narrowing their own roles to identifying pregnant women and advocating that they have an institutional delivery as one their most important tasks, making them agents of MDG 5 target achievement. This has engendered fear among brigadistas and parteras of being held individually responsible in the event of a maternal death, creating dissatisfaction with their role and reducing their motivation. While intended to improve maternal health, the pressure to reach targets has unintended negative implications for the relationship between women, the local volunteers and the formal health system, which needs to be addressed. Copyright © 2013 Reproductive Health Matters. Published by Elsevier Ltd. All rights reserved.

  11. Guidelines to PET measurements of the target occupancy in the brain for drug development

    Energy Technology Data Exchange (ETDEWEB)

    Takano, Akihiro; Varrone, Andrea; Gulyas, Balazs; Halldin, Christer [Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatric Research, Stockholm (Sweden); Salvadori, Piero [CNR Istituto di Fisiologia Clinica, Pisa (Italy); Gee, Antony [Kings College London, Department of Chemistry and Biology, Division of Imaging Sciences and Biomedical Engineering, London (United Kingdom); Windhorst, Albert; Lammertsma, Adriaan A. [VU University Medical Center, Department of Radiology and Nuclear Medicine, Amsterdam (Netherlands); Vercouillie, Johnny [Universite Francois Rabelais de Tours, UMR Inserm U930, Tours (France); Bormans, Guy [KU Leuven, Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, Leuven (Belgium)

    2016-11-15

    This guideline summarizes the current view of the European Association of Nuclear Medicine Drug Development Committee. The purpose of this guideline is to guarantee a high standard of PET studies that are aimed at measuring target occupancy in the brain within the framework of development programs of drugs that act within the central nervous system (CNS drugs). This guideline is intended to present information specifically adapted to European practice. The information provided should be applied within the context of local conditions and regulations. (orig.)

  12. Dynamic expression of Lgr5, a Wnt target gene, in the developing and mature mouse cochlea.

    Science.gov (United States)

    Chai, Renjie; Xia, Anping; Wang, Tian; Jan, Taha Adnan; Hayashi, Toshinori; Bermingham-McDonogh, Olivia; Cheng, Alan Gi-Lun

    2011-08-01

    The Wnt signaling pathway is a recurring theme in tissue development and homeostasis. Its specific roles during inner ear development are just emerging, but few studies have characterized Wnt target genes. Lgr5, a member of the G protein-coupled receptor family, is a Wnt target in the gastrointestinal and integumentary systems. Although its function is unknown, its deficiency leads to perinatal lethality due to gastrointestinal distension. In this study, we used a knock-in reporter mouse to examine the spatiotemporal expression of Lgr5 in the cochlear duct during embryonic and postnatal periods. In the embryonic day 15.5 (E15.5) cochlear duct, Lgr5-EGFP is expressed in the floor epithelium and overlapped with the prosensory markers Sox2, Jagged1, and p27(Kip1). Nascent hair cells and supporting cells in the apical turn of the E18.5 cochlear duct express Lgr5-EGFP, which becomes downregulated in hair cells and subsets of supporting cells in more mature stages. In situ hybridization experiments validated the reporter expression, which gradually decreases until the second postnatal week. Only the third row of Deiters' cells expresses Lgr5-EGFP in the mature organ of Corti. Normal cochlear development was observed in Lgr5(EGFP/EGFP) and Lgr5(EGFP/+) mice, which exhibited normal auditory thresholds. The expression pattern of Lgr5 contrasts with another Wnt target gene, Axin2, a feedback inhibitor of the Wnt pathway. Robust Axin2 expression was found in cells surrounding the embryonic cochlear duct and becomes restricted to tympanic border cells below the basilar membrane in the postnatal cochlea. Both Lgr5 and Axin2 act as Wnt targets in the cochlea because purified Wnt3a promoted and Wnt antagonist suppressed their expression. Their differential expression among cell populations highlights the dynamic but complex distribution of Wnt-activated cells in and around the embryonic and postnatal cochlea.

  13. Target and Non-Target Site Mechanisms Developed by Glyphosate-Resistant Hairy beggarticks (Bidens pilosa L. Populations from Mexico

    Directory of Open Access Journals (Sweden)

    Ricardo Alcántara-de la Cruz

    2016-10-01

    Full Text Available In 2014 hairy beggarticks (Bidens pilosa L. has been identified as being glyphosate-resistant in citrus orchards from Mexico. The target and non-target site mechanisms involved in the response to glyphosate of two resistant populations (R1 and R2 and one susceptible (S were studied. Experiments of dose-response, shikimic acid accumulation, uptake-translocation, enzyme activity and EPSPS gene sequencing were carried out in each population. The R1 and R2 populations were 20.4 and 2.8-fold less glyphosate sensitive, respectively, than the S population. The resistant populations showed a lesser shikimic acid accumulation than the S population. In the latter one, 24.9% of 14C-glyphosate was translocated to the roots at 96 h after treatment; in the R1 and R2 populations only 12.9 and 15.5%, respectively, was translocated. Qualitative results confirmed the reduced 14C-glyphosate translocation in the resistant populations. The EPSPS enzyme activity of the S population was 128.4 and 8.5-fold higher than the R1 and R2 populations of glyphosate-treated plants, respectively. A single (Pro-106-Ser, and a double (Thr-102-Ile followed by Pro-106-Ser mutations were identified in the EPSPS2 gene conferred high resistance in R1 population. Target-site mutations associated with a reduced translocation were responsible for the higher glyphosate resistance in the R1 population. The low-intermediate resistance of the R2 population was mediated by reduced translocation. This is the first glyphosate resistance case confirmed in hairy beggarticks in the world.

  14. Target and Non-target Site Mechanisms Developed by Glyphosate-Resistant Hairy beggarticks (Bidens pilosa L.) Populations from Mexico.

    Science.gov (United States)

    Alcántara-de la Cruz, Ricardo; Fernández-Moreno, Pablo T; Ozuna, Carmen V; Rojano-Delgado, Antonia M; Cruz-Hipolito, Hugo E; Domínguez-Valenzuela, José A; Barro, Francisco; De Prado, Rafael

    2016-01-01

    In 2014 hairy beggarticks ( Bidens pilosa L.) has been identified as being glyphosate-resistant in citrus orchards from Mexico. The target and non-target site mechanisms involved in the response to glyphosate of two resistant populations (R1 and R2) and one susceptible (S) were studied. Experiments of dose-response, shikimic acid accumulation, uptake-translocation, enzyme activity and 5-enolpyruvyl shikimate-3-phosphate synthase (EPSPS) gene sequencing were carried out in each population. The R1 and R2 populations were 20.4 and 2.8-fold less glyphosate sensitive, respectively, than the S population. The resistant populations showed a lesser shikimic acid accumulation than the S population. In the latter one, 24.9% of 14 C-glyphosate was translocated to the roots at 96 h after treatment; in the R1 and R2 populations only 12.9 and 15.5%, respectively, was translocated. Qualitative results confirmed the reduced 14 C-glyphosate translocation in the resistant populations. The EPSPS enzyme activity of the S population was 128.4 and 8.5-fold higher than the R1 and R2 populations of glyphosate-treated plants, respectively. A single (Pro-106-Ser), and a double (Thr-102-Ile followed by Pro-106-Ser) mutations were identified in the EPSPS2 gene conferred high resistance in R1 population. Target-site mutations associated with a reduced translocation were responsible for the higher glyphosate resistance in the R1 population. The low-intermediate resistance of the R2 population was mediated by reduced translocation. This is the first glyphosate resistance case confirmed in hairy beggarticks in the world.

  15. Developing Targeted Health Service Interventions Using the PRECEDE-PROCEED Model: Two Australian Case Studies

    Directory of Open Access Journals (Sweden)

    Jane L. Phillips

    2012-01-01

    Full Text Available Aims and Objectives. This paper provides an overview of the applicability of the PRECEDE-PROCEED Model to the development of targeted nursing led chronic illness interventions. Background. Changing health care practice is a complex and dynamic process that requires consideration of social, political, economic, and organisational factors. An understanding of the characteristics of the target population, health professionals, and organizations plus identification of the determinants for change are also required. Synthesizing this data to guide the development of an effective intervention is a challenging process. The PRECEDE-PROCEED Model has been used in global health care settings to guide the identification, planning, implementation, and evaluation of various health improvement initiatives. Design. Using a reflective case study approach, this paper examines the applicability of the PRECEDE-PROCEED Model to the development of targeted chronic care improvement interventions for two distinct Australian populations: a rapidly expanding and aging rural population with unmet palliative care needs and a disadvantaged urban community at higher risk of cardiovascular disease. Results. The PRECEDE-PROCEED Model approach demonstrated utility across diverse health settings in a systematic planning process. In environments characterized by increasing health care needs, limited resources, and growing community expectations, adopting planning tools such as PRECEDE-PROCEED Model at a local level can facilitate the development of the most effective interventions. Relevance to Clinical Practice. The PRECEDE-PROCEED Model is a strong theoretical model that guides the development of realistic nursing led interventions with the best chance of being successful in existing health care environments.

  16. Temporal interplay between efflux pumps and target mutations in development of antibiotic resistance in Escherichia coli.

    Science.gov (United States)

    Singh, Renu; Swick, Michelle C; Ledesma, Kimberly R; Yang, Zhen; Hu, Ming; Zechiedrich, Lynn; Tam, Vincent H

    2012-04-01

    The emergence of resistance presents a debilitating change in the management of infectious diseases. Currently, the temporal relationship and interplay between various mechanisms of drug resistance are not well understood. A thorough understanding of the resistance development process is needed to facilitate rational design of countermeasure strategies. Using an in vitro hollow-fiber infection model that simulates human drug treatment, we examined the appearance of efflux pump (acrAB) overexpression and target topoisomerase gene (gyrA and parC) mutations over time in the emergence of quinolone resistance in Escherichia coli. Drug-resistant isolates recovered early (24 h) had 2- to 8-fold elevation in the MIC due to acrAB overexpression, but no point mutations were noted. In contrast, high-level (≥ 64× MIC) resistant isolates with target site mutations (gyrA S83L with or without parC E84K) were selected more readily after 120 h, and regression of acrAB overexpression was observed at 240 h. Using a similar dosing selection pressure, the emergence of levofloxacin resistance was delayed in a strain with acrAB deleted compared to the isogenic parent. The role of efflux pumps in bacterial resistance development may have been underappreciated. Our data revealed the interplay between two mechanisms of quinolone resistance and provided a new mechanistic framework in the development of high-level resistance. Early low-level levofloxacin resistance conferred by acrAB overexpression preceded and facilitated high-level resistance development mediated by target site mutation(s). If this interpretation is correct, then these findings represent a paradigm shift in the way quinolone resistance is thought to develop.

  17. Interpreting adjoint and ensemble sensitivity toward the development of optimal observation targeting strategies

    Energy Technology Data Exchange (ETDEWEB)

    Ancell, B.C.; Hakim, G.J. [Univ. of Washington, Seattle, WA (United States)

    2007-12-15

    Two general methods, adjoint or singular vector methods, and ensemble-based methods, have been previously investigated to identify locations where observations would have a significant positive impact on a numerical weather model forecast. In this paper, we perform a basic comparison of targeting regions chosen to reduce the expected variance of a chosen forecast response function within an ensemble Kalman filter (EnKF) based on both an adjoint method and an ensemble method. Ensemble sensitivity is defined by linear regressions of a chosen forecast response function onto the model initial-time state variables, and is used to calculate variance reduction fields to provide targeting guidance for the ensemble-based method. Adjoint sensitivity is used to provide targeting guidance for the adjoint-based method. 90 ensemble forecasts are considered over a 24-hour forecast period, and the response function is chosen to represent the sea-level pressure at a single point in the Pacific Northwest United States. Targeting by ensemble guidance is shown to be a function of ensemble sensitivity and both the initial-time model state and observation variance. We find that large areas of variance reduction exist away from regions of large ensemble sensitivity, adjoint sensitivity, and the initial-time variance of the model state. For hypothetical aircraft observations, ensemble guidance is superior to adjoint guidance for 850 hPa temperature observations in a single case. This advantage increases as the number of flight tracks increases. In all cases, as more flight tracks are considered, diminishing returns on response function variance reduction are realized. Implications of these results for the development of targeting strategies are discussed. (orig.)

  18. Development and optimization of targeted radionuclide tumor therapy using folate based radiopharmaceuticals

    CERN Document Server

    Reber, Josefine Astrid

    The folate receptor (FR) has been used for a quarter of a century as a tumor-associated target for selective delivery of drugs and imaging agents to cancer cells. While several folic acid radioconjugates have been successfully employed for imaging purposes in (pre)clinical studies, a therapeutic application of folic acid radioconjugates has not yet reached the critical stage which would allow a clinical translation. Due to a substantial expression of the FR in the proximal tubule cells, radiofolates accumulate in the kidneys which are at risk of damage by particle-radiation. To improve this situation, we aimed to develop and evaluate strategies for the performance of FR-targeted radionuclide therapy by decreasing the renal uptake of radiofolates and thereby reducing potential nephrotoxic effects. Two different strategies were investigated. First, the combination of radiofolates with chemotherapeutic agents such as pemetrexed (PMX) and 5-fluorouracil (5-FU) and secondly, an approach based on radioiodinated fol...

  19. Stem cell-derived neurons in the development of targeted treatment for schizophrenia and bipolar disorder.

    Science.gov (United States)

    Watmuff, Bradley; Liu, Bangyan; Karmacharya, Rakesh

    2017-04-01

    The recent advent of induced pluripotent stem cells has enabled the study of patient-specific and disease-related neurons in vitro and has facilitated new directions of inquiry into disease mechanisms. With these approaches, we now have the possibility of correlating ex vivo cellular phenotypes with individual patient response to treatment and/or side effects, which makes targeted treatments for schizophrenia and bipolar disorder a distinct prospect in the coming years. Here, we briefly review the current state of stem cell-based models and explore studies that are providing new insights into the disease biology of schizophrenia and bipolar disorder, which are laying the foundations for the development of novel targeted therapies.

  20. GPCR homomers and heteromers: a better choice as targets for drug development than GPCR monomers?

    Science.gov (United States)

    Casadó, Vicent; Cortés, Antoni; Mallol, Josefa; Pérez-Capote, Kamil; Ferré, Sergi; Lluis, Carmen; Franco, Rafael; Canela, Enric I

    2009-11-01

    G protein-coupled receptors (GPCR) are targeted by many therapeutic drugs marketed to fight against a variety of diseases. Selection of novel lead compounds are based on pharmacological parameters obtained assuming that GPCR are monomers. However, many GPCR are expressed as dimers/oligomers. Therefore, drug development may consider GPCR as homo- and hetero-oligomers. A two-state dimer receptor model is now available to understand GPCR operation and to interpret data obtained from drugs interacting with dimers, and even from mixtures of monomers and dimers. Heteromers are distinct entities and therefore a given drug is expected to have different affinities and different efficacies depending on the heteromer. All these concepts would lead to broaden the therapeutic potential of drugs targeting GPCRs, including receptor heteromer-selective drugs with a lower incidence of side effects, or to identify novel pharmacological profiles using cell models expressing receptor heteromers.

  1. Development and Testing of a 212Pb/212Bi Peptide for Targeting Metastatic Melanoma

    Energy Technology Data Exchange (ETDEWEB)

    Fisher, Darrell R.

    2012-10-25

    The purpose of this project is to develop a new radiolabeled peptide for imaging and treating metastatic melanoma. The immunoconjugate consists of a receptor-specific peptide that targets melanoma cells. The beta-emitter lead-212 (half-life = 10.4 hours) is linked by coordination chemistry to the peptide. After injection, the peptide targets melanoma receptors on the surfaces of melanoma cells. Lead-212 decays to the alpha-emitter bismuth-212 (half-life = 60 minutes). Alpha-particles that hit melanoma cell nuclei are likely to kill the melanoma cell. For cancer cell imaging, the lead-212 is replaced by lead-203 (half-life = 52 hours). Lead-203 emits 279 keV photons (80.1% abundance) that can be imaged and measured for biodistribution analysis, cancer imaging, and quantitative dosimetry.

  2. Target development for 67Cu, 82Sr radionuclide production at the RIC-80 facility

    Science.gov (United States)

    Panteleev, V. N.; Barzakh, A. E.; Batist, L. Kh.; Fedorov, D. V.; Ivanov, V. S.; Krotov, S. A.; Molkanov, P. L.; Moroz, F. V.; Orlov, S. Yu.; Volkov, Yu. M.

    2018-01-01

    A high-current cyclotron C-80 capable of producing 40-80 MeV proton beams with a current of up to 200 μA has been constructed and commissioned at PNPI (Petersburg Nuclear Physics Institute). One of the main goals of cyclotron C-80 is the production of a wide spectrum of medical radionuclides for diagnostics and therapy. To date, the project development of a radioisotope facility RIC-80 (radioisotopes at cyclotron C-80) has been completed. The feature of the project is the use of a mass-separator combined with the ion-target device for obtaining ion beams of radioisotopes with a high purity of separation that is especially important for medical applications. The first results of a new high-temperature method for extracting 82Sr and 67Cu radioisotopes from irradiated targets have been presented.

  3. EFTTRA, a European collaboration for the development of fuels and targets for the transmutation

    Energy Technology Data Exchange (ETDEWEB)

    Babelot, J.F. [Commission of the European Communities, Karlsruhe (Germany). European Inst. for Transuranium Elements; Gruppelaar, H. [Netherlands Energy Research Foundation (ECN), Petten (Netherlands); Muehling, G. [Kernforschungszentrum Karlsruhe GmbH (Germany); Prunier, C. [CEA Centre d`Etudes Nucleaires de Cadarache, 13 - Saint-Paul-les-Durance (France); Rome, M. [Electricite de France (EDF), 69 -Villeurbanne (France). Service Etudes et Projets Thermiques et Nucleaires; Salvatores, M. [CEA Centre d`Etudes Nucleaires de Cadarache, 13 -Saint-Paul-les-Durance (France)

    1994-12-01

    In the frame of the research programmes on the transmutation of long lived nuclides, many experimental or theoretical investigations have to be carried out within European collaborations, owing mainly to the costs of such studies. Therefore, a group named `Experimental Feasibility of Targets for Transmutation` (EFTTRA), has been formed, with participants from CEA (France). ECN (The Netherlands), EDF (France), KFK (Germany) and ITU (European Commission), to organise joint experiments for the study of materials for the transmutation. So far, it was decided to focus the work on the transmutation of {sup 99}Tc (metal), of {sup 129}I (compound), and of Am (in an inert matrix). Irradiations will take place in parallel in the Phenix fast reactor in France, and in the high flux thermal reactor HFR in the Netherlands. These experiments, together with the related post-irradiation examinations, constitute the first phase of the EFTTRA collaboration. In subsequent phases, EFTTRA will contribute to the development of fuels and targets. (orig.).

  4. Overview on materials and technological developments for the LMJ cryogenic target assembly

    International Nuclear Information System (INIS)

    Reneaume, B.; Allegre, G.; Botrel, R.; Bourcier, H.; Bourdenet, R.; Breton, O.; Collier, R.; Dauteuil, C.; Durut, F.; Faivre, A.; Fleury, E.; Geoffray, I.; Geoffray, G.; Jeannot, L.; Jehanno, L.; Legaie, O.; Legay, G.; Meux, S.; Schunk, J.; Theobald, M.; Vasselin, C.; Perin, J.P.; Viargues, F.; Paquignon, G.

    2011-01-01

    The cryogenic target assemblies (CTAs) designed for Laser Megajoule (LMJ) experiments have many functions and have to meet severe specifications imposed by implosion physics, the CTA thermal environment, and the CTA interfaces with the Megajoule laser cryogenic target positioner. Therefore, CTA fabrication uses many challenging materials and requires several technological studies. During the last 2 years, many developments have enabled better collection of comprehensive data on target constitutive materials and improvements in the fabrication of the CTA base, hohlraum, and aluminum turret. Studies have been carried out (a) to better characterize thermal properties of materials allowing optimization of the thermal simulation of the hohlraum, (b) to improve the CTA base fabrication process in order optimize thermal studies of the LMJ experimental filling station (EFS), and (c) to determine coatings on the polyimide membrane that may limit the 300 K thermal effect on the micro-shell and increase the deuterium-tritium fuel lifetime. CTAs have been produced to evaluate fabrication knowledge, to characterize CTAs, to study air tightness, and to study filling and D 2 ice layering on the EFS. An overview of the results that have been obtained during the past 2 years is presented in this paper. (authors)

  5. Putting together the psoriasis puzzle: an update on developing targeted therapies

    Directory of Open Access Journals (Sweden)

    Leanne M. Johnson-Huang

    2012-07-01

    Full Text Available Psoriasis vulgaris is a chronic, debilitating skin disease that affects millions of people worldwide. There is no mouse model that accurately reproduces all facets of the disease, but the accessibility of skin tissue from patients has facilitated the elucidation of many pathways involved in the pathogenesis of psoriasis and highlighted the importance of the immune system in the disease. The pathophysiological relevance of these findings has been supported by genetic studies that identified polymorphisms in genes associated with NFκB activation, IL-23 signaling and T helper 17 (Th17-cell adaptive immune responses, and in genes associated with the epidermal barrier. Recently developed biologic agents that selectively target specific components of the immune system are highly effective for treating psoriasis. In particular, emerging therapeutics are focused on targeting the IL-23–Th17-cell axis, and several agents that block IL-17 signaling have shown promising results in early-phase clinical trials. This review discusses lessons learned about the pathogenesis of psoriasis from mouse-and patient-based studies, emphasizing how the outcomes of clinical trials with T-cell-targeted and cytokine-blocking therapies have clarified our understanding of the disease.

  6. Development of a Thomson scattering diagnostic for the Caltech jet-target experiment

    Science.gov (United States)

    Seo, Byong Hoon; Greig, Amelia; Bellan, Paul

    2016-10-01

    A Thomson scattering diagnostic is being developed for studying the Caltech jet-target impact experiment. This experiment has a high-speed MHD-driven jet impact a dense, high-mass target cloud. The compression of the jet upon impact simulates the compression of an imploding liner. A preliminary bench top system consisting of a low power laser, lenses, a beam rotator, a monochromator, and a PMT is being used for measuring the Rayleigh and eventually Raman scattering signals from atmospheric pressure N2 and O2. The laser is modulated at 500 Hz to 1 kHz and lock-in techniques are used to recover the low-amplitude signal. For the actual pulsed plasma experiment, the low-power laser will be replaced by a high power Nd:YAG laser. The detector will consist of a double monochromator consisting of two single monochromators separated by a mask in the focal plane to block Rayleigh scattered light; detection will be by an intensified, gated camera. The diagnostic will be used to study the compression and heating that occurs when the jet plasma collides with a dense, high mass target cloud. Supported by USDOE Grant DE-AR0000565.

  7. Advances in the Development of Molecularly Targeted Agents in Non-Small-Cell Lung Cancer.

    Science.gov (United States)

    Dolly, Saoirse O; Collins, Dearbhaile C; Sundar, Raghav; Popat, Sanjay; Yap, Timothy A

    2017-05-01

    Non-small-cell lung cancer (NSCLC) remains a significant global health challenge and the leading cause of cancer-related mortality. The traditional 'one-size-fits-all' treatment approach has now evolved into one that involves personalized strategies based on histological and molecular subtypes. The molecular era has revolutionized the treatment of patients harboring epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) and ROS1 gene aberrations. In the appropriately selected population, anti-tumor agents against these molecular targets can significantly improve progression-free survival. However, the emergence of acquired resistance is inevitable. Novel potent compounds with much improved and rational selectivity profiles, such as third-generation EGFR T790M resistance mutation-specific inhibitors, have been developed and added to the NSCLC armamentarium. To date, attempts to overcome resistance bypass pathways through downstream signaling blockade has had limited success. Furthermore, the majority of patients still do not harbor known driver genetic or epigenetic alterations and/or have no new available treatment options, with chemotherapy remaining their standard of care. Several potentially actionable driver aberrations have recently been identified, with the early clinical development of multiple inhibitors against these promising targets currently in progress. The advent of immune checkpoint inhibitors has led to significant benefit for advanced NSCLC patients with durable responses observed. Further interrogation of the underlying biology of NSCLC, coupled with modern clinical trial designs, is now required to develop novel targeted therapeutics rationally matched with predictive biomarkers of response, so as to further advance NSCLC therapeutics through the next decade.

  8. [Development of multi-target multi-spectral high-speed pyrometer].

    Science.gov (United States)

    Xiao, Peng; Dai, Jing-Min; Wang, Qing-Wei

    2008-11-01

    The plume temperature of a solid propellant rocket engine (SPRE) is a fundamental parameter in denoting combustion status. It is necessary to measure the temperature along both the axis and the radius of the engine. In order to measure the plume temperature distribution of a solid propellant rocket engine, the multi-spectral thermometry has been approved. Previously the pyrometer was developed in the Harbin Institute of Technology of China in 1999, which completed the measurement of SPRE plume temperature and its distribution with multi-spectral technique in aerospace model development for the first time. Following this experience, a new type of multi-target multi-spectral high-speed pyrometer used in the ground experiments of SPRE plume temperature measurement was developed. The main features of the instrument include the use of a dispersing prism and a photo-diode array to cover the entire spectral band of 0.4 to 1.1 microm. The optic fibers are used in order to collect and transmit the thermal radiation fluxes. The instrument can measure simultaneously the temperature and emissivity of eight spectra for six uniformly distributed points on the target surface, which are well defined by the hole on the field stop lens. A specially designed S/H (Sample/Hold) circuit, with 48 sample and hold units that were triggered with a signal, measures the multi-spectral and multi-target outputs. It can sample 48 signals with a less than 10ns time difference which is most important for the temperature calculation.

  9. Mammalian target of rapamycin is essential for cardiomyocyte survival and heart development in mice

    International Nuclear Information System (INIS)

    Zhang, Pengpeng; Shan, Tizhong; Liang, Xinrong; Deng, Changyan; Kuang, Shihuan

    2014-01-01

    Highlights: • mTOR is a critical regulator of many biological processes yet its function in heart is not well understood. • MCK-Cre/Mtor flox/flox mice were established to delete Mtor in cardiomyocytes. • The mTOR-mKO mice developed normally but die prematurely within 5 weeks after birth due to heart disease. • The mTOR-mKO mice had dilated myocardium and increased cell death. • mTOR-mKO hearts had reduced expression of metabolic genes and activation of mTOR target proteins. - Abstract: Mammalian target of rapamycin (mTOR) is a critical regulator of protein synthesis, cell proliferation and energy metabolism. As constitutive knockout of Mtor leads to embryonic lethality, the in vivo function of mTOR in perinatal development and postnatal growth of heart is not well defined. In this study, we established a muscle-specific mTOR conditional knockout mouse model (mTOR-mKO) by crossing MCK-Cre and Mtor flox/flox mice. Although the mTOR-mKO mice survived embryonic and perinatal development, they exhibited severe postnatal growth retardation, cardiac muscle pathology and premature death. At the cellular level, the cardiac muscle of mTOR-mKO mice had fewer cardiomyocytes due to apoptosis and necrosis, leading to dilated cardiomyopathy. At the molecular level, the cardiac muscle of mTOR-mKO mice expressed lower levels of fatty acid oxidation and glycolysis related genes compared to the WT littermates. In addition, the mTOR-mKO cardiac muscle had reduced Myh6 but elevated Myh7 expression, indicating cardiac muscle degeneration. Furthermore, deletion of Mtor dramatically decreased the phosphorylation of S6 and AKT, two key targets downstream of mTORC1 and mTORC2 mediating the normal function of mTOR. These results demonstrate that mTOR is essential for cardiomyocyte survival and cardiac muscle function

  10. The role of sensory perception in the development and targeting of tobacco products.

    Science.gov (United States)

    Carpenter, Carrie M; Wayne, Geoffrey Ferris; Connolly, Gregory N

    2007-01-01

    To examine tobacco industry research on smoking-related sensory effects, including differences in sensory perception across smoker groups, and to determine whether this research informed targeted product development and impacted the development of commercial tobacco products. We searched previously secret internal tobacco industry documents available online through document databases housed at Tobacco Documents Online, the British American Tobacco Document Archive and the Legacy Tobacco Documents Library. We identified relevant documents using a snowball sampling method to first search the databases using an initial set of key words and to then establish further search terms. Sensory research is a priority within the tobacco industry directly impacting commercial markets both in the United States and internationally. Sensory factors contribute to smoker satisfaction and product acceptance, and play an important role in controlling puffing behavior. Cigarette manufacturers have capitalized on distinct sensory preferences across gender, age and ethnic groups by tailoring products for specific populations. Regulation of tobacco products is needed to address product changes that are used to reinforce or contribute to tobacco dependence; for instance, the incorporation of additives that target attributes such as smoothness, harshness and aftertaste. Greater understanding of the role of sensory effects on smoking behavior may also help to inform the development of tobacco treatment options that support long-term tobacco abstinence.

  11. Development of a neurofeedback protocol targeting the frontal pole using near-infrared spectroscopy.

    Science.gov (United States)

    Kinoshita, Akihide; Takizawa, Ryu; Yahata, Noriaki; Homae, Fumitaka; Hashimoto, Ryuichiro; Sakakibara, Eisuke; Kawasaki, Shingo; Nishimura, Yukika; Koike, Shinsuke; Kasai, Kiyoto

    2016-11-01

    Neurofeedback has been studied with the aim of controlling cerebral activity. Near-infrared spectroscopy is a non-invasive neuroimaging technique used for measuring hemoglobin concentration changes in cortical surface areas with high temporal resolution. Thus, near-infrared spectroscopy may be useful for neurofeedback, which requires real-time feedback of repeated brain activation measurements. However, no study has specifically targeted neurofeedback, using near-infrared spectroscopy, in the frontal pole cortex. We developed an original near-infrared spectroscopy neurofeedback system targeting the frontal pole cortex. Over a single day of testing, each healthy participant (n = 24) received either correct or incorrect (Sham) feedback from near-infrared spectroscopy signals, based on a crossover design. Under correct feedback conditions, significant activation was observed in the frontal pole cortex (P = 0.000073). Additionally, self-evaluation of control and metacognitive beliefs were associated with near-infrared spectroscopy signals (P = 0.006). The neurofeedback system developed in this study might be useful for developing control of frontal pole cortex activation. © 2016 The Authors. Psychiatry and Clinical Neurosciences © 2016 Japanese Society of Psychiatry and Neurology.

  12. HAND2 Target Gene Regulatory Networks Control Atrioventricular Canal and Cardiac Valve Development.

    Science.gov (United States)

    Laurent, Frédéric; Girdziusaite, Ausra; Gamart, Julie; Barozzi, Iros; Osterwalder, Marco; Akiyama, Jennifer A; Lincoln, Joy; Lopez-Rios, Javier; Visel, Axel; Zuniga, Aimée; Zeller, Rolf

    2017-05-23

    The HAND2 transcriptional regulator controls cardiac development, and we uncover additional essential functions in the endothelial to mesenchymal transition (EMT) underlying cardiac cushion development in the atrioventricular canal (AVC). In Hand2-deficient mouse embryos, the EMT underlying AVC cardiac cushion formation is disrupted, and we combined ChIP-seq of embryonic hearts with transcriptome analysis of wild-type and mutants AVCs to identify the functionally relevant HAND2 target genes. The HAND2 target gene regulatory network (GRN) includes most genes with known functions in EMT processes and AVC cardiac cushion formation. One of these is Snai1, an EMT master regulator whose expression is lost from Hand2-deficient AVCs. Re-expression of Snai1 in mutant AVC explants partially restores this EMT and mesenchymal cell migration. Furthermore, the HAND2-interacting enhancers in the Snai1 genomic landscape are active in embryonic hearts and other Snai1-expressing tissues. These results show that HAND2 directly regulates the molecular cascades initiating AVC cardiac valve development. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  13. Targeting Bacterial Dsb Proteins for the Development of Anti-Virulence Agents

    Directory of Open Access Journals (Sweden)

    Roxanne P. Smith

    2016-07-01

    Full Text Available Recent years have witnessed a dramatic increase in bacterial antimicrobial resistance and a decline in the development of novel antibiotics. New therapeutic strategies are urgently needed to combat the growing threat posed by multidrug resistant bacterial infections. The Dsb disulfide bond forming pathways are potential targets for the development of antimicrobial agents because they play a central role in bacterial pathogenesis. In particular, the DsbA/DsbB system catalyses disulfide bond formation in a wide array of virulence factors, which are essential for many pathogens to establish infections and cause disease. These redox enzymes are well placed as antimicrobial targets because they are taxonomically widespread, share low sequence identity with human proteins, and many years of basic research have provided a deep molecular understanding of these systems in bacteria. In this review, we discuss disulfide bond catalytic pathways in bacteria and their significance in pathogenesis. We also review the use of different approaches to develop inhibitors against Dsb proteins as potential anti-virulence agents, including fragment-based drug discovery, high-throughput screening and other structure-based drug discovery methods.

  14. Development of a Near-Field Bistatic Synthetic Aperture Radar for Complex Target Reconstruction

    Directory of Open Access Journals (Sweden)

    David G. Johnson

    2012-01-01

    Full Text Available This paper begins with a description of the design, construction, and characterization of a small electromagnetic anechoic chamber, developed specifically to house a bistatic ISAR system for the analysis of rock samples. Particular emphasis is given to the practicalities of construction, with the intention of assisting those in a similar position, wishing to build an anechoic chamber on a tight budget. The second part of the paper outlines efficient algorithms that may be applied to the tomographic and topographic reconstruction of complex targets within the viewing geometry of this ISAR system.

  15. Overexpression of miR-19b Impairs Cardiac Development in Zebrafish by Targeting ctnnb1

    Directory of Open Access Journals (Sweden)

    Mengmeng Li

    2014-07-01

    Full Text Available Background: MicroRNAs are broadly accepted as crucial regulators of cardiovascular development, and dysregulation of their expression has been linked to cardiac disease. MicroRNA cluster miR-17-92 has been implicated in cardiac development and function, yet its defined mechanisms of action in this context are uncertain. Here, we focused on miR-19b, a key component of the miR-17-92 cluster proven to induce cardiomyocyte proliferation in vitro. We aimed to identify the biological significance of miR-19b in cardiac development and its underlying molecular mechanism of action in vivo. Methods: We micro-injected zebrafish embryos with different concentrations (0, 2, 4 and 8 μm of miR-19b mimics or a negative control, and assessed the embryo malformation rate, mortality rate, hatching rate and heart abnormalities at 72 hours post-fertilization (72 hpf. Results: We found that overexpression of miR-19b impacted left-right symmetry and cardiac development of zebrafish embryos, characterized by pericardial edema, slower heart rate and cardiac looping defects in a dose-dependent manner. Moreover, several important signaling molecules in the Wnt signaling pathway were abnormally expressed, suggesting that overexpression of miR-19b induces the inhibition of the Wnt signaling pathway by directly targeting ctnnb1. Interestingly, the deformed cardiac phenotype was partially rescued by treatment with the GSK3β inhibitor lithium chloride. Conclusion: Our findings suggest that miR-19b regulates laterality development and heart looping in zebrafish embryos by targeting ctnnb1.

  16. Targeting DNA Replication and Repair for the Development of Novel Therapeutics against Tuberculosis

    Directory of Open Access Journals (Sweden)

    Michael A. Reiche

    2017-11-01

    Full Text Available Mycobacterium tuberculosis is the etiological agent of tuberculosis (TB, an infectious disease which results in approximately 10 million incident cases and 1.4 million deaths globally each year, making it the leading cause of mortality from infection. An effective frontline combination chemotherapy exists for TB; however, this regimen requires the administration of four drugs in a 2 month long intensive phase followed by a continuation phase of a further 4 months with two of the original drugs, and is only effective for the treatment of drug-sensitive TB. The emergence and global spread of multidrug-resistant (MDR as well as extensively drug-resistant (XDR strains of M. tuberculosis, and the complications posed by co-infection with the human immunodeficiency virus (HIV and other co-morbidities such as diabetes, have prompted urgent efforts to develop shorter regimens comprising new compounds with novel mechanisms of action. This demands that researchers re-visit cellular pathways and functions that are essential to M. tuberculosis survival and replication in the host but which are inadequately represented amongst the targets of current anti-mycobacterial agents. Here, we consider the DNA replication and repair machinery as a source of new targets for anti-TB drug development. Like most bacteria, M. tuberculosis encodes a complex array of proteins which ensure faithful and accurate replication and repair of the chromosomal DNA. Many of these are essential; so, too, are enzymes in the ancillary pathways of nucleotide biosynthesis, salvage, and re-cycling, suggesting the potential to inhibit replication and repair functions at multiple stages. To this end, we provide an update on the state of chemotherapeutic inhibition of DNA synthesis and related pathways in M. tuberculosis. Given the established links between genotoxicity and mutagenesis, we also consider the potential implications of targeting DNA metabolic pathways implicated in the

  17. Targeting DNA Replication and Repair for the Development of Novel Therapeutics against Tuberculosis.

    Science.gov (United States)

    Reiche, Michael A; Warner, Digby F; Mizrahi, Valerie

    2017-01-01

    Mycobacterium tuberculosis is the etiological agent of tuberculosis (TB), an infectious disease which results in approximately 10 million incident cases and 1.4 million deaths globally each year, making it the leading cause of mortality from infection. An effective frontline combination chemotherapy exists for TB; however, this regimen requires the administration of four drugs in a 2 month long intensive phase followed by a continuation phase of a further 4 months with two of the original drugs, and is only effective for the treatment of drug-sensitive TB. The emergence and global spread of multidrug-resistant (MDR) as well as extensively drug-resistant (XDR) strains of M. tuberculosis , and the complications posed by co-infection with the human immunodeficiency virus (HIV) and other co-morbidities such as diabetes, have prompted urgent efforts to develop shorter regimens comprising new compounds with novel mechanisms of action. This demands that researchers re-visit cellular pathways and functions that are essential to M. tuberculosis survival and replication in the host but which are inadequately represented amongst the targets of current anti-mycobacterial agents. Here, we consider the DNA replication and repair machinery as a source of new targets for anti-TB drug development. Like most bacteria, M. tuberculosis encodes a complex array of proteins which ensure faithful and accurate replication and repair of the chromosomal DNA. Many of these are essential; so, too, are enzymes in the ancillary pathways of nucleotide biosynthesis, salvage, and re-cycling, suggesting the potential to inhibit replication and repair functions at multiple stages. To this end, we provide an update on the state of chemotherapeutic inhibition of DNA synthesis and related pathways in M. tuberculosis . Given the established links between genotoxicity and mutagenesis, we also consider the potential implications of targeting DNA metabolic pathways implicated in the development of drug

  18. Targeting the noradrenergic system for gender-sensitive medication development for tobacco dependence.

    Science.gov (United States)

    Verplaetse, Terril L; Weinberger, Andrea H; Smith, Philip H; Cosgrove, Kelly P; Mineur, Yann S; Picciotto, Marina R; Mazure, Carolyn M; McKee, Sherry A

    2015-04-01

    Tobacco use remains the leading cause of morbidity and mortality for both women and men in the United States, and women often experience poorer smoking cessation outcomes than men. Preliminary evidence suggests there are sex differences in medication effectiveness for smoking cessation. However, current medications do not take into account gender-sensitive treatment development and efficacy, underscoring the importance of this underdeveloped area of research. We reviewed preclinical and clinical evidence for gender differences in the inability to quit smoking by examining (a) the effect of increased negative affect and stress reactivity on smoking outcomes in women and (b) smoking for nicotine reinforcement in men. We also reviewed the current literature targeting the noradrenergic system as a novel gender-sensitive treatment strategy for tobacco dependence. We hypothesize that noradrenergic agents that normalize noradrenergic activity may differentially attenuate stress reactivity in women and nicotine-related reinforcement in men, indicating that targeting the noradrenergic system for smoking cessation may be effective for both genders, with benefits operating through sex-specific mechanisms. Converging lines of preclinical and clinical evidence suggest that gender-sensitive approaches to medication development for smoking cessation are a critical next step for addressing low quit rates and exacerbated health risks among women. Evidence reviewed indicates that smoking activates different brain systems modulated by noradrenergic activity in women versus men, and noradrenergic compounds may preferentially target these gender-sensitive systems. © The Author 2015. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  19. Development of technology for producing nickel-gallium cyclotron targets by galvanic methods

    International Nuclear Information System (INIS)

    Umerov, R.A.; Kim, A.A.; Tushakov, S.A.; Djuraeva, G.T.; Khudaybergenov, U.; Tahirova, M.N.; Uzakov, Ya.M.

    2006-01-01

    deposition, in many cases, it is possible to achieve very high-purity of some settled metals. This effect has a huge technological value as allows to avoid some additional impurities of undesirable isotopes. In turn the effect of refining of superimposed metals allows to a yield a radionuclide with very high radiochemical purity. 3. The electrochemical method allows to adjust very precisely both thickness of a covering, and physical properties of covering - density of a settled covering and its crystal structure. Besides, it is necessary to underline that on the contrary to other methods of producing of cyclotron targets, the electrochemical method does not require the complex of expensive instrumentation. We had explored various systems for gallium - nickel cyclotron targets productions. Systems for deposition of two-layer gallium - nickel targets, and conditions of deposition of gallium basic layer and coating nickel layer were selected. The requirements for reliable production of the two-layer cyclotron target with adjustable thickness of gallium and nickel layers were determined. Received results allow to develop technological parameters for production of gallium - nickel cyclotron targets. (author)

  20. The capsule of Streptococcus equi ssp. zooepidemicus is a target for attenuation in vaccine development.

    Science.gov (United States)

    Wei, Zigong; Fu, Qiang; Chen, Yaosheng; Cong, Peiqing; Xiao, Shuqi; Mo, Delin; He, Zhuyong; Liu, Xiaohong

    2012-06-29

    Streptococcus equi ssp. zooepidemicus (SEZ) is an important pathogen associated with a wide range of diseases in many mammalian species. The development of novel effective vaccines would be beneficial to control SEZ infection. In the present study, the importance of the SEZ capsule was examined using a newly constructed capsule-deficient mutant ΔhasB strain. Transmission electron microscopy confirmed a decrease in the abundance of extracellular capsular polysaccharide on the mutant SEZ. Compared to the parental wild-type SEZ, the ΔhasB mutant was highly attenuated in mice and provided 100% protection against lethal challenge when administered as a live vaccine. Real-time PCR analysis showed a marked increased in the levels of IL-4 and IFN-γ mRNA in immunized mice. The role that the capsule plays in SEZ pathogenicity was also explored with respect to the mechanistic design of an attenuated vaccine target. The capsule could resist complement C3 deposition on the surface of SEZ cells and aid in preventing complement-mediated opsonization and phagocytosis by cultured macrophages. These results suggest that the capsule of SEZ plays an important role in pathogenicity and may serve as a target for attenuation in vaccine development. Copyright © 2012 Elsevier Ltd. All rights reserved.

  1. THE PROGRAM-TARGET PLANNING AND MANAGEMENT OF DEVELOPMENT OF MEASURING EQUIPMENT PARK

    Directory of Open Access Journals (Sweden)

    Marichev Pavel Aleksandrovich

    2018-02-01

    Full Text Available Subject: study of the Park of Measuring Equipment (PME that includes hundreds of thousands of standard samples, measuring instruments, control and measuring devices and other measuring mechanisms with different areas of application, levels of reliability, service life, levels of technical perfection and levels of technical condition. Research objectives: 1. Development of a complex of mathematical models to simulate the processes of development of PME, control indicators of PME performance as a whole, purposefully control the stages of life cycle of measuring equipment samples. 2. Development of the method which, with a sufficient degree of validity and objectivity, would solve the tasks of management of procurement and repairs both in preparation of proposals for preliminary long-term plan documents (LTPD and to ensure control over the implementation of adopted plans. Thus, the method being developed should be fairly simple to use, easily adjustable for solving problems of different dimensions, suitable for solving the optimal control problem for PME as a whole, for a part of PME, and also suitable for solving a generalized problem for certain “aggregated objects” such as the Metrology Centers. Materials and methods: the methods of mathematical simulation, methods of comparative analysis, simplex method for solving linear programming problem, methods of program-target planning were used. Results: an approach to the solution of problems of program-target planning based on solving a series of linear programming problems has been developed. The results have been presented of using the approach both for formulation of proposals into the preliminary LTPD and also for introducing revisions (amendments to annual plans, which are implemented in the framework of the state defense order. Conclusions: the described method and algorithms constitute an effective tool for solving practical problems of target-oriented management of PME performance

  2. Development of surface perturbation target and thin silicon foil target used to research Rayleigh-Taylor instability in inertial confinement fusion experiment

    International Nuclear Information System (INIS)

    Zhou Bin; Sun Qi; Huang Yaodong; Shen Jun; Wu Guangming; Wang Jue

    2004-01-01

    The developments of the surface perturbation target and the thin silicon foil target used to research Rayleigh-Taylor instability in the resolved experiments of Inertial Confinement Fusion (ICF) are carried out. Based on the laser interference process combined with the figure-transfer process, the surface perturbation target with sine modulated perturbation is gotten, the wavelength is in the range of 20-100 μm and the amplitude is several micrometers. The thin silicon foil within the thickness about 3-4 μm is prepared by semiconductor process together with heavy-doped self-stop etching. Combined with ion beam etching, the check or the stripe patterns are transferred to the surface of thin silicon foils, and then the silicon grating foil is obtained

  3. Identification of estrogen target genes during zebrafish embryonic development through transcriptomic analysis.

    Directory of Open Access Journals (Sweden)

    Ruixin Hao

    Full Text Available Estrogen signaling is important for vertebrate embryonic development. Here we have used zebrafish (Danio rerio as a vertebrate model to analyze estrogen signaling during development. Zebrafish embryos were exposed to 1 µM 17β-estradiol (E2 or vehicle from 3 hours to 4 days post fertilization (dpf, harvested at 1, 2, 3 and 4 dpf, and subjected to RNA extraction for transcriptome analysis using microarrays. Differentially expressed genes by E2-treatment were analyzed with hierarchical clustering followed by biological process and tissue enrichment analysis. Markedly distinct sets of genes were up and down-regulated by E2 at the four different time points. Among these genes, only the well-known estrogenic marker vtg1 was co-regulated at all time points. Despite this, the biological functional categories targeted by E2 were relatively similar throughout zebrafish development. According to knowledge-based tissue enrichment, estrogen responsive genes were clustered mainly in the liver, pancreas and brain. This was in line with the developmental dynamics of estrogen-target tissues that were visualized using transgenic zebrafish containing estrogen responsive elements driving the expression of GFP (Tg(5xERE:GFP. Finally, the identified embryonic estrogen-responsive genes were compared to already published estrogen-responsive genes identified in male adult zebrafish (Gene Expression Omnibus database. The expressions of a few genes were co-regulated by E2 in both embryonic and adult zebrafish. These could potentially be used as estrogenic biomarkers for exposure to estrogens or estrogenic endocrine disruptors in zebrafish. In conclusion, our data suggests that estrogen effects on early embryonic zebrafish development are stage- and tissue- specific.

  4. Thymidylate synthase expression determines pemetrexed targets and resistance development in tumour cells.

    Directory of Open Access Journals (Sweden)

    Aitziber Buqué

    Full Text Available Although treatment options for cancer patients are increasing every year, the drug resistance problem remains very present. It is very difficult to find a drug that acts equally on tumours of the same histology as the individual's genetic characteristics often determine the response to treatment. Furthermore, tumours that initially respond to anti-tumour therapy are able to adapt and develop resistance to the drug, while others do not. In addition, this usually implies resistance development to agents to which the cells have not been exposed, a phenomenon called cross-resistance or multidrug resistance. Given this situation, it has been suggested that the most appropriate treatment would be able to act in parallel on multiple pathways constitutively altered in tumour cells. Pemetrexed is a multitargeted antifolate that exerts its activity against folate-dependent enzymes involved in de novo pyrimidine and purine synthesis. It is currently in use in combination with cisplatin against malignant pleural mesothelioma and non-squamous non-small cell lung cancer with favourable results. By real-time RT-PCR gene expression assays and restoration viability assays we demonstrated that Pemetrexed targets folate-dependent enzymes involved in de novo biosynthesis of purines differently depending on the intrinsic genetic characteristics of the tumour. These differences did not, however, interfere either with the initial response to the drug or with the activation of apoptotic pathways. In addition, these genetic fingerprints can differentiate two groups of tumours: those capable of developing resistance to antifolate, and not capable. These results may be useful to employ targets gene expression as resistance markers, a valuable tool for identifying patients likely to receive combination therapy to prevent the development of resistance.

  5. Development of a PVD-based manufacturing process of monolithic LEU irradiation targets for {sup 99}Mo production

    Energy Technology Data Exchange (ETDEWEB)

    Hollmer, Tobias

    2015-08-03

    {sup 99}Mo is the most important radioisotope in nuclear medicine. It is produced by fission of uranium in irradiation targets. The usage of cylindrical monolithic targets can ensure a safe supply of {sup 99}Mo and at the same reduce the amount of highly radioactive waste generated during production. To manufacture these targets, a novel PVD-based technique was developed. Both the feasibility and the high efficiency of this process were demonstrated in a prototype apparatus.

  6. An update on the LEU target development and conversion program for the MAPLE reactors and new processing facility

    International Nuclear Information System (INIS)

    Malkoske, G.R.; Eng, B.Sc; Eng, P.

    2002-01-01

    Historically, the production of molybdenum-99 in the NRU research reactors at Chalk River, Canada, has been extracted from reactor targets employing highly enriched uranium (HEU). A reliable supply of HEU metal from the United States used in the manufacture of targets for the NRU research reactor has been a key factor to enable MDS Nordion to develop a secure supply of medical isotopes for the international nuclear medicine community. The molybdenum extraction process from HEU targets provides predictable, consistent yields for our high-volume molybdenum production process. Each link of the isotope supply chain, from isotope production to ultimate use by the physician, has been established using this proven and established method of HEU target irradiation and processing to extract molybdenum-99. To ensure a continued reliable and timely supply of medical isotopes, MDS Nordion is completing the construction of two MAPLE reactors and a New Processing Facility. The design of the MAPLE facilities was based on an established process developed by Atomic Energy of Canada Ltd. (AECL)-extraction of isotopes from HEU target material. However, in concert with the global trend to utilize low enriched uranium (LEU) in research reactors, MDS Nordion has launched a three phase LEU Target Development and Conversion Program for the MAPLE facilities. Phase 1, the Initial Feasibility Study, which identified the technical issues to convert the MAPLE reactor targets from HEU to LEU for large scale commercial production was reported on at the RERTR-2000 conference. The second phase of the LEU Target Development and Conversion Program was developed with extensive consultation and involvement of experts knowledgeable in target development, process system design, enriched uranium conversion chemistry and commercial scale reactor operations and molybdenum production. This paper will provide an overview of the Phase 2 Conversion Development Program, report on progress to date, and further

  7. Plasma Membrane-Targeted PIN Proteins Drive Shoot Development in a Moss

    Science.gov (United States)

    Bennett, Tom A.; Liu, Maureen M.; Aoyama, Tsuyoshi; Bierfreund, Nicole M.; Braun, Marion; Coudert, Yoan; Dennis, Ross J.; O’Connor, Devin; Wang, Xiao Y.; White, Chris D.; Decker, Eva L.; Reski, Ralf; Harrison, C. Jill

    2014-01-01

    Summary Background Plant body plans arise by the activity of meristematic growing tips during development and radiated independently in the gametophyte (n) and sporophyte (2n) stages of the life cycle during evolution. Although auxin and its intercellular transport by PIN family efflux carriers are primary regulators of sporophytic shoot development in flowering plants, the extent of conservation in PIN function within the land plants and the mechanisms regulating bryophyte gametophytic shoot development are largely unknown. Results We have found that treating gametophytic shoots of the moss Physcomitrella patens with exogenous auxins and auxin transport inhibitors disrupts apical function and leaf development. Two plasma membrane-targeted PIN proteins are expressed in leafy shoots, and pin mutants resemble plants treated with auxins or auxin transport inhibitors. PIN-mediated auxin transport regulates apical cell function, leaf initiation, leaf shape, and shoot tropisms in moss gametophytes. pin mutant sporophytes are sometimes branched, reproducing a phenotype only previously seen in the fossil record and in rare natural moss variants. Conclusions Our results show that PIN-mediated auxin transport is an ancient, conserved regulator of shoot development. PMID:25448003

  8. Hepatitis B virus reverse transcriptase - Target of current antiviral therapy and future drug development.

    Science.gov (United States)

    Clark, Daniel N; Hu, Jianming

    2015-11-01

    Hepatitis B virus (HBV) infections rely on the proper functioning of the viral polymerase enzyme, a specialized reverse transcriptase (RT) with multiple activities. All currently approved antiviral drugs for the treatment of chronic HBV infection, except for interferon, target the RT and belong to the same chemical class - they are all nucleoside analogs. Viral DNA synthesis is carried out by the RT enzyme in several different steps, each with distinct RT conformational requirements. In principle, each stage may be targeted by distinct antiviral drugs. In particular, the HBV RT has the unique ability to initiate viral DNA synthesis using itself as a protein primer in a novel protein priming reaction. In order to help identify RT inhibitors and study their mechanisms of action, a number of experimental systems have been developed, each varying in its ability to dissect the protein priming stage and subsequent stages of viral DNA synthesis at the molecular level. Two of the most effective drugs to date, entecavir and tenofovir, can inhibit both the protein priming and the subsequent DNA elongation stages of HBV DNA synthesis. Interestingly, clevudine, a thymidine analog, can inhibit both protein priming and DNA elongation in a non-competitive manner and without being incorporated into the viral DNA. Thus, a nucleoside RT inhibitor (NRTI) can functionally mimic a non-NRTI (NNRTI) in its inhibition of the HBV RT. Therefore, novel NRTIs as well as NNRTIs may be developed to inhibit the DNA synthesis activity of the HBV RT. Furthermore, additional activities of the RT that are also essential to HBV replication, including specific recognition of the viral RNA and its packaging into viral nucleocapsids, may be exploited for antiviral development. To achieve a more potent inhibition of viral replication and ultimately cure chronic HBV infection, the next generation of anti-HBV therapies will likely need to include NRTIs, NNRTIs, and other agents that target the viral RT as

  9. Targeted disruption of fibrinogen like protein-1 accelerates hepatocellular carcinoma development

    Energy Technology Data Exchange (ETDEWEB)

    Nayeb-Hashemi, Hamed; Desai, Anal; Demchev, Valeriy [Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine. Brigham and Women' s Hospital and Harvard Medical School, Boston, MA 02115 (United States); Bronson, Roderick T. [Department of Microbiology and Immunology, Harvard Medical School, Boston, MA 02115 (United States); Hornick, Jason L. [Department of Pathology, Brigham and Women' s Hospital and Harvard Medical School, Boston, MA 02115 (United States); Cohen, David E. [Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine. Brigham and Women' s Hospital and Harvard Medical School, Boston, MA 02115 (United States); Ukomadu, Chinweike, E-mail: cukomadu@partners.org [Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine. Brigham and Women' s Hospital and Harvard Medical School, Boston, MA 02115 (United States)

    2015-09-18

    Fibrinogen like protein-1 (Fgl1) is a predominantly liver expressed protein that has been implicated as both a hepatoprotectant and a hepatocyte mitogen. Fgl1 expression is decreased in hepatocellular carcinoma (HCC) and its loss correlates with a poorly differentiated phenotype. To better elucidate the role of Fgl1 in hepatocarcinogenesis, we treated mice wild type or null for Fgl1 with diethyl nitrosamine and monitored for incidence of hepatocellular cancer. We find that mice lacking Fgl1 develop HCC at more than twice the rate of wild type mice. We show that hepatocellular cancers from Fgl1 null mice are molecularly distinct from those of the wild type mice. In tumors from Fgl1 null mice there is enhanced activation of Akt and downstream targets of the mammalian target of rapamycin (mTOR). In addition, there is paradoxical up regulation of putative hepatocellular cancer tumor suppressors; tripartite motif-containing protein 35 (Trim35) and tumor necrosis factor super family 10b (Tnfrsf10b). Taken together, these findings suggest that Fgl1 acts as a tumor suppressor in hepatocellular cancer through an Akt dependent mechanism and supports its role as a potential therapeutic target in HCC. - Highlights: • Fgl1 knockout mice (Fgl1KO) are more prone to carcinogen-induced liver cancer compared to wild type (WT) mates. • Tumors from the Fgl1KO are molecularly distinct with enhanced Akt and mTOR activity in comparison with Fgl1WT tumors. • Tumors from the Fgl1KO have enhanced expression of Trim35 and Tnfrsf10b, putative HCC tumor suppressors.

  10. Development and in vivo evaluation of functionalized ritonavir proliposomes for lymphatic targeting.

    Science.gov (United States)

    Ahammed, Vasif; Narayan, Reema; Paul, John; Nayak, Yogendra; Roy, Bisakha; Shavi, Gopal V; Nayak, Usha Y

    2017-08-15

    The aim of the present work was to prepare, characterize, and evaluate proliposomes containing lipophilic prodrug ritonavir for targeting towards CD4+ T cells in the lymphatic system. The liposomes were prepared by lipid thin film hydration method and lyophilized in the presence of cryoprotectant mannitol to obtain proliposomes. The optimized proliposomes by Central Composite Design, were surface modified with biotin. The proliposomes were evaluated for particle size, zeta potential, polydispersity index (PDI), entrapment efficiency, in vitro drug release, in vivo pharmacokinetics and biodistribution studies. The mean particle size was found to be in the range of 126.6 to 306.2nm with PDI of 0.340-1.00. The entrapment efficiency was found to be in the range of 18.9 to 86.2%. The formulations showed a zeta potential in the range of -18.1 to -20.2mv. Biotinylated proliposomes (LIP-5B) were in the size of 149.8±6.8nm with entrapment efficiency 61.6%. The % CDR of pure drug, conventional, biotinylated proliposome in 3h was found to be 58.3, 82.04, and 95.9% respectively. In vitro drug release and in vivo pharmacokinetics of the pure drug, optimized conventional proliposomes (LIP-5) and biotin proliposomes (LIP-5B) were executed. The AUC for the liposomes were found to be much higher in the spleen and thymus compared to that in the plasma which indicated that the developed formulations enhance the bioavailability and target specificity compared to that of the pure drug thereby enhancing bioavailability at target site. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Modified egg as a nutritional supplement during peak brain development: a new target for fortification.

    Science.gov (United States)

    Shapira, Niva

    2009-01-01

    Though eggs have the unique capacity, like breastmilk, to concentrate essential nutrients required for early growth and brain development of offspring - i.e. n-3 PUFA, increasingly deficient and sources contaminated - cholesterol and allergy concerns often exclude them from perinatal recommendations. Egg's potential contribution of key nutrients required for peak brain development are re-evaluated vis-à-vis fortification, accessibility, and risks. Contributions of standard (USDA) and fortified (selected market-available) egg compositions to perinatal requirements for critical brain-supporting nutrients were compared to human and cow milks, and risks and recommendations evaluated. Standard egg has already higher concentrations/kcal of iron, selenium, zinc, choline, vitamins B12 and E, and essential amino acids (plus taurine) than human milk. Fortified egg could further yield significant n-3 PUFA % recommendations for pregnancy-lactation (total n-3 69.6-75.0% [DRI=1400-1300 mg/day]), including DHA (120.1-129.3%, mostly approximately 80% [calculated DRI=140-130 mg/day]), plus antioxidant vitamins A (9.0-15.2%) and E (51.6-65.3%), and minerals iodine (33.6-44.5%) and selenium (33.7-39.3%); % recommendations for children (1-3 y) even more. Cholesterol, important for nerve membranes and learning, may not be generally contraindicated in childbearing-aged women (approximately 10.5% hypercholesterolemia), and early-life egg exposure may increase tolerance. Egg-inclusive perinatal nutrition programs have shown significant contributions. Eggs, especially target-fortified, may provide a unique nutritional supplement for peak brain development continously during pregnancy, nursing, and infancy (from 6 months), especially vs. insufficiencies. Missing nutritional opportunities by egg exclusion vs. concerns of hypercholesterolemia or allergy could be addressed individually, rather than as general recommendations, warranting further research and targeted egg design.

  12. Twist1 transcriptional targets in the developing atrio-ventricular canal of the mouse.

    Directory of Open Access Journals (Sweden)

    Pavle Vrljicak

    Full Text Available Malformations of the cardiovascular system are the most common type of birth defect in humans, frequently affecting the formation of valves and septa. During heart valve and septa formation, cells from the atrio-ventricular canal (AVC and outflow tract (OFT regions of the heart undergo an epithelial-to-mesenchymal transformation (EMT and invade the underlying extracellular matrix to give rise to endocardial cushions. Subsequent maturation of newly formed mesenchyme cells leads to thin stress-resistant leaflets. TWIST1 is a basic helix-loop-helix transcription factor expressed in newly formed mesenchyme cells of the AVC and OFT that has been shown to play roles in cell survival, cell proliferation and differentiation. However, the downstream targets of TWIST1 during heart valve formation remain unclear. To identify genes important for heart valve development downstream of TWIST1, we performed global gene expression profiling of AVC, OFT, atria and ventricles of the embryonic day 10.5 mouse heart by tag-sequencing (Tag-seq. Using this resource we identified a novel set of 939 genes, including 123 regulators of transcription, enriched in the valve forming regions of the heart. We compared these genes to a Tag-seq library from the Twist1 null developing valves revealing significant gene expression changes. These changes were consistent with a role of TWIST1 in controlling differentiation of mesenchymal cells following their transformation from endothelium in the mouse. To study the role of TWIST1 at the DNA level we performed chromatin immunoprecipitation and identified novel direct targets of TWIST1 in the developing heart valves. Our findings support a role for TWIST1 in the differentiation of AVC mesenchyme post-EMT in the mouse, and suggest that TWIST1 can exert its function by direct DNA binding to activate valve specific gene expression.

  13. Twist1 transcriptional targets in the developing atrio-ventricular canal of the mouse.

    Science.gov (United States)

    Vrljicak, Pavle; Cullum, Rebecca; Xu, Eric; Chang, Alex C Y; Wederell, Elizabeth D; Bilenky, Mikhail; Jones, Steven J M; Marra, Marco A; Karsan, Aly; Hoodless, Pamela A

    2012-01-01

    Malformations of the cardiovascular system are the most common type of birth defect in humans, frequently affecting the formation of valves and septa. During heart valve and septa formation, cells from the atrio-ventricular canal (AVC) and outflow tract (OFT) regions of the heart undergo an epithelial-to-mesenchymal transformation (EMT) and invade the underlying extracellular matrix to give rise to endocardial cushions. Subsequent maturation of newly formed mesenchyme cells leads to thin stress-resistant leaflets. TWIST1 is a basic helix-loop-helix transcription factor expressed in newly formed mesenchyme cells of the AVC and OFT that has been shown to play roles in cell survival, cell proliferation and differentiation. However, the downstream targets of TWIST1 during heart valve formation remain unclear. To identify genes important for heart valve development downstream of TWIST1, we performed global gene expression profiling of AVC, OFT, atria and ventricles of the embryonic day 10.5 mouse heart by tag-sequencing (Tag-seq). Using this resource we identified a novel set of 939 genes, including 123 regulators of transcription, enriched in the valve forming regions of the heart. We compared these genes to a Tag-seq library from the Twist1 null developing valves revealing significant gene expression changes. These changes were consistent with a role of TWIST1 in controlling differentiation of mesenchymal cells following their transformation from endothelium in the mouse. To study the role of TWIST1 at the DNA level we performed chromatin immunoprecipitation and identified novel direct targets of TWIST1 in the developing heart valves. Our findings support a role for TWIST1 in the differentiation of AVC mesenchyme post-EMT in the mouse, and suggest that TWIST1 can exert its function by direct DNA binding to activate valve specific gene expression.

  14. Plasmodium falciparum glutamate dehydrogenase a is dispensable and not a drug target during erythrocytic development

    LENUS (Irish Health Repository)

    Storm, Janet

    2011-07-14

    Abstract Background Plasmodium falciparum contains three genes encoding potential glutamate dehydrogenases. The protein encoded by gdha has previously been biochemically and structurally characterized. It was suggested that it is important for the supply of reducing equivalents during intra-erythrocytic development of Plasmodium and, therefore, a suitable drug target. Methods The gene encoding the NADP(H)-dependent GDHa has been disrupted by reverse genetics in P. falciparum and the effect on the antioxidant and metabolic capacities of the resulting mutant parasites was investigated. Results No growth defect under low and elevated oxygen tension, no up- or down-regulation of a number of antioxidant and NADP(H)-generating proteins or mRNAs and no increased levels of GSH were detected in the D10Δgdha parasite lines. Further, the fate of the carbon skeleton of [13C] labelled glutamine was assessed by metabolomic studies, revealing no differences in the labelling of α-ketoglutarate and other TCA pathway intermediates between wild type and mutant parasites. Conclusions First, the data support the conclusion that D10Δgdha parasites are not experiencing enhanced oxidative stress and that GDHa function may not be the provision of NADP(H) for reductive reactions. Second, the results imply that the cytosolic, NADP(H)-dependent GDHa protein is not involved in the oxidative deamination of glutamate but that the protein may play a role in ammonia assimilation as has been described for other NADP(H)-dependent GDH from plants and fungi. The lack of an obvious phenotype in the absence of GDHa may point to a regulatory role of the protein providing glutamate (as nitrogen storage molecule) in situations where the parasites experience a limiting supply of carbon sources and, therefore, under in vitro conditions the enzyme is unlikely to be of significant importance. The data imply that the protein is not a suitable target for future drug development against intra

  15. Mammalian target of rapamycin is essential for cardiomyocyte survival and heart development in mice

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Pengpeng [Key Laboratory of Swine Genetics and Breeding, Ministry of Agriculture, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070 (China); Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction, Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070 (China); Department of Animal Sciences, Purdue University, West Lafayette, IN 47907 (United States); Shan, Tizhong; Liang, Xinrong [Department of Animal Sciences, Purdue University, West Lafayette, IN 47907 (United States); Deng, Changyan [Key Laboratory of Swine Genetics and Breeding, Ministry of Agriculture, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070 (China); Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction, Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070 (China); Kuang, Shihuan, E-mail: skuang@purdue.edu [Department of Animal Sciences, Purdue University, West Lafayette, IN 47907 (United States)

    2014-09-12

    Highlights: • mTOR is a critical regulator of many biological processes yet its function in heart is not well understood. • MCK-Cre/Mtor{sup flox/flox} mice were established to delete Mtor in cardiomyocytes. • The mTOR-mKO mice developed normally but die prematurely within 5 weeks after birth due to heart disease. • The mTOR-mKO mice had dilated myocardium and increased cell death. • mTOR-mKO hearts had reduced expression of metabolic genes and activation of mTOR target proteins. - Abstract: Mammalian target of rapamycin (mTOR) is a critical regulator of protein synthesis, cell proliferation and energy metabolism. As constitutive knockout of Mtor leads to embryonic lethality, the in vivo function of mTOR in perinatal development and postnatal growth of heart is not well defined. In this study, we established a muscle-specific mTOR conditional knockout mouse model (mTOR-mKO) by crossing MCK-Cre and Mtor{sup flox/flox} mice. Although the mTOR-mKO mice survived embryonic and perinatal development, they exhibited severe postnatal growth retardation, cardiac muscle pathology and premature death. At the cellular level, the cardiac muscle of mTOR-mKO mice had fewer cardiomyocytes due to apoptosis and necrosis, leading to dilated cardiomyopathy. At the molecular level, the cardiac muscle of mTOR-mKO mice expressed lower levels of fatty acid oxidation and glycolysis related genes compared to the WT littermates. In addition, the mTOR-mKO cardiac muscle had reduced Myh6 but elevated Myh7 expression, indicating cardiac muscle degeneration. Furthermore, deletion of Mtor dramatically decreased the phosphorylation of S6 and AKT, two key targets downstream of mTORC1 and mTORC2 mediating the normal function of mTOR. These results demonstrate that mTOR is essential for cardiomyocyte survival and cardiac muscle function.

  16. Inhibiting the Mammalian target of rapamycin blocks the development of experimental cerebral malaria.

    Science.gov (United States)

    Gordon, Emile B; Hart, Geoffrey T; Tran, Tuan M; Waisberg, Michael; Akkaya, Munir; Skinner, Jeff; Zinöcker, Severin; Pena, Mirna; Yazew, Takele; Qi, Chen-Feng; Miller, Louis H; Pierce, Susan K

    2015-06-02

    Malaria is an infectious disease caused by parasites of several Plasmodium spp. Cerebral malaria (CM) is a common form of severe malaria resulting in nearly 700,000 deaths each year in Africa alone. At present, there is no adjunctive therapy for CM. Although the mechanisms underlying the pathogenesis of CM are incompletely understood, it is likely that both intrinsic features of the parasite and the human host's immune response contribute to disease. The kinase mammalian target of rapamycin (mTOR) is a central regulator of immune responses, and drugs that inhibit the mTOR pathway have been shown to be antiparasitic. In a mouse model of CM, experimental CM (ECM), we show that the mTOR inhibitor rapamycin protects against ECM when administered within the first 4 days of infection. Treatment with rapamycin increased survival, blocked breakdown of the blood-brain barrier and brain hemorrhaging, decreased the influx of both CD4(+) and CD8(+) T cells into the brain and the accumulation of parasitized red blood cells in the brain. Rapamycin induced marked transcriptional changes in the brains of infected mice, and analysis of transcription profiles predicted that rapamycin blocked leukocyte trafficking to and proliferation in the brain. Remarkably, animals were protected against ECM even though rapamycin treatment significantly increased the inflammatory response induced by infection in both the brain and spleen. These results open a new avenue for the development of highly selective adjunctive therapies for CM by targeting pathways that regulate host and parasite metabolism. Malaria is a highly prevalent infectious disease caused by parasites of several Plasmodium spp. Malaria is usually uncomplicated and resolves with time; however, in about 1% of cases, almost exclusively among young children, malaria becomes severe and life threatening, resulting in nearly 700,000 deaths each year in Africa alone. Among the most severe complications of Plasmodium falciparum infection

  17. Development of New Drugs for an Old Target — The Penicillin Binding Proteins

    Directory of Open Access Journals (Sweden)

    André Luxen

    2012-10-01

    Full Text Available The widespread use of β-lactam antibiotics has led to the worldwide appearance of drug-resistant strains. Bacteria have developed resistance to β-lactams by two main mechanisms: the production of β-lactamases, sometimes accompanied by a decrease of outer membrane permeability, and the production of low-affinity, drug resistant Penicillin Binding Proteins (PBPs. PBPs remain attractive targets for developing new antibiotic agents because they catalyse the last steps of the biosynthesis of peptidoglycan, which is unique to bacteria, and lies outside the cytoplasmic membrane. Here we summarize the “current state of the art” of non-β-lactam inhibitors of PBPs, which have being developed in an attempt to counter the emergence of β-lactam resistance. These molecules are not susceptible to hydrolysis by β-lactamases and thus present a real alternative to β-lactams. We present transition state analogs such as boronic acids, which can covalently bind to the active serine residue in the catalytic site. Molecules containing ring structures different from the β-lactam-ring like lactivicin are able to acylate the active serine residue. High throughput screening methods, in combination with virtual screening methods and structure based design, have allowed the development of new molecules. Some of these novel inhibitors are active against major pathogens, including methicillin-resistant Staphylococcus aureus (MRSA and thus open avenues new for the discovery of novel antibiotics.

  18. A New Development in Audiovisual Translation Studies: Focus on Target Audience Perception

    Directory of Open Access Journals (Sweden)

    John Denton

    2013-03-01

    Full Text Available Audiovisual translation is now a well-established sub-discipline of Translation Studies (TS: a position that it has reached over the last twenty years or so. Italian scholars and professionals in the field have made a substantial contribution to this successful development, a brief overview of which will be given in the first part of this article, inevitably concentrating on dubbing in the Italian context. Special attention will be devoted to the question of target audience perception, an area where researchers in the University of Bologna at Forlì have excelled. The second part of the article applies the methodology followed by the above mentioned researchers in a case study of how Italian end users perceive the dubbed version of the British film The History Boys (2006, which contains a plethora of culture-specific verbal and visual references to the English education system. The aim of the study was to ascertain: a whether translation/adaptation allows the transmission in this admittedly constrained medium of all the intended culture-bound issues, only too well known to the source audience, and, if so, to what extent, and b whether the target audience respondents to the e-questionnaire used were aware that they were missing information. The linked, albeit controversial, issue of quality assessment will also be addressed.

  19. Targeting acute myeloid leukemia stem cells: a review and principles for the development of clinical trials.

    Science.gov (United States)

    Pollyea, Daniel A; Gutman, Jonathan A; Gore, Lia; Smith, Clayton A; Jordan, Craig T

    2014-08-01

    Despite an increasingly rich understanding of its pathogenesis, acute myeloid leukemia remains a disease with poor outcomes, overwhelmingly due to disease relapse. In recent years, work to characterize the leukemia stem cell population, the disease compartment most difficult to eliminate with conventional therapy and most responsible for relapse, has been undertaken. This, in conjunction with advances in drug development that have allowed for increasingly targeted therapies to be engineered, raises the hope that we are entering an era in which the leukemia stem cell population can be eliminated, resulting in therapeutic cures for acute myeloid leukemia patients. For these therapies to become available, they must be tested in the setting of clinical trials. A long-established clinical trials infrastructure has been employed to shepherd new therapies from proof-of-concept to approval. However, due to the unique features of leukemia stem cells, drugs that are designed to specifically eliminate this population may not be adequately tested when applied to this model. Therefore, in this review article, we seek to identify the relevant features of acute myeloid leukemia stem cells for clinical trialists, discuss potential strategies to target leukemia stem cells, and propose a set of guidelines outlining the necessary elements of clinical trials to allow for the successful testing of stem cell-directed therapies. Copyright© Ferrata Storti Foundation.

  20. MEDICI: Mining Essentiality Data to Identify Critical Interactions for Cancer Drug Target Discovery and Development.

    Science.gov (United States)

    Harati, Sahar; Cooper, Lee A D; Moran, Josue D; Giuste, Felipe O; Du, Yuhong; Ivanov, Andrei A; Johns, Margaret A; Khuri, Fadlo R; Fu, Haian; Moreno, Carlos S

    2017-01-01

    Protein-protein interactions (PPIs) mediate the transmission and regulation of oncogenic signals that are essential to cellular proliferation and survival, and thus represent potential targets for anti-cancer therapeutic discovery. Despite their significance, there is no method to experimentally disrupt and interrogate the essentiality of individual endogenous PPIs. The ability to computationally predict or infer PPI essentiality would help prioritize PPIs for drug discovery and help advance understanding of cancer biology. Here we introduce a computational method (MEDICI) to predict PPI essentiality by combining gene knockdown studies with network models of protein interaction pathways in an analytic framework. Our method uses network topology to model how gene silencing can disrupt PPIs, relating the unknown essentialities of individual PPIs to experimentally observed protein essentialities. This model is then deconvolved to recover the unknown essentialities of individual PPIs. We demonstrate the validity of our approach via prediction of sensitivities to compounds based on PPI essentiality and differences in essentiality based on genetic mutations. We further show that lung cancer patients have improved overall survival when specific PPIs are no longer present, suggesting that these PPIs may be potentially new targets for therapeutic development. Software is freely available at https://github.com/cooperlab/MEDICI. Datasets are available at https://ctd2.nci.nih.gov/dataPortal.

  1. Non-Target Gene Mutations in the Development of Fluoroquinolone Resistance in Escherichia coli

    Science.gov (United States)

    Kern, W. V.; Oethinger, M.; Jellen-Ritter, A. S.; Levy, S. B.

    2000-01-01

    Mutations in loci other than genes for the target topoisomerases of fluoroquinolones, gyrA and parC, may play a role in the development of fluoroquinolone resistance in Escherichia coli. A series of mutants with increasing resistance to ofloxacin was obtained from an E. coli K-12 strain and five clinical isolates. First-step mutants acquired a gyrA mutation. Second-step mutants reproducibly acquired a phenotype of multiple antibiotic resistance (Mar) and organic solvent tolerance and showed enhanced fluoroquinolone efflux. None of the second-step mutants showed additional topoisomerase mutations. All second-step mutants showed constitutive expression of marA and/or overexpressed soxS. In some third-step mutants, fluoroquinolone efflux was further enhanced compared to that for second-step mutants, even when the mutant had acquired additional topoisomerase mutations. Attempts to circumvent the second-step Mar mutation by induction of the mar locus with sodium salicylate and thus to select for pure topoisomerase mutants at the second step were not successful. At least in vitro, non-target gene mutations accumulate in second- and third-step mutants upon exposure to a fluoroquinolone and typically include, but do not appear to be limited to, mutations in the mar or sox regulons with consequent increased drug efflux. PMID:10722475

  2. The drug-minded protein interaction database (DrumPID) for efficient target analysis and drug development.

    Science.gov (United States)

    Kunz, Meik; Liang, Chunguang; Nilla, Santosh; Cecil, Alexander; Dandekar, Thomas

    2016-01-01

    The drug-minded protein interaction database (DrumPID) has been designed to provide fast, tailored information on drugs and their protein networks including indications, protein targets and side-targets. Starting queries include compound, target and protein interactions and organism-specific protein families. Furthermore, drug name, chemical structures and their SMILES notation, affected proteins (potential drug targets), organisms as well as diseases can be queried including various combinations and refinement of searches. Drugs and protein interactions are analyzed in detail with reference to protein structures and catalytic domains, related compound structures as well as potential targets in other organisms. DrumPID considers drug functionality, compound similarity, target structure, interactome analysis and organismic range for a compound, useful for drug development, predicting drug side-effects and structure-activity relationships.Database URL:http://drumpid.bioapps.biozentrum.uni-wuerzburg.de. © The Author(s) 2016. Published by Oxford University Press.

  3. Development of low enrichment technologies for high density fuels and for isotope production targets

    International Nuclear Information System (INIS)

    Taboada, Horacio; Gonzalez, Alfredo G.

    2005-01-01

    Since more than twenty years ago, CNEA has carried out RERTR activities. Main goals are to convert the RA 6 reactor core from HEU to LEU, to get a comprehensive understanding of U-Mo/Al compounds phase formation in dispersed and monolithic fuels, to develop possible solutions to VHD dispersed and monolithic fuels technical problems, and to optimize techniques to recover U from silicide scrap samples. The future plans include: 1) Completion the RA 6 reactor conversion to LEU; 2) Qualification by irradiation of the promising solutions found for the high density fuels; 3) Irradiation of mini plates and full scale fuel assemblies at the RA 3 reactor and at higher flux and temperature reactors; 4) Optimization of LEU target and radiochemical techniques for radioisotope production. (author) [es

  4. Diverse targets of phytoplasma effectors: from plant development to defense against insects.

    Science.gov (United States)

    Sugio, Akiko; MacLean, Allyson M; Kingdom, Heather N; Grieve, Victoria M; Manimekalai, R; Hogenhout, Saskia A

    2011-01-01

    Phytoplasma research begins to bloom (75). Indeed, this review shows that substantial progress has been made with the identification of phytoplasma effectors that alter flower development, induce witches' broom, affect leaf shape, and modify plant-insect interactions. Phytoplasmas have a unique life cycle among pathogens, as they invade organisms of two distinct kingdoms, namely plants (Plantae) and insects (Animalia), and replicate intracellularly in both. Phytoplasmas release effectors into host cells of plants and insects to target host molecules, and in plants these effectors unload from the phloem to access distal tissues and alter basic developmental processes. The effectors provide phytoplasmas with a fitness advantage by modulating their plant and insect hosts. We expect that further research on the functional characterization of phytoplasma effectors will generate new knowledge that is relevant to fundamental aspects of plant sciences and entomology, and for agriculture by improving yields of crops affected by phytoplasma diseases. Copyright © 2011 by Annual Reviews. All rights reserved.

  5. Development and utilization of ``Plate Changer'' system for neutrino interaction locations in OPERA emulsion target

    Science.gov (United States)

    Yoshida, J.; Ariga, A.; Ban, T.; Hoshino, K.; Ishiguro, K.; Kazuyama, M.; Kim, S. H.; Kitagawa, N.; Kodama, K.; Komatsu, M.; Koshiba, S.; Matsuo, T.; Miyanishi, K.; Morishima, K.; Naganawa, N.; Naka, T.; Nakano, T.; Nakatsuka, Y.; Natsume, M.; Narita, K.; Omura, T.; Oya, M.; Sato, O.; Shiraishi, T.; Suzuki, K.; Kose, U.; Yoon, C. S.; Zama, Y.

    2013-02-01

    In the OPERA experiment, so-called Scan Back method is used to locate neutrino interaction vertices in the emulsion target named ECC (Emulsion Cloud Chamber). In Scan Back method, tracks detected in the most downstream emulsion plate in ECCs are followed to upstream plate by plate until it reaches to the interaction points. In order to treat a number of neutrino interactions recorded in OPERA, dedicated systems called Plate Changer has been developed and utilized to neutrino event location in Japan. The details of the system have been described in this report. Until the end of November 2012, 6223 Scan Back trials have been performed using this system, and strongly contributed to the detection of tau neutrino appearance.

  6. Development and utilization of ''Plate Changer'' system for neutrino interaction locations in OPERA emulsion target

    International Nuclear Information System (INIS)

    Yoshida, J; Ariga, A; Ban, T; Hoshino, K; Ishiguro, K; Kazuyama, M; Kitagawa, N; Komatsu, M; Koshiba, S; Miyanishi, K; Morishima, K; Naganawa, N; Naka, T; Nakano, T; Nakatsuka, Y; Natsume, M; Narita, K; Kim, S H; Kodama, K; Matsuo, T

    2013-01-01

    In the OPERA experiment, so-called Scan Back method is used to locate neutrino interaction vertices in the emulsion target named ECC (Emulsion Cloud Chamber). In Scan Back method, tracks detected in the most downstream emulsion plate in ECCs are followed to upstream plate by plate until it reaches to the interaction points. In order to treat a number of neutrino interactions recorded in OPERA, dedicated systems called Plate Changer has been developed and utilized to neutrino event location in Japan. The details of the system have been described in this report. Until the end of November 2012, 6223 Scan Back trials have been performed using this system, and strongly contributed to the detection of tau neutrino appearance.

  7. Development and performance evaluation of a dynamic phantom for biological dosimetry of moving targets

    Science.gov (United States)

    Gemmel, A.; Bert, C.; Saito, N.; von Neubeck, C.; Iancu, G.; K-Weyrather, W.; Durante, M.; Rietzel, E.

    2010-06-01

    A dynamic phantom has been developed to allow for measurement of 3D cell survival distributions and the corresponding distributions of the RBE-weighted dose (RBED) in the presence of motion. The phantom consists of two 96-microwell plates holding Chinese hamster ovary cells inside a container filled with culture medium and is placed on a movable stage. Basic biological properties of the phantom were investigated without irradiation and after irradiation with a carbon ion beam, using both a stationary (reference) exposure and exposure during motion of the phantom perpendicular to the beam with beam tracking. There was no statistically significant difference between plating efficiency measured in the microwells with and without motion (0.75) and values reported in the literature. Mean differences between measured and calculated cell survival for these two irradiation modes were within ±5% of the target dose of 6 Gy (RBE).

  8. Latest developments in our understanding of the pathogenesis of mesothelioma and the design of targeted therapies.

    Science.gov (United States)

    Bononi, Angela; Napolitano, Andrea; Pass, Harvey I; Yang, Haining; Carbone, Michele

    2015-10-01

    Malignant mesothelioma is an aggressive cancer whose pathogenesis is causally linked to occupational exposure to asbestos. Familial clusters of mesotheliomas have been observed in settings of genetic predisposition. Mesothelioma incidence is anticipated to increase worldwide in the next two decades. Novel treatments are needed, as current treatment modalities may improve the quality of life, but have shown modest effects in improving overall survival. Increasing knowledge on the molecular characteristics of mesothelioma has led to the development of novel potential therapeutic strategies, including: molecular targeted approaches, that is the inhibition of vascular endothelial growth factor with bevacizumab; immunotherapy with chimeric monoclonal antibody, immunotoxin, antibody drug conjugate, vaccine and viruses; inhibition of asbestos-induced inflammation, that is aspirin inhibition of HMGB1 activity may decrease or delay mesothelioma onset and/or growth. We elaborate on the rationale behind new therapeutic strategies, and summarize available preclinical and clinical results, as well as efforts still ongoing.

  9. [Development of a hydrogen and deuterium polarized gas target for application in storage rings]: Progress report

    International Nuclear Information System (INIS)

    Haeberli, W.

    1989-01-01

    This paper briefly discusses the following topics: the Wisconsin test facility for storage cells; results of target tests; the new UHV target test system; funding request for a new atomic beam system; and planning of storage ring experiments

  10. Development of a hydrogen and deuterium polarized gas target for application in storage rings

    Energy Technology Data Exchange (ETDEWEB)

    Haeberli, W.

    1992-02-01

    Polarized gas targets of atomic hydrogen and deuterium have significant advantages over conventional polarized targets, e.g. chemical and isotopic purity, large polarization including deuteron tensor polarization, absence of strong magnetic fields, rapid polarization reversal. While in principle the beam of polarized atoms from an atomic beam source (Stern-Gerlach spin separation) can be used as a polarized target, the target thickness achieved is too small for most applications. We propose to increase the target thickness by injecting the polarized atoms into a storage cell. Provided the atoms survive several hundred wall collisions without losing their polarization, it will be possible to achieve a target thickness of 10{sup 13} to 10{sup 14} atoms/cm{sup 2} by injection of polarized atoms from an atomic-beam source into suitable cells. Such targets are very attractive as internal targets in storage rings.

  11. Development of a hydrogen and deuterium polarized gas target for application in storage rings. Progress report

    Energy Technology Data Exchange (ETDEWEB)

    Haeberli, W.

    1992-02-01

    Polarized gas targets of atomic hydrogen and deuterium have significant advantages over conventional polarized targets, e.g. chemical and isotopic purity, large polarization including deuteron tensor polarization, absence of strong magnetic fields, rapid polarization reversal. While in principle the beam of polarized atoms from an atomic beam source (Stern-Gerlach spin separation) can be used as a polarized target, the target thickness achieved is too small for most applications. We propose to increase the target thickness by injecting the polarized atoms into a storage cell. Provided the atoms survive several hundred wall collisions without losing their polarization, it will be possible to achieve a target thickness of 10{sup 13} to 10{sup 14} atoms/cm{sup 2} by injection of polarized atoms from an atomic-beam source into suitable cells. Such targets are very attractive as internal targets in storage rings.

  12. An in vivo reporter of BMP signaling in organogenesis reveals targets in the developing kidney

    Directory of Open Access Journals (Sweden)

    Karolak Michele J

    2008-09-01

    Full Text Available Abstract Background Bone morphogenetic proteins (BMPs regulate essential processes during organogenesis, and a functional understanding of these secreted proteins depends on identification of their target cells. In this study, we generate a transgenic reporter for organogenesis studies that we use to define BMP pathway activation in the developing kidney. Results Mouse strains reporting on BMP pathway activation were generated by transgenically expressing β-galactosidase under the control of BMP responsive elements from Id1. Reporter expression corresponds well with immunoassays for pathway activation in all organs studied, validating the model. Using these reporters we have generated a detailed map of cellular targets of BMP signaling in the developing kidney. We find that SMAD dependent BMP signaling is active in collecting duct trunks, but not tips. Furthermore, glomerular endothelial cells, and proximal nephron tubules from the renal vesicle stage onward show pathway activation. Surprisingly, little activation is detected in the nephrogenic zone of the kidney, and in organ culture BMP treatment fails to activate SMAD dependent BMP signaling in nephron progenitor cells. In contrast, signaling is efficiently induced in collecting duct tips. Conclusion Transgenic reporters driven by control elements from BMP responsive genes such as Id1 offer significant advantages in sensitivity and consistency over immunostaining for studies of BMP pathway activation. They also provide opportunities for analysis of BMP signaling in organ and primary cell cultures subjected to experimental manipulation. Using such a reporter, we made the surprising finding that SMAD dependent BMP signaling is inactive in nephron progenitors, and that these cells are refractory to activation by applied growth factors. Furthermore, we find that the BMP pathway is not normally active in collecting duct tips, but that it can be ectopically activated by BMP treatment, offering a

  13. Development of a methodology for defining whole-building energy design targets for commercial buildings: Phase 2, Development Concept Stage Report

    Energy Technology Data Exchange (ETDEWEB)

    McKay, H.N. (Illuminating Engineering Society of North America, New York, NY (USA)); Deringer, J.J. (American Inst. of Architects, Washington, DC (USA)); Jones, J.W. (American Society of Heating, Refrigerating and Air-Conditioning Engineers, Inc., Atlanta, GA (USA)); Hall, J.D. (Deringer Group, Riva, MD (USA))

    1990-09-01

    This report documents eight tasks performed as part of the Whole-Building Energy Design Targets project, in which detailed conceptual approaches were produced for each element of the proposed Targets model. The eight task reports together describe the important modules proposed for inclusion in the Targets model: input module, energy module, characteristic development moduel, building cost module, analysis control module, energy cost module, search routines module, and economic analysis module. 16 refs., 16 figs., 5 tabs.

  14. Mechanical activation of mammalian target of rapamycin pathway is required for cartilage development.

    Science.gov (United States)

    Guan, Yingjie; Yang, Xu; Yang, Wentian; Charbonneau, Cherie; Chen, Qian

    2014-10-01

    Mechanical stress regulates development by modulating cell signaling and gene expression. However, the cytoplasmic components mediating mechanotransduction remain unclear. In this study, elimination of muscle contraction during chicken embryonic development resulted in a reduction in the activity of mammalian target of rapamycin (mTOR) in the cartilaginous growth plate. Inhibition of mTOR activity led to significant inhibition of chondrocyte proliferation, cartilage tissue growth, and expression of chondrogenic genes, including Indian hedgehog (Ihh), a critical mediator of mechanotransduction. Conversely, cyclic loading (1 Hz, 5% matrix deformation) of embryonic chicken growth plate chondrocytes in 3-dimensional (3D) collagen scaffolding induced sustained activation of mTOR. Mechanical activation of mTOR occurred in serum-free medium, indicating that it is independent of growth factor or nutrients. Treatment of chondrocytes with Rapa abolished mechanical activation of cell proliferation and Ihh gene expression. Cyclic loading of chondroprogenitor cells deficient in SH2-containing protein tyrosine phosphatase 2 (Shp2) further enhanced mechanical activation of mTOR, cell proliferation, and chondrogenic gene expression. This result suggests that Shp2 is an antagonist of mechanotransduction through inhibition of mTOR activity. Our data demonstrate that mechanical activation of mTOR is necessary for cell proliferation, chondrogenesis, and cartilage growth during bone development, and that mTOR is an essential mechanotransduction component modulated by Shp2 in the cytoplasm. © FASEB.

  15. Development of a Targeted Smoking Relapse-Prevention Intervention for Cancer Patients

    Science.gov (United States)

    Meltzer, Lauren R.; Meade, Cathy D.; Diaz, Diana B.; Carrington, Monica S.; Brandon, Thomas H.; Jacobsen, Paul B.; McCaffrey, Judith C.; Haura, Eric B.; Simmons, Vani N.

    2016-01-01

    We describe the series of iterative steps used to develop a smoking relapse-prevention intervention customized to the needs of cancer patients. Informed by relevant literature and a series of preliminary studies, an educational tool (DVD) was developed to target the unique smoking relapse risk factors among cancer patients. Learner verification interviews were conducted with 10 cancer patients who recently quit smoking to elicit feedback and inform the development of the DVD. The DVD was then refined using iterative processes and feedback from the learner verification interviews. Major changes focused on visual appeal, and the inclusion of additional testimonials and graphics to increase comprehension of key points and further emphasize the message that the patient is in control of their ability to maintain their smoking abstinence. Together, these steps resulted in the creation of a DVD titled Surviving Smokefree®, which represents the first smoking relapse-prevention intervention for cancer patients. If found effective, the Surviving Smokefree® DVD is an easily disseminable and low-cost portable intervention which can assist cancer patients in maintaining smoking abstinence. PMID:27476432

  16. Development of a Targeted Smoking Relapse-Prevention Intervention for Cancer Patients.

    Science.gov (United States)

    Meltzer, Lauren R; Meade, Cathy D; Diaz, Diana B; Carrington, Monica S; Brandon, Thomas H; Jacobsen, Paul B; McCaffrey, Judith C; Haura, Eric B; Simmons, Vani N

    2018-04-01

    We describe the series of iterative steps used to develop a smoking relapse-prevention intervention customized to the needs of cancer patients. Informed by relevant literature and a series of preliminary studies, an educational tool (DVD) was developed to target the unique smoking relapse risk factors among cancer patients. Learner verification interviews were conducted with 10 cancer patients who recently quit smoking to elicit feedback and inform the development of the DVD. The DVD was then refined using iterative processes and feedback from the learner verification interviews. Major changes focused on visual appeal, and the inclusion of additional testimonials and graphics to increase comprehension of key points and further emphasize the message that the patient is in control of their ability to maintain their smoking abstinence. Together, these steps resulted in the creation of a DVD titled Surviving Smokefree®, which represents the first smoking relapse-prevention intervention for cancer patients. If found effective, the Surviving Smokefree® DVD is an easily disseminable and low-cost portable intervention which can assist cancer patients in maintaining smoking abstinence.

  17. Essential proteins and possible therapeutic targets of Wolbachia endosymbiont and development of FiloBase--a comprehensive drug target database for Lymphatic filariasis.

    Science.gov (United States)

    Sharma, Om Prakash; Kumar, Muthuvel Suresh

    2016-01-25

    Lymphatic filariasis (Lf) is one of the oldest and most debilitating tropical diseases. Millions of people are suffering from this prevalent disease. It is estimated to infect over 120 million people in at least 80 nations of the world through the tropical and subtropical regions. More than one billion people are in danger of getting affected with this life-threatening disease. Several studies were suggested its emerging limitations and resistance towards the available drugs and therapeutic targets for Lf. Therefore, better medicine and drug targets are in demand. We took an initiative to identify the essential proteins of Wolbachia endosymbiont of Brugia malayi, which are indispensable for their survival and non-homologous to human host proteins. In this current study, we have used proteome subtractive approach to screen the possible therapeutic targets for wBm. In addition, numerous literatures were mined in the hunt for potential drug targets, drugs, epitopes, crystal structures, and expressed sequence tag (EST) sequences for filarial causing nematodes. Data obtained from our study were presented in a user friendly database named FiloBase. We hope that information stored in this database may be used for further research and drug development process against filariasis. URL: http://filobase.bicpu.edu.in.

  18. The miR-30 microRNA family targets smoothened to regulate hedgehog signalling in zebrafish early muscle development

    OpenAIRE

    Ketley, Ami; Warren, Anne; Holmes, Emily; Gering, Martin; Aboobaker, A. Aziz; Brook, J. David

    2013-01-01

    The importance of microRNAs in development is now widely accepted. However, identifying the specific targets of individual microRNAs and understanding their biological significance remains a major challenge. We have used the zebrafish model system to evaluate the expression and function of microRNAs potentially involved in muscle development and study their interaction with predicted target genes. We altered expression of the miR-30 microRNA family and generated phenotypes that mimicked misre...

  19. Modern condition and possibilities of development of a moral component in a target orientation of the teenager

    Directory of Open Access Journals (Sweden)

    Shylova Nina Ihorivna

    2016-10-01

    Full Text Available The article considers the basic criteria of a moral component in a target orientation of the teenager, whose level of development being defined through the testing of pupils in Mykolaiv city. The article present the results given by the usage of two techniques, defines the ways and prospects of the further development of a moral component in a target orientation of teenagers.

  20. Mechanisms of developing post-traumatic stress disorder: new targets for drug development and other potential interventions.

    Science.gov (United States)

    Wimalawansa, Sunil J

    2014-01-01

    amygdala and hippocampus, which are characteristics of patients with PTSD. Considering these abnormalities, neuroendocrine system needs to be considered as a key target for new drug development for prevention and treatment of PTSD.

  1. Role of aminoacyl-tRNA synthetases in infectious diseases and targets for therapeutic development.

    Science.gov (United States)

    Dewan, Varun; Reader, John; Forsyth, Karin-Musier

    2014-01-01

    Aminoacyl-tRNA synthetases (AARSs) play a pivotal role in protein synthesis and cell viability. These 22 "housekeeping" enzymes (1 for each standard amino acid plus pyrrolysine and o-phosphoserine) are specifically involved in recognizing and aminoacylating their cognate tRNAs in the cellular pool with the correct amino acid prior to delivery of the charged tRNA to the protein synthesis machinery. Besides serving this canonical function, higher eukaryotic AARSs, some of which are organized in the cytoplasm as a multisynthetase complex of nine enzymes plus additional cellular factors, have also been implicated in a variety of non-canonical roles. AARSs are involved in the regulation of transcription, translation, and various signaling pathways, thereby ensuring cell survival. Based in part on their versatility, AARSs have been recruited by viruses to perform essential functions. For example, host synthetases are packaged into some retroviruses and are required for their replication. Other viruses mimic tRNA-like structures in their genomes, and these motifs are aminoacylated by the host synthetase as part of the viral replication cycle. More recently, it has been shown that certain large DNA viruses infecting animals and other diverse unicellular eukaryotes encode tRNAs, AARSs, and additional components of the protein-synthesis machinery. This chapter will review our current understanding of the role of host AARSs and tRNA-like structures in viruses and discuss their potential as anti-viral drug targets. The identification and development of compounds that target bacterial AARSs, thereby serving as novel antibiotics, will also be discussed. Particular attention will be given to recent work on a number of tRNA-dependent AARS inhibitors and to advances in a new class of natural "pro-drug" antibiotics called Trojan Horse inhibitors. Finally, we will explore how bacteria that naturally produce AARS-targeting antibiotics must protect themselves against cell suicide using

  2. Sex-Specificity of Mineralocorticoid Target Gene Expression during Renal Development, and Long-Term Consequences

    Directory of Open Access Journals (Sweden)

    Laurence Dumeige

    2017-02-01

    Full Text Available Sex differences have been identified in various biological processes, including hypertension. The mineralocorticoid signaling pathway is an important contributor to early arterial hypertension, however its sex-specific expression has been scarcely studied, particularly with respect to the kidney. Basal systolic blood pressure (SBP and heart rate (HR were measured in adult male and female mice. Renal gene expression studies of major players of mineralocorticoid signaling were performed at different developmental stages in male and female mice using reverse transcription quantitative PCR (RT-qPCR, and were compared to those of the same genes in the lung, another mineralocorticoid epithelial target tissue that regulates ion exchange and electrolyte balance. The role of sex hormones in the regulation of these genes was also investigated in differentiated KC3AC1 renal cells. Additionally, renal expression of the 11 β-hydroxysteroid dehydrogenase type 2 (11βHSD2 protein, a regulator of mineralocorticoid specificity, was measured by immunoblotting and its activity was indirectly assessed in the plasma using liquid-chromatography coupled to mass spectrometry in tandem (LC-MSMS method. SBP and HR were found to be significantly lower in females compared to males. This was accompanied by a sex- and tissue-specific expression profile throughout renal development of the mineralocorticoid target genes serum and glucocorticoid-regulated kinase 1 (Sgk1 and glucocorticoid-induced leucine zipper protein (Gilz, together with Hsd11b2, Finally, the implication of sex hormones in this sex-specific expression profile was demonstrated in vitro, most notably for Gilz mRNA expression. We demonstrate a tissue-specific, sex-dependent and developmentally-regulated pattern of expression of the mineralocorticoid pathway that could have important implications in physiology and pathology.

  3. Sex-Specificity of Mineralocorticoid Target Gene Expression during Renal Development, and Long-Term Consequences

    Science.gov (United States)

    Dumeige, Laurence; Storey, Caroline; Decourtye, Lyvianne; Nehlich, Melanie; Lhadj, Christophe; Viengchareun, Say; Kappeler, Laurent; Lombès, Marc; Martinerie, Laetitia

    2017-01-01

    Sex differences have been identified in various biological processes, including hypertension. The mineralocorticoid signaling pathway is an important contributor to early arterial hypertension, however its sex-specific expression has been scarcely studied, particularly with respect to the kidney. Basal systolic blood pressure (SBP) and heart rate (HR) were measured in adult male and female mice. Renal gene expression studies of major players of mineralocorticoid signaling were performed at different developmental stages in male and female mice using reverse transcription quantitative PCR (RT-qPCR), and were compared to those of the same genes in the lung, another mineralocorticoid epithelial target tissue that regulates ion exchange and electrolyte balance. The role of sex hormones in the regulation of these genes was also investigated in differentiated KC3AC1 renal cells. Additionally, renal expression of the 11 β-hydroxysteroid dehydrogenase type 2 (11βHSD2) protein, a regulator of mineralocorticoid specificity, was measured by immunoblotting and its activity was indirectly assessed in the plasma using liquid-chromatography coupled to mass spectrometry in tandem (LC-MSMS) method. SBP and HR were found to be significantly lower in females compared to males. This was accompanied by a sex- and tissue-specific expression profile throughout renal development of the mineralocorticoid target genes serum and glucocorticoid-regulated kinase 1 (Sgk1) and glucocorticoid-induced leucine zipper protein (Gilz), together with Hsd11b2, Finally, the implication of sex hormones in this sex-specific expression profile was demonstrated in vitro, most notably for Gilz mRNA expression. We demonstrate a tissue-specific, sex-dependent and developmentally-regulated pattern of expression of the mineralocorticoid pathway that could have important implications in physiology and pathology. PMID:28230786

  4. Development andin vitroevaluation of mucoadhesive patches of methotrexate for targeted delivery in oral cancer.

    Science.gov (United States)

    Jin, Bao-Zhong; Dong, Xiao-Qi; Xu, Xin; Zhang, Feng-He

    2018-02-01

    The present study focused on the development of a mucoadhesive patch of methotrexate (MTX) for targeted delivery in oral cancer. Initially, MTX-loaded liposomes were prepared using the thin film hydration method, and had a mean diameter of 105.7-137.4 nm and percentage entrapment efficiency of 54.6±3.5. These liposomes were cast in optimized mucoadhesive film. The film was characterized by its release pattern, thickness, weight and percentage swelling index and the sustained release profile of the optimized film was evaluated. The developed liposomes and liposomes cast in the film formulation were evaluated for cytotoxicity in HSC-3 cells using an MTT assay, and a significant decrease in the half maximal inhibitory concentration of MTX was identified with the MTX-entrapped liposomal film, M-LP-F7. The results of the mitochondria-dependent intrinsic pathway demonstrated that there was significant mitochondrial membrane potential disruption with M-LP-F7 compared with the plain drug. M-LP-F7 increased the rate of apoptosis in HSC-3 cells by almost 3-fold. Elevated levels of reactive oxygen species provided evidence that M-LP-F7 exerts a pro-oxidant effect in HSC-3 cells.

  5. Development progress of wide LEU foils for Mo-99 irradiation target at KAERI

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Ki Hwan; Son, Myung Koon; Lee, Don Bae; Lee, Byung Chul; Kim, Chang Kyu [Korea Atomic Energy Research Institute , Taejon (Korea, Republic of)

    2005-07-01

    As the uranium foils for Mo-99 irradiation target, which are charged into a reactor, can be conventionally fabricated at laboratory scale, but not yet at a commercialized scale by a hot rolling method due to some problems in foil quality, productivity and economic efficiency, an attention has shifted to the development of new improved technology. Under these circumstances, an alternative fabrication method of U polycrystalline foils has been investigated using a cooling roll casting method, in order to produce a fission isotope {sup 99}Mo, the parent nuclide of {sup 99m}Tc. The fabrication method of wide LEU foils produced by a coolingroll casting was recently developed to improve the quality of the uranium foils and the economic efficiency of the foil fabrication with modifications of the casting apparatus and adjustments of the process parameters. A continuous polycrystalline LEU foil with a thickness range of 100 to 150{mu}m and a width of about 50 mm, exceeding 5m in length for a batch procedure, could be fabricated with a better quality of the uranium foil and a higher yield of the foil fabrication, through improvements of the casting apparatus and variations of the process parameters.

  6. Interventions targeting child undernutrition in developing countries may be undermined by dietary exposure to aflatoxin.

    Science.gov (United States)

    Watson, Sinead; Gong, Yun Yun; Routledge, Michael

    2017-06-13

    Child undernutrition, a form of malnutrition, is a major public health burden in developing countries. Supplementation interventions targeting the major micronutrient deficiencies have only reduced the burden of child undernutrition to a certain extent, indicating that there are other underlying determinants that need to be addressed. Aflatoxin exposure, which is also highly prevalent in developing countries, may be considered an aggravating factor for child undernutrition. Increasing evidence suggests that aflatoxin exposure can occur in any stage of life, including in utero through a trans-placental pathway and in early childhood (through contaminated weaning food and family food). Early life exposure to aflatoxin is associated with adverse effects on low birth weight, stunting, immune suppression, and the liver function damage. The mechanisms underlying impaired growth and aflatoxin exposure are still unclear but intestinal function damage, reduced immune function, and alteration in the insulin-like growth factor axis caused by the liver damage are the suggested hypotheses. Given the fact that both aflatoxin and child undernutrition are common in sub-Saharan Africa, effective interventions aimed at reducing undernutrition cannot be satisfactorily achieved until the interactive relationship between aflatoxin and child undernutrition is clearly understood, and an aflatoxin mitigation strategy takes effect in those vulnerable mothers and children.

  7. Reduced Treatment-Emergent Sexual Dysfunction as a Potential Target in the Development of New Antidepressants

    Directory of Open Access Journals (Sweden)

    David S. Baldwin

    2013-01-01

    Full Text Available Pleasurable sexual activity is an essential component of many human relationships, providing a sense of physical, psychological, and social well-being. Epidemiological and clinical studies show that depressive symptoms and depressive illness are associated with impairments in sexual function and satisfaction, both in untreated and treated patients. The findings of randomized placebo-controlled trials demonstrate that most of the currently available antidepressant drugs are associated with the development or worsening of sexual dysfunction, in a substantial proportion of patients. Sexual difficulties during antidepressant treatment often resolve as depression lifts but can endure over long periods and may reduce self-esteem and affect mood and relationships adversely. Sexual dysfunction during antidepressant treatment is typically associated with many possible causes, but the risk and type of dysfunction vary with differing compounds and should be considered when making decisions about the relative merits and drawbacks of differing antidepressants. A range of interventions can be considered when managing patients with sexual dysfunction associated with antidepressants, including the prescription of phosphodiesterase-5 inhibitors, but none of these approaches can be considered “ideal.” As treatment-emergent sexual dysfunction is less frequent with certain drugs, presumably related to differences in their pharmacological properties, and because current management approaches are less than ideal, a reduced burden of treatment-emergent sexual dysfunction represents a tolerability target in the development of novel antidepressants.

  8. Targeting an Essential GTPase Obg for the Development of Broad-Spectrum Antibiotics.

    Directory of Open Access Journals (Sweden)

    Josephine A Bonventre

    Full Text Available A promising new drug target for the development of novel broad-spectrum antibiotics is the highly conserved small GTPase Obg (YhbZ, CgtA, a protein essential for the survival of all bacteria including Neisseria gonorrhoeae (GC. GC is the agent of gonorrhea, a prevalent sexually transmitted disease resulting in serious consequences on reproductive and neonatal health. A preventive anti-gonorrhea vaccine does not exist, and options for effective antibiotic treatments are increasingly limited. To address the dire need for alternative antimicrobial strategies, we have designed and optimized a 384-well GTPase assay to identify inhibitors of Obg using as a model Obg protein from GC, ObgGC. The assay was validated with a pilot screen of 40,000 compounds and achieved an average Z' value of 0.58 ± 0.02, which suggests a robust assay amenable to high-throughput screening. We developed secondary assessments for identified lead compounds that utilize the interaction between ObgGC and fluorescent guanine nucleotide analogs, mant-GTP and mant-GDP, and an ObgGC variant with multiple alterations in the G-domains that prevent nucleotide binding. To evaluate the broad-spectrum potential of ObgGC inhibitors, Obg proteins of Klebsiella pneumoniae and methicillin-resistant Staphylococcus aureus were assessed using the colorimetric and fluorescence-based activity assays. These approaches can be useful in identifying broad-spectrum Obg inhibitors and advancing the therapeutic battle against multidrug resistant bacteria.

  9. Advances in the Development of PET Ligands Targeting Histone Deacetylases for the Assessment of Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Tetsuro Tago

    2018-01-01

    Full Text Available Epigenetic alterations of gene expression have emerged as a key factor in several neurodegenerative diseases. In particular, inhibitors targeting histone deacetylases (HDACs, which are enzymes responsible for deacetylation of histones and other proteins, show therapeutic effects in animal neurodegenerative disease models. However, the details of the interaction between changes in HDAC levels in the brain and disease progression remain unknown. In this review, we focus on recent advances in development of radioligands for HDAC imaging in the brain with positron emission tomography (PET. We summarize the results of radiosynthesis and biological evaluation of the HDAC ligands to identify their successful results and challenges. Since 2006, several small molecules that are radiolabeled with a radioisotope such as carbon-11 or fluorine-18 have been developed and evaluated using various assays including in vitro HDAC binding assays and PET imaging in rodents and non-human primates. Although most compounds do not readily cross the blood-brain barrier, adamantane-conjugated radioligands tend to show good brain uptake. Until now, only one HDAC radioligand has been tested clinically in a brain PET study. Further PET imaging studies to clarify age-related and disease-related changes in HDACs in disease models and humans will increase our understanding of the roles of HDACs in neurodegenerative diseases.

  10. Behaviour change communication targeting four health behaviours in developing countries: a review of change techniques.

    Science.gov (United States)

    Briscoe, Ciara; Aboud, Frances

    2012-08-01

    Behaviour change communication is vital for increasing the enactment of particular behaviours known to promote health and growth. The techniques used to change behaviour are important for determining how successful the intervention is. In order to integrate findings from different interventions, we need to define and organize the techniques previously used and connect them to effectiveness data. This paper reviews 24 interventions and programs implemented to change four health behaviours related to child health in developing countries: the use of bed nets, hand washing, face washing and complementary feeding. The techniques employed are organized under six categories: information, performance, problem solving, social support, materials, and media. The most successful interventions use three or even four categories of techniques, engaging participants at the behavioural, social, sensory, and cognitive levels. We discuss the link between techniques and theories. We propose that program development would be more systematic if researchers considered a menu of technique categories appropriate for the targeted behaviour and audience when designing their studies. Copyright © 2012 Elsevier Ltd. All rights reserved.

  11. Development of a replication-competent lentivirus assay for dendritic cell-targeting lentiviral vectors

    Directory of Open Access Journals (Sweden)

    Daniel C Farley

    Full Text Available It is a current regulatory requirement to demonstrate absence of detectable replication-competent lentivirus (RCL in lentiviral vector products prior to use in clinical trials. Immune Design previously described an HIV-1-based integration-deficient lentiviral vector for use in cancer immunotherapy (VP02. VP02 is enveloped with E1001, a modified Sindbis virus glycoprotein which targets dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN expressed on dendritic cells in vivo. Vector enveloped with E1001 does not transduce T-cell lines used in standard HIV-1-based RCL assays, making current RCL testing formats unsuitable for testing VP02. We therefore developed a novel assay to test for RCL in clinical lots of VP02. This assay, which utilizes a murine leukemia positive control virus and a 293F cell line expressing the E1001 receptor DC-SIGN, meets a series of evaluation criteria defined in collaboration with US regulatory authorities and demonstrates the ability of the assay format to amplify and detect a hypothetical RCL derived from VP02 vector components. This assay was qualified and used to test six independent GMP production lots of VP02, in which no RCL was detected. We propose that the evaluation criteria used to rationally design this novel method should be considered when developing an RCL assay for any lentiviral vector.

  12. Structures of Cryptococcus neoformans protein farnesyltransferase reveal strategies for developing inhibitors that target fungal pathogens.

    Science.gov (United States)

    Hast, Michael A; Nichols, Connie B; Armstrong, Stephanie M; Kelly, Shannon M; Hellinga, Homme W; Alspaugh, J Andrew; Beese, Lorena S

    2011-10-07

    Cryptococcus neoformans is a fungal pathogen that causes life-threatening infections in immunocompromised individuals, including AIDS patients and transplant recipients. Few antifungals can treat C. neoformans infections, and drug resistance is increasing. Protein farnesyltransferase (FTase) catalyzes post-translational lipidation of key signal transduction proteins and is essential in C. neoformans. We present a multidisciplinary study validating C. neoformans FTase (CnFTase) as a drug target, showing that several anticancer FTase inhibitors with disparate scaffolds can inhibit C. neoformans and suggesting structure-based strategies for further optimization of these leads. Structural studies are an essential element for species-specific inhibitor development strategies by revealing similarities and differences between pathogen and host orthologs that can be exploited. We, therefore, present eight crystal structures of CnFTase that define the enzymatic reaction cycle, basis of ligand selection, and structurally divergent regions of the active site. Crystal structures of clinically important anticancer FTase inhibitors in complex with CnFTase reveal opportunities for optimization of selectivity for the fungal enzyme by modifying functional groups that interact with structurally diverse regions. A substrate-induced conformational change in CnFTase is observed as part of the reaction cycle, a feature that is mechanistically distinct from human FTase. Our combined structural and functional studies provide a framework for developing FTase inhibitors to treat invasive fungal infections.

  13. Development of Detector Systems for Internal and Fixed Target Heavy Ion Physics Experiments

    International Nuclear Information System (INIS)

    Golubev, Pavel

    2003-04-01

    This thesis deals with intermediate energy heavy ion reactions with the particular aim to study the nuclear matter equation of state which defines the relation between statistical parameters of a fermionic system. The development of equipment for two experiments, CA47 at The Svedberg Laboratory in Uppsala, Sweden and R16 at Kernfysisch Versneller Inst. (KVI), Groningen, The Netherlands, are described. CA47 contains the CHICSi detector, a modular, ultra-high vacuum (UHV) compatible, multi-detector system, covering a solid angle of 3pi sr around the collision point. Together with two auxiliary detector systems CHICSi is placed at the cluster-jet target chamber of the CELSIUS storage ring. This thesis gives a technical overview of the detector and the development carried out in order to achieve the desired detection performance. Some laboratory and in-beam tests are described and the analysis of the first experimental results is discussed. The nuclear intensity interferometry experiment (R16) was performed in a dedicated beam-line of the AGOR superconducting cyclotron. Small-angle two-particle correlations were measured for the E/A = 61 MeV 36 Ar + 27 Al, 112 Sn, 124 Sn reactions, together with singles spectra. The experimental energy distributions of neutrons and light charged particles for the 36 Ar + 27 Al reaction have been analyzed with a Maxwellian multi-source prescription. These results, together with correlation function data, are used to extract information on the size of the emitting sources and their time evolution

  14. Development progress of wide LEU foils for Mo-99 irradiation target at KAERI

    International Nuclear Information System (INIS)

    Kim, Ki Hwan; Son, Myung Koon; Lee, Don Bae; Lee, Byung Chul; Kim, Chang Kyu

    2005-01-01

    As the uranium foils for Mo-99 irradiation target, which are charged into a reactor, can be conventionally fabricated at laboratory scale, but not yet at a commercialized scale by a hot rolling method due to some problems in foil quality, productivity and economic efficiency, an attention has shifted to the development of new improved technology. Under these circumstances, an alternative fabrication method of U polycrystalline foils has been investigated using a cooling roll casting method, in order to produce a fission isotope 99 Mo, the parent nuclide of 99m Tc. The fabrication method of wide LEU foils produced by a coolingroll casting was recently developed to improve the quality of the uranium foils and the economic efficiency of the foil fabrication with modifications of the casting apparatus and adjustments of the process parameters. A continuous polycrystalline LEU foil with a thickness range of 100 to 150μm and a width of about 50 mm, exceeding 5m in length for a batch procedure, could be fabricated with a better quality of the uranium foil and a higher yield of the foil fabrication, through improvements of the casting apparatus and variations of the process parameters

  15. Myocardin is a direct transcriptional target of Mef2, Tead and Foxo proteins during cardiovascular development.

    Science.gov (United States)

    Creemers, Esther E; Sutherland, Lillian B; McAnally, John; Richardson, James A; Olson, Eric N

    2006-11-01

    Myocardin is a transcriptional co-activator of serum response factor (Srf), which is a key regulator of the expression of smooth and cardiac muscle genes. Consistent with its role in regulating cardiovascular development, myocardin is the earliest known marker specific to both the cardiac and smooth muscle lineages during embryogenesis. To understand how the expression of this early transcriptional regulator is initiated and maintained, we scanned 90 kb of genomic DNA encompassing the myocardin gene for cis-regulatory elements capable of directing myocardin transcription in cardiac and smooth muscle lineages in vivo. Here, we describe an enhancer that controls cardiovascular expression of the mouse myocardin gene during mouse embryogenesis and adulthood. Activity of this enhancer in the heart and vascular system requires the combined actions of the Mef2 and Foxo transcription factors. In addition, the Tead transcription factor is required specifically for enhancer activation in neural-crest-derived smooth muscle cells and dorsal aorta. Notably, myocardin also regulates its own enhancer, but in contrast to the majority of myocardin target genes, which are dependent on Srf, myocardin acts through Mef2 to control its enhancer. These findings reveal an Srf-independent mechanism for smooth and cardiac muscle-restricted transcription and provide insight into the regulatory mechanisms responsible for establishing the smooth and cardiac muscle phenotypes during development.

  16. Integrating Biodiversity and Ecosystem Services in the Post-2015 Development Agenda: Goal Structure, Target Areas and Means of Implementation

    Directory of Open Access Journals (Sweden)

    Paul L. Lucas

    2013-12-01

    Full Text Available The United Nations’ discussions on defining a new set of post-2015 development goals focus on poverty eradication and sustainable development. Biodiversity and ecosystem services are essential for poverty eradication, which is also one of the foundations of the Strategic Plan for Biodiversity of the Convention on Biological Diversity (CBD. Based on an assessment of current proposals of goals and targets, and a quantitative pathway analysis to meet long term biodiversity and food security goals, this paper discusses how biodiversity and ecosystem services can be integrated into a broad set of goals and targets, and concludes with relevant target areas and means of implementation for which specific targets need to be defined. Furthermore, it responds to the call of the CBD to consider the Strategic Plan for Biodiversity and the related Aichi biodiversity targets in the post-2015 development agenda. The paper’s analysis identifies three overlapping but also supplemental ways to integrate biodiversity and ecosystem services in the post-2015 agenda: integrated goals, goals addressing earth system functioning and goals addressing environmental limits. It further concludes seven target areas to be included under the goals to address biodiversity and ecosystem services in the context of food and agriculture: access to food, demand for agricultural products, sustainable intensification, ecosystem fragmentation, protected areas, essential ecosystem services and genetic diversity. The Strategic Plan for Biodiversity provides a good basis for integrating biodiversity and ecosystem services in the post-2015 development agenda. Many Aichi targets address the proposed target areas and the means of implementation discussed, while they need to be complemented with targets that specifically address human well-being, as well as institutions and governance.

  17. Development of novel agents for idiopathic pulmonary fibrosis: progress in target selection and clinical trial design.

    Science.gov (United States)

    O'Riordan, Thomas G; Smith, Victoria; Raghu, Ganesh

    2015-10-01

    Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal disease. Until recently, the standard therapy for this disease has been essentially supportive, with the exception of a minority of patients who were eligible for lung transplantation. The development pathway for novel medications for IPF has been complicated. There have been several challenges, including an incomplete understanding of the pathogenesis, unpredictable clinical course, lack of validated biomarkers, the low clinical predictive value of animal models of lung injury, and the need to commit to large clinical trials of long duration to obtain initial evidence of clinical efficacy. Despite these challenges, the combination of recent advances in translational medicine and the unprecedented increase in clinical data accumulated from recent large clinical trials has stimulated an increase in the number of clinical development programs for IPF. Clinical programs are increasingly characterized by rational target selection, preclinical optimization of therapeutic molecules, and an emphasis on efficient clinical trial design. A lower rate of functional decline in patients treated with pirfenidone and nintedanib was demonstrated in large clinical trials. In October 2014, these two drugs became the first agents to be approved by the US Food and Drug Administration for the treatment of IPF. (Pirfenidone had already been approved in several countries outside the United States.) In November 2014, the European Medicines Agency approved the use of nintedanib for IPF. The landscape for management of IPF has markedly changed with the advent of approved therapeutic options for IPF. In this article, we review the strategies that are being used to increase the likelihood of success in clinical development programs of novel disease-modifying agents in IPF.

  18. Development of an immunotherapeutic adenovirus targeting hormone-independent prostate cancer

    Directory of Open Access Journals (Sweden)

    Kim JS

    2013-11-01

    Full Text Available Jae Sik Kim,1 Sang Don Lee,2 Sang Jin Lee,3 Moon Kee Chung21Department of Urology, The Catholic University of Korea Incheon St Mary's Hospital, Incheon, 2Pusan National University Yangsan Hospital and Research Institute for Convergence of Biomedical Science and Technology, Yangsan, 3Genitourinary Cancer Branch, National Cancer Center, Goyang, KoreaBackground: To develop a targeting therapy for hormone-independent prostate cancer, we constructed and characterized conditionally replicating oncolytic adenovirus (Ad equipped with mRFP(monomeric red fluorescence protein/ttk (modified herpes simplex virus thymidine kinase This construct was then further modified to express both mRFP/ttk and a soluble form of cytokine FLT3L (fms-related tyrosine kinase 3 ligand simultaneously.Methods: To construct the recombinant oncolytic adenovirus, E1a and E4 genes, which are necessary for adenovirus replication, were controlled by the prostate-specific enhancer sequence (PSES targeting prostate cancer cells expressing prostate-specific antigen (PSA and prostate-specific membrane antigen (PSMA. Simultaneously, it expressed the mRFP/ttk fusion protein in order to be able to elicit the cytotoxic effect.Results: The Ad5/35PSES.mRFP/ttk chimeric recombinant adenovirus was generated successfully. When replication of Ad5/35PSES.mRFP/ttk was evaluated in prostate cancer cell lines under fluorescence microscopy, red fluorescence intensity increased more in LNCaP cells, suggesting that the mRFP/ttk fusion protein was folded functionally. In addition, the replication assay including wild-type adenovirus as a positive control showed that PSES-positive cells (LNCaP and CWR22rv permitted virus replication but not PSES-negative cells (DU145 and PC3. Next, we evaluated the killing activity of this recombinant adenovirus. The Ad5/35PSES.mRFP/ttk killed LNCaP and CWR22rv more effectively. Unlike PSES-positive cells, DU145 and PC3 were resistant to killing by this recombinant

  19. Inertial confinement fusion target component fabrication and technology development support: Annual report, October 1, 1997--September 30, 1998

    Energy Technology Data Exchange (ETDEWEB)

    Gibson, J. [ed.

    1998-12-01

    During this period, General Atomics (GA) and their partner Schafer Corporation were assigned 17 formal tasks in support of the Inertial Confinement Fusion (ICF) program and its five laboratories. A portion of the effort on these tasks included providing direct ``On-site Support`` at Lawrence Livermore National Laboratory (LLNL), Los Alamos National Laboratory (LANL), and Sandia National Laboratory Albuquerque (SNLA). They fabricated and delivered over 1,200 hohlraum mandrels and numerous other micromachined components to LLNL, LANL, and SNLA. They produced more than 1,300 glass and plastic target capsules for LLNL, LANL, SNLA, and the University of Rochester/Laboratory for Laser Energetics (UR/LLE). They also delivered nearly 2,000 various target foils and films for Naval Research Lab (NRL) and UR/LLE in FY98. This report describes these target fabrication activities and the target fabrication and characterization development activities that made the deliveries possible. During FY98, great progress was made by the GA/Schafer-UR/LLE-LANL team in the design, procurement, installation, and testing of the OMEGA Cryogenic Target System (OCTS) that will field cryogenic targets on OMEGA. The design phase was concluded for all components of the OCTS and all major components were procured and nearly all were fabricated. Many of the components were assembled and tested, and some have been shipped to UR/LLE. The ICF program is anticipating experiments at the OMEGA laser and the National Ignition Facility (NIF) which will require targets containing cryogenic layered D{sub 2} or deuterium-tritium (DT) fuel. They are part of the National Cryogenic Target Program and support experiments at LLNL and LANL to generate and characterize cryogenic layers for these targets. They also contributed cryogenic support and developed concepts for NIF cryogenic targets. This report summarizes and documents the technical progress made on these tasks.

  20. Inertial confinement fusion target component fabrication and technology development support: Annual report, October 1, 1997 - September 30, 1998

    International Nuclear Information System (INIS)

    Gibson, J.

    1998-12-01

    During this period, General Atomics (GA) and their partner Schafer Corporation were assigned 17 formal tasks in support of the Inertial Confinement Fusion (ICF) program and its five laboratories. A portion of the effort on these tasks included providing direct ''On-site Support'' at Lawrence Livermore National Laboratory (LLNL), Los Alamos National Laboratory (LANL), and Sandia National Laboratory Albuquerque (SNLA). They fabricated and delivered over 1,200 hohlraum mandrels and numerous other micromachined components to LLNL, LANL, and SNLA. They produced more than 1,300 glass and plastic target capsules for LLNL, LANL, SNLA, and the University of Rochester/Laboratory for Laser Energetics (UR/LLE). They also delivered nearly 2,000 various target foils and films for Naval Research Lab (NRL) and UR/LLE in FY98. This report describes these target fabrication activities and the target fabrication and characterization development activities that made the deliveries possible. During FY98, great progress was made by the GA/Schafer-UR/LLE-LANL team in the design, procurement, installation, and testing of the OMEGA Cryogenic Target System (OCTS) that will field cryogenic targets on OMEGA. The design phase was concluded for all components of the OCTS and all major components were procured and nearly all were fabricated. Many of the components were assembled and tested, and some have been shipped to UR/LLE. The ICF program is anticipating experiments at the OMEGA laser and the National Ignition Facility (NIF) which will require targets containing cryogenic layered D 2 or deuterium-tritium (DT) fuel. They are part of the National Cryogenic Target Program and support experiments at LLNL and LANL to generate and characterize cryogenic layers for these targets. They also contributed cryogenic support and developed concepts for NIF cryogenic targets. This report summarizes and documents the technical progress made on these tasks

  1. Initial development of efficient, low-debris laser targets for the Sandia soft x-ray projection lithography effort

    Energy Technology Data Exchange (ETDEWEB)

    Rockett, P.D.; Hunter, J.A. [Sandia National Labs., Albuquerque, NM (United States); Kubiak, G.D. [Sandia National Labs., Livermore, CA (United States)] [and others

    1997-03-01

    During the fiscal years 92-94 a joint group from Sandia/New Mexico and Sandia/California studied the development of new laser-plasma targets for projection x-ray or EUV (extreme ultraviolet) lithography. Our experimental and theoretical analyses incorporated target design as an integral part of the lithographic optical system. Targets studied included thick solid targets, thin-foil metal-coated targets, and cryogenic targets. Our complete measurement suite consisted of x-ray conversion efficiency measurements, source size imaging, source x-ray angular distribution measurements, debris collection, and source EUV spectrum. Target evaluation also included the variation of laser characteristics, such as, laser intensity, spot size, wavelength, pulselength, and pulseshape. Over the course of these experiments we examined targets using KrF (248nm), XeCl (308nm), and CO{sub 2} (10.6 {mu}m) lasers. While debris issues now dominate research in this area, final details were concluded on our understanding of material spectra and radiation transport of 13 run light in laser-plasmas. Additionally, conclusive results were obtained with 308 rim light, showing the pulselength threshold below which plumes no longer limited the transmission of (and thus the conversion efficiency to) 13 nm radiation.

  2. Studies in Multifunctional Drug Development: Preparation and Evaluation of 11beta-Substituted Estradiol-Drug Conjugates, Cell Membrane Targeting Imaging Agents, and Target Multifunctional Nanoparticles

    Science.gov (United States)

    Dao, KinhLuan Lenny D.

    Cancer is the second leading cause of death after cardiovascular disease in the United State. Despite extensive research in development of antitumor drugs, most of these therapeutic entities often possess nonspecific toxicity, thus they can only be used to treat tumors in higher doses or more frequently. Because of the cytotoxicity and severe side effects, the drug therapeutic window normally is limited. Beside the toxicity issue, antitumor drug are also not selectively taken up by tumor cells, thus the necessitating concentrations that would eradicate the tumor can often not be used. In addition, tumor cells tend to develop resistance against the anticancer drugs after prolonged treatment. Therefore, alleviating the systemic cytotoxicity and side effects, improving in tumor selectivity, high potency, and therapeutic efficacy are still major obstacles in the area of anticancer drug development. A more promising approach for developing a selective agent for cancer is to conjugate a potent therapeutic drug, or an imaging agent with a targeting group, such as antibody or a high binding-specificity small molecule, that selectively recognize the overexpressed antigens or proteins on tumor cells. My research combines several approaches to describe this strategy via using different targeting molecules to different diseases, as well as different potent cytotoxic drugs for different therapies. Three studies related to the preparation and biological evaluation of new therapeutic agents, such as estradiol-drug hybrids, cell membrane targeted molecular imaging agents, and multifunctional NPs will be discussed. The preliminary results of these studies indicated that our new reagents achieved their initial objectives and can be further improved for optimized synthesis and in vivo experiments. The first study describes the method in which we employed a modular assembly approach to synthesize a novel 11beta-substituted steroidal anti-estrogen. The key intermediate was synthesized

  3. The kinetic mechanism of Human Thymidine Phosphorylase - a molecular target for cancer drug development.

    Science.gov (United States)

    Deves, Candida; Rostirolla, Diana Carolina; Martinelli, Leonardo Kras Borges; Bizarro, Cristiano Valim; Santos, Diogenes Santiago; Basso, Luiz Augusto

    2014-03-04

    Human Thymidine Phosphorylase (HTP), also known as the platelet-derived endothelial cell growth factor (PD-ECGF) or gliostatin, catalyzes the reversible phosphorolysis of thymidine (dThd) to thymine and 2-deoxy-α-d-ribose-1-phosphate (2dR1P). HTP is a key enzyme in the pyrimidine salvage pathway involved in dThd homeostasis in cells. HTP is a target for anticancer drug development as its enzymatic activity promotes angiogenesis. Here, we describe cloning, expression, and purification to homogeneity of recombinant TYMP-encoded HTP. Peptide fingerprinting and the molecular mass value of the homogenous protein confirmed its identity as HTP assessed by mass spectrometry. Size exclusion chromatography showed that HTP is a dimer in solution. Kinetic studies revealed that HTP displayed substrate inhibition for dThd. Initial velocity and isothermal titration calorimetry (ITC) studies suggest that HTP catalysis follows a rapid-equilibrium random bi-bi kinetic mechanism. ITC measurements also showed that dThd and Pi binding are favorable processes. The pH-rate profiles indicated that maximal enzyme activity was achieved at low pH values. Functional groups with apparent pK values of 5.2 and 9.0 are involved in dThd binding and groups with pK values of 6.1 and 7.8 are involved in phosphate binding.

  4. The Knowledge Base for Achieving the Sustainable Development Goal Targets on Water Supply, Sanitation and Hygiene.

    Science.gov (United States)

    Hutton, Guy; Chase, Claire

    2016-05-27

    Safe drinking water, sanitation, and hygiene (WASH) are fundamental to an improved standard of living. Globally, 91% of households used improved drinking water sources in 2015, while for improved sanitation it is 68%. Wealth disparities are stark, with rural populations, slum dwellers and marginalized groups lagging significantly behind. Service coverage is significantly lower when considering the new water and sanitation targets under the sustainable development goals (SDGs) which aspire to a higher standard of 'safely managed' water and sanitation. Lack of access to WASH can have an economic impact as much as 7% of Gross Domestic Product, not including the social and environmental consequences. Research points to significant health and socio-economic consequences of poor nutritional status, child growth and school performance caused by inadequate WASH. Groundwater over-extraction and pollution of surface water bodies have serious impacts on water resource availability and biodiversity, while climate change exacerbates the health risks of water insecurity. A significant literature documents the beneficial impacts of WASH interventions, and a growing number of impact evaluation studies assess how interventions are optimally financed, implemented and sustained. Many innovations in behavior change and service delivery offer potential for scaling up services to meet the SDGs.

  5. Pan-genome analysis of Clostridium botulinum reveals unique targets for drug development.

    Science.gov (United States)

    Bhardwaj, Tulika; Somvanshi, Pallavi

    2017-08-05

    Clostridium botulinum, a formidable pathogen is responsible for the emerging cause of food poisoning cases on the global canvas. The endemicity of bacterium Clostridium botulinum is reflected by the sudden hospital outbreaks and increased resistance towards multiple drugs. Therefore, a combined approach of in-silico comparative genomic analysis with statistical analysis was applied to overcome the limitation of bench-top technologies. Owing to the paucity of genomic data available by the advent of third generation sequencing technologies, several 'omics' technologies were applied to understand the underlying evolutionary pattern and lifestyle of the bacterial pathogen using phylogenomics. The calculation of pan-genome, core genome and singletons provides view of genetic repertoire of the bacterial pathogen lineage at the successive level, orthology shared and specific gene subsets. In addition, assessment of pathogenomic potential, resistome, toxin/antitoxin family in successive pathogenic strains of Clostridium botulinum aids in revealing more specific targets for drug design and development. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. The Knowledge Base for Achieving the Sustainable Development Goal Targets on Water Supply, Sanitation and Hygiene

    Science.gov (United States)

    Hutton, Guy; Chase, Claire

    2016-01-01

    Safe drinking water, sanitation, and hygiene (WASH) are fundamental to an improved standard of living. Globally, 91% of households used improved drinking water sources in 2015, while for improved sanitation it is 68%. Wealth disparities are stark, with rural populations, slum dwellers and marginalized groups lagging significantly behind. Service coverage is significantly lower when considering the new water and sanitation targets under the sustainable development goals (SDGs) which aspire to a higher standard of ‘safely managed’ water and sanitation. Lack of access to WASH can have an economic impact as much as 7% of Gross Domestic Product, not including the social and environmental consequences. Research points to significant health and socio-economic consequences of poor nutritional status, child growth and school performance caused by inadequate WASH. Groundwater over-extraction and pollution of surface water bodies have serious impacts on water resource availability and biodiversity, while climate change exacerbates the health risks of water insecurity. A significant literature documents the beneficial impacts of WASH interventions, and a growing number of impact evaluation studies assess how interventions are optimally financed, implemented and sustained. Many innovations in behavior change and service delivery offer potential for scaling up services to meet the SDGs. PMID:27240389

  7. Development of Molecularly Imprinted Polymers to Target Polyphenols Present in Plant Extracts

    Directory of Open Access Journals (Sweden)

    Catarina Gomes

    2017-11-01

    Full Text Available The development of molecularly imprinted polymers (MIPs to target polyphenols present in vegetable extracts was here addressed. Polydatin was selected as a template polyphenol due to its relatively high size and amphiphilic character. Different MIPs were synthesized to explore preferential interactions between the functional monomers and the template molecule. The effect of solvent polarity on the molecular imprinting efficiency, namely owing to hydrophobic interactions, was also assessed. Precipitation and suspension polymerization were examined as a possible way to change MIPs morphology and performance. Solid phase extraction and batch/continuous sorption processes were used to evaluate the polyphenols uptake/release in individual/competitive assays. Among the prepared MIPs, a suspension polymerization synthesized material, with 4-vinylpyridine as the functional monomer and water/methanol as solvent, showed a superior performance. The underlying cause of such a significant outcome is the likely surface imprinting process caused by the amphiphilic properties of polydatin. The uptake and subsequent selective release of polyphenols present in natural extracts was successfully demonstrated, considering a red wine solution as a case study. However, hydrophilic/hydrophobic interactions are inevitable (especially with complex natural extracts and the tuning of the polarity of the solvents is an important issue for the isolation of the different polyphenols.

  8. Development of genetic markers in Eucalyptus species by target enrichment and exome sequencing.

    Directory of Open Access Journals (Sweden)

    Modhumita Ghosh Dasgupta

    Full Text Available The advent of next-generation sequencing has facilitated large-scale discovery, validation and assessment of genetic markers for high density genotyping. The present study was undertaken to identify markers in genes supposedly related to wood property traits in three Eucalyptus species. Ninety four genes involved in xylogenesis were selected for hybridization probe based nuclear genomic DNA target enrichment and exome sequencing. Genomic DNA was isolated from the leaf tissues and used for on-array probe hybridization followed by Illumina sequencing. The raw sequence reads were trimmed and high-quality reads were mapped to the E. grandis reference sequence and the presence of single nucleotide variants (SNVs and insertions/ deletions (InDels were identified across the three species. The average read coverage was 216X and a total of 2294 SNVs and 479 InDels were discovered in E. camaldulensis, 2383 SNVs and 518 InDels in E. tereticornis, and 1228 SNVs and 409 InDels in E. grandis. Additionally, SNV calling and InDel detection were conducted in pair-wise comparisons of E. tereticornis vs. E. grandis, E. camaldulensis vs. E. tereticornis and E. camaldulensis vs. E. grandis. This study presents an efficient and high throughput method on development of genetic markers for family- based QTL and association analysis in Eucalyptus.

  9. The Knowledge Base for Achieving the Sustainable Development Goal Targets on Water Supply, Sanitation and Hygiene

    Directory of Open Access Journals (Sweden)

    Guy Hutton

    2016-05-01

    Full Text Available Safe drinking water, sanitation, and hygiene (WASH are fundamental to an improved standard of living. Globally, 91% of households used improved drinking water sources in 2015, while for improved sanitation it is 68%. Wealth disparities are stark, with rural populations, slum dwellers and marginalized groups lagging significantly behind. Service coverage is significantly lower when considering the new water and sanitation targets under the sustainable development goals (SDGs which aspire to a higher standard of ‘safely managed’ water and sanitation. Lack of access to WASH can have an economic impact as much as 7% of Gross Domestic Product, not including the social and environmental consequences. Research points to significant health and socio-economic consequences of poor nutritional status, child growth and school performance caused by inadequate WASH. Groundwater over-extraction and pollution of surface water bodies have serious impacts on water resource availability and biodiversity, while climate change exacerbates the health risks of water insecurity. A significant literature documents the beneficial impacts of WASH interventions, and a growing number of impact evaluation studies assess how interventions are optimally financed, implemented and sustained. Many innovations in behavior change and service delivery offer potential for scaling up services to meet the SDGs.

  10. Blunting the knife: development of vaccines targeting digestive proteases of blood-feeding helminth parasites.

    Science.gov (United States)

    Pearson, Mark S; Ranjit, Najju; Loukas, Alex

    2010-08-01

    Proteases are pivotal to parasitism, mediating biological processes crucial to worm survival including larval migration through tissue, immune evasion/modulation and nutrient acquisition by the adult parasite. In haematophagous parasites, many of these proteolytic enzymes are secreted from the intestine (nematodes) or gastrodermis (trematodes) where they act to degrade host haemoglobin and serum proteins as part of the feeding process. These proteases are exposed to components of the immune system of the host when the worms ingest blood, and therefore present targets for the development of anti-helminth vaccines. The protective effects of current vaccine antigens against nematodes that infect humans (hookworm) and livestock (barber's pole worm) are based on haemoglobin-degrading intestinal proteases and act largely as a result of the neutralisation of these proteases by antibodies that are ingested with the blood-meal. In this review, we survey the current status of helminth proteases that show promise as vaccines and describe their vital contribution to a parasitic existence.

  11. THE DEVELOPMENT OF THE EUROPEAN BANKING INDUSTRY THROUGH THE TARGET PAYMENTS SYSTEM

    Directory of Open Access Journals (Sweden)

    LUCIAN-ION MEDAR

    2017-12-01

    Full Text Available The creation of the Single Euro Payments Area is in full swing and the completion of the Economic and Monetary Union is the moment of consolidation, of preparing the conditions in all Member States to enable them to cope with the global financial challenges and prosper. The markets for small value payments in euro within the European Union have been very fragmented. There was a need for a project (SEPA with a major impact on national payment markets in order to unify and standardize them in a single domestic market. Trans-European Automated Realtime Gross Settlement Express Transfer System (TARGET is a trans-European automated real-time gross settlement system - which meets the needs of consumers by offering services at a harmonized level in the European Union. Now, however, the banking clientele needs some education about banking operations taking place at the level of the European banking system. The initial project was proposed and promoted by the European Central Bank together with the European Commission and supported by the central banks of the European Union. However, the implementation and continued development of the SEPA-Single Euro Payments Area process is the responsibility of the financial institutions, and the final beneficiaries are indisputably the individuals and legal entities that represent their "clientele". The Eurosystem has cooperated with national central banks to implement standards that facilitate the rapid automation of payment systems by offering TAREGET 2-Securities (T2S banking clients.

  12. Recent developments in the nanostructured materials functionalized with ruthenium complexes for targeted drug delivery to tumors

    Directory of Open Access Journals (Sweden)

    Thangavel P

    2017-04-01

    Full Text Available Prakash Thangavel,1 Buddolla Viswanath,1 Sanghyo Kim1,2 1Department of Bionanotechnology, Gachon University, Bokjeong-Dong, Sujeong-Gu, Seongnam-Si, Gyeonggi-Do, 2Graduate Gachon Medical Research Institute, Gil Medical Center, Incheon, Republic of Korea Abstract: In recent years, the field of metal-based drugs has been dominated by other existing precious metal drugs, and many researchers have focused their attention on the synthesis of various ruthenium (Ru complexes due to their potential medical and pharmaceutical applications. The beneficial properties of Ru, which make it a highly promising therapeutic agent, include its variable oxidation states, low toxicity, high selectivity for diseased cells, ligand exchange properties, and the ability to mimic iron binding to biomolecules. In addition, Ru complexes have favorable adsorption properties, along with excellent photochemical and photophysical properties, which make them promising tools for photodynamic therapy. At present, nanostructured materials functionalized with Ru complexes have become an efficient way to administer Ru-based anticancer drugs for cancer treatment. In this review, the recent developments in the nanostructured materials functionalized with Ru complexes for targeted drug delivery to tumors are discussed. In addition, information on “traditional” (ie, non-nanostructured Ru-based cancer therapies is included in a precise manner. Keywords: metallodrugs, nanotechnology, cancer treatment, cell apoptosis, DNA damage, toxicity

  13. Recent developments in the nanostructured materials functionalized with ruthenium complexes for targeted drug delivery to tumors.

    Science.gov (United States)

    Thangavel, Prakash; Viswanath, Buddolla; Kim, Sanghyo

    2017-01-01

    In recent years, the field of metal-based drugs has been dominated by other existing precious metal drugs, and many researchers have focused their attention on the synthesis of various ruthenium (Ru) complexes due to their potential medical and pharmaceutical applications. The beneficial properties of Ru, which make it a highly promising therapeutic agent, include its variable oxidation states, low toxicity, high selectivity for diseased cells, ligand exchange properties, and the ability to mimic iron binding to biomolecules. In addition, Ru complexes have favorable adsorption properties, along with excellent photochemical and photophysical properties, which make them promising tools for photodynamic therapy. At present, nanostructured materials functionalized with Ru complexes have become an efficient way to administer Ru-based anticancer drugs for cancer treatment. In this review, the recent developments in the nanostructured materials functionalized with Ru complexes for targeted drug delivery to tumors are discussed. In addition, information on "traditional" (ie, non-nanostructured) Ru-based cancer therapies is included in a precise manner.

  14. Bio-Guided Targeting for Preservative and Anti-Ageing Cosmetic Ingredient Development

    Directory of Open Access Journals (Sweden)

    Emilie Destandau

    2014-01-01

    Full Text Available To develop a new antioxidant, antibacterial and natural cosmetic ingredient without cytotoxicity to skin cells, bioactive molecules contained in Kalanchoe pinnata leaf methanolic extract were targeted using semi-preparative HPLC fractionation linked to biological activity tests. Chromatographic effluent was collected at the column outlet into a 96 deep-well microplate, filling successively all the wells. After freeze-drying, the microplate was ready to use for different biological tests such as antimicrobial activity on microorganisms, skin cell viability and antioxidant activity on human keratinocyte cells. The injection of only 2.64 mg of crude extract into the HPLC system reveals a good correlation between the chromatographic peaks and the different biological activities. One fraction is mainly of interest since good antibacterial and antioxidant activities without cytotoxicity are observed. The analysis of this fraction using mass spectrometry allows the identification of glycoside derivatives of quercetin, isorhamnetin and kaempferol. Thus, a correlation between biological activity and the presence of these flavonoids is obtained. This screening method allows a rapid fractionation associated with a biological activity evaluation and a first molecular identification, saving time by limiting sample treatments and solvent consumption.

  15. Development of a Glycosaminoglycan Derived, Selectin Targeting Anti-Adhesive Coating to Treat Endothelial Cell Dysfunction

    Directory of Open Access Journals (Sweden)

    James R. Wodicka

    2017-03-01

    Full Text Available Endothelial cell (EC dysfunction is associated with many disease states including deep vein thrombosis (DVT, chronic kidney disease, sepsis and diabetes. Loss of the glycocalyx, a thin glycosaminoglycan (GAG-rich layer on the EC surface, is a key feature of endothelial dysfunction and increases exposure of EC adhesion molecules such as selectins, which are involved in platelet binding to ECs. Once bound, platelets cause thrombus formation and an increased inflammatory response. We have developed a GAG derived, selectin targeting anti-adhesive coating (termed EC-SEAL consisting of a dermatan sulfate backbone and multiple selectin-binding peptides designed to bind to inflamed endothelium and prevent platelet binding to create a more quiescent endothelial state. Multiple EC-SEAL variants were evaluated and the lead variant was found to preferentially bind to selectin-expressing ECs and smooth muscle cells (SMCs and inhibit platelet binding and activation in a dose-dependent manner. In an in vivo model of DVT, treatment with the lead variant resulted in reduced thrombus formation. These results indicate that EC-SEAL has promise as a potential therapeutic in the treatment of endothelial dysfunction.

  16. More than Just Openness: Developing and Validating a Measure of Targeted Parent-Child Communication about Alcohol

    OpenAIRE

    Miller-Day, Michelle; Kam, Jennifer A.

    2010-01-01

    Research addressing parent-child communication on the topic of alcohol use relies heavily on assessing frequency of discussions and general assessments of openness in parent-child communication, ignoring the complexity of this communication phenomenon. This study adds to the literature by articulating a conceptualization and developing a measurement of parent-child communication—targeted parent-child communication about alcohol—and comparing the efficacy of targeted parent-child communication...

  17. Development of LEU targets for 99Mo production and their chemical processing status 1989

    International Nuclear Information System (INIS)

    Vandegrift, G.F.; Kwok, J.D.; Chamberlain, D.B.; Hoh, J.C.; Streets, E.W.; Vogler, S.; Thresh, H.R.; Domagala, R.F.; Wiencek, T.C.; Matos, J.E.

    1991-01-01

    Most of the world's supply of Tc-99m for medical purposes is currently produced from Mo-99 derived from the fissioning of high enriched uranium (HEU). Substitution of low enriched uranium (LEU) silicide fuel for the HEU alloy and aluminide fuels used in current target designs will allow equivalent Mo-99 yields with no change in target geometries. Substitution of uranium metal will also allow the substitution of LEU for HEU. Efforts performed in 1989 focused on (1) fabrication of a uranium metal target by Hot Isostatic Pressing uranium metal foil to zirconium, (2) experimental investigation of the dissolution step for U 3 Si 2 targets, allowing us to present a conceptual design for the dissolution process and equipment, and (3) investigation of the procedures used to reclaim irradiated uranium from Mo-production targets, allowing us to further analyze the waste and by-product problems associated with the substitution of LEU for HEU. (orig.)

  18. L,L-diaminopimelate aminotransferase from Chlamydomonas reinhardtii: a target for algaecide development.

    Science.gov (United States)

    Dobson, Renwick C J; Girón, Irma; Hudson, André O

    2011-01-01

    In some bacterial species and photosynthetic cohorts, including algae, the enzyme L,L-diaminopimelate aminotransferase (DapL) (E.C. 2.6.1.83) is involved in the anabolism of the essential amino acid L-lysine. DapL catalyzes the conversion of tetrahydrodipicolinate (THDPA) to L,L-diaminopimelate (L,L-DAP), in one step bypassing the DapD, DapC and DapE enzymatic reactions present in the acyl DAP pathways. Here we present an in vivo and in vitro characterization of the DapL ortholog from the alga Chlamydomonas reinhardtii (Cr-DapL). The in vivo analysis illustrated that the enzyme is able to functionally complement the E. coli dap auxotrophs and was essential for plant development in Arabidopsis. In vitro, the enzyme was able to inter-convert THDPA and L,L-DAP, showing strong substrate specificity. Cr-DapL was dimeric in both solution and when crystallized. The structure of Cr-DapL was solved in its apo form, showing an overall architecture of a α/β protein with each monomer in the dimer adopting a pyridoxal phosphate-dependent transferase-like fold in a V-shaped conformation. The active site comprises residues from both monomers in the dimer and shows some rearrangement when compared to the apo-DapL structure from Arabidopsis. Since animals do not possess the enzymatic machinery necessary for the de novo synthesis of the amino acid L-lysine, enzymes involved in this pathway are attractive targets for the development of antibiotics, herbicides and algaecides.

  19. L,L-diaminopimelate aminotransferase from Chlamydomonas reinhardtii: a target for algaecide development.

    Directory of Open Access Journals (Sweden)

    Renwick C J Dobson

    Full Text Available In some bacterial species and photosynthetic cohorts, including algae, the enzyme L,L-diaminopimelate aminotransferase (DapL (E.C. 2.6.1.83 is involved in the anabolism of the essential amino acid L-lysine. DapL catalyzes the conversion of tetrahydrodipicolinate (THDPA to L,L-diaminopimelate (L,L-DAP, in one step bypassing the DapD, DapC and DapE enzymatic reactions present in the acyl DAP pathways. Here we present an in vivo and in vitro characterization of the DapL ortholog from the alga Chlamydomonas reinhardtii (Cr-DapL. The in vivo analysis illustrated that the enzyme is able to functionally complement the E. coli dap auxotrophs and was essential for plant development in Arabidopsis. In vitro, the enzyme was able to inter-convert THDPA and L,L-DAP, showing strong substrate specificity. Cr-DapL was dimeric in both solution and when crystallized. The structure of Cr-DapL was solved in its apo form, showing an overall architecture of a α/β protein with each monomer in the dimer adopting a pyridoxal phosphate-dependent transferase-like fold in a V-shaped conformation. The active site comprises residues from both monomers in the dimer and shows some rearrangement when compared to the apo-DapL structure from Arabidopsis. Since animals do not possess the enzymatic machinery necessary for the de novo synthesis of the amino acid L-lysine, enzymes involved in this pathway are attractive targets for the development of antibiotics, herbicides and algaecides.

  20. Inertial confinement fusion target component fabrication and technology development support: Annual report, October 1, 1995--September 30, 1996

    International Nuclear Information System (INIS)

    Hoppe, M.

    1997-02-01

    On December 30, 1990, the U.S. Department of Energy entered into a contract with General Atomics (GA) to be the Inertial Confinement Fusion (ICF) Target Component Fabrication and Technology Development Support contractor. In September 1995 this contract ended and a second contract was issued for us to continue this ICF target support work. This report documents the technical activities of the period October 1, 1995 through September 30, 1996. During this period, GA and our partners WJ Schafer Associates (WJSA) and Soane Technologies, Inc. (STI) were assigned 14 formal tasks in support of the Inertial Confinement Fusion program and its five laboratories. A portion of the effort on these tasks included providing direct open-quotes Onsite Supportclose quotes at Lawrence Livermore National Laboratory (LLNL), Los Alamos National Laboratory (LANL), and Sandia National Laboratory Albuquerque (SNLA). We fabricated and delivered over 800 gold-plated hohlraum mandrels to LLNL, LANL and SNLA. We produced nearly 1,200 glass and plastic target capsules for LLNL, LANL, SNLA and University of Rochester/Laboratory for Laser Energetics (UR/LLE). We also delivered over 100 flat foil targets for Naval Research Lab (NRL) and SNLA in FY96. This report describes these target fabrication activities and the target fabrication and characterization development activities that made the deliveries possible. The ICF program is anticipating experiments at the OMEGA laser and the National Ignition Facility (NIF) which will require capsules containing cryogenic layered D 2 or deuterium-tritium (DT) fuel. We are part of the National Cryogenic Target Program to create and demonstrate viable ways to generate and characterize cryogenic layers. Substantial progress has been made on ways to both create and characterize viable layers. During FY96, significant progress was made in the design of the OMEGA Cryogenic Target System that will field cryogenic targets on OMEGA

  1. Development and evaluation of a targeted orchard sprayer using machine vision technology

    Directory of Open Access Journals (Sweden)

    H Asaei

    2016-09-01

    Full Text Available Introduction In conventional methods of spraying in orchards, the amount of pesticide sprayed, is not targeted. The pesticide consumption data indicates that the application rate of pesticide in greenhouses and orchards is more than required. Less than 30% of pesticide sprayed actually reaches nursery canopies while the rest are lost and wasted. Nowadays, variable rate spray applicators using intelligent control systems can greatly reduce pesticide use and off-target contamination of environment in nurseries and orchards. In this research a prototype orchard sprayer based on machine vision technology was developed and evaluated. This sprayer performs real-time spraying based on the tree canopy structure and its greenness extent which improves the efficiency of spraying operation in orchards. Materials and Methods The equipment used in this study comprised of three main parts generally: 1- Mechanical Equipment 2- Data collection and image processing system 3- Electronic control system Two booms were designed to support the spray nozzles and to provide flexibility in directing the spray nozzles to the target. The boom comprised two parts, the vertical part and inclined part. The vertical part of the boom was used to spray one side of the trees during forward movement of the tractor and inclined part of the boom was designed to spray the upper half of the tree canopy. Three nozzles were considered on each boom. On the vertical part of the boom, two nozzles were placed, whereas one other nozzle was mounted on the inclined part of the boom. To achieve different tree heights, the vertical part of the boom was able to slide up and down. Labview (version 2011 was used for real time image processing. Images were captured through RGB cameras mounted on a horizontal bar attached on top of the tractor to take images separately for each side of the sprayer. Images were captured from the top of the canopies looking downward. The triggering signal for

  2. The miR-30 microRNA family targets smoothened to regulate hedgehog signalling in zebrafish early muscle development.

    Science.gov (United States)

    Ketley, Ami; Warren, Anne; Holmes, Emily; Gering, Martin; Aboobaker, A Aziz; Brook, J David

    2013-01-01

    The importance of microRNAs in development is now widely accepted. However, identifying the specific targets of individual microRNAs and understanding their biological significance remains a major challenge. We have used the zebrafish model system to evaluate the expression and function of microRNAs potentially involved in muscle development and study their interaction with predicted target genes. We altered expression of the miR-30 microRNA family and generated phenotypes that mimicked misregulation of the Hedgehog pathway. Inhibition of the miR-30 family increases activity of the pathway, resulting in elevated ptc1 expression and increased numbers of superficial slow-muscle fibres. We show that the transmembrane receptor smoothened is a target of this microRNA family. Our results indicate that fine coordination of smoothened activity by the miR-30 family allows the correct specification and differentiation of distinct muscle cell types during zebrafish embryonic development.

  3. The miR-30 microRNA family targets smoothened to regulate hedgehog signalling in zebrafish early muscle development.

    Directory of Open Access Journals (Sweden)

    Ami Ketley

    Full Text Available The importance of microRNAs in development is now widely accepted. However, identifying the specific targets of individual microRNAs and understanding their biological significance remains a major challenge. We have used the zebrafish model system to evaluate the expression and function of microRNAs potentially involved in muscle development and study their interaction with predicted target genes. We altered expression of the miR-30 microRNA family and generated phenotypes that mimicked misregulation of the Hedgehog pathway. Inhibition of the miR-30 family increases activity of the pathway, resulting in elevated ptc1 expression and increased numbers of superficial slow-muscle fibres. We show that the transmembrane receptor smoothened is a target of this microRNA family. Our results indicate that fine coordination of smoothened activity by the miR-30 family allows the correct specification and differentiation of distinct muscle cell types during zebrafish embryonic development.

  4. A QFD-Based Mathematical Model for New Product Development Considering the Target Market Segment

    Directory of Open Access Journals (Sweden)

    Liang-Hsuan Chen

    2014-01-01

    Full Text Available Responding to customer needs is important for business success. Quality function deployment provides systematic procedures for converting customer needs into technical requirements to ensure maximum customer satisfaction. The existing literature mainly focuses on the achievement of maximum customer satisfaction under a budgetary limit via mathematical models. The market goal of the new product for the target market segment is usually ignored. In this study, the proposed approach thus considers the target customer satisfaction degree for the target market segment in the model by formulating the overall customer satisfaction as a function of the quality level. In addition, the proposed approach emphasizes the cost-effectiveness concept in the design stage via the achievement of the target customer satisfaction degree using the minimal total cost. A numerical example is used to demonstrate the applicability of the proposed approach and its characteristics are discussed.

  5. IDH mutations in cancer and progress toward development of targeted therapeutics.

    Science.gov (United States)

    Dang, L; Yen, K; Attar, E C

    2016-04-01

    Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are key metabolic enzymes, converting isocitrate to α-ketoglutarate (αKG).IDH1 and IDH2 mutations have been identified in multiple tumor types, including gliomas and myeloid malignancies such as acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Here we provide an overview of the function of normal and mutated IDH, discuss the role of IDH mutations in tumorigenesis and progression and review the key clinical considerations when treating IDH-mutated tumors based on emerging clinical data from mutant IDH1/2 inhibitor trials. IDH1 and IDH2 mutations confer neomorphic activity in the mutant protein, resulting in the conversion of αKG to the oncometabolite, D-2-hydroxyglutarate (2-HG). The subsequent accumulation of 2-HG results in epigenetic dysregulation via inhibition of αKG-dependent histone and DNA demethylases, and a block in cellular differentiation. There is growing preclinical and clinical evidence suggesting that IDHmutations are involved in neoplasia. Furthermore, preclinical studies assessing small molecule inhibitors of mutant IDH1/2 enzymes have provided proof of concept that this approach decreases intracellular 2-HG levels, reverses epigenetic dysregulation and induces cellular differentiation. Phase I studies of mutant IDH inhibitors are currently ongoing in patients with IDH-mutant hematologic and solid tumors, with early data in hematologic tumors suggesting a manageable safety profile as well as clinical benefit, with a mechanism of action based on differentiation of malignant cells. Inhibition of mutant IDH shows promise as a treatment approach in hematologic malignancies, with further development ongoing in solid tumors and glioma. The mutant IDH inhibitors may have clinical utility both as single agents and in combination strategies that target additional oncogenic pathways. © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical

  6. Optimized nonclinical safety assessment strategies supporting clinical development of therapeutic monoclonal antibodies targeting inflammatory diseases.

    Science.gov (United States)

    Brennan, Frank R; Cauvin, Annick; Tibbitts, Jay; Wolfreys, Alison

    2014-05-01

    An increasing number of immunomodulatory monoclonal antibodies (mAbs) and IgG Fc fusion proteins are either approved or in early-to-late stage clinical trials for the treatment of chronic inflammatory conditions, autoimmune diseases and organ transplant rejection. The exquisite specificity of mAbs, in combination with their multi-functional properties, high potency, long half-life (permitting intermittent dosing and prolonged pharamcological effects), and general lack of off-target toxicity makes them ideal therapeutics. Dosing with mAbs for these severe and debilitating but often non life-threatening diseases is usually prolonged, for several months or years, and not only affects adults, including sensitive populations such as woman of child-bearing potential (WoCBP) and the elderly, but also children. Immunosuppression is usually a therapeutic goal of these mAbs and when administered to patients whose treatment program often involves other immunosuppressive therapies, there is an inherent risk for frank immunosuppression and reduced host defence which when prolonged increases the risk of infection and cancer. In addition when mAbs interact with the immune system they can induce other adverse immune-mediated drug reactions such as infusion reactions, cytokine release syndrome, anaphylaxis, immune-complex-mediated pathology and autoimmunity. An overview of the nonclinical safety assessment and risk mitigation strategies utilized to characterize these immunomodulatory mAbs and Fc fusion proteins to support first-in human (FIH) studies and futher clinical development in inflammatory disease indications is provided. Specific emphasis is placed on the design of studies to qualify animal species for toxicology studies, early studies to investigate safety and define PK/PD relationships, FIH-enabling and chronic toxicology studies, immunotoxicity, developmental, reproductive and juvenile toxicity studies and studies to determine the potential for immunosuppression and

  7. Development and evaluation of intestinal targeted mucoadhesive microspheres of Bacillus coagulans.

    Science.gov (United States)

    Alli, Sk Md Athar; Ali, Sk Md Ajhar; Samanta, Amalesh

    2011-11-01

    Intestinal targeted mucoadhesive microsphere of probiotics may provide numerous associated health benefits. To develop mucoadhesive microspheres that will deliver viable probiotic cells into gut protectively against harsh environmental conditions of stomach for extended period. Core mucoadhesive microspheres of Bacillus coagulans were prepared using hypromellose, following coacervation and phase separation technique and were then coated with hypromellose phthalate to achieve their site-specific release. Microspheres were evaluated for percent yield, entrapment efficiency, surface morphology, particle size and size distribution, flow property, swelling property, mucoadhesion property by the in vitro wash-off and the ex vivo mucoadhesive strength tests, in vitro release profile and release kinetic, in vivo probiotic activity, and stability. The values for kinetic constant and regression coefficient of model-dependent approaches and the difference factor, the similarity factor, and the Rescigno index of model-independent approaches were determined for accessing and comparing in vitro performance. Microsphere formulation batches have percent yield value between 56.26% and 69.13% and entrapment efficiency value between 66.95% and 77.89%. Microspheres were coarser with spherical shape having mean particle size from 28.03 to 48.31 μm. In vitro B. coagulans release profile follows zero-order kinetics and depends on the grade of hypromellose and the B. coagulans-to-hypromellose ratio. Experimental microspheres rendered adequate stability to B. coagulans at room temperature. Microspheres had delivered B. coagulans in simulated intestinal condition following zero-order kinetics, protectively in simulated gastric condition, exhibiting appreciable mucoadhesion in intestinal condition, which could be useful to achieve site-specific delivery for extended period.

  8. Application of the pyrochemical DOS, developed by the CEA, within reprocessing of CERCER transmutation fuel targets

    Energy Technology Data Exchange (ETDEWEB)

    Mendes, E.; Ducasse, T.; Bertrand, M. [CEA, Centre de Marcoule, Nuclear Energy Division, Radiochemistry and Processes Department, SMCS, LDPS, F-30207 Bagnols-sur-Ceze (France); Miguirditchian, M. [CEA, Centre de Marcoule, Nuclear Energy Division, Radiochemistry and Processes Department, SMCS, LCPE, F-30207 Bagnols-sur-Ceze (France)

    2016-07-01

    Pyrochemical technology using high-temperature molten salts and molten metal media presents a potential interest for an overall separation and transmutation strategy for long-lived radionuclides. Within the frame of the two French acts on radioactive waste management, a pyrochemical research/development program was launched at the CEA Marcoule in the late 90's. The second step is the actinides back-extraction, which consists in a liquid/liquid oxidative stripping of the An from aluminium matrix into molten chloride media. The DOS process has been successfully demonstrated for treatment of oxide type fuels within the last years: the core of the process has been already assessed and the studies have shown high selectivity and a quantitative recovery of actinides. Within the framework of the SACSESS European research program, the pyrochemical activities focused on applications of the DOS process to reprocess CERCER transmutation targets. These particular types of fuels consist of a mixture of minor actinides (MA) oxides diluted in an inert (oxide MgO) matrices. The behaviour of matrices material was first investigated regarding the solubility in the fluoride salt, starting from both oxide powders or sintered pellets. The saturation of Mg in the salt could be estimated at ∼ 3 wt%. Regarding the reductive extraction, as expected no Mg was reduced by the metallic phase. The present work also highlights that Mg has low impact on the extraction efficiency of U as long as the salt is not saturated. Once the saturation occurs, the efficiency starts to decrease. So we recommend recycling the salt when Mg saturation is reached.

  9. DEVELOPMENT OF THE METHOD OF DETERMINING THE TARGET FUNCTION OF OPTIMIZATION OF POWER PLANT

    Directory of Open Access Journals (Sweden)

    O. Maksymovа

    2017-08-01

    Full Text Available It has been proposed the application of an optimization criterion based on properties of target functions, taken from the elements of technical, economic and thermodynamic analyses. Marginal costs indicators of energy for different energy products have also been identified. Target function of the power plant optimization was proposed, that considers energy expenditure in the presented plant and in plants closing the energy sources generation and consumption balance.

  10. Summary abstract: microspot target development with seeded and patterned plasma polymers

    International Nuclear Information System (INIS)

    Letts, S.A.; Miller, D.E.; Corley, R.A.; Tillotson, T.M.; Witt, L.A.

    1985-01-01

    In inertial confinement fusion (ICF) energy is transferred from the laser to the target through the interaction of extremely high intensity laser light with the target plasma. To better understand laser-plasma interactions, a new class of targets was designed to study long scale-length plasmas (many hundred times the laser wavelength) by measurement of the temperature and density of the plasma as a function of time. The specifications for the target called for a freestanding hydrocarbon polymer (CH) film with a sharply defined spot (microspot) in the center seeded with either silicon or sulfur. The target film was fabricated using a three-step procedure which consisted of deposition of the hydrocarbon film, definition of the microspot, and then deposition of a seeded spot through a mask. In the final assembly step, the film containing the microspot was mounted over a 1.5 mm diam hole in a support. The support was either a plastic ring or a copper foil electroplated with 3 μm of gold. The fabrication of this type of target is described

  11. Development of whole-building energy design targets for commercial buildings: Phase 1, Planning: Volume 2, Technical report

    Energy Technology Data Exchange (ETDEWEB)

    Crawley, D.B.; Briggs, R.S.; Jones, J.W.; Seaton, W.W.; Kaufman, J.E.; Deringer, J.J.; Kennett, E.W.

    1987-08-01

    This is the second volume of the Phase 1 report and discusses the 10 tasks performed in Phase 1. The objective of this research is to develop a methodology for setting energy design targets to provide voluntary guidelines for the buildings industry. The whole-building energy targets project is being conducted at the Pacific Northwest Laboratory (PNL) for the US Department of Energy (DOE) to encourage the construction of energy-efficient buildings by informing designers and owners about cost-effective goals for energy use in new commercial buildings. The outcome of this research will be a flexible methodology for setting such targets. The tasks are listed and discussed in this report as follows: Task 1 - Develop Detailed Project Goals and Objectives; Task 2 - Establish Buildings-Industry Liaison; Task 3 - Develop Approaches to the Energy Targets Model, Building Operations, and Climate; Task 4 - Develop an Approach for Treating Economic Considerations; Task 5 - Develop an Approach for Treating Energy Sources; Task 6 - Collect Energy-Use Data; Task 7 - Survey Energy Expert Opinion; Task 8 - Evaluation Procedure Specification and Integration; Task 9 - Phase 1 Report Development; and Task 10 - Phase 1 Review Planning.

  12. Inertial confinement fusion target component fabrication and technology development support. Annual report, October 1, 1996--September 30, 1997

    Energy Technology Data Exchange (ETDEWEB)

    Gibson, J. [ed.

    1998-03-01

    This report documents the technical activities of the period October 1, 1996 through September 30, 1997. During this period, GA and their partner Schafer Corporation were assigned 13 formal tasks in support of the ICF program and its five laboratories. A portion of the effort on these tasks included providing direct {open_quotes}Onsite Support{close_quotes} at Lawrence Livermore National Laboratory (LLNL), Los Alamos National Laboratory (LANL), and Sandia National Laboratory Albuquerque (SNLA). Over 700 gold-plated hohlraum mandrels were fabricated and delivered to LLNL, LANL and SNLA. More than 1600 glass and plastic target capsules were produced for LLNL, LANL, SNLA and University of Rochester/Laboratory for Laser Energetics (UR/LLE). Nearly 2000 various target foils and films were delivered for Naval Research Lab (NRL) and UR/LLE in FY97. This report describes these target fabrication activities and the target fabrication and characterization development activities that made the deliveries possible. The ICF program is anticipating experiments at the OMEGA laser and the National Ignition Facility (NIF) which will require targets containing cryogenic layered D{sub 2} or deuterium-tritium (DT) fuel. This project is part of the National Cryogenic Target Program and support experiments at LLNL and LANL to generate and characterize cryogenic layers for these targets. During FY97, significant progress was made in the design and component testing of the OMEGA Cryogenic Target System that will field cryogenic targets on OMEGA. This included major design changes, reduction in equipment, and process simplifications. This report summarizes and documents the technical progress made on these tasks.

  13. Inertial confinement fusion target component fabrication and technology development support. Annual report, October 1, 1996 - September 30, 1997

    International Nuclear Information System (INIS)

    Gibson, J.

    1998-03-01

    This report documents the technical activities of the period October 1, 1996 through September 30, 1997. During this period, GA and their partner Schafer Corporation were assigned 13 formal tasks in support of the ICF program and its five laboratories. A portion of the effort on these tasks included providing direct open-quotes Onsite Supportclose quotes at Lawrence Livermore National Laboratory (LLNL), Los Alamos National Laboratory (LANL), and Sandia National Laboratory Albuquerque (SNLA). Over 700 gold-plated hohlraum mandrels were fabricated and delivered to LLNL, LANL and SNLA. More than 1600 glass and plastic target capsules were produced for LLNL, LANL, SNLA and University of Rochester/Laboratory for Laser Energetics (UR/LLE). Nearly 2000 various target foils and films were delivered for Naval Research Lab (NRL) and UR/LLE in FY97. This report describes these target fabrication activities and the target fabrication and characterization development activities that made the deliveries possible. The ICF program is anticipating experiments at the OMEGA laser and the National Ignition Facility (NIF) which will require targets containing cryogenic layered D 2 or deuterium-tritium (DT) fuel. This project is part of the National Cryogenic Target Program and support experiments at LLNL and LANL to generate and characterize cryogenic layers for these targets. During FY97, significant progress was made in the design and component testing of the OMEGA Cryogenic Target System that will field cryogenic targets on OMEGA. This included major design changes, reduction in equipment, and process simplifications. This report summarizes and documents the technical progress made on these tasks

  14. Embedding sexual and reproductive health and rights in a transformational development framework: lessons learned from the MDG targets and indicators.

    Science.gov (United States)

    Yamin, Alicia Ely; Boulanger, Vanessa M

    2013-11-01

    This paper explores the intended and unintended consequences of the selection of MDG 5 as a global goal, together with its respective targets and indicators, and places what happened to MDG 5, and sexual and reproductive health and rights more broadly, into the context of the development model that was encoded in the MDGs. Over the last decade, as the MDGs increasingly took centre stage in development and their use evolved, they were inappropriately converted from global goals into national planning targets. This conversion was particularly detrimental in the case of MDG 5. It not only created a narrowing in terms of policies and programming, but also had an enormous impact on the discourse of development itself, reshaping the field in terms of the organization and dissemination of knowledge, and underscoring that the process of setting targets and indicators is far from neutral but encodes normative values. Looking forward, it is not adequate to propose an MDG+ framework based on the same structure. Sexual and reproductive health and rights must be placed back into the global discourse, using development to empower women and marginalized populations, and to address structural inequalities that are fundamental to sustained social change. The new development framework should include a strong narrative of social transformation in which fit-for-purpose targets and indicators play a role, but do not overtake or restrict the broader aims of advancing social, political, and gender justice. Copyright © 2013 Reproductive Health Matters. Published by Elsevier Ltd. All rights reserved.

  15. Progress and Challenges in Developing Aptamer-Functionalized Targeted Drug Delivery Systems

    Directory of Open Access Journals (Sweden)

    Feng Jiang

    2015-10-01

    Full Text Available Aptamers, which can be screened via systematic evolution of ligands by exponential enrichment (SELEX, are superior ligands for molecular recognition due to their high selectivity and affinity. The interest in the use of aptamers as ligands for targeted drug delivery has been increasing due to their unique advantages. Based on their different compositions and preparation methods, aptamer-functionalized targeted drug delivery systems can be divided into two main categories: aptamer-small molecule conjugated systems and aptamer-nanomaterial conjugated systems. In this review, we not only summarize recent progress in aptamer selection and the application of aptamers in these targeted drug delivery systems but also discuss the advantages, challenges and new perspectives associated with these delivery systems.

  16. SWATHtoMRM: Development of High-Coverage Targeted Metabolomics Method Using SWATH Technology for Biomarker Discovery.

    Science.gov (United States)

    Zha, Haihong; Cai, Yuping; Yin, Yandong; Wang, Zhuozhong; Li, Kang; Zhu, Zheng-Jiang

    2018-03-02

    The complexity of metabolome presents a great analytical challenge for quantitative metabolite profiling, and restricts the application of metabolomics in biomarker discovery. Targeted metabolomics using multiple-reaction monitoring (MRM) technique has excellent capability for quantitative analysis, but suffers from the limited metabolite coverage. To address this challenge, we developed a new strategy, namely, SWATHtoMRM, which utilizes the broad coverage of SWATH-MS technology to develop high-coverage targeted metabolomics method. Specifically, SWATH-MS technique was first utilized to untargeted profile one pooled biological sample and to acquire the MS 2 spectra for all metabolites. Then, SWATHtoMRM was used to extract the large-scale MRM transitions for targeted analysis with coverage as high as 1000-2000 metabolites. Then, we demonstrated the advantages of SWATHtoMRM method in quantitative analysis such as coverage, reproducibility, sensitivity, and dynamic range. Finally, we applied our SWATHtoMRM approach to discover potential metabolite biomarkers for colorectal cancer (CRC) diagnosis. A high-coverage targeted metabolomics method with 1303 metabolites in one injection was developed to profile colorectal cancer tissues from CRC patients. A total of 20 potential metabolite biomarkers were discovered and validated for CRC diagnosis. In plasma samples from CRC patients, 17 out of 20 potential biomarkers were further validated to be associated with tumor resection, which may have a great potential in assessing the prognosis of CRC patients after tumor resection. Together, the SWATHtoMRM strategy provides a new way to develop high-coverage targeted metabolomics method, and facilitates the application of targeted metabolomics in disease biomarker discovery. The SWATHtoMRM program is freely available on the Internet ( http://www.zhulab.cn/software.php ).

  17. Inertial confinement fusion target component fabrication and technology development support. Annual report, October 1, 1994--September 30, 1995

    Energy Technology Data Exchange (ETDEWEB)

    Hoppe, M. [ed.

    1996-05-01

    On December 30, 1990, the US Department of Energy entered into a contract with General Atomics (GA) to be the Inertial Confinement Fusion (ICF) Target Component Fabrication and Technology Development Support contractor. This report documents the technical activities of the period October 1, 1994 through September 30, 1995. During this period, GA was assigned 15 tasks in support of the Inertial Confinement Fusion program and its laboratories. A portion of the effort on these tasks included providing direct ``Onsite Support`` at Lawrence Livermore National Laboratory (LLNL), Los Alamos National Laboratory (LANL), and Sandia National Laboratory Albuquerque (SNLA). The ICF program is anticipating experiments at the National Ignition Facility (NIF) and the OMEGA Upgrade. Both facilities will require capsules containing layered D{sub 2} or deuterium-tritium (D-T) fuel. The authors are part of the National Cryogenic Target Program to create and demonstrate viable ways to generate and characterize cryogenic layers. Progress has been made on ways to both create viable layers and to characterize them. They continued engineering, assembly and testing of equipment for a cryogenic target handling system for University of Rochester`s Laboratory for Laser Energetics (UR/LLE) that will fill, transport, layer, and characterize targets filled with cryogenic fuel, and insert these cryogenic targets into the OMEGA Upgrade target chamber for laser implosion experiments. This report summarizes and documents the technical progress made on these tasks.

  18. Inertial confinement fusion target component fabrication and technology development support. Annual report, October 1, 1994--September 30, 1995

    International Nuclear Information System (INIS)

    Hoppe, M.

    1996-05-01

    On December 30, 1990, the US Department of Energy entered into a contract with General Atomics (GA) to be the Inertial Confinement Fusion (ICF) Target Component Fabrication and Technology Development Support contractor. This report documents the technical activities of the period October 1, 1994 through September 30, 1995. During this period, GA was assigned 15 tasks in support of the Inertial Confinement Fusion program and its laboratories. A portion of the effort on these tasks included providing direct ''Onsite Support'' at Lawrence Livermore National Laboratory (LLNL), Los Alamos National Laboratory (LANL), and Sandia National Laboratory Albuquerque (SNLA). The ICF program is anticipating experiments at the National Ignition Facility (NIF) and the OMEGA Upgrade. Both facilities will require capsules containing layered D 2 or deuterium-tritium (D-T) fuel. The authors are part of the National Cryogenic Target Program to create and demonstrate viable ways to generate and characterize cryogenic layers. Progress has been made on ways to both create viable layers and to characterize them. They continued engineering, assembly and testing of equipment for a cryogenic target handling system for University of Rochester's Laboratory for Laser Energetics (UR/LLE) that will fill, transport, layer, and characterize targets filled with cryogenic fuel, and insert these cryogenic targets into the OMEGA Upgrade target chamber for laser implosion experiments. This report summarizes and documents the technical progress made on these tasks

  19. Development of an odour-baited insecticidal target system for the suppression of adults of the new world screwworm fly

    International Nuclear Information System (INIS)

    Allsopp, R.

    1992-02-01

    To provide a rapidly deployable supplemental means of effectively suppressing screwworms, the parameters needed to develop an odour-baited insecticidal target system were established. Electro-antennograph studies indicated the relative attractancy of swormlure component, identified candidate attractants and established that 4-methyl phenol and dimethyl sulphide more strongly attract male than female flies. Wind tunnel studies showed that the swormlure stimulates upwind flight and prolonged searching. By means of electric nets it was shown that screwworms fly directly to the target and land without circling. Black is the most effective colour for targets. The optimal size of the target was not identified, but those of 0.25 m 2 were found to be as effective as much larger ones. Targets are effective only when baited with swormlure. Excellent control of the rate of release of the attractant mixture was achieved by placing it in 120 micron thick polyethylene sachets with the exception that dimethyl disulphide must be dispensed separately form 1 mm thick polyethylene sachets. Of the insecticides tested when applied to black cloth targets, deltamethrin proved to be the most effective. Refs, figs and tabs

  20. Development of A Chimeric Antigen Receptor Targeting C-Type Lectin-Like Molecule-1 for Human Acute Myeloid Leukemia

    Directory of Open Access Journals (Sweden)

    Eduardo Laborda

    2017-10-01

    Full Text Available The treatment of patients with acute myeloid leukemia (AML with targeted immunotherapy is challenged by the heterogeneity of the disease and a lack of tumor-exclusive antigens. Conventional immunotherapy targets for AML such as CD33 and CD123 have been proposed as targets for chimeric antigen receptor (CAR-engineered T-cells (CAR-T-cells, a therapy that has been highly successful in the treatment of B-cell leukemia and lymphoma. However, CD33 and CD123 are present on hematopoietic stem cells, and targeting with CAR-T-cells has the potential to elicit long-term myelosuppression. C-type lectin-like molecule-1 (CLL1 or CLEC12A is a myeloid lineage antigen that is expressed by malignant cells in more than 90% of AML patients. CLL1 is not expressed by healthy Hematopoietic Stem Cells (HSCs, and is therefore a promising target for CAR-T-cell therapy. Here, we describe the development and optimization of an anti-CLL1 CAR-T-cell with potent activity on both AML cell lines and primary patient-derived AML blasts in vitro while sparing healthy HSCs. Furthermore, in a disseminated mouse xenograft model using the CLL1-positive HL60 cell line, these CAR-T-cells completely eradicated tumor, thus supporting CLL1 as a promising target for CAR-T-cells to treat AML while limiting myelosuppressive toxicity.

  1. Activated Ras alters lens and corneal development through induction of distinct downstream targets

    Directory of Open Access Journals (Sweden)

    Reneker Lixing

    2010-01-01

    Full Text Available Abstract Background Mammalian Ras genes regulate diverse cellular processes including proliferation and differentiation and are frequently mutated in human cancers. Tumor development in response to Ras activation varies between different tissues and the molecular basis for these variations are poorly understood. The murine lens and cornea have a common embryonic origin and arise from adjacent regions of the surface ectoderm. Activation of the fibroblast growth factor (FGF signaling pathway induces the corneal epithelial cells to proliferate and the lens epithelial cells to exit the cell cycle. The molecular mechanisms that regulate the differential responses of these two related tissues have not been defined. We have generated transgenic mice that express a constitutively active version of human H-Ras in their lenses and corneas. Results Ras transgenic lenses and corneal epithelial cells showed increased proliferation with concomitant increases in cyclin D1 and D2 expression. This initial increase in proliferation is sustained in the cornea but not in the lens epithelial cells. Coincidentally, cdk inhibitors p27Kip1 and p57Kip2 were upregulated in the Ras transgenic lenses but not in the corneas. Phospho-Erk1 and Erk2 levels were elevated in the lens but not in the cornea and Spry 1 and Spry 2, negative regulators of Ras-Raf-Erk signaling, were upregulated more in the corneal than in the lens epithelial cells. Both lens and corneal differentiation programs were sensitive to Ras activation. Ras transgenic embryos showed a distinctive alteration in the architecture of the lens pit. Ras activation, though sufficient for upregulation of Prox1, a transcription factor critical for cell cycle exit and initiation of fiber differentiation, is not sufficient for induction of terminal fiber differentiation. Expression of Keratin 12, a marker of corneal epithelial differentiation, was reduced in the Ras transgenic corneas. Conclusions Collectively, these

  2. Development of Real Time PCR Using Novel Genomic Target for Detection of Multiple Salmonella Serovars from Milk and Chickens

    Science.gov (United States)

    Background: A highly sensitive and specific novel genomic and plasmid target-based PCR platform was developed to detect multiple Salmonella serovars (S. Heidelberg, S. Dublin, S. Hadar, S. Kentucky and S. Enteritidis). Through extensive genome mining of protein databases of these serovars and compar...

  3. Development of a methodology for defining whole-building energy design targets for commercial buildings: Phase 2, Development concept stage report

    Energy Technology Data Exchange (ETDEWEB)

    Jones, J.W. (American Society of Heating, Refrigerating and Air-Conditioning Engineers, Inc., Atlanta, GA (USA)); Deringer, J.J. (American Inst. of Architects, Washington, DC (USA)); McKay, H.N. (Illuminating Engineering Society of North America, New York, NY (USA))

    1990-09-01

    Since 1985, the Pacific Northwest Laboratory (PNL) has managed the Whole-Building Energy Design Targets project for the US Department of Energy (DOE) Office of Building Technologies (formerly the Office of Buildings and Community Systems). The primary focus of the Targets project is to develop a flexible methodology for buildings industry use in setting energy performance guidelines for commercial buildings and for determining compliance with those guidelines. The project is being conducted as a two-phase effort. In Phase 1, Planning, the project team determined the research that was necessary for developing the Targets methodology. In the concept stage of Phase 2, Development, the team sought to define the technical and software development concepts upon which the overall Targets methodology will be based. The concept stage work is documented in four volumes, of which this summary volume is the first. The three other volumes are Volume 2: Technical Concept Development Task Reports, Volume 3: Workshop Summaries, and Volume 4: Software Concept Development Task Reports. 8 refs., 14 figs.

  4. Development of a Software for Quantitative Evaluation Radiotherapy Target and Organ-at-Risk Segmentation Comparison

    NARCIS (Netherlands)

    Kalpathy-Cramer, Jayashree; Awan, Musaddiq; Bedrick, Steven; Rasch, Coen R. N.; Rosenthal, David I.; Fuller, Clifton D.

    2014-01-01

    Modern radiotherapy requires accurate region of interest (ROI) inputs for plan optimization and delivery. Target delineation, however, remains operator-dependent and potentially serves as a major source of treatment delivery error. In order to optimize this critical, yet observer-driven process, a

  5. Target validation for FCV technology development in Japan from energy competition point of view

    International Nuclear Information System (INIS)

    ENDO Eiichi

    2006-01-01

    The objective of this work is to validate the technical targets in the governmental hydrogen energy road-map of Japan by analyzing market penetration of fuel cell vehicle(FCV)s and effects of fuel price and carbon tax on it from technology competition point of view. In this analysis, an energy system model of Japan based on MARKAL is used. The results of the analysis show that hydrogen FCVs could not have cost-competitiveness until 2030 without carbon tax, including the governmental actual plan of carbon tax. However, as the carbon tax rate increases, instead of conventional vehicles including gasoline hybrid electric vehicle, hydrogen FCVs penetrate to the market earlier and more. By assuming higher fuel price and severer carbon tax rate, market share of hydrogen FCVs approaches to the governmental goal. This suggests that cheaper vehicle cost and/or hydrogen price than those targeted in the road-map is required. At the same time, achievement of the technical targets in the road-map also allows to attain the market penetration target of hydrogen FCVs in some possible conditions. (authors)

  6. Turning Defense into Offense: Development of Defensin Mimetics as Novel Antibiotics targeting Lipid II

    NARCIS (Netherlands)

    Varney, K.M.; Bonvin, A.M.J.J.|info:eu-repo/dai/nl/113691238; Pazgier, M.; Malin, J.; Yu, W.; Ateh, E.; Oashi, T.; Lu, W.|info:eu-repo/dai/nl/412350289; Huang, J.; Diepeveen-de Buin, M.; Bryant, J.; Breukink, E.J.|info:eu-repo/dai/nl/120305100; MacKerell, A.D.; de Leeuw, E.P.H.

    2013-01-01

    We have previously reported on the functional interaction of Lipid II with human alpha-defensins, a class of antimicrobial peptides. Lipid II is an essential precursor for bacterial cell wall biosynthesis and an ideal and validated target for natural antibiotic compounds. Using a combination of

  7. Design and development of a magnetic device for mesenchymal stem cell retaining in deep targets

    Science.gov (United States)

    Banis, G. C.

    2017-12-01

    This paper focuses on the retaining of mesenchymal stem cells in blood flow conditions using the appropriate magnetic field. Mesenchymal stem cells can be tagged with magnetic nanoparticles and thus, they can be manipulated from distance, through the application of an external magnetic field. In this paper the case of kidney as target of the therapy is being studied.

  8. Target irradiation facility and targetry development at 160 MeV proton beam of Moscow linac

    CERN Document Server

    Zhuikov, B L; Konyakhin, N A; Vincent, J

    1999-01-01

    A facility has been built and successfully operated with the 160 MeV proton beam of Moscow Meson factory LINAC, Institute for Nuclear Research (INR) of Russian Academy of Science, Troitsk. The facility was created for various isotope production goals as well as for fundamental nuclear investigations at high intensity beam (100 mu A and more). An important part of the facility targetry system is a high-intensity beam monitoring collimator device. Measurements of the temperature distribution between collimator sectors, cooling water flow and temperature, and the beam current, provide an opportunity to compute beam losses and beam position. The target holder design allows easy insertion by manipulator and simultaneous bombardment of several different targets of various types and forms, and variation of proton energy on each target over a wide range below 160 MeV. The main target utilized for commercial sup 8 sup 2 Sr isotope production is metallic rubidium in a stainless-steel container. A regular wet chemistry ...

  9. Development of whole-building energy design targets for commercial buildings: Phase 1, Planning: Volume 1, Final report

    Energy Technology Data Exchange (ETDEWEB)

    Crawley, D.B.; Briggs, R.S.; Jones, J.W.; Seaton, W.W.; Kaufman, J.E.; Deringer, J.J.; Kennett, E.W.

    1987-04-01

    This report describes background research for preparation of a plan for development of whole-building energy targets for new commercial buildings. The lead laboratory for this program is the Pacific Northwest Laboratory. A wide variety of expertise and resources from industry, academia, other government entities, and other DOE laboratories are used in planning, reviewing and conducting research activities. Cooperative and complementary research development, and technology transfer activities with other interested organizations are actively pursued.

  10. Inertial confinement fusion target component fabrication and technology development support: Annual report, October 1, 1993--September 30, 1994

    International Nuclear Information System (INIS)

    Hoppe, M.

    1995-04-01

    On December 30, 1990, the US Department of Energy entered into a contract with General Atomics (GA) to be the Inertial Confinement Fusion (ICF) Target Component Fabrication and Technology Development Support contractor. During the period, GA was assigned 17 tasks in support of the Inertial Confinement Fusion program and its laboratories. This year they achieved full production capabilities for the micromachining, dimensional characterization and gold plating of hohlraums. They fabricated and delivered 726 gold-plated mandrels of 27 different types to LLNL and 48 gold-plated mandrels of two different types to LANL. They achieved full production capabilities in composite capsule production ad delivered in excess of 240 composite capsules. They continuously work to improve performance and capabilities. They were also directed to dismantle, remove, and disposition all equipment at the previous contractor (KMSF) that had radioactive contamination levels low enough that they could be exposed to the general public without radiological constraints. GA was also directed to receive and store the tritium fill equipment. They assisted LANL in the development of techniques for characterization of opaque targets. They developed deuterated and UV-opaque polymers for use by the University of Rochester's Laboratory for Laser Energetics (UR/LLE) and devised a triple-orifice droplet generator to demonstrate the controlled-mass nature of the microencapsulation process. The ICF program is anticipating experiments at NIF and the Omega Upgrade. Both facilities will require capsules containing layered D 2 or D-T fuel. They continued engineering and assembly of equipment for a cryogenic target handling system for UR/LLE that will fill, transport, layer, and characterize targets filled with cryogenic deuterium or deuterium-tritium fuel, and insert these cryogenic targets into the OMEGA Upgrade target chamber for laser implosion experiments

  11. More than just openness: developing and validating a measure of targeted parent-child communication about alcohol.

    Science.gov (United States)

    Miller-Day, Michelle; Kam, Jennifer A

    2010-06-01

    Research addressing parent-child communication on the topic of alcohol use relies heavily on assessing frequency of discussions and general assessments of openness in parent-child communication, ignoring the complexity of this communication phenomenon. This study adds to the literature by articulating a conceptualization and developing a measurement of parent-child communication-targeted parent-child communication about alcohol-and comparing the efficacy of targeted parent-child communication about alcohol in predicting positive expectancies of alcohol use and recent alcohol use. The predictive power of general openness in parent-child communication and frequency of communication about alcohol also were assessed. Students in fifth and sixth grade (N = 1,407) from 29 public schools completed surveys. Targeted parent-child communication about alcohol was negatively associated with both outcomes. Frequency and general openness were only negatively associated with positive expectancies regarding alcohol. Implications of these findings for the etiology and prevention of substance use are discussed.

  12. Orexin Receptor Targets for Anti-Relapse Medication Development in Drug Addiction

    Directory of Open Access Journals (Sweden)

    Ronald E. See

    2011-06-01

    Full Text Available Drug addiction is a chronic illness characterized by high rates of relapse. Relapse to drug use can be triggered by re-exposure to drug-associated cues, stressful events, or the drug itself after a period of abstinence. Pharmacological intervention to reduce the impact of relapse-instigating factors offers a promising target for addiction treatment. Growing evidence has implicated an important role of the orexin/hypocretin system in drug reward and drug-seeking, including animal models of relapse. Here, we review the evidence for the role of orexins in modulating reward and drug-seeking in animal models of addiction and the potential for orexin receptors as specific targets for anti-relapse medication approaches.

  13. Dynamics of target recognition by interstitial axon branching along developing cortical axons.

    Science.gov (United States)

    Bastmeyer, M; O'Leary, D D

    1996-02-15

    Corticospinal axons innervate their midbrain, hindbrain, and spinal targets by extending collateral branches interstitially along their length. To establish that the axon shaft rather than the axonal growth cone is responsible for target recognition in this system, and to characterize the dynamics of interstitial branch formation, we have studied this process in an in vivo-like setting using slice cultures from neonatal mice containing the entire pathway of corticospinal axons. Corticospinal axons labeled with the dye 1,1'-dioctodecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (or Dil) were imaged using time-lapse video microscopy of their pathway overlying the basilar pons, their major hindbrain target. The axon shaft millimeters behind the growth cone exhibits several dynamic behaviors, including the de novo formation of varicosities and filopodia-like extensions, and a behavior that we term "pulsation," which is characterized by a variable thickening and thining of short segments of the axon. An individual axon can have multiple sites of branching activity, with many of the branches being transient. These dynamic behaviors occur along the portion of the axon shaft overlying the basilar pons, but not just caudal to it. Once the collaterals extend into the pontine neuropil, they branch further in the neuropil, while the parent axon becomes quiescent. Thus, the branching activity is spatially restricted to specific portions of the axon, as well as temporally restricted to a relatively brief time window. These findings provide definitive evidence that collateral branches form de novo along corticospinal axons and establish that the process of target recognition in this system is a property of the axon shaft rather than the leading growth cone.

  14. Developing a Novel Therapeutic Strategy Targeting Kallikrein-4 to Inhibit Prostate Cancer Growth and Metastasis

    Science.gov (United States)

    2015-08-01

    Kallikrein-related peptidase 4 (KLK4) is a rational therapeutic target for prostate cancer (PCa) as it is up-regulated in both localised and bone...both localised and bone metastatic cancerous tissue, and is an independent biomarker discriminating between benign and malignant prostate tissue [1,2...cellular function . siKLK4(A), siKLK4(B) and siControl are currently being conjugated onto HBP-peptide by collaborators from AIBN. siRNA sequences are

  15. A QFD-Based Mathematical Model for New Product Development Considering the Target Market Segment

    OpenAIRE

    Chen, Liang-Hsuan; Chen, Cheng-Nien

    2014-01-01

    Responding to customer needs is important for business success. Quality function deployment provides systematic procedures for converting customer needs into technical requirements to ensure maximum customer satisfaction. The existing literature mainly focuses on the achievement of maximum customer satisfaction under a budgetary limit via mathematical models. The market goal of the new product for the target market segment is usually ignored. In this study, the proposed approach thus consider...

  16. Development of Polymer Microcapsules Functionalized with Fucoidan to Target P-Selectin Overexpressed in Cardiovascular Diseases.

    Science.gov (United States)

    Li, Bo; Juenet, Maya; Aid-Launais, Rachida; Maire, Murielle; Ollivier, Véronique; Letourneur, Didier; Chauvierre, Cédric

    2017-02-01

    New tools for molecular imaging and targeted therapy for cardiovascular diseases are still required. Herein, biodegradable microcapsules (MCs) made of polycyanoacrylate and polysaccharide and functionalized with fucoidan (Fuco-MCs) are designed as new carriers to target arterial thrombi overexpressing P-selectin. Physicochemical characterizations demonstrated that microcapsules have a core-shell structure and that fucoidan is present onto the surface of Fuco-MCs. Furthermore, their sizes range from 2 to 6 µm and they are stable on storage over 30 d at 4 °C. Flow cytometry experiments evidenced the binding of Fuco-MCs for human activated platelets as compared to MCs (mean fluorescence intensity: 12 008 vs. 9, p microcapsules reveal excellent compatibility with 3T3 cells in cytotoxicity assay. One hour after intravenous injection of microcapsules, histological analysis revealed that Fuco-MCs are localized in the rat abdominal aortic aneurysm thrombotic wall and that the binding in the healthy aorta is low. In conclusion, these microcapsules appear as promising carriers for targeting of tissues characterized by P-selectin overexpression and for their molecular imaging or treatment. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. Development of a multicomponent vaccine for Streptococcus pyogenes based on the antigenic targets of IVIG.

    Science.gov (United States)

    Reglinski, Mark; Lynskey, Nicola N; Choi, Yoon Jung; Edwards, Robert J; Sriskandan, Shiranee

    2016-04-01

    Despite over a century of research and the careful scrutiny of many promising targets, there is currently no vaccine available for the prevention of Streptococcus pyogenes infection. Through analysis of the protective, anti-streptococcal components of pooled human immunoglobulin, we previously identified ten highly conserved and invariant S. pyogenes antigens that contribute to anti-streptococcal immunity in the adult population. We sought to emulate population immunity to S. pyogenes through a process of active vaccination, using the antigens targeted by pooled human immunoglobulin. Seven targets were produced recombinantly and mixed to form a multicomponent vaccine (Spy7). Vaccinated mice were challenged with S. pyogenes isolates representing four globally relevant serotypes (M1, M3, M12 and M89) using an established model of invasive disease. Vaccination with Spy7 stimulated the production of anti-streptococcal antibodies, and limited systemic dissemination of M1 and M3 S. pyogenes from an intramuscular infection focus. Vaccination additionally attenuated disease severity due to M1 S. pyogenes as evidenced by reduction in weight loss, and modulated cytokine release. Spy7 vaccination successfully stimulated the generation of protective anti-streptococcal immunity in vivo. Identification of reactive antigens using pooled human immunoglobulin may represent a novel route to vaccine discovery for extracellular bacteria. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  18. Development And Characterization Of A Liner-On-Target Injector For Staged Z-Pinch Experiments

    Science.gov (United States)

    Valenzuela, J. C.; Conti, F.; Krasheninnikov, I.; Narkis, J.; Beg, F.; Wessel, F. J.; Rahman, H. U.

    2016-10-01

    We present the design and optimization of a liner-on-target injector for Staged Z-pinch experiments. The injector is composed of an annular high atomic number (e.g. Ar, Kr) gas-puff and an on-axis plasma gun that delivers the ionized deuterium target. The liner nozzle injector has been carefully studied using Computational Fluid Dynamics (CFD) simulations to produce a highly collimated 1 cm radius gas profile that satisfies the theoretical requirement for best performance on the 1 MA Zebra current driver. The CFD simulations produce density profiles as a function of the nozzle shape and gas. These profiles are initialized in the MHD MACH2 code to find the optimal liner density for a stable, uniform implosion. We use a simple Snowplow model to study the plasma sheath acceleration in a coaxial plasma gun to help us properly design the target injector. We have performed line-integrated density measurements using a CW He-Ne laser to characterize the liner gas and the plasma gun density as a function of time. The measurements are compared with models and calculations and benchmarked accordingly. Advanced Research Projects Agency - Energy, DE-AR0000569.

  19. Evaluation of different insecticides and fabric types for development of treated targets for stable fly (Diptera: Muscidae) control.

    Science.gov (United States)

    Hogsette, Jerome A; Nalli, Alyce; Foil, Lane D

    2008-06-01

    Stable fly, Stomoxys calcitrans (L.) (Diptera: Muscidae), once only a pest of pastured cattle, has become a serious pest of range cattle in the United States. Because of the difficulties associated with stable fly management under range conditions, a pesticide-impregnated cloth target is being developed as a management tool. We conducted studies to determine the influence of weather, time, fabric type, insecticide type, and insecticide concentration on the mortality of stable flies from a susceptible laboratory colony exposed for 30 s to treated cloth targets. We found that 100% of the flies exposed to trigger (Trigger-Royal Box, 65% polyester and 35% cotton) fabric targets that were treated with 0.1% h-cyhalothrin or 0.1% zeta-cypermethrin and weathered outdoors in Gainesville, FL., for up to 3 mo, were dead within 20 min after a 30-s exposure. The results of this study support the concept that treated targets can be developed for integration into stable fly control programs.

  20. Development of windowless liquid lithium targets for fragmentation and fission of 400-kW uranium beams

    CERN Document Server

    Nolen, J A; Hassanein, A; Novick, V J; Plotkin, P; Specht, J R

    2003-01-01

    The driver linac of the proposed rare isotope accelerator facility is designed to deliver 2x10 sup 1 sup 3 uranium ions per second at 400 MeV/u on target for radionuclide production via the fission and fragmentation mechanisms. The ion optics of the large acceptance, high-resolution fragment separators that follow the production target require primary beam spot widths of 1 mm. To cope with the resulting high power densities, windowless liquid lithium targets are being developed. The present designs build on existing experience with liquid lithium and liquid sodium systems that have been used for fusion and fission applications. However, no completely windowless systems have been developed or tested to date. For the beam power indicated above (400 kW), the flow requirements are up to about 20 m/s and 10 l/s linear and volume flow rates, respectively. The required target thickness is 1-1.5 g/cm sup 2 (2-3 cm lithium thickness). At this time a prototype windowless system with a lithium thickness of 1-2 cm is und...

  1. How can China reach its CO2 intensity reduction targets by 2020? A regional allocation based on equity and development

    International Nuclear Information System (INIS)

    Yi Wenjing; Zou Lele; Guo Jie; Wang Kai; Wei Yiming

    2011-01-01

    In late 2009, the Chinese government committed to cut its carbon dioxide emissions per unit of gross domestic product (GDP) by 40% to 45% of 2005 levels by 2020. This has raised the issue of how to allocate the CO 2 reduction target regionally to meet the national reduction target. To meet this objective, the following aspects may be taken into consideration: equity principles, 'common but differentiated responsibilities'; intensity reduction target fulfillment; and economic difference and reduction potential among provinces. This paper selects per capita GDP, accumulated fossil fuel related CO 2 emissions and energy consumption per unit of industrial added value as indicators for emission reduction capacity, responsibility and potential, respectively. Based on these three indicators, a comprehensive index is developed and an intensity allocation model constructed. As decision makers may have different preferences when allocating the reduction burden, we allocate different weights to the indicators, analyzing the results using cluster analysis. The following aspects may also be considered together with the national regional development strategy to determine how to share the burden: the reduction potential of various regions; implementation potential of the plans; and promotion of a highly efficient low carbon economic development model. - Research highlights: → We compiled a comprehensive index using per capita GDP, accumulated fossil fuel related CO 2 emissions and energy consumption per unit of industrial added value as indicators for emission reduction capacity, responsibility and potential, respectively. → National CO 2 intensity reduction target is allocated according to different index values of provinces. → Equity principles were taken into account when allocating the target.

  2. Harnessing the fruits of nature for the development of multi-targeted cancer therapeutics.

    Science.gov (United States)

    Sarkar, Fazlul H; Li, Yiwei

    2009-11-01

    Cancer cells exhibit deregulation in multiple cellular signaling pathways. Therefore, treatments using specific agents that target only one pathway usually fail in cancer therapy. The combination treatments using chemotherapeutic agents with distinct molecular mechanisms are considered more promising for higher efficacy; however, using multiple agents contributes to added toxicity. Emerging evidence has shown that some "natural products" such as isoflavones, indole-3-carbinol (I3C) and its in vivo dimeric product 3,3'-diindolylmethane (DIM), and curcumin among many others, have growth inhibitory and apoptosis inducing effects on human and animal cancer cells mediated by targeting multiple cellular signaling pathways in vitro without causing unwanted toxicity in normal cells. Therefore, these non-toxic "natural products" from natural resources could be useful in combination with conventional chemotherapeutic agents for the treatment of human malignancies with lower toxicity and higher efficacy. In fact, recently increasing evidence from pre-clinical in vivo studies and clinical trials have shown some success in support of the use of rational design of multi-targeted therapies for the treatment of cancers using conventional chemotherapeutic agents in combination with "natural products". These studies have provided promising results and further opened-up newer avenues for cancer therapy. In this review article, we have succinctly summarized the known effects of "natural products" especially by focusing on isoflavones, indole-3-carbinol (I3C) and its in vivo dimeric product 3,3'-diindolylmethane (DIM), and curcumin, and provided a comprehensive view on the molecular mechanisms underlying the principle of cancer therapy using combination of "natural products" with conventional therapeutics.

  3. Mental health and development: targeting people with mental health conditions as a vulnerable group

    National Research Council Canada - National Science Library

    Drew, Natalie; Faydi, Edwige; Freeman, Melvyn; Funk, Michelle; Kettaneh, Audrey; Van Ommeren, Mark

    2010-01-01

    .... It argues that mental health should be included in sectoral and broader development strategies and plans, and that development stakeholders have important roles to play in ensuring that people...

  4. Development of a methodology for defining whole-building energy design targets for commercial buildings: Phase 2, Development concept stage report

    Energy Technology Data Exchange (ETDEWEB)

    Jones, J.W. (American Society of Heating, Refrigerating and Air-Conditioning Engineers, Inc., Atlanta, GA (USA)); Deringer, J.J. (Deringer Group, Riva, MD (USA)); Hall, J.D. (American Inst. of Architects, Washington, DC (USA)) (comps.)

    1990-09-01

    The Whole-Building Energy Design Targets project is being conducted for the US Department of Energy (DOE) by the Pacific Northwest Laboratory (PNL). The objective of the project is to develop a flexible methodology for setting energy performance guidelines with which architects, engineers, planners, and owners can assess energy efficiency in commercial building design. This volume, the third in the four-volume report on the Targets project concept stage, contains the minutes of the workshops as well as summaries of the expert's written comments prepared at the close of each workshop. In Section 2, the building energy simulation workshop is summarized. Section 3 provides a summary of the building cost workshop.

  5. Development of behavioral parameters and ERPs in a novel-target visual detection paradigm in children, adolescents and young adults.

    Science.gov (United States)

    Rojas-Benjumea, María Ángeles; Sauqué-Poggio, Ana María; Barriga-Paulino, Catarina I; Rodríguez-Martínez, Elena I; Gómez, Carlos M

    2015-07-04

    The present study analyzes the development of ERPs related to the process of selecting targets based on their novelty. One hundred and sixty-seven subjects from 6 to 26 years old were recorded with 30 electrodes during a visual target novelty paradigm. Behavioral results showed good performance in children that improved with age: a decrease in RTs and errors and an increase in the d' sensitivity parameter with age were obtained. In addition, the C response bias parameter evolved from a conservative to a neutral bias with age. Fronto-polar Selection Positivity (FSP) was statistically significant in all the age groups when standards and targets were compared. There was a statistically significant difference in the posterior Selection Negativity (SN) between the target and standard conditions in all age groups. The P3a component obtained was statistically significant in the emergent adult (18-21 years) and young adult (22-26 years) groups. The modulation of the P3b component by novel targets was statistically significant in all the age groups, but it decreased in amplitude with age. Peak latencies of the FSP and P3b components decreased with age. The results reveal differences in the ERP indexes for the cognitive evaluation of the stimuli presented, depending on the age of the subjects. The ability of the target condition to induce the modulation of the studied components would depend on the posterior-anterior gradient of cortex maturation and on the gradient of maturation of the low to higher order association areas.

  6. Development of novel drug delivery prototypes devices for targeted delivery drug therapy at the molecular level in aqueous media.

    Science.gov (United States)

    George, Roy; Oberhozer, Theunis Gerhardus; Perchyonok, Victoria Tamara

    2011-09-01

    A novel approach in target specific molecular prototype drug delivery system concerns the attempt to employ radical affording substances (RAS) or radical quenching substances (RQS) as prodrugs able to produce irreversible damage on the desired target and therefore to stimulate cellular apoptosis. However, radical species generated can react quickly within the chemical environment prior to reaching its proper site of action. In this short communication, we report our investigations towards developing two alternative novel, simple, flexible and effective drug delivery systems that provide optimal dosage of drugs precisely where and when needed and therefore achieve and sustain a complex delivery profile. We have demonstrated the application of two effective molecular prototype delivery systems able to harness free radical reactivity within the laboratory where biological processes can be studied and controlled, leading to the prevention of disease and the development of new treatments for disease states mediated by free radicals.

  7. Animal models for medications development targeting alcohol abuse using selectively bred rat lines: Neurobiological and pharmacological validity

    Science.gov (United States)

    Bell, Richard L.; Sable, Helen J.K.; Colombo, Giancarlo; Hyytia, Petri; Rodd, Zachary A.; Lumeng, Lawrence

    2012-01-01

    The purpose of this review paper is to present evidence that rat animal models of alcoholism provide an ideal platform for developing and screening medications that target alcohol abuse and dependence. The focus is on the 5 oldest international rat lines that have been selectively bred for a high alcohol-consumption phenotype. The behavioral and neurochemical phenotypes of these rat lines are reviewed and placed in the context of the clinical literature. The paper presents behavioral models for assessing the efficacy of pharmaceuticals for the treatment of alcohol abuse and dependence in rodents, with particular emphasis on rats. Drugs that have been tested for their effectiveness in reducing alcohol/ethanol consumption and/or self-administration by these rat lines and their putative site of action are summarized. The paper also presents some current and future directions for developing pharmacological treatments targeting alcohol abuse and dependence. PMID:22841890

  8. A Synthetic Biology Project - Developing a single-molecule device for screening drug-target interactions.

    Science.gov (United States)

    Firman, Keith; Evans, Luke; Youell, James

    2012-07-16

    This review describes a European-funded project in the area of Synthetic Biology. The project seeks to demonstrate the application of engineering techniques and methodologies to the design and construction of a biosensor for detecting drug-target interactions at the single-molecule level. Production of the proteins required for the system followed the principle of previously described "bioparts" concepts (a system where a database of biological parts - promoters, genes, terminators, linking tags and cleavage sequences - is used to construct novel gene assemblies) and cassette-type assembly of gene expression systems (the concept of linking different "bioparts" to produce functional "cassettes"), but problems were quickly identified with these approaches. DNA substrates for the device were also constructed using a cassette-system. Finally, micro-engineering was used to build a magnetoresistive Magnetic Tweezer device for detection of single molecule DNA modifying enzymes (motors), while the possibility of constructing a Hall Effect version of this device was explored. The device is currently being used to study helicases from Plasmodium as potential targets for anti-malarial drugs, but we also suggest other potential uses for the device. Copyright © 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  9. Evaluating the Development of Biocatalytic Technology for the Targeted Removal of Perchlorate from Drinking Water.

    Science.gov (United States)

    Hutchison, Justin M; Guest, Jeremy S; Zilles, Julie L

    2017-06-20

    Removing micropollutants is challenging in part because of their toxicity at low concentrations. A biocatalytic approach could harness the high affinity of enzymes for their substrates to address this challenge. The potential of biocatalysis relative to mature (nonselective ion exchange, selective ion exchange, and whole-cell biological reduction) and emerging (catalysis) perchlorate-removal technologies was evaluated through a quantitative sustainable design framework, and research objectives were prioritized to advance economic and environmental sustainability. In its current undeveloped state, the biocatalytic technology was approximately 1 order of magnitude higher in cost and environmental impact than nonselective ion exchange. Biocatalyst production was highly correlated with cost and impact. Realistic improvement scenarios targeting biocatalyst yield, biocatalyst immobilization for reuse, and elimination of an electron shuttle could reduce total costs to $0.034 m -3 and global warming potential (GWP) to 0.051 kg CO 2 eq m -3 : roughly 6.5% of cost and 7.3% of GWP of the background from drinking water treatment and competitive with the best performing technology, selective ion exchange. With less stringent perchlorate regulatory limits, ion exchange technologies had increased cost and impact, in contrast to biocatalytic and catalytic technologies. Targeted advances in biocatalysis could provide affordable and sustainable treatment options to protect the public from micropollutants.

  10. Development and evaluation of macrophage targeted multidrug therapy against visceral leishmaniasis

    Directory of Open Access Journals (Sweden)

    Prachi sharma

    2017-05-01

    Full Text Available In this study, we fabricated PCL-nanoparticles by encapsulating dual drugs as amphotericin B and doxorubicin via double-emulsion solvent evaporation method also incorporated with ligand-lectin for targeting the infested macrophage cells and prove importance against VL. Different independent processing parameters were assessed systematically to enhance the incorporation of the dual agents with different properties (AmB and DOX, hydrophobic & hydrophilic molecule, respectively into PCL-NPs and control particle size. Approaches investigated for the enhancement of drug entrapment efficiencies and smaller particle size included the influence of the drug content, polymer content, sonication time etc. The mean particle size and zeta potential of PCL-NPs were 236.7 ± 0.04 nm in diameter and -9.11 ± 3.46 mV, respectively. The entrapment efficiencies of AmB and DOX were 82.1 ± 1.39 and 75.20 ± 0.14 %, respectively. Antileishmanial activities of the formulations and various combination approaches were assessed using macrophage-specific ligand-lectin. The prepared plain and lectin coated PCL-NPs based systems showed remarkable potential for passive and active intra macrophage targeting, respectively and the approach could be a successful alternative to the currently available drug regimens against VL. Multidrug resistance can be improved by combination delivery of encapsulated anti VL drugs. Thus, the co-encapsulation of AmB and DOX should reduce side effects of both drugs while increasing efficacy.

  11. Development of oligoclonal nanobodies for targeting the tumor-associated glycoprotein 72 antigen

    DEFF Research Database (Denmark)

    Sharifzadeh, Zahra; Rahbarizadeh, Fatemeh; Shokrgozar, Mohammad Ali

    2013-01-01

    The tumor-associated glycoprotein 72 (TAG-72) is a membrane mucin whose over-expression is correlated with advanced tumor stage and increased invasion and metastasis. In this study, we identified a panel of four nanobodies, single variable domains of dromedary heavy-chain antibodies that specific......The tumor-associated glycoprotein 72 (TAG-72) is a membrane mucin whose over-expression is correlated with advanced tumor stage and increased invasion and metastasis. In this study, we identified a panel of four nanobodies, single variable domains of dromedary heavy-chain antibodies...... that specifically recognize the TAG-72 antigen. All selected nanobodies were shown to selectively bind to this cancer-related molecule with low-nanomolar affinities and do not cross-react with other antigens, such as MUC1 or HER2. Furthermore, they can detect TAG-72 in concentrations as low as 5 U/ml which...... nanobody recognizes a distinct epitope on the TAG-72 antigen that is different from the one recognized by the mouse anti-TAG-72 antibody, CC49. Considering their high specificity, reduced immunogenicity and multi-targeting behavior, these oligoclonal nanobodies represent a promising tool to target TAG-72...

  12. Genomewide DNA methylation analysis reveals novel targets for drug development in mantle cell lymphoma.

    Science.gov (United States)

    Leshchenko, Violetta V; Kuo, Pei-Yu; Shaknovich, Rita; Yang, David T; Gellen, Tobias; Petrich, Adam; Yu, Yiting; Remache, Yvonne; Weniger, Marc A; Rafiq, Sarwish; Suh, K Stephen; Goy, Andre; Wilson, Wyndham; Verma, Amit; Braunschweig, Ira; Muthusamy, Natarajan; Kahl, Brad S; Byrd, John C; Wiestner, Adrian; Melnick, Ari; Parekh, Samir

    2010-08-19

    Mantle cell lymphoma (MCL) is a mostly incurable malignancy arising from naive B cells (NBCs) in the mantle zone of lymph nodes. We analyzed genomewide methylation in MCL patients with the HELP (HpaII tiny fragment Enrichment by Ligation-mediated PCR) assay and found significant aberrancy in promoter methylation patterns compared with normal NBCs. Using biologic and statistical criteria, we further identified 4 hypermethylated genes CDKN2B, MLF-1, PCDH8, and HOXD8 and 4 hypomethylated genes CD37, HDAC1, NOTCH1, and CDK5 when aberrant methylation was associated with inverse changes in mRNA levels. Immunohistochemical analysis of an independent cohort of MCL patient samples confirmed CD37 surface expression in 93% of patients, validating its selection as a target for MCL therapy. Treatment of MCL cell lines with a small modular immunopharmaceutical (CD37-SMIP) resulted in significant loss of viability in cell lines with intense surface CD37 expression. Treatment of MCL cell lines with the DNA methyltransferase inhibitor decitabine resulted in reversal of aberrant hypermethylation and synergized with the histone deacetylase inhibitor suberoylanilide hydroxamic acid in induction of the hypermethylated genes and anti-MCL cytotoxicity. Our data show prominent and aberrant promoter methylation in MCL and suggest that differentially methylated genes can be targeted for therapeutic benefit in MCL.

  13. CPTAC Collaborates with Molecular & Cellular Proteomics to Address Reproducibility in Targeted Assay Development | Office of Cancer Clinical Proteomics Research

    Science.gov (United States)

    The journal Molecular & Cellular Proteomics (MCP), in collaboration with the Clinical Proteomic Tumor Analysis Consortium (CPTAC) of the National Cancer Institute (NCI), part of the National Institutes of Health, announce new guidelines and requirements for papers describing the development and application of targeted mass spectrometry measurements of peptides, modified peptides and proteins (Mol Cell Proteomics 2017; PMID: 28183812).  NCI’s participation is part of NIH’s overall effort to address the r

  14. Development, evaluation, and application of sediment quality targets for assessing and managing contaminated sediments in Tampa Bay, Florida

    Science.gov (United States)

    MacDonald, D.D.; Carr, R.S.; Eckenrod, D.; Greening, H.; Grabe, S.; Ingersoll, C.G.; Janicki, S.; Janicki, T.; Lindskoog, R.A.; Long, E.R.; Pribble, R.; Sloane, G.; Smorong, D.E.

    2004-01-01

    Tampa Bay is a large, urban estuary that is located in west central Florida. Although water quality conditions represent an important concern in this estuary, information from numerous sources indicates that sediment contamination also has the potential to adversely affect aquatic organisms, aquatic-dependent wildlife, and human health. As such, protecting relatively uncontaminated areas of the bay from contamination and reducing the amount of toxic chemicals in contaminated sediments have been identified as high-priority sediment management objectives for Tampa Bay. To address concerns related to sediment contamination in the bay, an ecosystem-based framework for assessing and managing sediment quality conditions was developed that included identification of sediment quality issues and concerns, development of ecosystem goals and objectives, selection of ecosystem health indicators, establishment of metrics and targets for key indicators, and incorporation of key indicators, metrics, and targets into watershed management plans and decision-making processes. This paper describes the process that was used to select and evaluate numerical sediment quality targets (SQTs) for assessing and managing contaminated sediments. These SQTs included measures of sediment chemistry, whole-sediment and pore-water toxicity, and benthic invertebrate community structure. In addition, the paper describes how the SQTs were used to develop site-specific concentration-response models that describe how the frequency of adverse biological effects changes with increasing concentrations of chemicals of potential concern. Finally, a key application of the SQTs for defining sediment management areas is discussed.

  15. Progress in the Design of the Stabilized Liner Compressor for MTF/MIF Plasma Target Development

    Science.gov (United States)

    Frese, Sherry; Frese, Michael; Turchi, Peter; Gale, Don

    2016-10-01

    The Stabilized Liner Compressor (SLC) seeks to extend concepts for repetitive, rotationally stabilized, liquid-metal liners driven by free-pistons to much higher drive pressures (25 vs 5 kpsi) and faster implosion speeds (2000 vs 100 m/s) than previously demonstrated. Such extension is needed to enable experiments with magnetized-plasma targets presently offering sizes and lifetimes of 10's cm diam and 10's microsec. SLC represents the confluence of several difficult technologies, including pulsed high pressures, high-speed rotating machinery and alkali-metal (Na, NaK) handling. Solution of the two-dimensional, unsteady, compressible flow of a rotating liquid-metal liner requires advanced numerical techniques. We report the use of the 2-1/2 dimensional MHD code MACH2 to explore flow options, including magnetic flux compression, and to provide pulsed pressure distributions for mechanical design. Supported by ARPA-E ALPHA Program.

  16. Snake Venom PLA2, a Promising Target for Broad-Spectrum Antivenom Drug Development

    Directory of Open Access Journals (Sweden)

    Huixiang Xiao

    2017-01-01

    Full Text Available Snakebite envenomation is a neglected global health problem, causing substantial mortality, disability, and psychological morbidity, especially in rural tropical and subtropical zones. Antivenin is currently the only specific medicine for envenomation. However, it is restricted by cold storage, snakebite diagnosis, and high price. Snake venom phospholipase A2s (svPLA2s are found in all kinds of venomous snake families (e.g., Viperidae, Elapidae, and Colubridae. Along with their catalytic activity, svPLA2s elicit a wide variety of pharmacological effects that play a pivotal role in envenomation damage. Hence, neutralization of the svPLA2s could weaken or inhibit toxic damage. Here we overviewed the latest knowledge on the distribution, pathophysiological effects, and inhibitors of svPLA2s to elucidate the potential for a novel, wide spectrum antivenom drug targeting svPLA2s.

  17. New tracers developed in positron emission tomography: a possible second breath in targeting tumour hypoxia?

    International Nuclear Information System (INIS)

    Baillet, G.; Groheux, D.; Barre, E.; Toubert, M.E.; Dechaud, C.; Teyton, P.; Moretti, J.L.; Le Beau de Hemricourt, E.

    2007-01-01

    There is an increasing interest for targeting of tumor hypoxia and our paper aimed to emphasize the main points of this topic. We review new insights at cellular level and focus on the leading part of hypoxia inducible factor one alpha and its connections with angio genesis. We shortly describe different methods to assess tissue hypoxia then zoom on to positron emission tomography and its acknowledged tracers 18 F-fluoro misonidazole and 18 F-fluoro-erythro-nitroimidazole. Recent studies concerning two new promising tracers Cu(II)-di-acetyl-bis(N(4)-methyl-thio-semicarbazone) and FAZA are reviewed, and the respective value of the tracers is discussed. (N.C.)

  18. Intra-Target Microdosing - A Novel Drug Development Approach: Proof of Concept, Safety, and Feasibility Study in Humans.

    Science.gov (United States)

    Burt, T; MacLeod, D; Lee, K; Santoro, A; DeMasi, D K; Hawk, T; Feinglos, M; Rowland, M; Noveck, R J

    2017-09-01

    Intra-Target Microdosing (ITM) is a novel drug development approach aimed at increasing the efficiency of first-in-human (FIH) testing of new molecular entities (NMEs). ITM combines intra-target drug delivery and "microdosing," the subpharmacological systemic exposure. We hypothesized that when the target tissue is small (about 1/100th of total body mass), ITM can lead to target therapeutic-level exposure with minimal (microdose) systemic exposure. Each of five healthy male volunteers received insulin microdose into the radial artery or full therapeutic dose intravenously in separate visits. Insulin and glucose levels were similar between systemic administration and ITM administration in the ipsilateral hand, and glucose levels demonstrated a reduction in the ipsilateral hand but not in the contralateral hand. Positron emission tomography (PET) imaging of 18 F-fluorodeoxyglucose (FDG) uptake demonstrated differences between the ipsilateral and contralateral arms. The procedures were safe and well-tolerated. Results are consistent with ITM proof-of-concept (POC) and demonstrate the ethical, regulatory, and logistical feasibility of the approach. © 2017 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

  19. Retrotransposon-centered analysis of piRNA targeting shows a shift from active to passive retrotransposon transcription in developing mouse testes

    DEFF Research Database (Denmark)

    Mourier, Tobias

    2011-01-01

    . As expected, young RTEs display a much higher level of piRNA targeting than old RTEs. Further, irrespective of age, RTE loci near protein-coding coding genes are targeted to a greater extent than RTE loci far from genes. During development, a shift in piRNA targeting is observed, with a clear increase...... transcripts from other cellular RNAs. During germline development, the main target of piRNAs switch between different types of RTEs. Using the piRNA targeting of RTEs as an indicator of RTE activity, and considering the entire population of genomic RTE loci along with their age and location, this study aims...... at further elucidating the dynamics of RTE activity during mouse germline development. RESULTS: Due to the inherent sequence redundancy between RTE loci, assigning piRNA targeting to specific loci is problematic. This limits the analysis, although certain features of piRNA targeting of RTE loci are apparent...

  20. Co-development of diagnostic vectors to support targeted therapies and theranostics: Essential tools in Personalized Cancer Therapy.

    Directory of Open Access Journals (Sweden)

    Nicholas C Nicolaides

    2014-06-01

    Full Text Available Novel technologies are being developed to improve patient therapy through the identification of targets and surrogate molecular signatures that can help direct appropriate treatment regimens for efficacy and drug safety. This is particularly the case in oncology whereby patient tumor and biofluids are routinely isolated and analyzed for genetic, immunohistochemical and/or soluble markers to determine if a predictive biomarker signature exists as a means for selecting optimal treatment. Improvements in diagnostics that can prescreen predictive response biomarker profiles will continue to optimize the ability to enhance patient therapy via molecularly defined disease-specific treatment. A goal for drug developers is to identify and implement new strategies that can rapidly enable the development of beneficial disease-specific therapies for broad, patient-specific targeting without the need of tedious predictive biomarker discovery and validation efforts, currently a bottleneck for development timelines. Here we discuss the use of co-developing diagnostic-targeting vectors to identify patients whose malignant tissue can specifically uptake a drug linked vector prior to treatment. Using this system, a patient can be predetermined in real time as to whether or not their tumor(s can uptake a drug-linked diagnostic vector, thus inferring the uptake of a similar vector linked to an anti-cancer agent. If tumor-specific uptake is observed, then the patient may be suitable for drug-linked vector therapy and have a higher likelihood of clinical benefit while patients with no tumor uptake should consider other therapeutic options. This approach offers complementary opportunities to rapidly develop broad tumor-specific agents for use in personalized medicine.

  1. Fish early life stage: Developing AOPs to support targeted reduction and replacement

    Science.gov (United States)

    There is an interest in developing alternatives to the fish early-life stage (FELS) test (OECD test guideline 210), for predicting adverse chronic toxicity outcomes (e.g., impacts on growth and survival). Development and characterization of adverse outcome pathways (AOPs) related...

  2. Firm Foundations: The Effectiveness of an Educational Psychologist Developed Intervention Targeting Early Numeracy Skills

    Science.gov (United States)

    Somerville, Ros; Ayre, Kate; Tunbridge, Daniel; Cole, Katy; Stollery, Richard; Sanders, Mary

    2015-01-01

    This study evaluates the efficacy of a mathematics intervention devised by Essex Educational Psychology Service (EPS), UK. The intervention was designed to develop understanding and skills across four key domains within arithmetical development, by applying the principles of errorless learning, distributed practice and teaching to mastery. A…

  3. Identification of Estrogen Target Genes during Zebrafish Embryonic Development through Transcriptomic Analysis

    Science.gov (United States)

    Estrogen signaling is important for vertebrate embryonic development. Here we have used zebrafish (Danio rerio) as a vertebrate model to analyze estrogen signaling during development. Zebrafish embryos were exposed to 1 μM 17β-estradiol (E2) or vehicle from 3 hours to 4 days post...

  4. Disorders of sex development : insights from targeted gene sequencing of a large international patient cohort

    NARCIS (Netherlands)

    Eggers, Stefanie; Sadedin, Simon; van den Bergen, Jocelyn A.; Robevska, Gorjana; Ohnesorg, Thomas; Hewitt, Jacqueline; Lambeth, Luke; Bouty, Aurore; Knarston, Ingrid M.; Tiong Yang Tan,; Cameron, Fergus; Werther, George; Hutson, John; O'Connell, Michele; Grover, Sonia R.; Heloury, Yves; Zacharin, Margaret; Bergman, Philip; Kimber, Chris; Brown, Justin; Webb, Nathalie; Hunter, Matthew F.; Srinivasan, Shubha; Titmuss, Angela; Verge, Charles F.; Mowat, David; Smith, Grahame; Smith, Janine; Ewans, Lisa; Shalhoub, Carolyn; Crock, Patricia; Cowell, Chris; Leong, Gary M.; Ono, Makato; Lafferty, Antony R.; Huynh, Tony; Visser, Uma; Choong, Catherine S.; McKenzie, Fiona; Pachter, Nicholas; Thompson, Elizabeth M.; Couper, Jennifer; Baxendale, Anne; Gecz, Jozef; Wheeler, Benjamin J.; Jefferies, Craig; MacKenzie, Karen; Hofman, Paul; Carter, Philippa; King, Richard I.; Krausz, Csilla; van Ravenswaaij-Arts, Conny M. A.; Looijenga, Leendert; Drop, Sten; Riedl, Stefan; Cools, Martine; Dawson, Angelika; Juniarto, Achmad Zulfa; Khadilkar, Vaman; Khadilkar, Anuradha; Bhatia, Vijayalakshmi; Vu Chi Dung, [No Value; Atta, Irum; Raza, Jamal; Nguyen Thi Diem Chi,; Tran Kiem Hao,; Harley, Vincent; Koopman, Peter; Warne, Garry; Faradz, Sultana; Oshlack, Alicia; Ayers, Katie L.; Sinclair, Andrew H.

    2016-01-01

    Background: Disorders of sex development (DSD) are congenital conditions in which chromosomal, gonadal, or phenotypic sex is atypical. Clinical management of DSD is often difficult and currently only 13% of patients receive an accurate clinical genetic diagnosis. To address this we have developed a

  5. Exploration of miRNAs and target genes of cytoplasmic male sterility line in cotton during flower bud development.

    Science.gov (United States)

    Nie, Hushuai; Wang, Yumei; Su, Ying; Hua, Jinping

    2018-04-07

    Cytoplasmic male sterility (CMS) lines provide crucial material to harness heterosis for crop plants, which serves as an important strategy for hybrid seed production. However, the molecular mechanism remains obscure. Although microRNAs (miRNAs) play important roles in vegetative growth and reproductive growth, there are few reports on miRNAs regulating the development of male sterility in Upland cotton. In present study, 12 small RNA libraries were constructed and sequenced for two development stages of flower buds from a CMS line and its maintainer line. Based on the results, 256 novel miRNAs were allocated to 141 new miRNA families, and 77 known miRNAs belonging to 54 conserved miRNA families were identified as well. Comparative analysis revealed that 61 novel and 10 conserved miRNAs were differentially expressed. Further transcriptome analysis identified 232 target genes for these miRNAs, which participated in cellular developmental process, cell death, pollen germination, and sexual reproduction. In addition, expression patterns of typical miRNA and the negatively regulated target genes, such as PPR, ARF, AP2, and AFB, were verified by qRT-PCR in cotton flower buds. These targets were previously reported to be related to reproduction development and male sterility, suggesting that miRNAs might act as regulators of CMS occurrence. Some miRNAs displayed specific expression profiles in special developmental stages of CMS line and its fertile hybrid (F 1 ). Present study offers new information on miRNAs and their related target genes in exploiting CMS mechanism, and revealing the miRNA regulatory networks in Upland cotton.

  6. Development and application of deep convolutional neural network in target detection

    Science.gov (United States)

    Jiang, Xiaowei; Wang, Chunping; Fu, Qiang

    2018-04-01

    With the development of big data and algorithms, deep convolution neural networks with more hidden layers have more powerful feature learning and feature expression ability than traditional machine learning methods, making artificial intelligence surpass human level in many fields. This paper first reviews the development and application of deep convolutional neural networks in the field of object detection in recent years, then briefly summarizes and ponders some existing problems in the current research, and the future development of deep convolutional neural network is prospected.

  7. MicroRNA-275 and its target Vitellogenin-2 are crucial in ovary development and blood digestion of Haemaphysalis longicornis.

    Science.gov (United States)

    Hao, Jiawei; Luo, Jin; Chen, Ze; Ren, Qiaoyun; Guo, Jinxia; Liu, Xiaocui; Chen, Qiuyu; Wu, Feng; Wang, Zhen; Luo, Jianxun; Yin, Hong; Wang, Hui; Liu, Guangyuan

    2017-05-22

    The hard tick Haemaphysalis longicornis is widely distributed in eastern Asia, New Zealand and Australia and is considered the major vector of Theileria and Babesia, harmful parasites to humans and animals. Female ticks need successful blood meals to complete the life-cycle. Therefore, elucidation of the underlying molecular mechanisms of H. longicornis development and reproduction is considered important for developing control strategies against the tick and tick-borne pathogens. Luciferase assays were used to identify the targets of micro RNA miR-275 in vitro. RNAi of Vitellogenin (Vg) was used in phenotype rescue experiments of ticks with miR-275 inhibition, and these analyses were used to identify the authentic target of miR-275 in vivo. The expression of miR-275 in different tissues and developmental stages of ticks was assessed by real-time PCR. To elucidate the functions of miR-275 in female ticks, we injected a miR-275 antagomir into female ticks and observed the phenotypic changes. Statistical analyses were performed with GraphPad5 using Student's t-test. In this study, we identified Vg-2 as an authentic target of miR-275 both in vitro and in vivo by luciferase assays and phenotype rescue experiments. miR-275 plays the regulatory role in a tissue-specific manner and differentially in developmental stages. Silencing of miR-275 resulted in blood digestion problems, substantially impaired ovary development and significantly reduced egg mass (P development. These findings improve the molecular understanding of tick development and reproduction.

  8. Development and application of two semi-automated tools for targeted medical product surveillance in a distributed data network.

    Science.gov (United States)

    Connolly, John G; Wang, Shirley V; Fuller, Candace C; Toh, Sengwee; Panozzo, Catherine A; Cocoros, Noelle; Zhou, Meijia; Gagne, Joshua J; Maro, Judith C

    2017-12-01

    An important component of the Food and Drug Administration's Sentinel Initiative is the active post-market risk identification and analysis (ARIA) system, which utilizes semi-automated, parameterized computer programs to implement propensity-score adjusted and self-controlled risk interval designs to conduct targeted surveillance of medical products in the Sentinel Distributed Database. In this manuscript, we review literature relevant to the development of these programs and describe their application within the Sentinel Initiative. These quality-checked and publicly available tools have been successfully used to conduct rapid, replicable, and targeted safety analyses of several medical products. In addition to speed and reproducibility, use of semi-automated tools allows investigators to focus on decisions regarding key methodological parameters. We also identified challenges associated with the use of these methods in distributed and prospective datasets like the Sentinel Distributed Database, namely uncertainty regarding the optimal approach to estimating propensity scores in dynamic data among data partners of heterogeneous size. Future research should focus on the methodological challenges raised by these applications as well as developing new modular programs for targeted surveillance of medical products.

  9. A role for fragment-based drug design in developing novel lead compounds for central nervous system targets

    Directory of Open Access Journals (Sweden)

    Michael J. Wasko

    2015-09-01

    Full Text Available Hundreds of millions of U.S. dollars are invested in the research and development of a single drug. Lead compound development is an area ripe for new design strategies. Therapeutic lead candidates have been traditionally found using high-throughput in vitro pharmacologic screening, a costly method for assaying thousands of compounds. This approach has recently been augmented by virtual screening, which employs computer models of the target protein to narrow the search for possible leads. A variant of virtual screening is fragment-based drug design, an emerging in silico lead discovery method that introduces low molecular weight fragments, rather than intact compounds, into the binding pocket of the receptor model. These fragments serve as starting points for growing the lead candidate. Current efforts in virtual fragment-based drug design within central nervous system (CNS targets are reviewed, as is a recent rule-based optimization strategy in which new molecules are generated within a 3D receptor binding pocket using the fragment as a scaffold. This process places special emphasis on creating synthesizable molecules but also exposes computational questions worth addressing. Fragment-based methods provide a viable, relatively low-cost alternative for therapeutic lead discovery and optimization that can be applied to CNS targets to augment current design strategies.

  10. Targeting Parents for Childhood Weight Management: Development of a Theory-Driven and User-Centered Healthy Eating App.

    Science.gov (United States)

    Curtis, Kristina Elizabeth; Lahiri, Sudakshina; Brown, Katherine Elizabeth

    2015-06-18

    The proliferation of health promotion apps along with mobile phones' array of features supporting health behavior change offers a new and innovative approach to childhood weight management. However, despite the critical role parents play in children's weight related behaviors, few industry-led apps aimed at childhood weight management target parents. Furthermore, industry-led apps have been shown to lack a basis in behavior change theory and evidence. Equally important remains the issue of how to maximize users' engagement with mobile health (mHealth) interventions where there is growing consensus that inputs from the commercial app industry and the target population should be an integral part of the development process. The aim of this study is to systematically design and develop a theory and evidence-driven, user-centered healthy eating app targeting parents for childhood weight management, and clearly document this for the research and app development community. The Behavior Change Wheel (BCW) framework, a theoretically-based approach for intervention development, along with a user-centered design (UCD) philosophy and collaboration with the commercial app industry, guided the development process. Current evidence, along with a series of 9 focus groups (total of 46 participants) comprised of family weight management case workers, parents with overweight and healthy weight children aged 5-11 years, and consultation with experts, provided data to inform the app development. Thematic analysis of focus groups helped to extract information related to relevant theoretical, user-centered, and technological components to underpin the design and development of the app. Inputs from parents and experts working in the area of childhood weight management helped to identify the main target behavior: to help parents provide appropriate food portion sizes for their children. To achieve this target behavior, the behavioral diagnosis revealed the need for eliciting change in

  11. Positive Youth Development Programs Targeting Students with Greater Psychosocial Needs: Subjective Outcome Evaluation

    Directory of Open Access Journals (Sweden)

    Daniel T. L. Shek

    2008-01-01

    Full Text Available The Tier 2 Program of the Project P.A.T.H.S. (Positive Adolescent Training through Holistic Social Programmes targets adolescents with greater psychosocial needs, and the related programs were designed and implemented by school social workers. After completion of the Tier 2 Program, 2,173 students in 52 schools responded to the Subjective Outcome Evaluation Form (Form C, assessing their views of the program, instructors, and perceived effectiveness of the program. Based on the consolidated reports submitted by the agencies to the funding body, the research team aggregated the consolidated data to form a “reconstructed” overall profile of the perceptions of the program participants. Four major types of program were identified, including programs based on the adventure-based counseling approach (N = 8, programs concentrated on volunteer training and services (N = 7, programs incorporating both adventure-based counseling and volunteer training elements (N = 30, and other programs with different foci (N = 7. Results showed that high proportions of the respondents had positive perceptions of the programs and the instructors, and roughly four-fifths of the respondents regarded the program as helpful to them. The present study provides support for the effectiveness of the Tier 2 Program of P.A.T.H.S. in Hong Kong for the experimental implementation phase.

  12. DEVELOPING A VACCINE AGAINST MULTIPLE PSYCHOACTIVE TARGETS: A CASE STUDY OF HEROIN

    Science.gov (United States)

    Stowe, G. Neil; Schlosburg, Joel E.; Vendruscolo, Leandro F.; Edwards, Scott; Misra, Kaushik K.; Schulteis, Gery; Zakhari, Joseph S.; Koob, George F.; Janda, Kim D.

    2012-01-01

    Heroin addiction is a wide-reaching problem with a spectrum of damaging social consequences. Currently approved heroin addiction medications include drugs that bind at the same receptors (e.g. opioid receptors) occupied by heroin and/or its metabolites in the brain, but undesired side effects of these treatments, maintenance dependence and relapse to drug taking remains problematic. A vaccine capable of blocking heroin’s effects could provide an economical, long-lasting and sustainable adjunct to heroin addiction therapy without the side effects associated with available treatment options. Heroin, however, presents a particularly challenging vaccine target as it is metabolized to multiple psychoactive molecules of differing lipophilicity, with differing abilities to cross the blood brain barrier. In this review, we discuss the opiate scaffolding and hapten design considerations to confer immunogenicity as well as the specificity of the immune response towards structurally similar opiates. In addition, we detail different strategies employed in the design of immunoconjugates for a vaccine-based therapy for heroin addiction treatment. PMID:22229311

  13. Design, development and optimization of oral colon targeted drug delivery system of azathioprine using biodegradable polymers.

    Science.gov (United States)

    Nath, Bipul; Nath, L K

    2013-01-01

    The present study was aimed at designing a microflora triggered colon targeted drug delivery system (MCDDS) based on swellable polysaccharide, Sterculia gum in combination with biodegradable polymers with a view to specifically deliver azathioprine in the colonic region for the treatment of IBD with reduced systemic toxicity. The microflora degradation properties of Sterculia gum was investigated in rat caecal phosphate buffer medium. The polysaccharide tablet cores were coated to different film thicknesses with blends of Eudragit RLPO and chitosan and overcoated with Eudragit L00 to provide acid and intestinal resistance. Swelling and drug release studies were carried out in simulated gastric fluid, SGF (pH 1.2), simulated intestinal fluid, SIF (pH 6.8) and simulated colonic fluid, SCF (pH 7.4 under anaerobic environment), respectively. Drug release study in SCF revealed that swelling force of the Sterculia gum could concurrently drive the drug out of the polysaccharide core due to the rupture of the chitosan/Eudargit coating in microflora activated environment. The degradation of chitosan was the rate-limiting factor for drug release in the colon. Drug release from the MCDDS was directly proportional to the concentration of the pore former (chitosan), but inversely related to the Eudragit RLPO coating thickness.

  14. Vasopressin as a target for antidepressant development: an assessment of the available evidence.

    LENUS (Irish Health Repository)

    Scott, Lucinda V

    2012-02-03

    Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis is one of the key biological abnormalities described in major depressive disorder, occurring in 30-50% of depressed subjects. Corticotropin-releasing hormone (CRH) and vasopressin (AVP) are the main regulators of this stress system, with the two neuropeptides acting synergistically in bringing about adrenocorticotropin (ACTH) release from the anterior pituitary and cortisol from the adrenal gland. Based on the demonstration of elevated cerebrospinal fluid levels of CRH in depressives, and other evidence, it has been postulated that excess CRH and the resultant increased HPA forward drive form the basis of neuroendocrine dysregulation in depression. However, there is an accumulating body of evidence to support a significant role for AVP in the regulation of pituitary-adrenal activity in health and also in depressive disorder. This review, based on a Medline search from 1980 to 2001, focuses on the functional neuroanatomy, receptor pharmacology, VP synergism with CRH, and the data from clinical and pre-clinical studies that support an important role for AVP in the pathophysiology of major depression. We suggest that future antidepressants may target the vasopressinergic system.

  15. Development and Evaluation of a Learning Intervention Targeting First-Year Resident Defibrillation Skills.

    Science.gov (United States)

    Jeffers, Justin; Eppich, Walter; Trainor, Jennifer; Mobley, Bonnie; Adler, Mark

    2016-04-01

    The aim of the study was to evaluate an educational intervention targeting the acquisition and retention of critical core skills of defibrillation in first-year pediatric residents using simulation-based training and deliberate practice. From January 2011 to April 2012, a total of 23 first-year pediatric residents participated in a pretest-posttest study. An initial survey evaluated previous experience, training, and comfort. The scoring tool was designed and validated using a standard setting procedure and 60% was determined to be the minimum passing score. The 1-hour educational intervention included a brief video describing the defibrillator, 10 to 15 minutes of hands-on time with the defibrillator, and 30 minutes of simulation-based scenarios using deliberate practice with real-time feedback. The number of subjects who achieved competency in defibrillation skills increased from 8 to 16 of 23 (35% vs 70%, P defibrillation (282-189 s, P defibrillation skills by first-year pediatric residents. In the process, we uncovered educational gaps in cardiopulmonary resuscitation and other resuscitation skills that need to be addressed in future educational interventions and training.

  16. Development of Reagents for Application of At-211 to Targeted Radionuclide Therapy of Cancer

    International Nuclear Information System (INIS)

    Wilbur, D. Scott

    2011-01-01

    This grant covered only a period of 4 months as the major portion of the award was returned to DOE due to an award of funding from NIH that covered the same research objectives. A letter regarding the termination of the research is attached as the last page of the Final Report. The research conducted was limited due to the short period of this grant, but the results obtained in that period are outlined in the Final Report. The studies addressed in the research effort were directed at a problem that is of critical importance to the in vivo application of the alpha-particle emitting radionuclide At-211. That problem, low in vivo stability of many astatinated molecules, severely limits the use of At-211 in therapeutic applications. The advances sought in the studies were expected to expand the types of biomolecules that can be used as carriers of At-211, and provide improved in vivo targeting of the radiation dose compared with the dose delivered to normal tissue.

  17. APC-targeted RAA1 degradation mediates the cell cycle and root development in plants.

    Science.gov (United States)

    Xu, Yunyuan; Cao, Hong; Chong, Kang

    2010-03-01

    Protein degradation by the ubiquitin-proteasome system is necessary for a normal cell cycle. As compared with knowledge of the mechanism in animals and yeast, that in plants is less known. Here we summarize research into the regulatory mechanism of protein degradation in the cell cycle in plants. Anaphase-promoting complex/cyclosome (APC), in the E3 family of enzymes, plays an important role in maintaining normal mitosis. APC activation and substrate specificity is determined by its activators, which can recognize the destruction box (D-box) in APC target proteins. Oryza sativa root architecture-associated 1 (OsRAA1) with GTP-binding activity was originally cloned from rice. Overexpression of of OsRAA1 inhibits the growth of primary roots in rice. Knockdown lines showed reduced height of seedlings because of abnormal cell division. OsRAA1 transgenic rice and fission yeast show a higher proportion of metaphase cells than that of controls, which suggests a blocked transition from metaphase to anaphase during mitosis. OsRAA1 co-localizes with spindle tubulin. It contains the D-box motif and interacts with OsRPT4 of the regulatory particle of 26S proteasome. OsRAA1 may be a cell cycle inhibitor that can be degraded by the ubiquitin-proteasome system, and its disruption is necessary for the transition from metaphase to anaphase during root growth in rice.

  18. APC-targeted RAAI degradation mediates the cell cycle and root development in plants

    Science.gov (United States)

    Cao, Hong; Chong, Kang

    2010-01-01

    Protein degradation by the ubiquitin-proteasome system is necessary for a normal cell cycle. As compared with knowledge of the mechanism in animals and yeast, that in plants is less known. Here we summarize research into the regulatory mechanism of protein degradation in the cell cycle in plants. Anaphase-promoting complex/cyclosome (APC), in the E3 family of enzymes, plays an important role in maintaining normal mitosis. APC activation and substrate specificity is determined by its activators, which can recognize the destruction box (D-box) in APC target proteins. Oryza sativa root architecture-associated I (OsRAA1) with GTP-binding activity was originally cloned from rice. Overexpression of of OsRAA1 inhibits the growth of primary roots in rice. Knockdown lines showed reduced height of seedlings because of abnormal cell division. OsRAA1 transgenic rice and fission yeast show a higher proportion of metaphase cells than that of controls, which suggests a blocked transition from metaphase to anaphase during mitosis. OsRAA1 co-localizes with spindle tubulin. It contains the D-box motif and interacts with OsRPT4 of the regulatory particle of 26S proteasome. OsRAA1 may be a cell cycle inhibitor that can be degraded by the ubiquitin-proteasome system, and its disruption is necessary for the transition from metaphase to anaphase during root growth in rice. PMID:20037474

  19. Cutting edge: the Foxp3 target miR-155 contributes to the development of regulatory T cells.

    Science.gov (United States)

    Kohlhaas, Susan; Garden, Oliver A; Scudamore, Cheryl; Turner, Martin; Okkenhaug, Klaus; Vigorito, Elena

    2009-03-01

    Foxp3 is a transcription factor that is essential for the normal development of regulatory T cells (Tregs). In the absence of microRNAs (miRNAs), Foxp3(+) Tregs develop but fail to maintain immune homeostasis, leading to a scurfy-like disease. Global analysis of the network of genes regulated by Foxp3 has identified the miRNA miR-155, which is highly expressed in Tregs, as a direct target of Foxp3. In this study we report that miR-155-deficient mice have reduced numbers of Tregs, both in the thymus and periphery, due to impaired development. However, we found no evidence for defective suppressor activity of miR-155-deficient Tregs, either in vitro or in vivo. Our results indicate that miR-155 contributes to Treg development, but that additional miRNAs control Treg function.

  20. Brain derived neurotrophic factor mediated learning, fear acquisition and extinction as targets for developing novel treatments for anxiety

    Directory of Open Access Journals (Sweden)

    Karina Soares de Oliveira

    Full Text Available ABSTRACT Anxiety and obsessive-compulsive related disorders are highly prevalent and disabling disorders for which there are still treatment gaps to be explored. Fear is a core symptom of these disorders and its learning is highly dependent on the activity of the neurotrophin brain-derived neurotrophic factor (BDNF. Should BDNF-mediated fear learning be considered a target for the development of novel treatments for anxiety and obsessive-compulsive related disorders? We review the evidence that suggests that BDNF expression is necessary for the acquisition of conditioned fear, as well as for the recall of its extinction. We describe the findings related to fear learning and genetic/epigenetic manipulation of Bdnf expression in animals and BDNF allelic variants in humans. Later, we discuss how manipulation of BDNF levels represents a promising potential treatment target that may increase the benefits of therapies that extinguish previously conditioned fear.

  1. A false-alarm aware methodology to develop robust and efficient multi-scale infrared small target detection algorithm

    Science.gov (United States)

    Moradi, Saed; Moallem, Payman; Sabahi, Mohamad Farzan

    2018-03-01

    False alarm rate and detection rate are still two contradictory metrics for infrared small target detection in an infrared search and track system (IRST), despite the development of new detection algorithms. In certain circumstances, not detecting true targets is more tolerable than detecting false items as true targets. Hence, considering background clutter and detector noise as the sources of the false alarm in an IRST system, in this paper, a false alarm aware methodology is presented to reduce false alarm rate while the detection rate remains undegraded. To this end, advantages and disadvantages of each detection algorithm are investigated and the sources of the false alarms are determined. Two target detection algorithms having independent false alarm sources are chosen in a way that the disadvantages of the one algorithm can be compensated by the advantages of the other one. In this work, multi-scale average absolute gray difference (AAGD) and Laplacian of point spread function (LoPSF) are utilized as the cornerstones of the desired algorithm of the proposed methodology. After presenting a conceptual model for the desired algorithm, it is implemented through the most straightforward mechanism. The desired algorithm effectively suppresses background clutter and eliminates detector noise. Also, since the input images are processed through just four different scales, the desired algorithm has good capability for real-time implementation. Simulation results in term of signal to clutter ratio and background suppression factor on real and simulated images prove the effectiveness and the performance of the proposed methodology. Since the desired algorithm was developed based on independent false alarm sources, our proposed methodology is expandable to any pair of detection algorithms which have different false alarm sources.

  2. Turmeric (Curcuma longa): miRNAs and their regulating targets are involved in development and secondary metabolite pathways.

    Science.gov (United States)

    Singh, Noopur; Sharma, Ashok

    Turmeric has been used as a therapeutic herb over centuries in traditional medicinal systems due to the presence of several secondary metabolite compounds. microRNAs are known to regulate gene expression at the post-transcriptional level by transcriptional cleavage or translation repression. miRNAs have been demonstrated to play an active role in secondary metabolism regulation. The present work was focused on the identification of the miRNAs involved in the regulation of secondary metabolite and development process of turmeric. Eighteen miRNA families were identified for turmeric. Sixteen miRNA families were observed to regulate 238 target transcripts. LncRNAs targets of the putative miRNA candidates were also predicted. Our results indicated their role in binding, reproduction, stress, and other developmental processes. Gene annotation and pathway analysis illustrated the biological function of the targets regulated by the putative miRNAs. The miRNA-mediated gene regulatory network also revealed co-regulated targets that were regulated by two or more miRNA families. miR156 and miR5015 were observed to be involved in rhizome development. miR5021 showed regulation for terpenoid backbone biosynthesis and isoquinoline alkaloid biosynthesis pathways. The flavonoid biosynthesis pathway was observed to be regulated by miR2919. The analysis revealed the probable involvement of three miRNAs (miR1168.2, miR156b and miR1858) in curcumin biosynthesis. Other miRNAs were found to be involved in the growth and developmental process of turmeric. Phylogenetic analysis of selective miRNAs was also performed. Copyright © 2017 Académie des sciences. Published by Elsevier Masson SAS. All rights reserved.

  3. Development and evaluation of targeted psychological skills training for oncology nurses in managing stressful patient and family encounters.

    Science.gov (United States)

    Traeger, Lara; Park, Elyse R; Sporn, Nora; Repper-DeLisi, Jennifer; Convery, Mary Susan; Jacobo, Michelle; Pirl, William F

    2013-07-01

    To reduce workplace stress by developing a brief psychological skills training for nurses and to evaluate program feasibility, acceptability, and preliminary efficacy in decreasing burnout and stress. Intervention development and evaluation. Outpatient chemotherapy unit at a comprehensive cancer center. 26 infusion nurses and oncology social workers. Focus groups were conducted with nurses. Results informed the development and evaluation of training for nurses. Participants completed the Maslach Burnout Inventory and Perceived Stress Scale post-training. Burnout and stress. Focus groups indicated strong commitment among nurses to psychosocial care and supported the idea that relationships with patients and families were sources of reward and stress. Stressors included factors that interfered with psychosocial care such as difficult family dynamics, patient behaviors and end-of-life care issues. Psychological skills training was developed to address these stressors. Evaluations suggested that the program was feasible and acceptable to nurses. At two months, participants showed reductions in emotional exhaustion (p = 0.02) and stress (p = 0.04). Psychological skills training for managing difficult encounters showed feasibility, acceptability, and potential benefit in reducing emotional exhaustion and stress. Brief training that targets sources of clinical stress may be useful for nurses in outpatient chemotherapy units. Specific stressors in relationships with patients and families present challenges to nurses' therapeutic use of self. Targeted psychological skills training may help nurses problem-solve difficult encounters while taking care of themselves. System-level strategies are needed to support and promote training participation.

  4. Neuronal process structure and growth proteins are targets of heavy PTM regulation during brain development

    DEFF Research Database (Denmark)

    Edwards, Alistair V G; Schwämmle, Veit; Larsen, Martin Røssel

    2014-01-01

    UNLABELLED: Brain development is a process requiring precise control of many different cell types. One method to achieve this is through specific and temporally regulated modification of proteins in order to alter structure and function. Post-translational modification (PTM) of proteins is known...... on protein-level events, this study also provides significant insight into detailed roles for individual modified proteins in the developing brain, helping to advance the understanding of the complex protein-driven processes that underlie development. Finally, the use of a novel bioinformatic analytical tool...... provides one of the most comprehensive sets of individual PTM site regulation data for mammalian brain tissue. This will provide a valuable resource for those wishing to perform comparisons or meta-analyses of large scale PTMomic data, as are becoming increasingly common. Furthermore, being focussed...

  5. The early origins of food preferences: targeting the critical windows of development.

    Science.gov (United States)

    Gugusheff, Jessica Rose; Ong, Zhi Yi; Muhlhausler, Beverly Sara

    2015-02-01

    The nutritional environment to which an individual is exposed during the perinatal period plays a crucial role in determining his or her future metabolic health outcomes. Studies in rodent models have demonstrated that excess maternal intake of high-fat and/or high-sugar "junk foods" during pregnancy and lactation can alter the development of the central reward pathway, particularly the opioid and dopamine systems, and program an increased preference for junk foods in the offspring. More recently, there have been attempts to define the critical windows of development during which the opioid and dopamine systems within the reward pathway are most susceptible to alteration and to determine whether it is possible to reverse these effects through nutritional interventions applied later in development. This review discusses the progress made to date in these areas, highlights the apparent importance of sex in determining these effects, and considers the potential implications of the findings from rodent models in the human context. © FASEB.

  6. Metabotropic glutamate receptor 5 - a promising target in drug development and neuroimaging

    Energy Technology Data Exchange (ETDEWEB)

    Pillai, Rajapillai L.I.; Tipre, Dnyanesh N. [Stony Brook University Health Science Center, Department of Psychiatry, Stony Brook, NY (United States)

    2016-06-15

    This review summarizes the contributions by various teams of scientists in assessing the metabotropic glutamate receptor 5 (mGluR5) as a biomarker in neuropsychiatric disorders and diseases. Development of positive and negative allosteric modulators of mGluR5 is reviewed, as is the development of PET radioligands that have the potential to measure mGluR5 receptor density in neurological disorders and during therapeutic interventions. PET imaging provides an effective tool to assess the specificity of new drugs, select dose regimens in clinical trials, and study drug mechanisms of action. We summarize and deliver comparative analyses of mGluR5-specific PET radiotracers and their applications in understanding the pathophysiology of mGluR5-related nervous system disorders and to speed up drug development. (orig.)

  7. Jarid1b targets genes regulating development and is involved in neural differentiation

    DEFF Research Database (Denmark)

    Schmitz, Sandra U; Albert, Mareike; Malatesta, Martina

    2011-01-01

    H3K4 methylation is associated with active transcription and in combination with H3K27me3 thought to keep genes regulating development in a poised state. The contribution of enzymes regulating trimethylation of lysine 4 at histone 3 (H3K4me3) levels to embryonic stem cell (ESC) self-renewal and d...

  8. Developing and testing ScrollQuest: A video game targeting rejection sensitivity in adolescents

    NARCIS (Netherlands)

    Tuijnman, A.; Granic, I.; Whitkin, J.; Engels, R.C.M.E.

    2017-01-01

    Depression affects a large proportion of adolescents and current interventions only have moderate effects. With the potential of video games for emotional and mental health in mind, we developed a video game for rejection sensitivity, which is a major risk factor for depression. A process of

  9. Disorders of sex development: Insights from targeted gene sequencing of a large international patient cohort

    NARCIS (Netherlands)

    S. Eggers (Stefanie); Sadedin, S. (Simon); van den Bergen, J.A. (Jocelyn A.); Robevska, G. (Gorjana); Ohnesorg, T. (Thomas); J. Hewitt (Joanne); Lambeth, L. (Luke); Bouty, A. (Aurore); Knarston, I.M. (Ingrid M.); Tan, T.Y. (Tiong Yang); F.J. Cameron (Fergus); Werther, G. (George); Hutson, J. (John); O'Connell, M. (Michele); Grover, S.R. (Sonia R.); Heloury, Y. (Yves); M. Zacharin (Margaret); Bergman, P. (Philip); Kimber, C. (Chris); Brown, J. (Justin); Webb, N. (Nathalie); Hunter, M.F. (Matthew F.); Shubha Srinivasan; Titmuss, A. (Angela); Verge, C.F. (Charles F.); D. Mowat (David); Smith, G. (Grahame); Smith, J. (Janine); Ewans, L. (Lisa); Shalhoub, C. (Carolyn); Crock, P. (Patricia); Cowell, C. (Chris); Leong, G.M. (GaryM.); Ono, M. (Makato); Lafferty, A.R. (Antony R.); Huynh, T. (Tony); Visser, U. (Uma); Choong, C.S. (Catherine S.); McKenzie, F. (Fiona); Pachter, N. (Nicholas); E.M. Thompson (Elizabeth M.); Couper, J. (Jennifer); Baxendale, A. (Anne); J. Gecz (Jozef); Wheeler, B.J. (Benjamin J.); Jefferies, C. (Craig); MacKenzie, K. (Karen); Hofman, P. (Paul); Carter, P. (Philippa); King, R.I. (Richard I.); C. Krausz (Csilla); C.M.A. van Ravenswaaij-Arts (Conny); L.H.J. Looijenga (Leendert); Drop, S. (Sten); Riedl, S. (Stefan); M.L. Cools (Martine); Dawson, A. (Angelika); A.Z. Juniarto (Achmad); Khadilkar, V. (Vaman); Khadilkar, A. (Anuradha); Bhatia, V. (Vijayalakshmi); Dũng, V.C. (Vũ Chí); Atta, I. (Irum); Raza, J. (Jamal); thi Diem Chi, N. (Nguyen); Hao, T.K. (Tran Kiem); V.R. Harley (Vincent); P. Koopman (Peter); Warne, G. (Garry); S.M.H. Faradz (Sultana); Oshlack, A. (Alicia); Ayers, K.L. (Katie L.); A. Sinclair (Andrew)

    2016-01-01

    textabstractBackground: Disorders of sex development (DSD) are congenital conditions in which chromosomal, gonadal, or phenotypic sex is atypical. Clinical management of DSD is often difficult and currently only 13% of patients receive an accurate clinical genetic diagnosis. To address this we have

  10. DEVELOPMENT OF A HAZARDOUS WASTE INCINERATOR TARGET ANALYTE LIST OF PRODUCTS OF INCOMPLETE COMBUSTION

    Science.gov (United States)

    The report gives results of pilot-scale incineration testing to develop a comprehensive list of products of incomplete combustion (PICs) from hazardous waste combustion (HWC) systems. Project goals were to: (1) identify the total mass of organic compounds sufficiently to estimate...

  11. Development of HER2-targeted nanobodies for molecular optical imaging and therapy of breast cancer

    NARCIS (Netherlands)

    Kijanka, M.M.

    2014-01-01

    Breast cancer is a complex disease and the most prevalent cancer in women worldwide. It has been estimated that 1 in 8 women and 1 in 1,000 men will develop breast cancer. Surgical-, chemical- and radiation based therapies are available to breast cancer patients. Early detection of cancer is crucial

  12. Myocardin is a direct transcriptional target of Mef2, Tead and Foxo proteins during cardiovascular development

    NARCIS (Netherlands)

    Creemers, Esther E.; Sutherland, Lillian B.; McAnally, John; Richardson, James A.; Olson, Eric N.

    2006-01-01

    Myocardin is a transcriptional co-activator of serum response factor (Srf), which is a key regulator of the expression of smooth and cardiac muscle genes. Consistent with its role in regulating cardiovascular development, myocardin is the earliest known marker specific to both the cardiac and smooth

  13. Aligning Best Practices to Develop Targeted Critical Thinking Skills and Habits

    Science.gov (United States)

    Heft, Ilea E.; Scharff, Lauren F. V.

    2017-01-01

    This project evaluated the effectiveness of a course design within an upper-level biology course that incorporated what prior scholarship of teaching and learning (SoTL) research has suggested to be best practices for developing critical thinking skills while also managing the grading load on the instructor. These efforts centered on the…

  14. Scaffold proteins LACK and TRACK as potential drug targets in kinetoplastid parasites: Development of inhibitors.

    Science.gov (United States)

    Qvit, Nir; Schechtman, Deborah; Pena, Darlene Aparecida; Berti, Denise Aparecida; Soares, Chrislaine Oliveira; Miao, Qianqian; Liang, Liying Annie; Baron, Lauren A; Teh-Poot, Christian; Martínez-Vega, Pedro; Ramirez-Sierra, Maria Jesus; Churchill, Eric; Cunningham, Anna D; Malkovskiy, Andrey V; Federspiel, Nancy A; Gozzo, Fabio Cesar; Torrecilhas, Ana Claudia; Manso Alves, Maria Julia; Jardim, Armando; Momar, Ndao; Dumonteil, Eric; Mochly-Rosen, Daria

    2016-04-01

    Parasitic diseases cause ∼ 500,000 deaths annually and remain a major challenge for therapeutic development. Using a rational design based approach, we developed peptide inhibitors with anti-parasitic activity that were derived from the sequences of parasite scaffold proteins LACK (Leishmania's receptor for activated C-kinase) and TRACK (Trypanosoma receptor for activated C-kinase). We hypothesized that sequences in LACK and TRACK that are conserved in the parasites, but not in the mammalian ortholog, RACK (Receptor for activated C-kinase), may be interaction sites for signaling proteins that are critical for the parasites' viability. One of these peptides exhibited leishmanicidal and trypanocidal activity in culture. Moreover, in infected mice, this peptide was also effective in reducing parasitemia and increasing survival without toxic effects. The identified peptide is a promising new anti-parasitic drug lead, as its unique features may limit toxicity and drug-resistance, thus overcoming central limitations of most anti-parasitic drugs.

  15. The Kdo biosynthetic pathway toward OM biogenesis as target in antibacterial drug design and development.

    Science.gov (United States)

    Cipolla, Laura; Polissi, Alessandra; Airoldi, Cristina; Galliani, Paolo; Sperandeo, Paola; Nicotra, Francesco

    2009-03-01

    Despite important advances made in the last century, infectious diseases caused by pathogenic microrganisms are still a major threat to human health. This is worsened by the occurrence of new forms of bacterial resistance against antibiotics, that are the main remedy against infectious diseases, and their rapid spreading across bacterial species, pose additional threats to our health. Thus, the necessity to develop new weapons against pathogenic bacteria is widely recognized as a major challenge for modern drug research. Traditional antibiotic discovery procedures have so far focused on inhibiting the main processes of the bacterial cell (replication, transcription, translation, and peptidoglycan synthesis). This review will give an overview of the therapeutic strategies to cure infectious diseases caused by Gram-negative bacteria through the development of inhibitors of Kdo biosynthesis. Kdo is a monsaccharide essential for OM biogenesis, OM being an essential cellular structure shared by all Gram-negative bacteria. Hence, inhibitors of its biosynthesis can have a broad-spectrum antibacterial activity.

  16. Conceptual Soundness, Metric Development, Benchmarking, and Targeting for PATH Subprogram Evaluation

    Energy Technology Data Exchange (ETDEWEB)

    Mosey. G.; Doris, E.; Coggeshall, C.; Antes, M.; Ruch, J.; Mortensen, J.

    2009-01-01

    The objective of this study is to evaluate the conceptual soundness of the U.S. Department of Housing and Urban Development (HUD) Partnership for Advancing Technology in Housing (PATH) program's revised goals and establish and apply a framework to identify and recommend metrics that are the most useful for measuring PATH's progress. This report provides an evaluative review of PATH's revised goals, outlines a structured method for identifying and selecting metrics, proposes metrics and benchmarks for a sampling of individual PATH programs, and discusses other metrics that potentially could be developed that may add value to the evaluation process. The framework and individual program metrics can be used for ongoing management improvement efforts and to inform broader program-level metrics for government reporting requirements.

  17. Developing Novel PepT1-Targeted Modulators for Inflammatory Bowel Disease (IBD) Therapy

    Science.gov (United States)

    2016-10-01

    Docking, Transgenic mouse, IBD 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 19a. NAME OF RESPONSIBLE PERSON USAMRMC...based discovery approach and transgenic mice models, with a long-term objective of developing innovative medicines for IBD. 2. KEYWORDS Homology...Docking, Transgenic mouse. 3. ACCOMPLISHMENTS  What were the major goals of the project? The overarching research goal of this project is to

  18. Targeted therapies in development for non-small cell lung cancer

    OpenAIRE

    Reungwetwattana, Thanyanan; Dy, Grace Kho

    2013-01-01

    The iterative discovery in various malignancies during the past decades that a number of aberrant tumorigenic processes and signal transduction pathways are mediated by "druggable" protein kinases has led to a revolutionary change in drug development. In non-small cell lung cancer (NSCLC), the ErbB family of receptors (e.g., EGFR [epidermal growth factor receptor], HER2 [human epidermal growth factor receptor 2]), RAS (rat sarcoma gene), BRAF (v-raf murine sarcoma viral oncogene homolog B1), ...

  19. Development of Quorum-Based Anti-Virulence Therapeutics Targeting Gram-Negative Bacterial Pathogens

    Directory of Open Access Journals (Sweden)

    Wen Shan Yew

    2013-08-01

    Full Text Available Quorum sensing is a cell density-dependent signaling phenomenon used by bacteria for coordination of population-wide phenotypes, such as expression of virulence genes, antibiotic resistance and biofilm formation. Lately, disruption of bacterial communication has emerged as an anti-virulence strategy with enormous therapeutic potential given the increasing incidences of drug resistance in pathogenic bacteria. The quorum quenching therapeutic approach promises a lower risk of resistance development, since interference with virulence generally does not affect the growth and fitness of the bacteria and, hence, does not exert an associated selection pressure for drug-resistant strains. With better understanding of bacterial communication networks and mechanisms, many quorum quenching methods have been developed against various clinically significant bacterial pathogens. In particular, Gram-negative bacteria are an important group of pathogens, because, collectively, they are responsible for the majority of hospital-acquired infections. Here, we discuss the current understanding of existing quorum sensing mechanisms and present important inhibitory strategies that have been developed against this group of pathogenic bacteria.

  20. Development of a new approach for targeted gene editing in primordial germ cells using TALENs in Xenopus

    Directory of Open Access Journals (Sweden)

    Keisuke Nakajima

    2015-02-01

    Full Text Available A gene of interest can be efficiently modified using transcription activator-like effector nucleases (TALENs (Christian et al., 2010;Li et al., 2011. However, if a target gene is essential for development, growth and fertility, use of TALENs with high mutagenic activity in F0 frogs could result in developmental disorders or sterility, which would reduce the number of F1 progeny and make F1 phenotypical analysis difficult. We used the 3′ untranslated region of DEADSouth gene (DS-3′ of Xenopus tropicalis to solve this problem, because the addition of the DS-3′ to mRNA is known to induce primordial germ cell (PGC-specific expression and reduce the stability in somatic cells of mRNA in Xenopus laevis. At first, we inserted the X. tropicalis DS-3′ downstream of the EGFP termination codon and confirmed that the EGFP expression was specifically detected in PGCs for three weeks. Therefore, we inserted the DS-3′ downstream of the termination codon of the TALEN coding sequence. The tyrosinase gene was selected as the target gene for TALEN because the bi-allelic mutation of this gene is easily discernible by the albino phenotype. When fertilized eggs were microinjected with TALEN mRNAs fused to the DS-3′, their sperm and oocytes had a high rate (84–100% of target-gene modification in contrast to the lower rate (0–45% of nucleotide alteration observed in somatic cells.

  1. Development and in vivo quantitative magnetic resonance imaging of polymer micelles targeted to the melanocortin 1 receptor.

    Science.gov (United States)

    Barkey, Natalie M; Preihs, Christian; Cornnell, Heather H; Martinez, Gary; Carie, Adam; Vagner, Josef; Xu, Liping; Lloyd, Mark C; Lynch, Vincent M; Hruby, Victor J; Sessler, Jonathan L; Sill, Kevin N; Gillies, Robert J; Morse, David L

    2013-08-22

    Recent emphasis has focused on the development of rationally designed polymer-based micelle carriers for drug delivery. The current work tests the hypothesis that target specificity can be enhanced by micelles with cancer-specific ligands. In particular, we describe the synthesis and characterization of a new gadolinium texaphyrin (Gd-Tx) complex encapsulated in an IVECT micellar system, stabilized through Fe(III) cross-linking and targeted with multiple copies of a specific ligand for the melanocortin 1 receptor (MC1R), which has been evaluated as a cell-surface marker for melanoma. On the basis of comparative MRI experiments, we have been able to demonstrate that these Gd-Tx micelles are able to target MC1R-expressing xenograft tumors in vitro and in vivo more effectively than various control systems, including untargeted or un-cross-linked Gd-Tx micelles. Taken in concert, the findings reported herein support the conclusion that appropriately designed micelles are able to deliver contrast agent payloads to tumors expressing the MC1R.

  2. A Cellular MicroRNA Facilitates Regulatory T Lymphocyte Development by Targeting the FOXP3 Promoter TATA-Box Motif.

    Science.gov (United States)

    Zhang, Yiwen; Liu, Weiwei; Chen, Yingshi; Liu, Jun; Wu, Kang; Su, Lishi; Zhang, Wanying; Jiang, Yawen; Zhang, Xu; Zhang, Yijun; Liu, Chao; Tao, Liang; Liu, Bingfeng; Zhang, Hui

    2018-02-01

    The CD4 + CD25 + FOXP3 + regulatory T cells (Tregs) mediate immunological self-tolerance and suppress various immune responses. FOXP3 is a key transcriptional factor for the generation and development of Tregs. Its expression is regulated by various cytokines including TGF-β, IL-2, and IL-10. It is important to further identify the regulatory factors for Tregs. Given that many microRNAs (miRNAs) could specifically interact with the core promoter region and specifically enhance the transcription of many target genes, we searched for any possible miRNA(s) targeting the core promoter region of the FOXP3 gene. We found that miR-4281, an miRNA specifically expressed in hominids, can potently and specifically upregulate FOXP3 expression by directly interacting with the TATA-box motif in the human FOXP3 promoter. Consequently, miR-4281 significantly accelerated the differentiation of human naive cells to induced Tregs (iTregs) that possess immune suppressor functions and weaken the development of graft-versus-host disease in a humanized mouse model. Interestingly, iTregs induced by the combination of TGF-β, IL-2, and chemically synthesized miR-4281 were more stable and functional than those induced by TGF-β and IL-2 alone. Moreover, we found that the IL-2/STAT5 signal transduction upregulates FOXP3 expression not only through the classical pathway, but also by enhancing the expression of the miR-4281 precursor gene ( SNCB ) and, correspondingly, miR-4281. This study reveals a novel mechanism regulating FOXP3 expression and human iTreg development and, therefore, offers a new therapeutic target to manipulate immunosuppressive system. Copyright © 2018 by The American Association of Immunologists, Inc.

  3. Community-based oral health promotion practices targeted at children and adolescents in Finland--developing an assessment tool.

    Science.gov (United States)

    Blomqvist, Pia; Ojala, Ellinoora; Kettunen, Tarja; Poskiparta, Marita; Kasila, Kirsti

    2014-06-01

    To develop an assessment tool for evaluating oral health promotion practices and to evaluate community-based oral health promotion practices targeted at children and adolescents with this tool. A theoretical framework about health promotion planning, implementation and evaluation was made on the basis of a literature review. Then, information about Finnish community-based oral health promotion practices (n=12) targeted at children and adolescents was collected using semi-structured interviews. Also, related documents, for example action plans and reports, were collected when available. Next, an assessment tool based on the theoretical framework was developed, and the recorded and transcribed interview data and other documents were evaluated with this tool. The assessment tool proved to be practical: it pointed out the strengths and weaknesses of the practices. The tool revealed strengths in the implementation and deficiencies in the planning and evaluation of oral health promotion practices. One-quarter of the 12 practices assessed could be considered 'good practices'. There is a need to improve the planning and evaluation of oral health promotion practices. The assessment tool developed in this study might be useful for practitioners both in the field of oral health promotion and general health promotion. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  4. The Cytoplasmic Prolyl-tRNA Synthetase of the Malaria Parasite is a Dual-Stage Target for Drug Development

    Science.gov (United States)

    Herman, Jonathan D.; Pepper, Lauren R.; Cortese, Joseph F.; Estiu, Guillermina; Galinsky, Kevin; Zuzarte-Luis, Vanessa; Derbyshire, Emily R.; Ribacke, Ulf; Lukens, Amanda K.; Santos, Sofia A.; Patel, Vishal; Clish, Clary B.; Sullivan, William J.; Zhou, Huihao; Bopp, Selina E.; Schimmel, Paul; Lindquist, Susan; Clardy, Jon; Mota, Maria M.; Keller, Tracy L.; Whitman, Malcolm; Wiest, Olaf; Wirth, Dyann F.; Mazitschek, Ralph

    2015-01-01

    The emergence of drug resistance is a major limitation of current antimalarials. The discovery of new druggable targets and pathways including those that are critical for multiple life cycle stages of the malaria parasite is a major goal for the development of the next-generation of antimalarial drugs. Using an integrated chemogenomics approach that combined drug-resistance selection, whole genome sequencing and an orthogonal yeast model, we demonstrate that the cytoplasmic prolyl-tRNA synthetase (PfcPRS) of the malaria parasite Plasmodium falciparum is a biochemical and functional target of febrifugine and its synthetic derivatives such as halofuginone. Febrifugine is the active principle of a traditional Chinese herbal remedy for malaria. We show that treatment with febrifugine derivatives activated the amino acid starvation response in both P. falciparum and a transgenic yeast strain expressing PfcPRS. We further demonstrate in the P. berghei mouse model of malaria that halofuginol, a new halofuginone analog that we developed, is highly active against both liver and asexual blood stages of the malaria parasite. Halofuginol, unlike halofuginone and febrifugine, is well tolerated at efficacious doses, and represents a promising lead for the development of dual-stage next generation antimalarials. PMID:25995223

  5. L,L-diaminopimelate aminotransferase (DapL: A putative target for the development of narrow-spectrum antibacterial compounds

    Directory of Open Access Journals (Sweden)

    Alexander J Triassi

    2014-09-01

    Full Text Available Despite the urgent need for sustained development of novel antibacterial compounds to combat the drastic rise in antibiotic resistant and emerging bacterial infections, only a few clinically relevant antibacterial drugs have been recently developed. One of the bottlenecks impeding the development of novel antibacterial compounds is the identification of new enzymatic targets. The nutritionally essential amino acid anabolic pathways, for example lysine biosynthesis, provide an opportunity to explore the development of antibacterial compounds, since human genomes do not possess the genes necessary to synthesize these amino acids de novo. The diaminopimelate (DAP/lysine (lys anabolic pathways are attractive targets for antibacterial development since the penultimate lys precursor meso-DAP (m-DAP is a cross-linking amino acid in the peptidoglycan (PG cell wall of most Gram-negative bacteria and lys plays a similar role in the PG of most Gram-positive bacteria, in addition to its role as one of the 20 proteogenic amino acids. The L,L-diaminopimelate aminotransferase (DapL pathway was recently identified as a novel variant of the DAP/lys anabolic pathways. The DapL pathway has been identified in the pathogenic bacteria belonging to the genus; Chlamydia, Leptospira and Treponema. The dapL gene has been identified in the genomes of 381 or approximately 13% of the 2,771 bacteria that have been sequenced, annotated and reposited in the NCBI database, as of May 23, 2014. The narrow distribution of the DapL pathway in the bacterial domain provides an opportunity for the development and or discovery of narrow spectrum antibacterial compounds.

  6. Development of a Risk Algorithm to Better Target STI Testing and Treatment Among Australian Aboriginal and Torres Strait Islander People.

    Science.gov (United States)

    Wand, Handan; Bryant, Joanne; Pitts, Marian; Delaney-Thiele, Dea; Kaldor, John M; Worth, Heather; Ward, James

    2017-10-01

    Identifying and targeting those at greatest risk will likely play a significant role in developing the most efficient and cost-effective sexually transmissible infections (STI) prevention programs. We aimed to develop a risk prediction algorithm to identify those who are at increased risk of STI. A cohort (N = 2320) of young sexually active Aboriginal and Torres Strait Islander people (hereafter referred to as Aboriginal people) were included in this study. The primary outcomes were self-reported high-risk sexual behaviors and past STI diagnosis. In developing a risk algorithm, our study population was randomly assigned to either a development (67%) or an internal validation data set (33%). Logistic regression models were used to create a risk prediction algorithm from the development data set for males and females separately. In the risk prediction models, older age, methamphetamine, ecstasy, and cannabis use, and frequent alcohol intake were all consistently associated with high-risk sexual behaviors as well as with a past STI diagnosis; identifying as gay/bisexual was one of the strongest factors among males. Those who had never tested for STIs, 52% (males) and 66% (females), had a risk score >15, and prevalence of undiagnosed STI was estimated between 30 and 40%. Since universal STI screening is not cost-effective, nor practical in many settings, targeted screening strategies remain a crucial and effective approach to managing STIs among young Aboriginal people. Risk prediction tools such as the one developed in this study may help in prioritizing screening for STIs among those most at risk.

  7. Rational targeting of the urokinase receptor (uPAR): development of antagonists and non-invasive imaging probes

    DEFF Research Database (Denmark)

    Kriegbaum, M C; Persson, M; Haldager, L

    2011-01-01

    -ray crystallography and surface plasmon resonance studies. Importantly, these structural studies also define possible druggable target sites in uPAR for small molecules and provide guidelines for the development of reporter groups applicable for non-invasive molecular imaging of uPAR expression in vivo by positron...... emission tomography. In this review, we will discuss recent advances in our perception of the structure-function relationships of uPAR ligation and how these may assist translational research in preclinical intervention studies of uPAR function....

  8. Force Protection via UGV-UAV Collaboration: Development of Control Law for Vision Based Target Tracking on SUAV

    National Research Council Canada - National Science Library

    Liang, Lee S

    2007-01-01

    .... The VBTT system includes a miniaturized gimbaled camera that allows autonomous target tracking while providing concurrent estimates of target motion including its position velocity and heading...

  9. Multi-laboratory evaluations of the performance of Catellicoccus marimammalium PCR assays developed to target gull fecal sources

    Science.gov (United States)

    Sinigalliano, Christopher D.; Ervin, Jared S.; Van De Werfhorst, Laurie C.; Badgley, Brian D.; Ballestée, Elisenda; Bartkowiaka, Jakob; Boehm, Alexandria B.; Byappanahalli, Muruleedhara N.; Goodwin, Kelly D.; Gourmelon, Michèle; Griffith, John; Holden, Patricia A.; Jay, Jenny; Layton, Blythe; Lee, Cheonghoon; Lee, Jiyoung; Meijer, Wim G.; Noble, Rachel; Raith, Meredith; Ryu, Hodon; Sadowsky, Michael J.; Schriewer, Alexander; Wang, Dan; Wanless, David; Whitman, Richard; Wuertz, Stefan; Santo Domingo, Jorge W.

    2013-01-01

    Here we report results from a multi-laboratory (n = 11) evaluation of four different PCR methods targeting the 16S rRNA gene of Catellicoccus marimammalium originally developed to detect gull fecal contamination in coastal environments. The methods included a conventional end-point PCR method, a SYBR® Green qPCR method, and two TaqMan® qPCR methods. Different techniques for data normalization and analysis were tested. Data analysis methods had a pronounced impact on assay sensitivity and specificity calculations. Across-laboratory standardization of metrics including the lower limit of quantification (LLOQ), target detected but not quantifiable (DNQ), and target not detected (ND) significantly improved results compared to results submitted by individual laboratories prior to definition standardization. The unit of measure used for data normalization also had a pronounced effect on measured assay performance. Data normalization to DNA mass improved quantitative method performance as compared to enterococcus normalization. The MST methods tested here were originally designed for gulls but were found in this study to also detect feces from other birds, particularly feces composited from pigeons. Sequencing efforts showed that some pigeon feces from California contained sequences similar to C. marimammalium found in gull feces. These data suggest that the prevalence, geographic scope, and ecology of C. marimammalium in host birds other than gulls require further investigation. This study represents an important first step in the multi-laboratory assessment of these methods and highlights the need to broaden and standardize additional evaluations, including environmentally relevant target concentrations in ambient waters from diverse geographic regions.

  10. Development of radioactively labelled cancer seeking biomolecules for targeted radiotherapy. Greece

    International Nuclear Information System (INIS)

    Varvarigou, Alexandra D.; Archimandritis, Spyridon C.

    2000-01-01

    Within the framework of the above project we are studying the labelling of biomolecules, peptides and antibodies, with radionuclides emitting β - and γ radiation. More specifically, for the time being, we have investigated the labelling of peptides with Re-188 and of antibodies with Sm-153 and Re-188. The radiolabelled derivatives are further evaluated in vivo for possible application in Oncology. For these radiobiological studies we are trying to apply ectopic and orthotopic tumour animal models and to develop, in collaboration with other national and foreign institutes, proper imaging devices for small animal imaging

  11. Development of radioactively labelled cancer seeking biomolecules for targeted therapy. India

    International Nuclear Information System (INIS)

    Pillai, M.R.A.

    2000-01-01

    The work done towards the development of bifunctional chelating agents, modified peptide and their radiolabelling studies with 90 Y and 188 Re are reported. Bifunctional chelating agents DOTA, TETA and DAHPES were synthesised. DOTA-Lanreotide (Mauritius) was synthesised from Lanreotide. 90 Y and 188 Re used in the studies were obtained from 90 Sr- 90 Y and 188 W- 188 Re generators. Complexation studies of DOTA and Mauritius with 90 Y and that of DAHPES and EC with 188 Re were carried out. Cell labelling of 90 Y-DOTA-Lanreotide with a cell line expressing somatostatin receptors was also carried out

  12. Development and validation of a HILIC- MS/MS multi-targeted method for metabolomics applications.

    Science.gov (United States)

    Virgiliou, Christina; Sampsonidis, Ioannis; Gika, Helen G; Raikos, Nikolaos; Theodoridis, Georgios A

    2015-07-14

    The paper reports the development of a multi-analyte method and its application in metabolic profiling of biological fluids. The initial aim of the method was the quantification of metabolites existing in cell culture medium used in in-vitro fertilisation (IVF) and in other biological fluids related to embryo growth. Since most of these analytes are polar primary metabolites a hydrophilic interaction liquid chromatography (HILIC) system was selected. The analytical system comprised Ultra (High) performance liquid chromatography (UHPLC) with detection on a triple quadrupole mass spectrometer operating in both positive and negative modes. Mobile phase and gradient elution conditions were studied with the aim to achieve the highest coverage of metabolic space in a single injection namely the largest number of analytes that could be detected and quantified. The developed method provides absolute quantitation of ca. 100 metabolites belonging to key metabolite classes such as sugars, aminoacids, nucleotides, organic acids and amines. Following validation, the method was applied for the metabolic profiling of hundreds of samples of spent culture medium originating from human IVF procedures and several hundreds of biological samples such as amniotic fluid, human urine and blood serum from pregnant women. The bioanalytical end-point was to provide assistance in the process of embryo transfer and improving IVF success rates but also to provide insight in complications related to the subsequent embryo growth during pregnancy. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  13. Extracellular vesicles as emerging targets in cancer: Recent development from bench to bedside.

    Science.gov (United States)

    Wu, Kerui; Xing, Fei; Wu, Shih-Ying; Watabe, Kounosuke

    2017-12-01

    Extracellular vesicles (EVs) have emerged as important players of cancer initiation and progression through cell-cell communication. They have been recognized as critical mediators of extracellular communications, which promote transformation, growth invasion, and drug-resistance of cancer cells. Interestingly, the secretion and uptake of EVs are regulated in a more controlled manner than previously anticipated. EVs are classified into three groups, (i) exosomes, (ii) microvesicles (MVs), and (iii) apoptotic bodies (ABs), based on their sizes and origins, and novel technologies to isolate and distinguish these EVs are evolving. The biologically functional molecules harbored in these EVs, including nucleic acids, lipids, and proteins, have been shown to induce key signaling pathways in both tumor and tumor microenvironment (TME) cells for exacerbating tumor development. While tumor cell-derived EVs are capable of reprogramming stromal cells to generate a proper tumor cell niche, stromal-derived EVs profoundly affect the growth, resistance, and stem cell properties of tumor cells. This review summarizes and discusses these reciprocal communications through EVs in different types of cancers. Further understanding of the pathophysiological roles of different EVs in tumor progression is expected to lead to the discovery of novel biomarkers in liquid biopsy and development of tumor specific therapeutics. This review will also discuss the translational aspects of EVs and therapeutic opportunities of utilizing EVs in different cancer types. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Immunocompetent mouse allograft models for development of therapies to target breast cancer metastasis.

    Science.gov (United States)

    Yang, Yuan; Yang, Howard H; Hu, Ying; Watson, Peter H; Liu, Huaitian; Geiger, Thomas R; Anver, Miriam R; Haines, Diana C; Martin, Philip; Green, Jeffrey E; Lee, Maxwell P; Hunter, Kent W; Wakefield, Lalage M

    2017-05-09

    Effective drug development to combat metastatic disease in breast cancer would be aided by the availability of well-characterized preclinical animal models that (a) metastasize with high efficiency, (b) metastasize in a reasonable time-frame, (c) have an intact immune system, and (d) capture some of the heterogeneity of the human disease. To address these issues, we have assembled a panel of twelve mouse mammary cancer cell lines that can metastasize efficiently on implantation into syngeneic immunocompetent hosts. Genomic characterization shows that more than half of the 30 most commonly mutated genes in human breast cancer are represented within the panel. Transcriptomically, most of the models fall into the luminal A or B intrinsic molecular subtypes, despite the predominance of an aggressive, poorly-differentiated or spindled histopathology in all models. Patterns of immune cell infiltration, proliferation rates, apoptosis and angiogenesis differed significantly among models. Inherent within-model variability of the metastatic phenotype mandates large cohort sizes for intervention studies but may also capture some relevant non-genetic sources of variability. The varied molecular and phenotypic characteristics of this expanded panel of models should aid in model selection for development of antimetastatic therapies in vivo, and serve as a useful platform for predictive biomarker identification.

  15. Scaffold proteins LACK and TRACK as potential drug targets in kinetoplastid parasites: Development of inhibitors

    Directory of Open Access Journals (Sweden)

    Nir Qvit

    2016-04-01

    Full Text Available Parasitic diseases cause ∼500,000 deaths annually and remain a major challenge for therapeutic development. Using a rational design based approach, we developed peptide inhibitors with anti-parasitic activity that were derived from the sequences of parasite scaffold proteins LACK (Leishmania's receptor for activated C-kinase and TRACK (Trypanosoma receptor for activated C-kinase. We hypothesized that sequences in LACK and TRACK that are conserved in the parasites, but not in the mammalian ortholog, RACK (Receptor for activated C-kinase, may be interaction sites for signaling proteins that are critical for the parasites' viability. One of these peptides exhibited leishmanicidal and trypanocidal activity in culture. Moreover, in infected mice, this peptide was also effective in reducing parasitemia and increasing survival without toxic effects. The identified peptide is a promising new anti-parasitic drug lead, as its unique features may limit toxicity and drug-resistance, thus overcoming central limitations of most anti-parasitic drugs.

  16. Development of a computerised decisions support system for renal risk drugs targeting primary healthcare.

    Science.gov (United States)

    Helldén, Anders; Al-Aieshy, Fadiea; Bastholm-Rahmner, Pia; Bergman, Ulf; Gustafsson, Lars L; Höök, Hans; Sjöviker, Susanne; Söderström, Anders; Odar-Cederlöf, Ingegerd

    2015-07-06

    To assess general practitioners (GPs) experience from the implementation and use of a renal computerised decision support system (CDSS) for drug dosing, developed for primary healthcare, integrated into the patient's electronic health record (EHR), and building on estimation of the patient's creatinine clearance (ClCG). Qualitative research design by a questionnaire and a focus group discussion. Eight GPs at two primary healthcare centres (PHCs). The GP at PHC 1, and the project group, developed and tested the technical solution of the CDSS. Proof-of-concept was tested by seven GPs at PHC 2. They also participated in a group discussion and answered a questionnaire. A web window in the EHR gave drug and dosage in relation to ClCG. Each advice was according to three principles: If? Why? Because. (1) The GPs' experience of 'easiness to use' and 'perceived usefulness' at PHC 2, based on loggings of use, answers from a questionnaire using a 5-point Likert scale, and answers from a focus group discussion. (2) The number of patients aged 65 years and older with an estimation of ClCG before and after the implementation of the CDSS. The GPs found the CDSS fast, simple and easy to use. They appreciated the automatic presentation of the CICG status on opening the medication list, and the ability to actively look up specific drug recommendations in two steps. The CDSS scored high on the Likert scale. All GPs wanted to continue the use of the CDSS and to recommend it to others. The number of patients with an estimated ClCG increased 1.6-fold. Acceptance of the simple graphical interface of this push and pull renal CDSS was high among the primary care physicians evaluating this proof of concept. The graphical model should be useful for further development of renal decision support systems. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  17. From screen to target: insights and approaches into the development of anti-virulence compounds

    Directory of Open Access Journals (Sweden)

    Katherine SH Beckham

    2014-09-01

    Full Text Available The detailed understanding of host-pathogen interactions provides exciting opportunities to interfere with the infection process. Anti-virulence compounds aim to modulate or pacify pathogenesis by reducing expression of critical virulence determinants. In particular, prevention of attachment by inhibiting adhesion mechanisms has been the subject of intense research. Whilst it has proven relatively straightforward to develop robust screens for potential antivirulence compounds, understanding their precise mode of action has proven much more challenging. In this review we illustrate this challenge from our own experiences working with the salicylidene acylhydrazide group of compounds. We aim to provide a useful perspective to guide researchers interested in this field and to avoid some of the obvious pitfalls.

  18. Development of 87Sr/86Sr maps as targeted strategy to support wine quality.

    Science.gov (United States)

    Durante, Caterina; Bertacchini, Lucia; Cocchi, Marina; Manzini, Daniela; Marchetti, Andrea; Rossi, Maria Cecilia; Sighinolfi, Simona; Tassi, Lorenzo

    2018-07-30

    This study summarizes the results obtained from a systematic and long-term project aimed at the development of tools to assess the provenance of food in the oenological sector. In particular, 87 Sr/ 86 Sr isotope ratios were measured on statistically representative set of soils, vine branches and wines sampled in the production district of Modena, worldwide known for the Lambrusco wines production. The obtained data were used to build strontium isotopic maps able to objectively support the Lambrusco PDO wines origin as well as other products of the Modena district. Finally, a strong relationship was found between the 87 Sr/ 86 Sr isotope ratios of soils and vine branches on a large scale, highlighting and confirming once more the idea that plants can also represent an optimal sampling device to support geographical traceability. Copyright © 2018 Elsevier Ltd. All rights reserved.

  19. Emerging Targets for Developing T Cell-Mediated Vaccines for Human Immunodeficiency Virus (HIV-1

    Directory of Open Access Journals (Sweden)

    Danushka K. Wijesundara

    2017-10-01

    Full Text Available Human immunodeficiency virus (HIV-1 has infected >75 million individuals globally, and, according to the UN, is responsible for ~2.1 million new infections and 1.1 million deaths each year. Currently, there are ~37 million individuals with HIV infection and the epidemic has already resulted in 35 million deaths. Despite the advances of anti-retroviral therapy (ART, a cost-effective vaccine remains the best long-term solution to end the HIV-1 epidemic especially given that the vast majority of infected individuals live in poor socio-economic regions of the world such as Sub-Saharan Africa which limits their accessibility to ART. The modest efficacy of the RV144 Thai trial provides hope that a vaccine for HIV-1 is possible, but as markers for sterilizing immunity are unknown, the design of an effective vaccine is empirical, although broadly cross-reactive neutralizing antibodies (bNAb that can neutralize various quasispecies of HIV-1 are considered crucial. Since HIV-1 transmission often occurs at the genito-rectal mucosa and is cell-associated, there is a need to develop vaccines that can elicit CD8+ T cell immunity with the capacity to kill virus infected cells at the genito-rectal mucosa and the gut. Here we discuss the recent progress made in developing T cell-mediated vaccines for HIV-1 and emphasize the need to elicit mucosal tissue-resident memory CD8+ T (CD8+ Trm cells. CD8+ Trm cells will likely form a robust front-line defense against HIV-1 and eliminate transmitter/founder virus-infected cells which are responsible for propagating HIV-1 infections following transmission in vast majority of cases.

  20. Fungal Biofilms: Targets for the Development of Novel Strategies in Plant Disease Management.

    Science.gov (United States)

    Villa, Federica; Cappitelli, Francesca; Cortesi, Paolo; Kunova, Andrea

    2017-01-01

    The global food supply has been facing increasing challenges during the first decades of the 21 st century. Disease in plants is an important constraint to worldwide crop production, accounting for 20-40% of its annual harvest loss. Although the use of resistant varieties, good water management and agronomic practices are valid management tools in counteracting plant diseases, there are still many pathosystems where fungicides are widely used for disease management. However, restrictive regulations and increasing concern regarding the risk to human health and the environment, along with the incidence of fungicide resistance, have discouraged their use and have prompted for a search for new efficient, ecologically friendly and sustainable disease management strategies. The recent evidence of biofilm formation by fungal phytopathogens provides the scientific framework for designing and adapting methods and concepts developed by biofilm research that could be integrated in IPM practices. In this perspective paper, we provide evidence to support the view that the biofilm lifestyle plays a critical role in the pathogenesis of plant diseases. We describe the main factors limiting the durability of single-site fungicides, and we assemble the current knowledge on pesticide resistance in the specific context of the biofilm lifestyle. Finally, we illustrate the potential of antibiofilm compounds at sub-lethal concentrations for the development of an innovative, eco-sustainable strategy to counteract phytopathogenic fungi. Such fungicide-free solutions will be instrumental in reducing disease severity, and will permit more prudent use of fungicides decreasing thus the selection of resistant forms and safeguarding the environment.

  1. Deletion of Foxp3+ regulatory T cells in genetically targeted mice supports development of intestinal inflammation

    Directory of Open Access Journals (Sweden)

    Boehm Franziska

    2012-07-01

    Full Text Available Abstract Background Mice lacking Foxp3+ regulatory T (Treg cells develop severe tissue inflammation in lung, skin, and liver with premature death, whereas the intestine remains uninflamed. This study aims to demonstrate the importance of Foxp3+ Treg for the activation of T cells and the development of intestinal inflammation. Methods Foxp3-GFP-DTR (human diphtheria toxin receptor C57BL/6 mice allow elimination of Foxp3+ Treg by treatment with Dx (diphtheria toxin. The influence of Foxp3+ Treg on intestinal inflammation was tested using the CD4+ T-cell transfer colitis model in Rag−/− C57BL/6 mice and the acute DSS-colitis model. Results Continuous depletion of Foxp3+ Treg in Foxp3-GFP-DTR mice led to dramatic weight loss and death of mice by day 28. After 10 days of depletion of Foxp3+ Treg, isolated CD4+ T-cells were activated and produced extensive amounts of IFN-γ, IL-13, and IL-17A. Transfer of total CD4+ T-cells isolated from Foxp3-GFP-DTR mice did not result in any changes of intestinal homeostasis in Rag−/− C57BL/6 mice. However, administration of DTx between days 14 and 18 after T-cell reconstitution, lead to elimination of Foxp3+ Treg and to immediate weight loss due to intestinal inflammation. This pro-inflammatory effect of Foxp3+ Treg depletion consecutively increased inflammatory cytokine production. Further, the depletion of Foxp3+ Treg from Foxp3-GFP-DTR mice increased the severity of acute dSS-colitis accompanied by 80% lethality of Treg-depleted mice. CD4+ effector T-cells from Foxp3+ Treg-depleted mice produced significantly more pro-inflammatory cytokines. Conclusion Intermittent depletion of Foxp3+ Treg aggravates intestinal inflammatory responses demonstrating the importance of Foxp3+ Treg for the balance at the mucosal surface of the intestine.

  2. Targeted disruption of CD1d prevents NKT cell development in pigs.

    Science.gov (United States)

    Yang, Guan; Artiaga, Bianca L; Hackmann, Timothy J; Samuel, Melissa S; Walters, Eric M; Salek-Ardakani, Shahram; Driver, John P

    2015-06-01

    Studies in mice genetically lacking natural killer T (NKT) cells show that these lymphocytes make important contributions to both innate and adaptive immune responses. However, the usefulness of murine models to study human NKT cells is limited by the many differences between mice and humans, including that their NKT cell frequencies, subsets, and distribution are dissimilar. A more suitable model may be swine that share many metabolic, physiological, and growth characteristics with humans and are also similar for NKT cells. Thus, we analyzed genetically modified pigs made deficient for CD1d that is required for the development of Type I invariant NKT (iNKT) cells that express a semi-invariant T-cell receptor (TCR) and Type II NKT cells that use variable TCRs. Peripheral blood analyzed by flow cytometry and interferon-γ enzyme-linked immuno spot assays demonstrated that CD1d-knockout pigs completely lack iNKT cells, while other leukocyte populations remain intact. CD1d and NKT cells have been shown to be involved in shaping the composition of the commensal microbiota in mice. Therefore, we also compared the fecal microbiota profile between pigs expressing and lacking NKT cells. However, no differences were found between pigs lacking or expressing CD1d. Our results are the first to show that knocking-out CD1d prevents the development of NKT cells in a non-rodent species. CD1d-deficient pigs should offer a useful model to more accurately determine the contribution of NKT cells for human immune responses. They also have potential for understanding how NKT cells impact the health of commercial swine.

  3. Anticancer drug development from traditional cytotoxic to targeted therapies: evidence of shorter drug research and development time, and shorter drug lag in Japan.

    Science.gov (United States)

    Kawabata-Shoda, E; Masuda, S; Kimura, H

    2012-10-01

    Concern about the drug lag, the delay in marketing approval between one country and another, for anticancer drugs has increased in Japan. Although a number of studies have investigated the drug lag, none has investigated it in relation to the transition of anticancer therapy from traditional cytotoxic drugs to molecularly targeted agents. Our aim was to investigate current trend in oncology drug lag between the US and Japan and identify oncology drugs approved in only one of the two countries. Publicly and commercially available data sources were used to identify drugs approved in the US and Japan as of 31 December 2010 and the data used to calculate the drug lag for individual drugs. Fifty-one drugs were approved in both the US and Japan, whereas 34 and 19 drugs were approved only in the US or Japan, respectively. Of the 19 drugs approved only in Japan, 12 had not been subject to development for a cancer indication in the US, and all were approved before 1996 in Japan. Of the 34 drugs approved only in the US, 20 had not been subject to development in Japan, and none was in the top 25 by annual US anticancer drug-class sales. For drugs approved in both countries, the mean approval lag of the molecularly targeted drugs (MTDs) was significantly shorter than that of the non-molecularly targeted drugs (non-MTDs) (3·3 vs. 5·4 years). Further, mean R&D time of the MTDs was significantly shorter than that of non-MTDs (10·0 vs. 13·7 years). The price of MTDs had increased on average by 6·6% annually in the US, whereas it had decreased on average by 4·3% biyearly in Japan. The emergence of new molecularly targeted agents has contributed to reducing the approval lag, most likely due to improvements in R&D strategy. © 2012 Blackwell Publishing Ltd.

  4. Targeting surface nucleolin with a multivalent pseudopeptide delays development of spontaneous melanoma in RET transgenic mice

    Directory of Open Access Journals (Sweden)

    Briand Jean-Paul

    2010-06-01

    Full Text Available Abstract Background The importance of cell-surface nucleolin in cancer biology was recently highlighted by studies showing that ligands of nucleolin play critical role in tumorigenesis and angiogenesis. By using a specific antagonist that binds the C-terminal tail of nucleolin, the HB-19 pseudopeptide, we recently reported that HB-19 treatment markedly suppressed the progression of established human breast tumor cell xenografts in the athymic nude mice without apparent toxicity. Methods The in vivo antitumoral action of HB-19 treatment was assessed on the spontaneous development of melanoma in the RET transgenic mouse model. Ten days old RET mice were treated with HB-19 in a prophylactic setting that extended 300 days. In parallel, the molecular basis for the action of HB-19 was investigated on a melanoma cell line (called TIII derived from a cutaneous nodule of a RET mouse. Results HB-19 treatment of RET mice caused a significant delay in the onset of cutaneous tumors, several-months delay in the incidence of large tumors, a lower frequency of cutaneous nodules, and a reduction of visceral metastatic nodules while displaying no toxicity to normal tissue. Moreover, microvessel density was significantly reduced in tumors recovered from HB-19 treated mice compared to corresponding controls. Studies on the melanoma-derived tumor cells demonstrated that HB-19 treatment of TIII cells could restore contact inhibition, impair anchorage-independent growth, and reduce their tumorigenic potential in mice. Moreover, HB-19 treatment caused selective down regulation of transcripts coding matrix metalloproteinase 2 and 9, and tumor necrosis factor-α in the TIII cells and in melanoma tumors of RET mice. Conclusions Although HB-19 treatment failed to prevent the development of spontaneous melanoma in the RET mice, it delayed for several months the onset and frequency of cutaneous tumors, and exerted a significant inhibitory effect on visceral metastasis

  5. Development of additive [{sup 11}C]CO{sub 2} target system in the KOTRON-13 cyclotron and its application for [{sup 11}C]radiopharmaceutical production

    Energy Technology Data Exchange (ETDEWEB)

    Moon, Byung Seok; Lee, Hong Jin [Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 463-707 (Korea, Republic of); Lee, Won Kyung [Technical Support Team, Duchembio, Seoul 121-844 (Korea, Republic of); Hur, Min Goo; Yang, Seung Dae [Radiation Instrumentation Research Division, Korea Atomic Energy Research Institute, Jeongeup 580-185 (Korea, Republic of); Lee, Byung Chul, E-mail: leebc2001@gmail.com [Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 463-707 (Korea, Republic of); Center for Nanomolecular Imaging and Innovative Drug Development, Advanced Institutes of Convergence Technology, Suwon 443-270 (Korea, Republic of); Kim, Sang Eun [Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 463-707 (Korea, Republic of); Center for Nanomolecular Imaging and Innovative Drug Development, Advanced Institutes of Convergence Technology, Suwon 443-270 (Korea, Republic of); Smart Humanity Convergence Center, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 443-270 (Korea, Republic of)

    2015-08-01

    The KOTRON-13 cyclotron, which was developed in South Korea for the production of medical radioisotopes, has the structural limitation of only one beam-output port, restricting the production of the carbon-11 isotope. In the present study, we investigate the design of a switchable target system and develop an effective carbon-11 target in the KOTRON-13 cyclotron, for combination with the fluorine-18 target. The target system was designed by introducing a sliding-type element between the fluorine-18 and carbon-11 targets, a tailor-made C-11 target and its cooling system. For the efficient production of [{sup 11}C]CO{sub 2}, the desirable target shape and internal volume were determined by a Stopping and Range of Ions in Matter (SRIM) simulation program, and the target grid was modified to resist the cavity pressure during beam irradiation. We evaluated the [{sup 11}C]CO{sub 2} production while varying the material and thickness of the target foil, oxygen content of the nitrogen gas, and target loading pressure. Using sliding-type equipment including an additional gate valve and a high vacuum in a beam line, the bi-directional conversion between the fluorine-18 and carbon-11 targets was efficient regarding the accurate beam irradiation on both targets. The optimal [{sup 11}C]CO{sub 2} production for 30 min irradiation at 60 μA (86.6 ± 1.7 GBq in the target at EOB) was observed at a thickness of 19 μm with HAVAR® material as a target foil and a target loading pressure of 24 bar with nitrogen plus 300 ppb of oxygen gas. Additionally, the coolant cavity system in the target grid and target chamber is useful to remove the heat transferred to the target body by the internal convection of water and thereby ensure the stability of the [{sup 11}C]CO{sub 2} production under a high beam current. In the application of C-11 labeled radiopharmaceuticals such as [{sup 11}C]PIB, [{sup 11}C]DASB, [{sup 11}C]PBR28, [{sup 11}C]Methionine and [{sup 11}C]Clozapine, the radiochemical

  6. An illustrated leaflet containing antiretroviral information targeted for low-literate readers: development and evaluation.

    Science.gov (United States)

    Dowse, Ros; Ramela, Thato; Browne, Sara H

    2011-12-01

    To apply a dual visual/textual modal approach in developing and evaluating a medicine information leaflet with pictograms suitable for low-literate HIV/AIDS patients. To identify and recommend best practices in this type of information design. A simple leaflet incorporating pictograms was designed for an antiretroviral regimen. Cognitive testing for understanding was conducted in 39 low-literate, South African, antiretroviral-naïve adults. Participants were required to locate and explain the information, and were questioned on their opinion of leaflet layout and contents. Average understanding of the leaflet was 60%. Basic medication information was the best understood. An overall lack of knowledge of HIV/AIDS and its core concepts was found. Only half the participants considered this simple leaflet "easy" to read. All endorsed the inclusion of pictograms. This testing method used in ARV-naïve individuals was invaluable in identifying areas needing modification before its use in patients. Text associated with pictograms was more noticeable and better understood, but only if they were closely juxtaposed. Leaflet design should consider culture and literacy skills, be informed by learning theory and design principles, include visuals to enhance appeal and improve understanding, and involve end-users. Verbal counseling should accompany written information. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  7. Use of a bacteriophage lysin to identify a novel target for antimicrobial development.

    Directory of Open Access Journals (Sweden)

    Raymond Schuch

    Full Text Available We identified an essential cell wall biosynthetic enzyme in Bacillus anthracis and an inhibitor thereof to which the organism did not spontaneously evolve measurable resistance. This work is based on the exquisite binding specificity of bacteriophage-encoded cell wall-hydrolytic lysins, which have evolved to recognize critical receptors within the bacterial cell wall. Focusing on the B. anthracis-specific PlyG lysin, we first identified its unique cell wall receptor and cognate biosynthetic pathway. Within this pathway, one biosynthetic enzyme, 2-epimerase, was required for both PlyG receptor expression and bacterial growth. The 2-epimerase was used to design a small-molecule inhibitor, epimerox. Epimerox prevented growth of several Gram-positive pathogens and rescued mice challenged with lethal doses of B. anthracis. Importantly, resistance to epimerox was not detected (<10(-11 frequency in B. anthracis and S. aureus. These results describe the use of phage lysins to identify promising lead molecules with reduced resistance potential for antimicrobial development.

  8. Development and application of a multi-targeting reference plasmid as calibrator for analysis of five genetically modified soybean events.

    Science.gov (United States)

    Pi, Liqun; Li, Xiang; Cao, Yiwei; Wang, Canhua; Pan, Liangwen; Yang, Litao

    2015-04-01

    Reference materials are important in accurate analysis of genetically modified organism (GMO) contents in food/feeds, and development of novel reference plasmid is a new trend in the research of GMO reference materials. Herein, we constructed a novel multi-targeting plasmid, pSOY, which contained seven event-specific sequences of five GM soybeans (MON89788-5', A2704-12-3', A5547-127-3', DP356043-5', DP305423-3', A2704-12-5', and A5547-127-5') and sequence of soybean endogenous reference gene Lectin. We evaluated the specificity, limit of detection and quantification, and applicability of pSOY in both qualitative and quantitative PCR analyses. The limit of detection (LOD) was as low as 20 copies in qualitative PCR, and the limit of quantification (LOQ) in quantitative PCR was 10 copies. In quantitative real-time PCR analysis, the PCR efficiencies of all event-specific and Lectin assays were higher than 90%, and the squared regression coefficients (R(2)) were more than 0.999. The quantification bias varied from 0.21% to 19.29%, and the relative standard deviations were from 1.08% to 9.84% in simulated samples analysis. All the results demonstrated that the developed multi-targeting plasmid, pSOY, was a credible substitute of matrix reference materials, and could be used as a reliable reference calibrator in the identification and quantification of multiple GM soybean events.

  9. Development and Refinement of a Targeted Sexual Risk Reduction Intervention for Women With a History of Childhood Sexual Abuse.

    Science.gov (United States)

    Senn, Theresa E; Braksmajer, Amy; Hutchins, Heidi; Carey, Michael P

    2017-11-01

    Childhood sexual abuse (CSA) is associated with sexual risk behavior in adulthood. Traditional sexual risk reduction interventions do not meet the unique needs of women who have been sexually abused. In the current paper, we describe the four-stage process we followed to develop and refine a targeted sexual risk reduction intervention for this population. First, initial quantitative work revealed that the intervention should address how maladaptive thoughts related to traumatic sexualization, trust, powerlessness, and guilt/shame (traumagenic dynamics constructs) influence current sexual behavior. Second, qualitative interviews with 10 women who reported a history of CSA ( M age = 34 years; 90% African American) as well as current sexual risk behavior provided support for targeting maladaptive thoughts associated with these traumagenic dynamics constructs. Third, based on the qualitative and quantitative results, we developed a 5-session, group-delivered intervention to address the maladaptive thoughts that occurred as a result of CSA, as well as the cognitive-behavioral determinants of sexual risk behavior. This intervention drew heavily on cognitive behavioral techniques to address cognitions associated with CSA and the links between these cognitions and current sexual risk behavior. Techniques from trauma-based therapies, as well as motivational techniques, were also incorporated into the intervention. Finally, we refined the intervention with 24 women ( M age = 33 years; 79% African American), and assessed feasibility and acceptability. These women reported high levels of satisfaction with the intervention. The resultant intervention is currently being evaluated in a small, randomized controlled trial.

  10. Remote sensing data exploiration for geologic characterization of difficult targets : Laboratory Directed Research and Development project 38703 final report.

    Energy Technology Data Exchange (ETDEWEB)

    Costin, Laurence S.; Walker, Charles A.; Lappin, Allen R.; Hayat, Majeed M. (University of New Mexico, Albuquerque, NM); Ford, Bridget K.; Paskaleva, Biliana (University of New Mexico, Albuquerque, NM); Moya, Mary M.; Mercier, Jeffrey Alan (University of Arizona, Tucson, AZ); Stormont, John C. (University of New Mexico, Albuquerque, NM); Smith, Jody Lynn

    2003-09-01

    Characterizing the geology, geotechnical aspects, and rock properties of deep underground facility sites can enhance targeting strategies for both nuclear and conventional weapons. This report describes the results of a study to investigate the utility of remote spectral sensing for augmenting the geological and geotechnical information provided by traditional methods. The project primarily considered novel exploitation methods for space-based sensors, which allow clandestine collection of data from denied sites. The investigation focused on developing and applying novel data analysis methods to estimate geologic and geotechnical characteristics in the vicinity of deep underground facilities. Two such methods, one for measuring thermal rock properties and one for classifying rock types, were explored in detail. Several other data exploitation techniques, developed under other projects, were also examined for their potential utility in geologic characterization.

  11. Formulation development and evaluation of metronidazole magnetic nanosuspension as a magnetic-targeted and polymeric-controlled drug delivery system

    International Nuclear Information System (INIS)

    Latha, Subbiah; Selvamani, Palanisamy; Kumar, Chelladurai Senthil; Sharavanan, Palaniappan; Suganya, Govindan; Beniwal, Vijender Singh; Rao, Poduri Rama

    2009-01-01

    A nanosuspension of magnetically tagged metronidazole was developed by the solvent displacement method coupled with ultrasonication and was evaluated for its physicochemical properties. The drug release from metronidazole magnetic nanosuspension at pH 1.2 and 7.0 shows maximum correlation coefficient for zero order and Higuchi model, respectively. The anthelmintic activity of the formulated metronidazole magnetic nanosuspension was evaluated on Indian earthworms (Pheretima poi). Metronidazole magnetic nanosuspension at a dose of 10 and 50 mg/ml shortened by 31% and 34%, respectively, the mean time to death of the earthworms when compared against a non-magnetic metronidazole suspension. Thus, the developed metronidazole magnetic nanosuspension showed potent, controlled and targeted drug action and might be a good therapeutic avenue in combating infectious GI disorders.

  12. Research and Development of Non-Spectroscopic MEMS-Based Sensor Arrays for Targeted Gas Detection

    Energy Technology Data Exchange (ETDEWEB)

    Loui, A; McCall, S K

    2011-10-24

    The ability to monitor the integrity of gas volumes is of interest to the stockpile surveillance community. Specifically, the leak detection of noble gases, at relevant concentration ranges and distinguished from other chemical species that may be simultaneously present, is particularly challenging. Aside from the laboratory-based method of gas chromatography-mass spectrometry (GC-MS), where samples may be collected by solid-phase microextraction (SPME) or cryofocusing, the other major approaches for gas-phase detection employ lasers typically operating in the mid-infrared wavelength region. While mass spectrometry can readily detect noble gases - the helium leak detector is an obvious example - laser-based methods such as infrared (IR) or Raman spectroscopy are completely insensitive to them as their monatomic nature precludes a non-zero dipole moment or changes in polarizability upon excitation. Therefore, noble gases can only be detected by one of two methods: (1) atomic emission spectroscopies which require the generation of plasmas through laser-induced breakdown, electrical arcing, or similar means; (2) non-spectroscopic methods which measure one or more physical properties (e.g., mass, thermal conductivity, density). In this report, we present our progress during Fiscal Year 2011 (FY11) in the research and development of a non-spectroscopic method for noble gas detection. During Fiscal Year 2010 (FY10), we demonstrated via proof-of-concept experiments that the combination of thermal conductivity detection (TCD) and coating-free damped resonance detection (CFDRD) using micro-electromechanical systems (MEMS) could provide selective sensing of these inert species. Since the MEMS-based TCD technology was directly adapted from a brassboard prototype commissioned by a previous chemical sensing project, FY11 efforts focused on advancing the state of the newer CFDRD method. This work, guided by observations previously reported in the open literature, has not only

  13. Arginyltransferase ATE1 is targeted to the neuronal growth cones and regulates neurite outgrowth during brain development.

    Science.gov (United States)

    Wang, Junling; Pavlyk, Iuliia; Vedula, Pavan; Sterling, Stephanie; Leu, N Adrian; Dong, Dawei W; Kashina, Anna

    2017-10-01

    Arginylation is an emerging protein modification mediated by arginyltransferase ATE1, shown to regulate embryogenesis and actin cytoskeleton, however its functions in different physiological systems are not well understood. Here we analyzed the role of ATE1 in brain development and neuronal growth by producing a conditional mouse knockout with Ate1 deletion in the nervous system driven by Nestin promoter (Nes-Ate1 mice). These mice were weaker than wild type, resulting in low postnatal survival rates, and had abnormalities in the brain that suggested defects in neuronal migration. Cultured Ate1 knockout neurons showed a reduction in the neurite outgrowth and the levels of doublecortin and F-actin in the growth cones. In wild type, ATE1 prominently localized to the growth cones, in addition to the cell bodies. Examination of the Ate1 mRNA sequence reveals the existence of putative zipcode-binding sequences involved in mRNA targeting to the cell periphery and local translation at the growth cones. Fluorescence in situ hybridization showed that Ate1 mRNA localized to the tips of the growth cones, likely due to zipcode-mediated targeting, and this localization coincided with spots of localization of arginylated β-actin, which disappeared in the presence of protein synthesis inhibitors. We propose that zipcode-mediated co-targeting of Ate1 and β-actin mRNA leads to localized co-translational arginylation of β-actin that drives the growth cone migration and neurite outgrowth. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  14. Targeting Pin1 by inhibitor API-1 regulates microRNA biogenesis and suppresses hepatocellular carcinoma development.

    Science.gov (United States)

    Pu, Wenchen; Li, Jiao; Zheng, Yuanyuan; Shen, Xianyan; Fan, Xin; Zhou, Jian-Kang; He, Juan; Deng, Yulan; Liu, Xuesha; Wang, Chun; Yang, Shengyong; Chen, Qiang; Liu, Lunxu; Zhang, Guolin; Wei, Yu-Quan; Peng, Yong

    2018-01-30

    Hepatocellular carcinoma (HCC) is a leading cause of cancer death worldwide, but there are few effective treatments. Aberrant microRNA (miRNA) biogenesis is correlated with HCC development. We previously demonstrated that prolyl isomerase Pin1 participates in miRNA biogenesis and is a potential HCC treatment target. However, how Pin1 modulates miRNA biogenesis remains obscure. Here, we present in vivo evidence that Pin1 overexpression is directly linked to the development of HCC. Administration with Pin1 inhibitor API-1, a novel and specific small molecule targeting Pin1 PPIase domain and inhibiting Pin1 cis-trans isomerizing activity, suppresses in vitro cell proliferation and migration of HCC cells. But API-1-induced Pin1 inhibition is insensitive to HCC cells with low Pin1 expression and/or low XPO5 phosphorylation. Mechanistically, Pin1 recognizes and isomerizes the phosphorylated Serine-Proline (pS-P) motif of pXPO5 and passivates pXPO5. Pin1 inhibition by API-1 maintains the active conformation of pXPO5, restores XPO5-driven precursor miRNA nuclear-to-cytoplasm export, activating anticancer miRNA biogenesis, and leading to both in vitro HCC suppression and HCC suppression in xenograft mice. Experimental evidence suggests Pin1 inhibition by API-1 upregulates miRNA biogenesis via retaining active XPO5 conformation and suppresses HCC development, revealing the mechanism of Pin1-mediated miRNA biogenesis and unequivocally supports API-1 as a novel drug candidate for HCC therapy, especially for Pin1-overexpressing, ERK-activated HCC. This article is protected by copyright. All rights reserved. © 2018 by the American Association for the Study of Liver Diseases.

  15. Developing Performance Cost Index Targets for ASHRAE Standard 90.1 Appendix G – Performance Rating Method - Rev.1

    Energy Technology Data Exchange (ETDEWEB)

    Rosenberg, Michael I. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Hart, Philip R. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States)

    2016-03-01

    Appendix G, the Performance Rating Method in ASHRAE Standard 90.1 has been updated to make two significant changes for the 2016 edition, to be published in October of 2016. First, it allows Appendix G to be used as a third path for compliance with the standard in addition to rating beyond code building performance. This prevents modelers from having to develop separate building models for code compliance and beyond code programs. Using this new version of Appendix G to show compliance with the 2016 edition of the standard, the proposed building design needs to have a performance cost index (PCI) less than targets shown in a new table based on building type and climate zone. The second change is that the baseline design is now fixed at a stable level of performance set approximately equal to the 2004 code. Rather than changing the stringency of the baseline with each subsequent edition of the standard, compliance with new editions will simply require a reduced PCI (a PCI of zero is a net-zero building). Using this approach, buildings of any era can be rated using the same method. The intent is that any building energy code or beyond code program can use this methodology and merely set the appropriate PCI target for their needs. This report discusses the process used to set performance criteria for compliance with ASHRAE Standard 90.1-2016 and suggests a method for demonstrating compliance with other codes and beyond code programs.

  16. Developing Performance Cost Index Targets for ASHRAE Standard 90.1 Appendix G – Performance Rating Method

    Energy Technology Data Exchange (ETDEWEB)

    Rosenberg, Michael I. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Hart, Philip R. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States)

    2016-02-16

    Appendix G, the Performance Rating Method in ASHRAE Standard 90.1 has been updated to make two significant changes for the 2016 edition, to be published in October of 2016. First, it allows Appendix G to be used as a third path for compliance with the standard in addition to rating beyond code building performance. This prevents modelers from having to develop separate building models for code compliance and beyond code programs. Using this new version of Appendix G to show compliance with the 2016 edition of the standard, the proposed building design needs to have a performance cost index (PCI) less than targets shown in a new table based on building type and climate zone. The second change is that the baseline design is now fixed at a stable level of performance set approximately equal to the 2004 code. Rather than changing the stringency of the baseline with each subsequent edition of the standard, compliance with new editions will simply require a reduced PCI (a PCI of zero is a net-zero building). Using this approach, buildings of any era can be rated using the same method. The intent is that any building energy code or beyond code program can use this methodology and merely set the appropriate PCI target for their needs. This report discusses the process used to set performance criteria for compliance with ASHRAE Standard 90.1-2016 and suggests a method for demonstrating compliance with other codes and beyond code programs.

  17. Developing therapeutic 'arrows' with the precision of William Tell: the time has come for targeted therapies in kidney disease.

    Science.gov (United States)

    Mundel, Peter; Greka, Anna

    2015-07-01

    A core mission for modern medicine is the development of precision therapeutics. Cancer therapies have been at the leading edge of this effort, while nephrology has lagged on the path to precision medicine. Breaking the stalemate, recent work revealed CD80 (B7-1) as a candidate for targeted therapy in the treatment of resistant nephrotic syndrome. This review aims to summarize the current state of our understanding of podocyte CD80 biology, its therapeutic implications and the challenges that lie ahead in essential future validation studies. The CD80 targeting agent abatacept (CTLA4-Ig), approved to treat rheumatoid arthritis, was shown to induce remission of nephrotic range proteinuria in four patients with recurrence of disease posttransplant and one patient with primary, treatment resistant nephrotic syndrome. The concept of 'CD80-positive' proteinuric kidney disease due to podocyte CD80 staining in patient kidney biopsies was introduced as a molecular biomarker to define disease and guide treatment. The mechanism of action of CTLA4-Ig in podocytes was shown to centre on β1 integrin activation in a T-cell independent fashion. Subsequent work revealed a putative role for podocyte CD80 in diabetic kidney disease. These studies have direct implications for patient care, and intense interest has focused on validating these findings in upcoming clinical trials.

  18. Dendritic cell immunoreceptor is a new target for anti-AIDS drug development: identification of DCIR/HIV-1 inhibitors.

    Directory of Open Access Journals (Sweden)

    Alexandra A Lambert

    Full Text Available The HIV-1 pandemic continues to expand while no effective vaccine or cure is yet available. Existing therapies have managed to limit mortality and control viral proliferation, but are associated with side effects, do not cure the disease and are subject to development of resistance. Finding new therapeutic targets and drugs is therefore crucial. We have previously shown that the dendritic cell immunoreceptor (DCIR, a C-type lectin receptor expressed on dendritic cells (DCs, acts as an attachment factor for HIV-1 to DCs and contributes to HIV-1 transmission to CD4(+ T lymphocytes (CD4TL. Directly involved in HIV-1 infection, DCIR is expressed in apoptotic or infected CD4TL and promotes trans-infection to bystander cells. Here we report the 3D modelling of the extracellular domain of DCIR. Based on this structure, two surface accessible pockets containing the carbohydrate recognition domain and the EPS binding motif, respectively, were targeted for screening of chemicals that will disrupt normal interaction with HIV-1 particle. Preliminary screening using Raji-CD4-DCIR cells allowed identification of two inhibitors that decreased HIV-1 attachment and propagation. The impact of these inhibitors on infection of DCs and CD4TL was evaluated as well. The results of this study thus identify novel molecules capable of blocking HIV-1 transmission by DCs and CD4TL.

  19. Development of pronuclear injection-based targeted transgenesis in mice through Cre-loxP site-specific recombination.

    Science.gov (United States)

    Ohtsuka, Masato

    2014-01-01

    Microinjection of DNA into the pronuclei of zygotes is the simplest and most widely used method for generating transgenic (Tg) mice. However, it is always associated with random integration of multiple copies of the transgene, resulting in unstable, low, or no transgene expression due to positional effects and/or repeat-induced gene silencing. In addition, random integration sometimes disrupts an endogenous gene that can affect the phenotypes of Tg mice. Our recently developed pronuclear injection-based targeted transgenesis (PITT) method enables the integration of a single-copy transgene into a predetermined genomic locus through Cre-loxP site-specific recombination. The PITT method enables stable and reliable transgene expression in Tg mice and is also applicable for generating knockdown mice. Therefore, the PITT method could represent next-generation transgenesis that overcomes the pitfalls of conventional transgenesis.

  20. [Aging and homeostasis. Development of novel AdipoR-targeted drugs with exercise-mimicking and anti-aging properties.

    Science.gov (United States)

    Okada-Iwabu, Miki; Yamauchi, Toshimasa; Iwabu, Masato; Kadowaki, Takashi

    We have so far clarified that adiponectin, an adipocyte-secreted physiologically active substance, is decreased with the onset of obesity and that lifestyle-related diseases are primarily accounted for by the systemically decreased action of adiponectin/adiponectin receptors(AdipoRs). The activation of adiponectin/AdipoR has caloric restrictive and exercise-mimicking effects thus prolonging lifespan. We were the first in the world to succeed in identifying small-molecule compounds that serve as seed compounds for candidate AdipoR-activating drugs. Moreover, we have also reported the crystal structures of AdipoRs. It is hoped that these milestones will accelerate our efforts at AdipoR structure-based drug discovery leading to the development of novel AdipoR-targeted anti-diabetic drugs with promising life-prolonging properties.

  1. Development of a personalized dosimetric tool for radiation protection in case of internal contamination and targeted radiotherapy in nuclear medicine

    International Nuclear Information System (INIS)

    Chiavassa, S.

    2005-12-01

    Current internal dosimetric estimations are based on the M.I.R.D. formalism and used standard mathematical models. These standard models are often far from a given patient morphology and do not allow to perform patient-specific dosimetry. The aim of this study was to develop a personalized dosimetric tool, which takes into account real patient morphology, composition and densities. This tool, called O.E.D.I.P.E., a French acronym of Tool for the Evaluation of Personalized Internal Dose, is a user-friendly graphical interface. O.E.D.I.P.E. allows to create voxel-based patient-specific geometries and associates them with the M.C.N.P.X. Monte Carlo code. Radionuclide distribution and absorbed dose calculation can be performed at the organ and voxel scale. O.E.D.I.P.E. can be used in nuclear medicine for targeted radiotherapy and in radiation protection in case of internal contamination. (author)

  2. Rational development of 4-aminopyridyl-based inhibitors targeting Trypanosoma cruzi CYP51 as anti-chagas agents.

    Science.gov (United States)

    Choi, Jun Yong; Calvet, Claudia M; Gunatilleke, Shamila S; Ruiz, Claudia; Cameron, Michael D; McKerrow, James H; Podust, Larissa M; Roush, William R

    2013-10-10

    A new series of 4-aminopyridyl-based lead inhibitors targeting Trypanosoma cruzi CYP51 (TcCYP51) has been developed using structure-based drug design as well as structure-property relationship (SPR) analyses. The screening hit starting point, LP10 (KD ≤ 42 nM; EC50 = 0.65 μM), has been optimized to give the potential leads 14t, 27i, 27q, 27r, and 27t, which have low-nanomolar binding affinity to TcCYP51 and significant activity against T. cruzi amastigotes cultured in human myoblasts (EC50 = 14-18 nM for 27i and 27r). Many of the optimized compounds have improved microsome stability, and most are selective against human CYPs 1A2, 2D6, and 3A4 (Trypanosoma brucei CYP51 (TbCYP51) orthologue has been characterized by X-ray structure analysis.

  3. Development and Implementation of New Control Law for Vision Based Target Tracking System Onboard Small Unmanned Aerial Vehicles

    National Research Council Canada - National Science Library

    Chong, Tay B

    2006-01-01

    ...) system onboard a small unmanned aerial vehicle (SUAV). The new control law allows for coordinated SUAV guidance and vision-based target tracking of stationary and moving targets in the presence of atmospheric disturbances and measurements noise...

  4. CTD² Dashboard: a searchable web interface to connect validated results from the Cancer Target Discovery and Development Network* | Office of Cancer Genomics

    Science.gov (United States)

    The Cancer Target Discovery and Development (CTD2) Network aims to use functional genomics to accelerate the translation of high-throughput and high-content genomic and small-molecule data towards use in precision oncology.

  5. Development and Characterization of a Camelid Single Domain Antibody-Urease Conjugate That Targets Vascular Endothelial Growth Factor Receptor 2.

    Science.gov (United States)

    Tian, Baomin; Wong, Wah Yau; Uger, Marni D; Wisniewski, Pawel; Chao, Heman

    2017-01-01

    Angiogenesis is the process of new blood vessel formation and is essential for a tumor to grow beyond a certain size. Tumors secrete the pro-angiogenic factor vascular endothelial growth factor, which acts upon local endothelial cells by binding to vascular endothelial growth factor receptors (VEGFRs). In this study, we describe the development and characterization of V21-DOS47, an immunoconjugate that targets VEGFR2. V21-DOS47 is composed of a camelid single domain anti-VEGFR2 antibody (V21) and the enzyme urease. The conjugate specifically binds to VEGFR2 and urease converts endogenous urea into ammonia, which is toxic to tumor cells. Previously, we developed a similar antibody-urease conjugate, L-DOS47, which is currently in clinical trials for non-small cell lung cancer. Although V21-DOS47 was designed from parameters learned from the generation of L-DOS47, additional optimization was required to produce V21-DOS47. In this study, we describe the expression and purification of two versions of the V21 antibody: V21H1 and V21H4. Each was conjugated to urease using a different chemical cross-linker. The conjugates were characterized by a panel of analytical techniques, including SDS-PAGE, size exclusion chromatography, Western blotting, and LC-MS E peptide mapping. Binding characteristics were determined by ELISA and flow cytometry assays. To improve the stability of the conjugates at physiologic pH, the pIs of the V21 antibodies were adjusted by adding several amino acid residues to the C-terminus. For V21H4, a terminal cysteine was also added for use in the conjugation chemistry. The modified V21 antibodies were expressed in the E. coli BL21 (DE3) pT7 system. V21H1 was conjugated to urease using the heterobifunctional cross-linker succinimidyl-[( N -maleimidopropionamido)-diethyleneglycol] ester (SM(PEG) 2 ), which targets lysine resides in the antibody. V21H4 was conjugated to urease using the homobifunctional cross-linker, 1,8-bis(maleimido)diethylene glycol

  6. Development and Characterization of a Camelid Single Domain Antibody–Urease Conjugate That Targets Vascular Endothelial Growth Factor Receptor 2

    Directory of Open Access Journals (Sweden)

    Baomin Tian

    2017-08-01

    Full Text Available Angiogenesis is the process of new blood vessel formation and is essential for a tumor to grow beyond a certain size. Tumors secrete the pro-angiogenic factor vascular endothelial growth factor, which acts upon local endothelial cells by binding to vascular endothelial growth factor receptors (VEGFRs. In this study, we describe the development and characterization of V21-DOS47, an immunoconjugate that targets VEGFR2. V21-DOS47 is composed of a camelid single domain anti-VEGFR2 antibody (V21 and the enzyme urease. The conjugate specifically binds to VEGFR2 and urease converts endogenous urea into ammonia, which is toxic to tumor cells. Previously, we developed a similar antibody–urease conjugate, L-DOS47, which is currently in clinical trials for non-small cell lung cancer. Although V21-DOS47 was designed from parameters learned from the generation of L-DOS47, additional optimization was required to produce V21-DOS47. In this study, we describe the expression and purification of two versions of the V21 antibody: V21H1 and V21H4. Each was conjugated to urease using a different chemical cross-linker. The conjugates were characterized by a panel of analytical techniques, including SDS-PAGE, size exclusion chromatography, Western blotting, and LC-MSE peptide mapping. Binding characteristics were determined by ELISA and flow cytometry assays. To improve the stability of the conjugates at physiologic pH, the pIs of the V21 antibodies were adjusted by adding several amino acid residues to the C-terminus. For V21H4, a terminal cysteine was also added for use in the conjugation chemistry. The modified V21 antibodies were expressed in the E. coli BL21 (DE3 pT7 system. V21H1 was conjugated to urease using the heterobifunctional cross-linker succinimidyl-[(N-maleimidopropionamido-diethyleneglycol] ester (SM(PEG2, which targets lysine resides in the antibody. V21H4 was conjugated to urease using the homobifunctional cross-linker, 1,8-bis

  7. Obesity Prevention from Conception: A Workshop to Guide the Development of a Pan-Canadian Trial Targeting the Gestational Period

    Science.gov (United States)

    Adamo, Kristi B; Shen, Garry X; Mottola, Michelle; Nascimento, Simony; Jean-Philippe, Sonia; Ferraro, Zachary M; Nerenberg, Kara; Smith, Graeme; Chari, Radha; Gaudet, Laura; Piccinini-Vallis, Helena; McDonald, Sarah; Atkinson, Stephanie; Godbout, Ariane; Robitaille, Julie; Davidge, Sandra T; Gruslin, Andrée; Prud’homme, Denis; Stacey, Dawn; Rossiter, Melissa; Goldfield, Gary S; Dodd, Jodie

    2014-01-01

    This report summarizes a meeting, Obesity Prevention from Conception, held in Ottawa in 2012. This planning workshop was funded by the Canadian Institutes of Health Research (CIHR) to bring together researchers with expertise in the area of maternal obesity (OB) and weight gain in pregnancy and pregnancy-related disease to attend a one-day workshop and symposium to discuss the development of a cross-Canada lifestyle intervention trial for targeting pregnant women. This future intervention will aim to reduce downstream OB in children through encouraging appropriate weight gain during the mother’s pregnancy. The workshop served to (i) inform the development of a lifestyle intervention for women with a high pre-pregnancy body mass index (BMI), (ii) identify site investigators across Canada, and (iii) guide the development of a grant proposal focusing on the health of mom and baby. A brief summary of the presentations as well as the focus groups is presented for use in planning future research.

  8. Obesity Prevention from Conception: A Workshop to Guide the Development of a Pan-Canadian Trial Targeting the Gestational Period

    Directory of Open Access Journals (Sweden)

    Kristi B. Adamo

    2014-01-01

    Full Text Available This report summarizes a meeting, Obesity Prevention from Conception , held in Ottawa in 2012. This planning workshop was funded by the Canadian Institutes of Health Research (CIHR to bring together researchers with expertise in the area of maternal obesity (OB and weight gain in pregnancy and pregnancy-related disease to attend a one-day workshop and symposium to discuss the development of a cross-Canada lifestyle intervention trial for targeting pregnant women. This future intervention will aim to reduce downstream OB in children through encouraging appropriate weight gain during the mother's pregnancy. The workshop served to (i inform the development of a lifestyle intervention for women with a high pre-pregnancy body mass index (BMI, (ii identify site investigators across Canada, and (iii guide the development of a grant proposal focusing on the health of mom and baby. A brief summary of the presentations as well as the focus groups is presented for use in planning future research.

  9. Development and Evaluation of Amphotericin B Loaded Iron Oxide Nanoparticles for Targeted Drug Delivery to Systemic Fungal Infections

    Science.gov (United States)

    Balabathula, Pavan

    A targeted nanotheronostic drug delivery system to diagnose and treat life threatening invasive fungal infections (IFIs) such as cryptococcal meningitis was designed, developed, characterized, and evaluated. To address the development processes, first, iron oxide nanoparticles (IONP) (34-40 nm) coated with bovine serum albumin (BSA), loaded and targeted with amphotericin B (AMB) (AMB-IONP) was formulated by applying a layer by layer approach. Several designs (A, B, C, D, & E) of AMB-IONP were developed and their physicochemical properties such as drug loading with HPLC method, particle size, poly dispersity index (PDI), and zeta-potential using dynamic light scattering (DLS) technique, morphology with transmission electronic microscopy (TEM), and in vitro drug release profile with dialysis method were evaluated. Second, uptake (with fluorescence microscopy and flow cytometry) and killing efficacy (with susceptibility testing) of AMB-IONP in fungal clinical isolates of Candida species were evaluated and compared with standard drug AMB deoxycholate (AMB-D) data. Third, the cellular uptake mechanisms with endocytosis inhibitors and intracellular trafficking using TEM for design D were evaluated in selected isolates. Fourth, a stable lyophilized AMB-IONP formulation was developed and was suitable for clinical trials. A validated isocratic HPLC method was developed and validated for the quantitative determination of AMB. Design D was determined to be the lead formulation with drug loading of 13.6+/-6.9 of AMB/mg of IONP. The size, zeta-potential, and PDI for all formulation designs were found to be in an optimum range for a nanomedicine with ≤36 nm, ˜ -20 mV, and ≤0.2, respectively. The TEM images confirmed that the nanoparticles were monodispersed and spherical in shape. The drug release profile indicated a burst release up to 3 hours for designs A and B, followed by a sustained drug release profile up to 72 hours. Designs C and D (with and without glutaraldehyde

  10. Analytical models for development of high performance metal targets irradiated in IPEN-CNEN/SP Cyclone 30 and Cyclone 18 cyclotrons

    International Nuclear Information System (INIS)

    Oliveira, Henrique Barcellos de

    2009-01-01

    Analytical models were developed that describe the basic elements for metal targets irradiation in cyclotrons. Important parameters such as maximum beam current value and thermal power deposited on target were obtained and compared with practical situations. In an unprecedented way, were determined analytically the features found in intense thermal transient situations, when high protons concentrations in a small region of the beam cause intense temperature gradients in small regions of the target. Comparing with results found in the literature showed that the developed models are satisfactory, in view of all limitations of the proposed model. (author)

  11. Identification of evolutionarily conserved exons as regulated targets for the splicing activator tra2β in development.

    Directory of Open Access Journals (Sweden)

    Sushma Grellscheid

    2011-12-01

    Full Text Available Alternative splicing amplifies the information content of the genome, creating multiple mRNA isoforms from single genes. The evolutionarily conserved splicing activator Tra2β (Sfrs10 is essential for mouse embryogenesis and implicated in spermatogenesis. Here we find that Tra2β is up-regulated as the mitotic stem cell containing population of male germ cells differentiate into meiotic and post-meiotic cells. Using CLIP coupled to deep sequencing, we found that Tra2β binds a high frequency of exons and identified specific G/A rich motifs as frequent targets. Significantly, for the first time we have analysed the splicing effect of Sfrs10 depletion in vivo by generating a conditional neuronal-specific Sfrs10 knock-out mouse (Sfrs10(fl/fl; Nestin-Cre(tg/+. This mouse has defects in brain development and allowed correlation of genuine physiologically Tra2β regulated exons. These belonged to a novel class which were longer than average size and importantly needed multiple cooperative Tra2β binding sites for efficient splicing activation, thus explaining the observed splicing defects in the knockout mice. Regulated exons included a cassette exon which produces a meiotic isoform of the Nasp histone chaperone that helps monitor DNA double-strand breaks. We also found a previously uncharacterised poison exon identifying a new pathway of feedback control between vertebrate Tra2 proteins. Both Nasp-T and the Tra2a poison exon are evolutionarily conserved, suggesting they might control fundamental developmental processes. Tra2β protein isoforms lacking the RRM were able to activate specific target exons indicating an additional functional role as a splicing co-activator. Significantly the N-terminal RS1 domain conserved between flies and humans was essential for the splicing activator function of Tra2β. Versions of Tra2β lacking this N-terminal RS1 domain potently repressed the same target exons activated by full-length Tra2β protein.

  12. Target post-evaluation of China's “12th Five-Year” oil and gas exploration and development planning and its “13th Five-Year” target prediction

    Directory of Open Access Journals (Sweden)

    Jiping Pan

    2016-03-01

    Full Text Available In the turn of 12th and 13th “Five-Year Plan” of China, the global oil and gas market changes greatly. In this regard, the target post-evaluation of the “12th Five-Year” oil and gas exploration and development planning was conducted, which is of significant importance to scientifically and reasonably making the specific “13th Five-Year” oil and gas exploration and development target planning. The post-evaluation results indicate that, in the period of “12th Five-Year Plan”, the oil and gas exploration and development targets of China were satisfactorily completed, but some deficiencies still existed. For example, the target of oil production (2 × 108 t was overfulfilled, while the target of oil reserves (65 × 108 t remained 6.4% outstanding. The target of gas reserves (3.5 × 1012 m3 was overfulfilled, while the target of gas production (1385 × 108 m3 remained 6.2% outstanding. Moreover, the targets of unconventional gases were not satisfactorily completed-shale gas being better than coalbed methane (CBM. Failures to fulfill some targets in “12th Five-Year Plan” were primarily attributed to the slowdown of oil and gas consumption growth, sharp drop of oil price, downgrading of resources, and changes of statistic basis under the new normal. The forecast results suggest that, in the period of “13th Five-Year Plan”, given USD50–70/bbl of world oil price, China's annual average incremental conventional oil and gas in place will be 10.0 × 108–12.0 × 108 t and 6000 × 108–8000 × 108 m3 respectively, annual average incremental shale gas and CBM in place will be 1000 × 108–2000 × 108 m3 and 500 × 108–1000 × 108 m3 respectively, and annual oil production will be about 2.0 × 108 t. By 2020, China's annual gas production will approach 1800 × 108–2000 × 108 m3 (shale gas: 200 × 108 m3, and CBM: 150 × 108 m3.

  13. Developing a multi-pollutant conceptual framework for the selection and targeting of interventions in water industry catchment management schemes.

    Science.gov (United States)

    Bloodworth, J W; Holman, I P; Burgess, P J; Gillman, S; Frogbrook, Z; Brown, P

    2015-09-15

    In recent years water companies have started to adopt catchment management to reduce diffuse pollution in drinking water supply areas. The heterogeneity of catchments and the range of pollutants that must be removed to meet the EU Drinking Water Directive (98/83/EC) limits make it difficult to prioritise areas of a catchment for intervention. Thus conceptual frameworks are required that can disaggregate the components of pollutant risk and help water companies make decisions about where to target interventions in their catchments to maximum effect. This paper demonstrates the concept of generalising pollutants in the same framework by reviewing key pollutant processes within a source-mobilisation-delivery context. From this, criteria are developed (with input from water industry professionals involved in catchment management) which highlights the need for a new water industry specific conceptual framework. The new CaRPoW (Catchment Risk to Potable Water) framework uses the Source-Mobilisation-Delivery concept as modular components of risk that work at two scales, source and mobilisation at the field scale and delivery at the catchment scale. Disaggregating pollutant processes permits the main components of risk to be ascertained so that appropriate interventions can be selected. The generic structure also allows for the outputs from different pollutants to be compared so that potential multiple benefits can be identified. CaRPow provides a transferable framework that can be used by water companies to cost-effectively target interventions under current conditions or under scenarios of land use or climate change. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  14. A novel humanized mouse model of Huntington disease for preclinical development of therapeutics targeting mutant huntingtin alleles.

    Science.gov (United States)

    Southwell, Amber L; Skotte, Niels H; Villanueva, Erika B; Østergaard, Michael E; Gu, Xiaofeng; Kordasiewicz, Holly B; Kay, Chris; Cheung, Daphne; Xie, Yuanyun; Waltl, Sabine; Dal Cengio, Louisa; Findlay-Black, Hailey; Doty, Crystal N; Petoukhov, Eugenia; Iworima, Diepiriye; Slama, Ramy; Ooi, Jolene; Pouladi, Mahmoud A; Yang, X William; Swayze, Eric E; Seth, Punit P; Hayden, Michael R

    2017-03-15

    Huntington disease (HD) is a neurodegenerative disease caused by a mutation in the huntingtin (HTT) gene. HTT is a large protein, interacts with many partners and is involved in many cellular pathways, which are perturbed in HD. Therapies targeting HTT directly are likely to provide the most global benefit. Thus there is a need for preclinical models of HD recapitulating human HTT genetics. We previously generated a humanized mouse model of HD, Hu97/18, by intercrossing BACHD and YAC18 mice with knockout of the endogenous mouse HD homolog (Hdh). Hu97/18 mice recapitulate the genetics of HD, having two full-length, genomic human HTT transgenes heterozygous for the HD mutation and polymorphisms associated with HD in populations of Caucasian descent. We have now generated a companion model, Hu128/21, by intercrossing YAC128 and BAC21 mice on the Hdh-/- background. Hu128/21 mice have two full-length, genomic human HTT transgenes heterozygous for the HD mutation and polymorphisms associated with HD in populations of East Asian descent and in a minority of patients from other ethnic groups. Hu128/21 mice display a wide variety of HD-like phenotypes that are similar to YAC128 mice. Additionally, both transgenes in Hu128/21 mice match the human HTT exon 1 reference sequence. Conversely, the BACHD transgene carries a floxed, synthetic exon 1 sequence. Hu128/21 mice will be useful for investigations of human HTT that cannot be addressed in Hu97/18 mice, for developing therapies targeted to exon 1, and for preclinical screening of personalized HTT lowering therapies in HD patients of East Asian descent. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  15. Composite Sequence-Structure Stability Models as Screening Tools for Identifying Vulnerable Targets for HIV Drug and Vaccine Development.

    Science.gov (United States)

    Manocheewa, Siriphan; Mittler, John E; Samudrala, Ram; Mullins, James I

    2015-11-04

    Rapid evolution and high sequence diversity enable Human Immunodeficiency Virus (HIV) populations to acquire mutations to escape antiretroviral drugs and host immune responses, and thus are major obstacles for the control of the pandemic. One strategy to overcome this problem is to focus drugs and vaccines on regions of the viral genome in which mutations are likely to cripple function through destabilization of viral proteins. Studies relying on sequence conservation alone have had only limited success in determining critically important regions. We tested the ability of two structure-based computational models to assign sites in the HIV-1 capsid protein (CA) that would be refractory to mutational change. The destabilizing mutations predicted by these models were rarely found in a database of 5811 HIV-1 CA coding sequences, with none being present at a frequency greater than 2%. Furthermore, 90% of variants with the low predicted stability (from a set of 184 CA variants whose replication fitness or infectivity has been studied in vitro) had aberrant capsid structures and reduced viral infectivity. Based on the predicted stability, we identified 45 CA sites prone to destabilizing mutations. More than half of these sites are targets of one or more known CA inhibitors. The CA regions enriched with these sites also overlap with peptides shown to induce cellular immune responses associated with lower viral loads in infected individuals. Lastly, a joint scoring metric that takes into account both sequence conservation and protein structure stability performed better at identifying deleterious mutations than sequence conservation or structure stability information alone. The computational sequence-structure stability approach proposed here might therefore be useful for identifying immutable sites in a protein for experimental validation as potential targets for drug and vaccine development.

  16. Histamine Promotes the Development of Monocyte-Derived Dendritic Cells and Reduces Tumor Growth by Targeting the Myeloid NADPH Oxidase

    Science.gov (United States)

    Wiktorin, Hanna G.; Lenox, Brianna; Ewald Sander, Frida; Aydin, Ebru; Aurelius, Johan; Thorén, Fredrik B.; Ståhlberg, Anders; Hermodsson, Svante; Hellstrand, Kristoffer

    2015-01-01

    The efficiency of immune-mediated clearance of cancer cells is hampered by immunosuppressive mediators in the malignant microenvironment, including NADPH oxidase–derived reactive oxygen species. We aimed at defining the effects of histamine, an inhibitor of the myeloid NADPH oxidase/NOX2, on the development of Ag-presenting dendritic cells (DCs) from myeloid precursors and the impact of these mechanisms for tumor growth. Histamine was found to promote the maturation of human DCs from monocytes by increasing the expression of HLA-DR and costimulatory molecules, which resulted in improved induction of Th cells with Th0 polarity. Experiments using wild-type and NOX2-deficient myelomonoblastic cells showed that histamine facilitated myeloid cell maturation only in cells capable of generating reactive oxygen species. Treatment of mice with histamine reduced the growth of murine EL-4 lymphomas in parallel with an increment of tumor-infiltrating DCs in NOX2-sufficient mice but not in NOX2-deficient (gp91phox−/−) mice. We propose that strategies to target the myeloid NADPH oxidase may facilitate the development of endogenous DCs in cancer. PMID:25870245

  17. Inhibition of protein synthesis and malaria parasite development by drug targeting of methionyl-tRNA synthetases.

    Science.gov (United States)

    Hussain, Tahir; Yogavel, Manickam; Sharma, Amit

    2015-04-01

    Aminoacyl-tRNA synthetases (aaRSs) are housekeeping enzymes that couple cognate tRNAs with amino acids to transmit genomic information for protein translation. The Plasmodium falciparum nuclear genome encodes two P. falciparum methionyl-tRNA synthetases (PfMRS), termed PfMRS(cyt) and PfMRS(api). Phylogenetic analyses revealed that the two proteins are of primitive origin and are related to heterokonts (PfMRS(cyt)) or proteobacteria/primitive bacteria (PfMRS(api)). We show that PfMRS(cyt) localizes in parasite cytoplasm, while PfMRS(api) localizes to apicoplasts in asexual stages of malaria parasites. Two known bacterial MRS inhibitors, REP3123 and REP8839, hampered Plasmodium growth very effectively in the early and late stages of parasite development. Small-molecule drug-like libraries were screened against modeled PfMRS structures, and several "hit" compounds showed significant effects on parasite growth. We then tested the effects of the hit compounds on protein translation by labeling nascent proteins with (35)S-labeled cysteine and methionine. Three of the tested compounds reduced protein synthesis and also blocked parasite growth progression from the ring stage to the trophozoite stage. Drug docking studies suggested distinct modes of binding for the three compounds, compared with the enzyme product methionyl adenylate. Therefore, this study provides new targets (PfMRSs) and hit compounds that can be explored for development as antimalarial drugs. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  18. Control of neurotransmission, behaviour and development, by photo-dynamic manipulation of tissue redox state of brain targets.

    Science.gov (United States)

    Kataoka, Y; Morii, H; Imamura, K; Cui, Y; Kobayashi, M; Watanabe, Y

    2000-12-01

    Reversible manipulation of local neurotransmission in brain areas, using controlled spatial and temporal resolution, is one of the powerful techniques used to investigate integrative aspects of brain function. We have developed a novel technique for rapidly inactivating local synaptic transmission, from outside the brain, within seconds or minutes via oxidation of target tissue using a photosensitive dye followed by photoirradiation (photo-dynamic tissue oxidation; PDTO). PDTO applied through a defined slit, sharply suppressed excitatory synaptic transmission in rat hippocampal slices and also suppressed in vivo hippocampal neurotransmission reversibly. Furthermore, we manipulated the voluntary movement of gerbils in free-field activity by application of PDTO to the striatum. Also, in freely moving kittens, the development of the visual cortex was manipulated by long-lasting application of PDTO to the eye. Thus, PDTO enables external manipulation of in vivo or in vitro neurotransmission in various clearly defined regions on the submillimeter scale. Suppression of neurotransmission occurred only within the photo-oxidized area which can be histochemically visualized.

  19. Small Molecules from Nature Targeting G-Protein Coupled Cannabinoid Receptors: Potential Leads for Drug Discovery and Development

    Directory of Open Access Journals (Sweden)

    Charu Sharma

    2015-01-01

    Full Text Available The cannabinoid molecules are derived from Cannabis sativa plant which acts on the cannabinoid receptors types 1 and 2 (CB1 and CB2 which have been explored as potential therapeutic targets for drug discovery and development. Currently, there are numerous cannabinoid based synthetic drugs used in clinical practice like the popular ones such as nabilone, dronabinol, and Δ9-tetrahydrocannabinol mediates its action through CB1/CB2 receptors. However, these synthetic based Cannabis derived compounds are known to exert adverse psychiatric effect and have also been exploited for drug abuse. This encourages us to find out an alternative and safe drug with the least psychiatric adverse effects. In recent years, many phytocannabinoids have been isolated from plants other than Cannabis. Several studies have shown that these phytocannabinoids show affinity, potency, selectivity, and efficacy towards cannabinoid receptors and inhibit endocannabinoid metabolizing enzymes, thus reducing hyperactivity of endocannabinoid systems. Also, these naturally derived molecules possess the least adverse effects opposed to the synthetically derived cannabinoids. Therefore, the plant based cannabinoid molecules proved to be promising and emerging therapeutic alternative. The present review provides an overview of therapeutic potential of ligands and plants modulating cannabinoid receptors that may be of interest to pharmaceutical industry in search of new and safer drug discovery and development for future therapeutics.

  20. An interactive, bilingual, culturally targeted website about living kidney donation and transplantation for hispanics: development and formative evaluation.

    Science.gov (United States)

    Gordon, Elisa J; Feinglass, Joe; Carney, Paula; Ramirez, Daney; Olivero, Maria; O'Connor, Kate; MacLean, Jessica; Brucker, James; Caicedo, Juan Carlos

    2015-04-20

    As the kidney shortage continues to grow, patients on the waitlist are increasingly turning to live kidney donors for transplantation. Despite having a disproportionately higher prevalence of end-stage kidney disease (ESKD), fewer waitlisted Hispanic patients received living donor kidney transplants (LDKTs) than non-Hispanic whites in 2014. Although lack of knowledge has been identified as a barrier to living kidney donation (LKD) among Hispanics, little is known about information needs, and few bilingual educational resources provide transplant-related information addressing Hispanics' specific concerns. This paper describes the process of developing a bilingual website targeted to the Hispanic community. The website was designed to increase knowledge about LKD among Hispanic patients with ESKD, their families, and the public, and was inspired by educational sessions targeted to Hispanic transplant patients provided by Northwestern University's Hispanic Kidney Transplant Program. Northwestern faculty partnered with the National Kidney Foundation of Illinois for expertise in ESKD and Hispanic community partners across the Chicago area. We established a Community Advisory Board (CAB) of 10 Chicago-area Hispanic community leaders to provide insight into cultural concerns and community and patients' needs. Website content development was informed by 9 focus groups with 76 adult Hispanic kidney transplant recipients, living kidney donors, dialysis patients, and the general Hispanic public. The website development effort was guided by community input on images, telenovela scripts, and messages. After initial development, formal usability testing was conducted with 18 adult Hispanic kidney transplant recipients, dialysis patients, and living kidney donors to identify ways to improve navigability, design, content, comprehension, and cultural sensitivity. Usability testing revealed consistently high ratings as "easy to navigate", "informative", and "culturally appropriate

  1. Development of beryllium-based neutron target system with three-layer structure for accelerator-based neutron source for boron neutron capture therapy.

    Science.gov (United States)

    Kumada, Hiroaki; Kurihara, Toshikazu; Yoshioka, Masakazu; Kobayashi, Hitoshi; Matsumoto, Hiroshi; Sugano, Tomei; Sakurai, Hideyuki; Sakae, Takeji; Matsumura, Akira

    2015-12-01

    The iBNCT project team with University of Tsukuba is developing an accelerator-based neutron source. Regarding neutron target material, our project has applied beryllium. To deal with large heat load and blistering of the target system, we developed a three-layer structure for the target system that includes a blistering mitigation material between the beryllium used as the neutron generator and the copper heat sink. The three materials were bonded through diffusion bonding using a hot isostatic pressing method. Based on several verifications, our project chose palladium as the intermediate layer. A prototype of the neutron target system was produced. We will verify that sufficient neutrons for BNCT treatment are generated by the device in the near future. Copyright © 2015 Elsevier Ltd. All rights reserved.

  2. Development of real-time assays for impedance-based detection of microbial double-stranded DNA targets: optimization and data analysis.

    Science.gov (United States)

    Ghindilis, Andrei L; Smith, Maria W; Messing, Dean S; Haynes, Vena N; Middleton, George B; Schwarzkopf, Kevin R; Campbell, Carmen E; Zhan, Changqing; Ulrich, Bruce; Frasier, Michael J; Schuele, Paul J; Evans, David R; Sezan, Ibrahim; Hartzell, John W; Simon, Holly M

    2012-05-15

    A real-time, label free assay was developed for microbial detection, utilizing double-stranded DNA targets and employing the next generation of an impedimetric sensor array platform designed by Sharp Laboratories of America (SLA). Real-time curves of the impedimetric signal response were obtained at fixed frequency and voltage for target binding to oligonucleotide probes attached to the sensor array surface. Kinetic parameters of these curves were analyzed by the integrated data analysis package for signal quantification. Non-specific binding presented a major challenge for assay development, and required assay optimization. For this, differences were maximized between binding curve kinetic parameters for probes binding to complementary targets versus non-target controls. Variables manipulated for assay optimization included target concentration, hybridization temperature, buffer concentration, and the use of surfactants. Our results showed that (i) different target-probe combinations required optimization of specific sets of variables; (ii) for each assay condition, the optimum range was relatively narrow, and had to be determined empirically; and (iii) outside of the optimum range, the assay could not distinguish between specific and non-specific binding. For each target-probe combination evaluated, conditions resulting in good separation between specific and non-specific binding signals were established, generating high confidence in the SLA impedimetric dsDNA assay results. Copyright © 2012 Elsevier B.V. All rights reserved.

  3. Recent advances in the development of 1,8-naphthalimide based DNA targeting binders, anticancer and fluorescent cellular imaging agents.

    Science.gov (United States)

    Banerjee, Swagata; Veale, Emma B; Phelan, Caroline M; Murphy, Samantha A; Tocci, Gillian M; Gillespie, Lisa J; Frimannsson, Daniel O; Kelly, John M; Gunnlaugsson, Thorfinnur

    2013-02-21

    The development of functional 1,8-naphthalimide derivatives as DNA targeting, anticancer and cellular imaging agents is a fast growing area and has resulted in several such derivatives entering into clinical trials. This review gives an overview of the many discoveries and the progression of the use of 1,8-naphthalimides as such agents and their applications to date; focusing mainly on mono-, bis-naphthalimide based structures, and their various derivatives (e.g. amines, polyamine conjugates, heterocyclic, oligonucleotide and peptide based, and those based on metal complexes). Their cytotoxicity, mode of action and cell-selectivity are discussed and compared. The rich photophysical properties of the naphthalimides (which are highly dependent on the nature and the substitution pattern of the aryl ring) make them prime candidates as probes as the changes in spectroscopic properties such as absorption, dichroism, and fluorescence can all be used to monitor their binding to biomolecules. This also makes them useful species for monitoring their uptake and location within cells without the use of co-staining. The photochemical properties of the compounds have also been exploited, for example, for photocleavage of nucleic acids and for the destruction of tumour cells.

  4. Intracellular distribution of the vitamin D receptor in the brain: comparison with classic target tissues and redistribution with development.

    Science.gov (United States)

    Eyles, D W; Liu, P Y; Josh, P; Cui, X

    2014-05-30

    Apart from its role in regulating calcium there is growing evidence that vitamin D is a neuroactive steroid capable of regulating multiple pathways important for both brain development and mature brain function. Vitamin D induces its genomic effects through its nuclear receptor the vitamin D receptor (VDR). Although there is abundant evidence for this receptor's presence in the mammalian brain from studies employing immunohistochemistry, Western blot or quantitative RNA studies there remains some dispute regarding the validity of these studies. In this study we provide unambiguous confirmation for the VDR in adult rodent brain using proteomic techniques. However Western blot experiments show that compared to more classic target organs such as the gut and kidney, VDR expression is quantitatively lower in the brain. In addition we have examined VDR subcellular distribution in the gut, kidney and brain from both embryonic and adult tissues. We show that in all embryonic tissues VDR distribution is mostly nuclear, however by adulthood it appears that at least in the gut and kidney, VDR presence in the plasma membrane is more prominent perhaps reflecting some change in VDR function with the maturation of these tissues. Finally the subcellular distribution of VDR in the embryo did not appear to be altered by vitamin D deficiency indicating that perhaps there are other mechanisms at play in vivo to stabilize this receptor in the absence of its ligand. Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.

  5. Structural analysis of Clostridium botulinum neurotoxin type D as a platform for the development of targeted secretion inhibitors.

    Science.gov (United States)

    Masuyer, Geoffrey; Davies, Jonathan R; Moore, Kevin; Chaddock, John A; Ravi Acharya, K

    2015-09-01

    The botulinum neurotoxin type D is one of seven highly potent toxins produced by Clostridium botulinum which inhibit neurotransmission at cholinergic nerve terminals. A functional fragment derived from the toxin, LHn, consisting of the catalytic and translocation domains, has been heralded as a platform for the development of targeted secretion inhibitors. These secretion inhibitors are aimed at retargeting the toxin towards a specific cell type to inhibit vesicular secretion. Here we report crystal structures of LHn from serotype D at 2.3 Å, and that of SXN101959 at 3.1 Å resolution. SXN101959, a derivative that combines LHn from serotype D with a fragment of the growth hormone releasing hormone, has previously revealed promising results in inhibiting growth hormone release in pituitary somatotrophs. These structures offer for the first time insights into the translocation domain interaction with the catalytic domain in serotype D. Furthermore, structural information from small-angle X-ray scattering of LHn/D is compared among serotypes A, B, and D. Taken together, these results demonstrate the robustness of the 'LHn fold' across serotypes and its use in engineering additional polypeptide components with added functionality. Our study demonstrates the suitability of botulinum neurotoxin, and serotype D in particular, as a basis for engineering novel secretion inhibitors.

  6. Fishing Technique of Long-Fingered Bats Was Developed from a Primary Reaction to Disappearing Target Stimuli.

    Directory of Open Access Journals (Sweden)

    Ostaizka Aizpurua

    Full Text Available Behavioral plasticity is a key feature allowing animals to broaden their dietary niche when novel food resources become available, and long-fingered bats provide an appropriate model system to study the underpinnings of behavioral plasticity, since although generally being an insectivorous species, some individuals have been reported to catch fish. Aiming to get insight into the origin of fishing behavior in long-fingered bats, we studied in the field the differences in sensorial and mechanical reactions to insect-like (stationary and fish-like (temporary prey stimuli between well-known piscivorous and strictly insectivorous individuals. Both piscivorous and insectivorous individuals exhibited a qualitatively similar reaction to temporary target stimuli (longer and deeper dips and terminal echolocation phase skewed towards buzz I compared to stationary stimuli. Nevertheless, the quantitative differences observed in the sensorial and mechanical features (the intensity of the shift was significantly greater in piscivorous than in insectivorous individuals show that piscivorous individuals have honed their capture technique likely enhancing the fishing success. Thus, our results suggest that the fishing technique was developed from a primary reaction shared by all long-fingered bats. All individuals seem to be mechanically and sensorially adapted to detect and capture fish, although under appropriate environmental conditions, they would further improve their technique by experience and/or social learning.

  7. Factors specifying the development of synapse number in the rat dentate gyrus: effects of partial target loss

    International Nuclear Information System (INIS)

    Lewis, E.R.; Cotman, C.W.

    1980-01-01

    The development of the dentate gyrus has been studied under conditions of partial reduction of granule cell number. Neonatal rats were subjected to X-irradiation, a procedure which reduces the number of granule cells to 20% of control values. In X-irradiated rats, quantitative analyses were performed on cells in the entorhinal cortex which give rise to the perforant path projection to the dentate granule cells, and on the remaining, undamaged dentate granule cells. These residual cells were examined morphologically for possible hyperdevelopment in comparison to granule cells from control animals. Granule cells in X-irradiated animals were similar to granule cells in control animals with respect to dendritic structure and synaptic density. The number of neurons in both the medical and lateral entorhinal cortices in X-irradiated animals appeared normal until day 12, at which time a selective reduction in cell numbers became apparent. By day 30, 25-55% of the cells of origin of the perforant path were absent in X-irradiated animals. It is hypothesized that these cells are subject to retrograde transynaptic degeneration as a result of target removal. Further, it appears that granule cells play an important role in determining the density of their innervation. (Auth.)

  8. The Development of a Melt-Extruded Shellac Carrier for the Targeted Delivery of Probiotics to the Colon

    Directory of Open Access Journals (Sweden)

    Noel M. Gately

    2017-09-01

    Full Text Available Hot melt extrusion (HME is considered an efficient technique in developing solid molecular dispersions, and has been demonstrated to provide sustained, modified and targeted drug delivery resulting in improved bioavailability. However, most commercial enteric or pH-responsive polymers are relatively difficult to process or have high Glass Transition Temperature (Tg values, making their use with temperature-sensitive drugs, probiotics or biologics not viable. Shellac is a natural thermoplastic, and after a review of current literature on the pharmaceutical HME process, a possible gap in the knowledge of the use of shellac to produce dosage forms by means of HME was identified. This work explores the possibility of SSB® 55 pharmaceutical-grade shellac as a melt-extrudable encapsulation polymer to entrap freeze-dried probiotic powder and to determine bacterial cell viability post-processing. Well-defined strands were produced from the physical mixture of shellac and Biocare® Bifidobacterium Probiotic. FTIR clarified that there are no significant interactions between the probiotic and polymer. All of the samples demonstrated less than 5% degradation over 24 h at pH of both 1.2 and 6.8. At pH 7.4, both loaded samples gave a similar dissolution trend with complete degradation achieved after 10–11 h. Following five-month storage, 57.8% reduction in viability was observed.

  9. The Development of a Melt-Extruded Shellac Carrier for the Targeted Delivery of Probiotics to the Colon.

    Science.gov (United States)

    Gately, Noel M; Kennedy, James E

    2017-09-22

    Hot melt extrusion (HME) is considered an efficient technique in developing solid molecular dispersions, and has been demonstrated to provide sustained, modified and targeted drug delivery resulting in improved bioavailability. However, most commercial enteric or pH-responsive polymers are relatively difficult to process or have high Glass Transition Temperature (Tg) values, making their use with temperature-sensitive drugs, probiotics or biologics not viable. Shellac is a natural thermoplastic, and after a review of current literature on the pharmaceutical HME process, a possible gap in the knowledge of the use of shellac to produce dosage forms by means of HME was identified. This work explores the possibility of SSB ® 55 pharmaceutical-grade shellac as a melt-extrudable encapsulation polymer to entrap freeze-dried probiotic powder and to determine bacterial cell viability post-processing. Well-defined strands were produced from the physical mixture of shellac and Biocare ® Bifidobacterium Probiotic. FTIR clarified that there are no significant interactions between the probiotic and polymer. All of the samples demonstrated less than 5% degradation over 24 h at pH of both 1.2 and 6.8. At pH 7.4, both loaded samples gave a similar dissolution trend with complete degradation achieved after 10-11 h. Following five-month storage, 57.8% reduction in viability was observed.

  10. Developments in the treatment of transfusion-dependent anemia in patients with myelodysplastic syndromes: epidemiology, etiology, genetics, and targeted therapies

    Directory of Open Access Journals (Sweden)

    Raza A

    2014-07-01

    Full Text Available Azra Raza, Nicholas Iverson, Abdullah M AliThe MDS Center, Columbia University, New York, NY, USAAbstract: Myelodysplastic syndromes are malignant hematopoietic stem cell disorders that present with variable cytopenias and predominantly affect the elderly. Treatment options are limited, with allogeneic transplant being the only potentially curative strategy. Recent mutational profiling studies have led to cataloguing of driver and passenger mutations most commonly affecting the epigenetic regulators and genes involved in RNA splicing. Despite improved understanding of the disease biology, these emerging molecular insights have not led to identification of novel therapeutic strategies. Although several drugs approved in the last decade improve the cytopenias, the relief is temporary, most likely due to the sequential activation of clones. Future advances depend upon identification of signaling pathways in dominant clones and targeting these with agents that might be known but need to be matched to suit the needs of individual patients in a longitudinal, dynamic fashion. Myelodysplastic syndromes are ideally suited for the development of such personalized medicine.Keywords: cancer, epigenetics, iron, MDS, myelodysplasia, splicing

  11. Potential Development of Tumor-Targeted Oral Anti-Cancer Prodrugs: Amino Acid and Dipeptide Monoester Prodrugs of Gemcitabine.

    Science.gov (United States)

    Tsume, Yasuhiro; Drelich, Adam J; Smith, David E; Amidon, Gordon L

    2017-08-10

    One of the main obstacles for cancer therapies is to deliver medicines effectively to target sites. Since stroma cells are developed around tumors, chemotherapeutic agents have to go through stroma cells in order to reach tumors. As a method to improve drug delivery to the tumor site, a prodrug approach for gemcitabine was adopted. Amino acid and dipeptide monoester prodrugs of gemcitabine were synthesized and their chemical stability in buffers, resistance to thymidine phosphorylase and cytidine deaminase, antiproliferative activity, and uptake/permeability in HFF cells as a surrogate to stroma cells were determined and compared to their parent drug, gemcitabine. The activation of all gemcitabine prodrugs was faster in pancreatic cell homogenates than their hydrolysis in buffer, suggesting enzymatic action. All prodrugs exhibited great stability in HFF cell homogenate, enhanced resistance to glycosidic bond metabolism by thymidine phosphorylase, and deamination by cytidine deaminase compared to their parent drug. All gemcitabine prodrugs exhibited higher uptake in HFF cells and better permeability across HFF monolayers than gemcitabine, suggesting a better delivery to tumor sites. Cell antiproliferative assays in Panc-1 and Capan-2 pancreatic ductal cell lines indicated that the gemcitabine prodrugs were more potent than their parent drug gemcitabine. The transport and enzymatic profiles of gemcitabine prodrugs suggest their potential for delayed enzymatic bioconversion and enhanced resistance to metabolic enzymes, as well as for enhanced drug delivery to tumor sites, and cytotoxic activity in cancer cells. These attributes would facilitate the prolonged systemic circulation and improved therapeutic efficacy of gemcitabine prodrugs.

  12. Design, development and characterization of multi-functionalized gold nanoparticles for biodetection and targeted boron delivery in BNCT applications.

    NARCIS (Netherlands)

    Mandal, S.; Bakeine, G.J.; Krol, S.; Ferrari, C.; Clerici, A.M.; Zonta, C.; Cansolino, L.; Ballarini, F.; Bortolussi, S.; Stella, S.; Protti, N.; Bruschi, P.; Altieri, S.

    2011-01-01

    The aim of this study is to optimize targeted boron delivery to cancer cells and its tracking down to the cellular level. To this end, we describe the design and synthesis of novel nanovectors that double as targeted boron delivery agents and fluorescent imaging probes. Gold nanoparticles were

  13. Development of a Novel Therapeutic Paradigm Utilizing a Mammary Gland-Targeted, Bin1-Knockout Mouse Model

    Science.gov (United States)

    2008-07-01

    Investigacion Medica Aplicada ( CIMA ), Universidad de Navarra Pamplona, Spain April 8-9, 2008 Abstract presented: “Targeting tumoral immune...Investigacion Medica Aplicada ( CIMA ), Universidad de Navarra Pamplona, Spain April 8-9, 2008 “Targeting tumoral immune tolerance with IDO inhibitors” (Invited

  14. Development of a high-density gas-jet target for nuclear astrophysics and reaction studies with rare isotope beams. Final Report

    Energy Technology Data Exchange (ETDEWEB)

    Uwe, Greife [Colorado School of Mines, Golden, CO (United States)

    2014-08-12

    The purpose of this project was to develop a high-density gas jet target that will enable a new program of transfer reaction studies with rare isotope beams and targets of hydrogen and helium that is not currently possible and will have an important impact on our understanding of stellar explosions and of the evolution of nuclear shell structure away from stability. This is the final closeout report for the project.

  15. Development of a high-density gas-jet target for nuclear astrophysics and reaction studies with rare isotope beams. Final Report

    International Nuclear Information System (INIS)

    Uwe, Greife

    2014-01-01

    The purpose of this project was to develop a high-density gas jet target that will enable a new program of transfer reaction studies with rare isotope beams and targets of hydrogen and helium that is not currently possible and will have an important impact on our understanding of stellar explosions and of the evolution of nuclear shell structure away from stability. This is the final closeout report for the project.

  16. A Robust Profitability Assessment Tool for Targeting Agricultural Investments in Developing Countries: Modeling Spatial Heterogeneity and Uncertainty

    Science.gov (United States)

    Quinn, J. D.; Zeng, Z.; Shoemaker, C. A.; Woodard, J.

    2014-12-01

    In sub-Saharan Africa, where the majority of the population earns their living from agriculture, government expenditures in many countries are being re-directed to the sector to increase productivity and decrease poverty. However, many of these investments are seeing low returns because they are poorly targeted. A geographic tool that accounts for spatial heterogeneity and temporal variability in the factors of production would allow governments and donors to optimize their investments by directing them to farmers for whom they are most profitable. One application for which this is particularly relevant is fertilizer recommendations. It is well-known that soil fertility in much of sub-Saharan Africa is declining due to insufficient nutrient inputs to replenish those lost through harvest. Since fertilizer application rates in sub-Saharan Africa are several times smaller than in other developing countries, it is often assumed that African farmers are under-applying fertilizer. However, this assumption ignores the risk farmers face in choosing whether or how much fertilizer to apply. Simply calculating the benefit/cost ratio of applying a given level of fertilizer in a particular year over a large, aggregated region (as is often done) overlooks the variability in yield response seen at different sites within the region, and at the same site from year to year. Using Ethiopia as an example, we are developing a 1 km resolution fertilizer distribution tool that provides pre-season fertilizer recommendations throughout the agricultural regions of the country, conditional on seasonal climate forecasts. By accounting for spatial heterogeneity in soil, climate, market and travel conditions, as well as uncertainty in climate and output prices at the time a farmer must purchase fertilizer, this stochastic optimization tool gives better recommendations to governments, fertilizer companies, and aid organizations looking to optimize the welfare benefits achieved by their

  17. Persistent Requirement and Alteration of the Key Targets of PRDM1 During Primordial Germ Cell Development in Mice.

    Science.gov (United States)

    Yamashiro, Chika; Hirota, Takayuki; Kurimoto, Kazuki; Nakamura, Tomonori; Yabuta, Yukihiro; Nagaoka, So I; Ohta, Hiroshi; Yamamoto, Takuya; Saitou, Mitinori

    2016-01-01

    Primordial germ cells (PGCs) are the foundation of totipotency and vital for reproduction and heredity. PGCs in mice arise from the epiblast around Embryonic Day (E) 7.0, migrate through the hindgut endoderm, and colonize and proliferate in the embryonic gonads until around E13.5 prior to their differentiation either into prospermatogonia or oogonia. PRDM1, a transcriptional repressor, plays an essential role in PGC specification that includes robustly repressing a somatic mesodermal program. Using an inducible conditional knockout system, we show here that PRDM1 is critically required throughout PGC development. When Prdm1 was deleted in migrating PGCs at E9.5 or E10.5, or in male gonadal PGCs at E11.5, PGCs were eliminated by apoptosis from around E10.5, E11.5, or E13.5, respectively. When Prdm1 was deleted in female gonadal PGCs at E11.5, PGCs progressed into the first meiotic prophase in an apparently normal fashion, but the oogonia exhibited an aberrant pachytene phenotype, undergoing abrupt apoptosis from around E16.5. The escape of a fraction of PGCs (∼10%) from the Prdm1 deletion was sufficient to recover fairly normal germ cell pools, both in male and female adults. The key targets of PRDM1 in migrating and/or gonadal PGCs, including genes for development, apoptosis, and prospermatogonial differentiation, showed only a modest overlap with those upon PGC specification, and were enriched with histone H3 lysine 27 trimethylation (H3K27me3). Our findings provide critical insight into the mechanism for maintaining the transcriptional integrity of PGCs. © 2016 by the Society for the Study of Reproduction, Inc.

  18. Stromal Activation Associated with Development of Prostate Cancer in Prostate-Targeted Fibroblast Growth Factor 8b Transgenic Mice

    Directory of Open Access Journals (Sweden)

    Teresa D. Elo

    2010-11-01

    Full Text Available Expression of fibroblast growth factor 8 (FGF-8 is commonly increased in prostate cancer. Experimental studies have provided evidence that it plays a role in prostate tumorigenesis and tumor progression. To study how increased FGF-8 affects the prostate, we generated and analyzed transgenic (TG mice expressing FGF-8b under the probasin promoter that targets expression to prostate epithelium. Prostates of the TG mice showed an increased size and changes in stromal and epithelialmorphology progressing fromatypia and prostatic intraepithelial neoplasia (mouse PIN, mPIN lesions to tumors with highly variable phenotype bearing features of adenocarcinoma, carcinosarcoma, and sarcoma. The development of mPIN lesions was preceded by formation of activated stroma containing increased proportion of fibroblastic cells, rich vasculature, and inflammation. The association between advancing stromal and epithelial alterations was statistically significant. Microarray analysis and validation with quantitative polymerase chain reaction revealed that expression of osteopontin and connective tissue growth factor was markedly upregulated in TG mouse prostates compared with wild type prostates. Androgen receptor staining was decreased in transformed epithelium and in hypercellular stroma but strongly increased in the sarcoma-like lesions. In conclusion, our data demonstrate that disruption of FGF signaling pathways by increased epithelial production of FGF-8b leads to strongly activated and atypical stroma, which precedes development of mPIN lesions and prostate cancer with mixed features of adenocarcinoma and sarcoma in the prostates of TG mice. The results suggest that increased FGF-8 in human prostate may also contribute to prostate tumorigenesis by stromal activation.

  19. Monte-Carlo model development for evaluation of current clinical target volume definition for heterogeneous and hypoxic glioblastoma.

    Science.gov (United States)

    Moghaddasi, L; Bezak, E; Harriss-Phillips, W

    2016-05-07

    Clinical target volume (CTV) determination may be complex and subjective. In this work a microscopic-scale tumour model was developed to evaluate current CTV practices in glioblastoma multiforme (GBM) external radiotherapy. Previously, a Geant4 cell-based dosimetry model was developed to calculate the dose deposited in individual GBM cells. Microscopic extension probability (MEP) models were then developed using Matlab-2012a. The results of the cell-based dosimetry model and MEP models were combined to calculate survival fractions (SF) for CTV margins of 2.0 and 2.5 cm. In the current work, oxygenation and heterogeneous radiosensitivity profiles were incorporated into the GBM model. The genetic heterogeneity was modelled using a range of α/β values (linear-quadratic model parameters) associated with different GBM cell lines. These values were distributed among the cells randomly, taken from a Gaussian-weighted sample of α/β values. Cellular oxygen pressure was distributed randomly taken from a sample weighted to profiles obtained from literature. Three types of GBM models were analysed: homogeneous-normoxic, heterogeneous-normoxic, and heterogeneous-hypoxic. The SF in different regions of the tumour model and the effect of the CTV margin extension from 2.0-2.5 cm on SFs were investigated for three MEP models. The SF within the beam was increased by up to three and two orders of magnitude following incorporation of heterogeneous radiosensitivities and hypoxia, respectively, in the GBM model. However, the total SF was shown to be overdominated by the presence of tumour cells in the penumbra region and to a lesser extent by genetic heterogeneity and hypoxia. CTV extension by 0.5 cm reduced the SF by a maximum of 78.6  ±  3.3%, 78.5  ±  3.3%, and 77.7  ±  3.1% for homogeneous and heterogeneous-normoxic, and heterogeneous hypoxic GBMs, respectively. Monte-Carlo model was developed to quantitatively evaluate SF for genetically

  20. Precision-cut kidney slices (PCKS to study development of renal fibrosis and efficacy of drug targeting ex vivo

    Directory of Open Access Journals (Sweden)

    Fariba Poosti

    2015-10-01

    Full Text Available Renal fibrosis is a serious clinical problem resulting in the greatest need for renal replacement therapy. No adequate preventive or curative therapy is available that could be clinically used to target renal fibrosis specifically. The search for new efficacious treatment strategies is therefore warranted. Although in vitro models using homogeneous cell populations have contributed to the understanding of the pathogenetic mechanisms involved in renal fibrosis, these models poorly mimic the complex in vivo milieu. Therefore, we here evaluated a precision-cut kidney slice (PCKS model as a new, multicellular ex vivo model to study the development of fibrosis and its prevention using anti-fibrotic compounds. Precision-cut slices (200-300 μm thickness were prepared from healthy C57BL/6 mouse kidneys using a Krumdieck tissue slicer. To induce changes mimicking the fibrotic process, slices were incubated with TGFβ1 (5 ng/ml for 48 h in the presence or absence of the anti-fibrotic cytokine IFNγ (1 µg/ml or an IFNγ conjugate targeted to PDGFRβ (PPB-PEG-IFNγ. Following culture, tissue viability (ATP-content and expression of α-SMA, fibronectin, collagen I and collagen III were determined using real-time PCR and immunohistochemistry. Slices remained viable up to 72 h of incubation, and no significant effects of TGFβ1 and IFNγ on viability were observed. TGFβ1 markedly increased α-SMA, fibronectin and collagen I mRNA and protein expression levels. IFNγ and PPB-PEG-IFNγ significantly reduced TGFβ1-induced fibronectin, collagen I and collagen III mRNA expression, which was confirmed by immunohistochemistry. The PKCS model is a novel tool to test the pathophysiology of fibrosis and to screen the efficacy of anti-fibrotic drugs ex vivo in a multicellular and pro-fibrotic milieu. A major advantage of the slice model is that it can be used not only for animal but also for (fibrotic human kidney tissue.

  1. Inertial confinement fusion target component fabrication and technology development support. Annual report 10/1/98 through 9/30/99

    International Nuclear Information System (INIS)

    Gibson, Jane

    1999-01-01

    General Atomics (GA) has served as the Inertial Confinement Fusion (ICF) Target Component Fabrication and Technology Development Support contractor for the U.S. Department of Energy since December 30, 1990. This report documents the technical activities of the period October 1, 1998 through September 30, 1999. During this period, GA and our partner Schafer Corporation were assigned 17 formal tasks in support of the ICF program and its five laboratories. A portion of the effort on these tasks included providing direct ''Onsite Support'' at Lawrence Livermore National Laboratory (LLNL), Los Alamos National Laboratory (LANL), and Sandia National Laboratory (SNL). We fabricated and delivered over 1790 hohlraum mandrels and numerous other micromachined components to LLNL, LANL, and SNL. We produced more than 1380 glass and plastic target capsules over a wide range of sizes and designs (plus over 300 near target-quality capsules) for LLNL, LANL, SNL, and University of Rochester/Laboratory for Laser Energetic (UR/LLE). We also delivered various target foils and films for Naval Research Lab (NRL) and UWLLE in FY99. We fabricated a device to polish NIF-sized beryllium shells and prepared a laboratory for the safe operation of beryllium polishing activities. This report describes these target fabrication activities and the target fabrication and characterization development activities that made the deliveries possible. During FY99, the GA/Schafer portion of the GA/Schafer-UR/LLE-LANL team effort for design, procurement, installation, and testing of the OMEGA Cryogenic Target System (OCTS) that will field cryogenic targets on OMEGA was completed. All components of the OCTS were procured, fabricated, assembled, tested, and shipped to UR/LLE. Only minor documentation tasks remain to be done in FY00. The ICF program is anticipating experiments at the OMEGA laser and the National Ignition Facility (NIF) which will require targets containing cryogenic layered D2 or deuterium

  2. Recent developments and on-line tests of uranium carbide targets for production of nuclides far from

    CERN Document Server

    V.N. Panteleev et al.

    The capacity of uranium carbide target materials of different structure and density for production of neutron-rich and heavy neutron-deficient isotopes have been investigated at the IRIS facility (PNPI) in the collaboration with Legnaro – GANIL – Orsay laboratories. The yields and release times of the species produced in the targets by the reactions induced by a 1 GeV proton beam of the PNPI synchrocyclotron have been measured. For the purpose to elaborate the most efficient and fast uranium carbide target prototype three kinds of the target materials were studied: a) a high density UC target material having ceramic-like structure with the density of 11 g/cm3 and the grain dimensions of about 200 microns; b) a high density UC target material with the density of 12 g/cm3 and the grain dimensions of about 20 microns prepared by the method of the powder metallurgy; c) a low density UCx target material with the density 3g/cm3 and the grain dimensions of about 20 microns prepared by the ISOLDE method. The comp...

  3. Development and optimization of a tumor targeting system based on microbial synthesized PHA biopolymers and PhaP mediated functional modification.

    Science.gov (United States)

    Fan, Fan; Wang, Leilei; Ouyang, Zhenlin; Wen, Yurong; Lu, Xiaoyun

    2018-04-01

    Polyhydroxyalkanoate (PHA) is a class of microbial synthesized biodegradable and biocompatible aliphatic polymer which has been developed into nanoparticles (NPs) for sustained release of hydrophobic compounds. Taking advantage of the natural PHA binding protein PhaP which could be steadily adsorbed onto PHA NPs through hydrophobic interaction, a tumor targeting system was developed in this study by presenting an epidermal growth factor receptor (EGFR)-targeting peptide (ETP) on the surface of PHA NPs, via PhaP mediated adsorption. To reveal the effects of residual emulsifiers on PhaP mediated ETP modification and optimize the tumor targeting capacity of the system, a novel emulsifier-free PHA NPs (EF-NPs) was fabricated together with other two kinds of conventional emulsifier-required PHA NPs (PVA-NPs and P68-NPs, which were prepared with poly(vinyl alcohol) (PVA) and Pluronic F68 as emulsifiers, respectively). By analyzing the surface hydrophobicity, the amount of adsorbed fusion protein, and the cellular uptake of all kinds of PHA NPs, our results demonstrated that EF-NPs with stronger surface hydrophobicity were the most proper formulation for further PhaP mediated ETP functionalization. The residual PVA and Pluronic F68 affected the modification efficiency and secondary structure of ETP-PhaP fusion protein, and finally obstructed the targeting effect of ETP-PhaP modified PVA-NPs and P68-NPs to EGFR over-expressed tumor cells. The animal experiment further confirmed the effectiveness and feasibility of in vivo application of ETP-PhaP functionalized EF-NPs, indicating that it could be served as a promising tumor targeting system with satisfactory EGFR targeting ability. This PhaP mediated bio-modification process also opens a wide way for developing various PHA-based targeting systems by presenting different tumor or other tissue-specific targeting peptides.

  4. REVIEW APPROACHES ECONOMIC DEVELOPMENT OF THE TERRITORY OF THE ARCTIC ZONE OF THE RUSSIAN FEDERATION, PRESENTED IN THE FORM OF TARGET SUBSPACE

    Directory of Open Access Journals (Sweden)

    N. I. Didenko

    2015-01-01

    Full Text Available This paper presents a conceptual idea of the organization of management of development of the Arctic area of the Russian Federation in the form of a set of target subspace. Among the possible types of target subspace comprising the Arctic zone of the Russian Federation, allocated seven subspace: basic city mobile Camps, site production of mineral resources, recreational area, fishing area, the Northern Sea Route, infrastructure protection safe existence in the Arctic. The task of determining the most appropriate theoretical approach for the development of each target subspaces. To this end, the theoretical approaches of economic growth and development of the theory of "economic base» (Economic Base Theory; resource theory (Staple Theory; Theory sectors (Sector Theory; theory of growth poles (Growth Pole Theory; neoclassical theory (Neoclassical Growth Theory; theory of inter-regional trade (Interregional Trade Theory; theory of the commodity cycle; entrepreneurial theory (Entrepreneurship Theories.

  5. Development of a questionnaire weighted scoring system to target diagnostic examinations for asthma in adults: a modelling study

    Directory of Open Access Journals (Sweden)

    Hazell Michelle L

    2004-12-01

    Full Text Available Abstract Background Identification and treatment of unrecognised asthmatics in the community is important for improving the health of the individual and minimising cost and quality of life burden. It is not practical to offer clinical diagnostic assessment to whole communities, and a simple tool such as a questionnaire is required to identify a smaller target group. Conventional questionnaire screening methods which separate individuals into positive and negative categories have resulted in large numbers of individuals requiring clinical assessment. This study has therefore developed and tested a weighted scoring system that prioritises those most urgently in need, based on their questionnaire responses. Methods A stratified random sample of adult respondents to a general practice postal questionnaire survey were categorised 'asthmatic' or 'non-asthmatic' according to three expert physicians' opinions. Based on this categorisation, logistic regression was used to derive weights reflecting the relative importance of each question in predicting asthma, allowing calculation of weighted scores reflecting likelihood of asthma. Respondents scoring higher than a chosen threshold would be offered diagnostic examination. Results Age and presence of wheeze were most influential (weight 3 and overall weighted scores ranged from -1 to 13. Positive predictive values (PPV were estimated. For example, setting the threshold score at nine gave an estimated PPV for asthma diagnosis of 93.5%, a threshold score of seven corresponded to PPV 78.8%. PPV estimates were supported by examining 145 individuals from a new survey. Conclusion Weighted scoring of questionnaire responses provides a method for evaluating the priority level of an individual 'at a glance', minimising the resource wastage of examining false positives.

  6. Development of vaccine for dyslipidemia targeted to a proprotein convertase subtilisin/kexin type 9 (PCSK9 epitope in mice.

    Directory of Open Access Journals (Sweden)

    Ryo Kawakami

    Full Text Available Proprotein convertase subtilisin/kexin type 9 (PCSK9 regulates expression of low-density lipoprotein (LDL receptors via receptor internalization and subsequent lysosomal degradation. Thus, an anti-PCSK9 antibody is well known as an anti-hyperlipidemia drug. Here, we aimed to develop vaccine for a long-term treatment of dyslipidemia targeted to PCSK9. In This study, we designed a peptide vaccine for mouse PCSK-9, which consisted of short peptides conjugated to keyhole limpet hemocyanin (KLH as a carrier protein. Vaccines were administered to male apolipoprotein E (ApoE deficient mice with adjuvants and significantly elicited an antibody response against PCSK9. The PCSK9 vaccines were administered to mice three times in 2-week intervals, and antibody titers and lipoprotein levels were evaluated up to 24 weeks after the first immunization to determine the therapeutic effect. Anti-PCSK9 antibody titers reached peak levels 6 weeks after the first immunization, and theses titers were maintained for up to 24 weeks. Decreased plasma levels of total cholesterol, very low-density lipoprotein (VLDL, and chylomicron (CM were maintained for up to 24 weeks. Immunized mice exhibited a significant increase in cell-surface LDL receptor expression. Stimulation with KLH, but not PCSK9, induced the production of INF-gamma and interleukin-4 (IL-4, as determined with ELISPOT assays, thus indicating that PCSK9 vaccine did not elicit T-cell activation in our vaccine system. The present anti-PCSK9 vaccine induced long-lasting anti-PCSK9 antibody production and improved lipoprotein profiles. Thus, anti-PCSK9 vaccine could become a new option for the treatment of dyslipidemia as a long-acting therapy in future.

  7. Development of effective tumor immunotherapy using a novel dendritic cell-targeting Toll-like receptor ligand.

    Directory of Open Access Journals (Sweden)

    Nadeeka H De Silva

    Full Text Available Although dendritic cell (DC-based immunotherapy shows little toxicity, improvements should be necessary to obtain satisfactory clinical outcome. Using interferon-gamma injection along with DCs, we previously obtained significant clinical responses against small or early stage malignant tumors in dogs. However, improvement was necessary to be effective to largely developed or metastatic tumors. To obtain effective methods applicable to those tumors, we herein used a DC-targeting Toll-like receptor ligand, h11c, and examined the therapeutic effects in murine subcutaneous and visceral tumor models and also in the clinical treatment of canine cancers. In murine experiments, most and significant inhibition of tumor growth and extended survival was observed in the group treated with the combination of h11c-activated DCs in combination with interferon-gamma and a cyclooxygenase2 inhibitor. Both monocytic and granulocytic myeloid-derived suppressor cells were significantly reduced by the combined treatment. Following the successful results in mice, the combined treatment was examined against canine cancers, which spontaneously generated like as those in human. The combined treatment elicited significant clinical responses against a nonepithelial malignant tumor and a malignant fibrous histiocytoma. The treatment was also successful against a bone-metastasis of squamous cell carcinoma. In the successful cases, the marked increase of tumor-responding T cells and decrease of myeloid-derived suppressor cells and regulatory T cells was observed in their peripheral blood. Although the combined treatment permitted the growth of lung cancer of renal carcinoma-metastasis, the marked elevated and long-term maintaining of the tumor-responding T cells was observed in the patient dog. Overall, the combined treatment gave rise to emphatic amelioration in DC-based cancer therapy.

  8. An off-line method to characterize the fission product release from uranium carbide-target prototypes developed for SPIRAL2 project

    Energy Technology Data Exchange (ETDEWEB)

    Hy, B.; Barre-Boscher, N. [Institut de Physique Nucleaire (UMR 8608) CNRS/IN2P3 - Universite Paris Sud, F-91406 ORSAY Cedex (France); Oezguemues, A., E-mail: ozgumus@in2p3.fr [Institut de Physique Nucleaire (UMR 8608) CNRS/IN2P3 - Universite Paris Sud, F-91406 ORSAY Cedex (France); Univ Paris Sud, UMR 8606, F-91406 ORSAY Cedex (France); Roussiere, B.; Tusseau-Nenez, S.; Lau, C.; Cheikh Mhamed, M.; Raynaud, M.; Said, A.; Kolos, K.; Cottereau, E.; Essabaa, S. [Institut de Physique Nucleaire (UMR 8608) CNRS/IN2P3 - Universite Paris Sud, F-91406 ORSAY Cedex (France); Tougait, O.; Pasturel, M. [Sciences Chimiques de Rennes (UMR 6226) CNRS - Universite de Rennes 1, Campus de Beaulieu, F-35042 RENNES Cedex (France)

    2012-10-01

    In the context of radioactive ion beams, fission targets, often based on uranium compounds, have been used for more than 50 years at isotope separator on line facilities. The development of several projects of second generation facilities aiming at intensities two or three orders of magnitude higher than today puts an emphasis on the properties of the uranium fission targets. A study, driven by Institut de Physique Nucleaire d'Orsay (IPNO), has been started within the SPIRAL2 project to try and fully understand the behavior of these targets. In this paper, we have focused on five uranium carbide based targets. We present an off-line method to characterize their fission product release and the results are examined in conjunction with physical characteristics of each material such as the microstructure, the porosity and the chemical composition.

  9. Retrotransposon-centered analysis of piRNA targeting shows a shift from active to passive retrotransposon transcription in developing mouse testes.

    Science.gov (United States)

    Mourier, Tobias

    2011-09-01

    Piwi-associated RNAs (piRNAs) bind transcripts from retrotransposable elements (RTE) in mouse germline cells and seemingly act as guides for genomic methylation, thereby repressing the activity of RTEs. It is currently unknown if and how Piwi proteins distinguish RTE transcripts from other cellular RNAs. During germline development, the main target of piRNAs switch between different types of RTEs. Using the piRNA targeting of RTEs as an indicator of RTE activity, and considering the entire population of genomic RTE loci along with their age and location, this study aims at further elucidating the dynamics of RTE activity during mouse germline development. Due to the inherent sequence redundancy between RTE loci, assigning piRNA targeting to specific loci is problematic. This limits the analysis, although certain features of piRNA targeting of RTE loci are apparent. As expected, young RTEs display a much higher level of piRNA targeting than old RTEs. Further, irrespective of age, RTE loci near protein-coding coding genes are targeted to a greater extent than RTE loci far from genes. During development, a shift in piRNA targeting is observed, with a clear increase in the relative piRNA targeting of RTEs residing within boundaries of protein-coding gene transcripts. Reanalyzing published piRNA sequences and taking into account the features of individual RTE loci provide novel insight into the activity of RTEs during development. The obtained results are consistent with some degree of proportionality between what transcripts become substrates for Piwi protein complexes and the level by which the transcripts are present in the cell. A transition from active transcription of RTEs to passive co-transcription of RTE sequences residing within protein-coding transcripts appears to take place in postnatal development. Hence, the previously reported increase in piRNA targeting of SINEs in postnatal testis development does not necessitate widespread active transcription of

  10. The Impact Of The Definition Of Target Market On The Design Process In New Product Development: The Case Of New Ford Cargo

    OpenAIRE

    Tokatlı, Akgün

    2004-01-01

    The economic success of manufacturing companies depends on their ability to identify the needs of the customers and to develop new products to meet those needs rapidly. Achieving this goal is not solely a marketing problem, nor it is solely a design or a manufacturing problem; it is in fact a product development problem involving all of these functions. The subject of this study is to analyse the concept of target market in the product development process and its interaction with product desi...

  11. Targeting Employment Expansion, Economic Growth and Development in Sub-Saharan Africa: Outlines of an Alternative Economic Programme for the Region

    OpenAIRE

    James Heintz; Robert Pollin

    2008-01-01

    This paper outlines the elements of a development-targeted economic framework aimed at creating decent employment opportunities as a strategy for realizing core human development goals in Africa. Four policy areas form the core of the paper: monetary policy and inflation, exchange rate policy, development finance and financial sector reforms, and public investment and fiscal policy. This paper draws heavily on three large UNDP-sponsored studies of employment-oriented economic policies in Keny...

  12. Observation and modeling of deep brain stimulation electrode depth in the pallidal target of the developing brain.

    Science.gov (United States)

    Lumsden, Daniel E; Ashmore, Jonathan; Charles-Edwards, Geoffrey; Selway, Richard; Lin, Jean-Pierre; Ashkan, Keyoumars

    2015-04-01

    It is unclear how brain growth with age affects electrode position in relation to target for children undergoing deep brain stimulation surgery. We aimed to model projected change in the distance between the entry point of the electrode into the brain and target during growth to adulthood. Modeling was performed using a neurodevelopmental magnetic resonance imaging database of age-specific templates in 6-month increments from 4 to 18 years of age. Coordinates were chosen for a set of entry points into both cerebral hemispheres and target positions within the globus pallidus internus on the youngest magnetic resonance imaging template. The youngest template was nonlinearly registered to the older templates, and the transformations generated by these registrations were applied to the original coordinates of entry and target positions, mapping these positions with increasing age. Euclidean geometry was used to calculate the distance between projected electrode entry and target with increasing age. A projected increase in distance between entry point and target of 5-10 mm was found from age 4 to 18 years. Most change appeared to occur before 7 years of age, after which minimal change in distance was found. Electrodes inserted during deep brain stimulation surgery are tethered at the point of entry to the skull. Brain growth, which could result in a relative retraction with respect to the original target position, appears to occur before 7 years of age, suggesting careful monitoring is needed for children undergoing implantation before this age. Reengineering of electrode design could avoid reimplantation surgery in young children undergoing deep brain stimulation. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Towards prostate cancer gene therapy: Development of a chlorotoxin-targeted nanovector for toxic (melittin) gene delivery.

    Science.gov (United States)

    Tarokh, Zahra; Naderi-Manesh, Hossein; Nazari, Mahboobeh

    2017-03-01

    Prostate cancer is the second leading cause of death due to cancer in men. Owing to shortcomings in the current treatments, other therapies are being considered. Toxic gene delivery is one of the most effective methods for cancer therapy. Cationic polymers are able to form stable nanoparticles via interaction with nucleic acids electrostatically. Branched polyethylenimine that contains amine groups has notable buffering capacity and the ability to escape from endosome through the proton sponge effect. However, the cytotoxicity of this polymer is high, and modification is one of the applicable strategies to overcome this problem. In this study, PEI was targeted with chlorotoxin (CTX) via N-succinimidyl 3-(2-pyridyldithio) propionate (SPDP) cross-linker. CTX can bind specifically to matrix metalloproteinase-2 that is overexpressed in certain cancers. Melittin as the major component of bee venom has been reported to have anti-cancer activity. This was thus selected to deliver to PC3 cell line. Flow cytometry analysis revealed that transfection efficiency of targeted nanoparticles is significantly higher compared to non-targeted nanoparticles. Targeted nanoparticles carrying the melittin gene also decreased cell viability of PC3 cells significantly while no toxic effects were observed on NIH3T3 cell line. Therefore, CTX-targeted nanoparticles carrying the melittin gene could serve as an appropriate gene delivery system for prostate and other MMP-2 positive cancer cells. Copyright © 2016 Elsevier B.V. All rights reserved.

  14. Targeted Peptide Measurements in Biology and Medicine: Best Practices for Mass Spectrometry-based Assay Development Using a Fit-for-Purpose Approach

    Energy Technology Data Exchange (ETDEWEB)

    Carr, Steven A.; Abbateillo, Susan E.; Ackermann, Bradley L.; Borchers, Christoph H.; Domon, Bruno; Deutsch, Eric W.; Grant, Russel; Hoofnagle, Andrew N.; Huttenhain, Ruth; Koomen, John M.; Liebler, Daniel; Liu, Tao; MacLean, Brendan; Mani, DR; Mansfield, Elizabeth; Neubert, Hendrik; Paulovich, Amanda G.; Reiter, Lukas; Vitek, Olga; Aebersold, Ruedi; Anderson, Leigh N.; Bethem, Robert; Blonder, Josip; Boja, Emily; Botelho, Julianne; Boyne, Michael; Bradshaw, Ralph A.; Burlingame, Alma S.; Chan, Daniel W.; Keshishian, Hasmik; Kuhn, Eric; Kingsinger, Christopher R.; Lee, Jerry S.; Lee, Sang-Won; Moritz, Robert L.; Oses-Prieto, Juan; Rifai, Nader; Ritchie, James E.; Rodriguez, Henry; Srinivas, Pothur R.; Townsend, Reid; Van Eyk , Jennifer; Whiteley, Gordon; Wiita, Arun; Weintraub, Susan

    2014-01-14

    Adoption of targeted mass spectrometry (MS) approaches such as multiple reaction monitoring (MRM) to study biological and biomedical questions is well underway in the proteomics community. Successful application depends on the ability to generate reliable assays that uniquely and confidently identify target peptides in a sample. Unfortunately, there is a wide range of criteria being applied to say that an assay has been successfully developed. There is no consensus on what criteria are acceptable and little understanding of the impact of variable criteria on the quality of the results generated. Publications describing targeted MS assays for peptides frequently do not contain sufficient information for readers to establish confidence that the tests work as intended or to be able to apply the tests described in their own labs. Guidance must be developed so that targeted MS assays with established performance can be made widely distributed and applied by many labs worldwide. To begin to address the problems and their solutions, a workshop was held at the National Institutes of Health with representatives from the multiple communities developing and employing targeted MS assays. Participants discussed the analytical goals of their experiments and the experimental evidence needed to establish that the assays they develop work as intended and are achieving the required levels of performance. Using this “fit-for-purpose” approach, the group defined three tiers of assays distinguished by their performance and extent of analytical characterization. Computational and statistical tools useful for the analysis of targeted MS results were described. Participants also detailed the information that authors need to provide in their manuscripts to enable reviewers and readers to clearly understand what procedures were performed and to evaluate the reliability of the peptide or protein quantification measurements reported. This paper presents a summary of the meeting and

  15. Development of a new anti-cancer agent for targeted radionuclide therapy: β- radiolabeled RAFT-RGD

    International Nuclear Information System (INIS)

    Petitprin, A.

    2013-01-01

    β-emitters radiolabeled RAFT-RGD as new agents for internal targeted radiotherapy. The αvβ3 integrin is known to play an important role in tumor-induced angiogenesis, tumor proliferation, survival and metastasis. Because of its overexpression on neo-endothelial cells such as those present in growing tumors, as well as on tumor cells of various origins, αvβ3 integrin is an attractive molecular target for diagnosis and therapy of the rapidly growing and metastatic tumors. A tetrameric RGD-based peptide, regioselectively addressable functionalized template-(cyclo-[RGDfK])4 (RAFT-RGD), specifically targets integrin αvβ3 in vitro and in vivo. RAFT-RGD has been used for tumor imaging and drug targeting. This study is the first to evaluate the therapeutic potential of the β-emitters radiolabeled tetrameric RGD peptide RAFT-RGD in a Nude mouse model of αvβ3 -expressing tumors. An injection of 37 MBq of 90 Y-RAFT-RGD or 177 Lu-RAFT-RGD in mice with αvβ3 -positive tumors caused a significant growth delay as compared with mice treated with 37 MBq of 90 Y-RAFT-RAD or 177 Lu-RAFT-RAD or untreated mice. In comparison, an injection of 30 MBq of 90 Y-RAFT-RGD had no efficacy for the treatment of αvβ3 -negative tumors. 90 Y-RAFT-RGD and 177 Lu-RAFT-RGD are potent αvβ3 -expressing tumor targeting agents for internal targeted radiotherapy. (author)

  16. The Steroid Catabolic Pathway of the Intracellular Pathogen Rhodococcus equi Is Important for Pathogenesis and a Target for Vaccine Development

    Science.gov (United States)

    van der Geize, R.; Grommen, A. W. F.; Hessels, G. I.; Jacobs, A. A. C.; Dijkhuizen, L.

    2011-01-01

    Rhodococcus equi causes fatal pyogranulomatous pneumonia in foals and immunocompromised animals and humans. Despite its importance, there is currently no effective vaccine against the disease. The actinobacteria R. equi and the human pathogen Mycobacterium tuberculosis are related, and both cause pulmonary diseases. Recently, we have shown that essential steps in the cholesterol catabolic pathway are involved in the pathogenicity of M. tuberculosis. Bioinformatic analysis revealed the presence of a similar cholesterol catabolic gene cluster in R. equi. Orthologs of predicted M. tuberculosis virulence genes located within this cluster, i.e. ipdA (rv3551), ipdB (rv3552), fadA6 and fadE30, were identified in R. equi RE1 and inactivated. The ipdA and ipdB genes of R. equi RE1 appear to constitute the α-subunit and β-subunit, respectively, of a heterodimeric coenzyme A transferase. Mutant strains RE1ΔipdAB and RE1ΔfadE30, but not RE1ΔfadA6, were impaired in growth on the steroid catabolic pathway intermediates 4-androstene-3,17-dione (AD) and 3aα-H-4α(3′-propionic acid)-5α-hydroxy-7aβ-methylhexahydro-1-indanone (5α-hydroxy-methylhexahydro-1-indanone propionate; 5OH-HIP). Interestingly, RE1ΔipdAB and RE1ΔfadE30, but not RE1ΔfadA6, also displayed an attenuated phenotype in a macrophage infection assay. Gene products important for growth on 5OH-HIP, as part of the steroid catabolic pathway, thus appear to act as factors involved in the pathogenicity of R. equi. Challenge experiments showed that RE1ΔipdAB could be safely administered intratracheally to 2 to 5 week-old foals and oral immunization of foals even elicited a substantial protective immunity against a virulent R. equi strain. Our data show that genes involved in steroid catabolism are promising targets for the development of a live-attenuated vaccine against R. equi infections. PMID:21901092

  17. Development of a Ga-68 labeled PET tracer with short linker for prostate-specific membrane antigen (PSMA) targeting.

    Science.gov (United States)

    Moon, Sung-Hyun; Hong, Mee Kyung; Kim, Young Ju; Lee, Yun-Sang; Lee, Dong Soo; Chung, June-Key; Jeong, Jae Min

    2018-04-05

    Glu-Urea-Lys (GUL) derivatives have been reported as prostate-specific membrane antigen (PSMA) agent. We developed derivatives of GUL conjugated with NOTA or DOTA via a thiourea linker and tested their feasibility as PSMA imaging agents after labeling with 68 Ga. NOTA-GUL and DOTA-GUL were synthesized and labeled with 68 Ga using generator-eluted 68 GaCl 3 in 0.1 M HCl in the presence of 1 M NaOAc at pH 5.5. The stabilities of 68 Ga-labeled compounds in human serum were tested at 37.5 °C. A competitive binding assay was performed using the PSMA-positive prostate cancer cell line 22Rv1 and [ 125 I]MIP-1072 (PSMA-specific binding agent) as a tracer. Biodistribution and micro-PET studies were performed using 22Rv1-xenograft BALB/c nude mice. The radiolabeling efficiency of NOTA-GUL (>99%) was higher than that of DOTA-GUL (92%). The IC 50 of Ga-NOTA-GUL was 18.3 nM. In the biodistribution study, tumor uptake of 68 Ga-NOTA-GUL (5.40% ID/g) was higher than that of 68 Ga-DOTA-GUL (4.66% ID/g) at 1 h. Tumor/muscle and tumor/blood uptake ratios of 68 Ga-NOTA-GUL (31.8 and 135, respectively) were significantly higher than those of 68 Ga-DOTA-GUL (16.1 and 31.1, respectively). The tumor/kidney uptake ratio of 68 Ga-NOTA-GUL was 3.4-fold higher than that of 68 Ga-DOTA-GUL. 68 Ga-NOTA-GUL showed specific uptake to PSMA positive tumor xenograft and was blocked by co-injection of the cold ligand. In conclusion, we successfully synthesized 68 Ga-NOTA-GUL and 68 Ga-DOTA-GUL for prostate cancer imaging. 68 Ga-NOTA-GUL showed better radiochemical and biodistribution results. 68 Ga-NOTA-GUL may be a promising PSMA targeting radiopharmaceutical. Copyright © 2018 Elsevier Ltd. All rights reserved.

  18. Streptococcus iniae M-like protein contributes to virulence in fish and is a target for live attenuated vaccine development.

    Directory of Open Access Journals (Sweden)

    Jeffrey B Locke

    2008-07-01

    Full Text Available Streptococcus iniae is a significant pathogen in finfish aquaculture, though knowledge of virulence determinants is lacking. Through pyrosequencing of the S. iniae genome we have identified two gene homologues to classical surface-anchored streptococcal virulence factors: M-like protein (simA and C5a peptidase (scpI.S. iniae possesses a Mga-like locus containing simA and a divergently transcribed putative mga-like regulatory gene, mgx. In contrast to the Mga locus of group A Streptococcus (GAS, S. pyogenes, scpI is located distally in the chromosome. Comparative sequence analysis of the Mgx locus revealed only one significant variant, a strain with an insertion frameshift mutation in simA and a deletion mutation in a region downstream of mgx, generating an ORF which may encode a second putative mga-like gene, mgx2. Allelic exchange mutagenesis of simA and scpI was employed to investigate the potential role of these genes in S. iniae virulence. Our hybrid striped bass (HSB and zebrafish models of infection revealed that M-like protein contributes significantly to S. iniae pathogenesis whereas C5a peptidase-like protein does not. Further, in vitro cell-based analyses indicate that SiMA, like other M family proteins, contributes to cellular adherence and invasion and provides resistance to phagocytic killing. Attenuation in our virulence models was also observed in the S. iniae isolate possessing a natural simA mutation. Vaccination of HSB with the Delta simA mutant provided 100% protection against subsequent challenge with a lethal dose of wild-type (WT S. iniae after 1,400 degree days, and shows promise as a target for live attenuated vaccine development.Analysis of M-like protein and C5a peptidase through allelic replacement revealed that M-like protein plays a significant role in S. iniae virulence, and the Mga-like locus, which may regulate expression of this gene, has an unusual arrangement. The M-like protein mutant created in this research

  19. The steroid catabolic pathway of the intracellular pathogen Rhodococcus equi is important for pathogenesis and a target for vaccine development.

    Directory of Open Access Journals (Sweden)

    R van der Geize

    2011-08-01

    Full Text Available Rhodococcus equi causes fatal pyogranulomatous pneumonia in foals and immunocompromised animals and humans. Despite its importance, there is currently no effective vaccine against the disease. The actinobacteria R. equi and the human pathogen Mycobacterium tuberculosis are related, and both cause pulmonary diseases. Recently, we have shown that essential steps in the cholesterol catabolic pathway are involved in the pathogenicity of M. tuberculosis. Bioinformatic analysis revealed the presence of a similar cholesterol catabolic gene cluster in R. equi. Orthologs of predicted M. tuberculosis virulence genes located within this cluster, i.e. ipdA (rv3551, ipdB (rv3552, fadA6 and fadE30, were identified in R. equi RE1 and inactivated. The ipdA and ipdB genes of R. equi RE1 appear to constitute the α-subunit and β-subunit, respectively, of a heterodimeric coenzyme A transferase. Mutant strains RE1ΔipdAB and RE1ΔfadE30, but not RE1ΔfadA6, were impaired in growth on the steroid catabolic pathway intermediates 4-androstene-3,17-dione (AD and 3aα-H-4α(3'-propionic acid-5α-hydroxy-7aβ-methylhexahydro-1-indanone (5α-hydroxy-methylhexahydro-1-indanone propionate; 5OH-HIP. Interestingly, RE1ΔipdAB and RE1ΔfadE30, but not RE1ΔfadA6, also displayed an attenuated phenotype in a macrophage infection assay. Gene products important for growth on 5OH-HIP, as part of the steroid catabolic pathway, thus appear to act as factors involved in the pathogenicity of R. equi. Challenge experiments showed that RE1ΔipdAB could be safely administered intratracheally to 2 to 5 week-old foals and oral immunization of foals even elicited a substantial protective immunity against a virulent R. equi strain. Our data show that genes involved in steroid catabolism are promising targets for the development of a live-attenuated vaccine against R. equi infections.

  20. Beyond CD19: Opportunities for Future Development of Targeted Immunotherapy in Pediatric Relapsed-Refractory Acute Leukemia