Approach range and velocity determination using laser sensors and retroreflector targets

NASA Technical Reports Server (NTRS)

Donovan, William J.

1991-01-01

A laser docking sensor study is currently in the third year of development. The design concept is considered to be validated. The concept is based on using standard radar techniques to provide range, velocity, and bearing information. Multiple targets are utilized to provide relative attitude data. The design requirements were to utilize existing space-qualifiable technology and require low system power, weight, and size yet, operate from 0.3 to 150 meters with a range accuracy greater than 3 millimeters and a range rate accuracy greater than 3 mm per second. The field of regard for the system is +/- 20 deg. The transmitter and receiver design features a diode laser, microlens beam steering, and power control as a function of range. The target design consists of five target sets, each having seven 3-inch retroreflectors, arranged around the docking port. The target map is stored in the sensor memory. Phase detection is used for ranging, with the frequency range-optimized. Coarse bearing measurement is provided by the scanning system (one set of binary optics) angle. Fine bearing measurement is provided by a quad detector. A MIL-STD-1750 A/B computer is used for processing. Initial test results indicate a probability of detection greater than 99 percent and a probability of false alarm less than 0.0001. The functional system is currently at the MIT/Lincoln Lab for demonstration.

Computational design optimization for microfluidic magnetophoresis

PubMed Central

Plouffe, Brian D.; Lewis, Laura H.; Murthy, Shashi K.

2011-01-01

Current macro- and microfluidic approaches for the isolation of mammalian cells are limited in both efficiency and purity. In order to design a robust platform for the enumeration of a target cell population, high collection efficiencies are required. Additionally, the ability to isolate pure populations with minimal biological perturbation and efficient off-chip recovery will enable subcellular analyses of these cells for applications in personalized medicine. Here, a rational design approach for a simple and efficient device that isolates target cell populations via magnetic tagging is presented. In this work, two magnetophoretic microfluidic device designs are described, with optimized dimensions and operating conditions determined from a force balance equation that considers two dominant and opposing driving forces exerted on a magnetic-particle-tagged cell, namely, magnetic and viscous drag. Quantitative design criteria for an electromagnetic field displacement-based approach are presented, wherein target cells labeled with commercial magnetic microparticles flowing in a central sample stream are shifted laterally into a collection stream. Furthermore, the final device design is constrained to fit on standard rectangular glass coverslip (60 (L)×24 (W)×0.15 (H) mm3) to accommodate small sample volume and point-of-care design considerations. The anticipated performance of the device is examined via a parametric analysis of several key variables within the model. It is observed that minimal currents (<500 mA) are required to generate magnetic fields sufficient to separate cells from the sample streams flowing at rate as high as 7 ml∕h, comparable to the performance of current state-of-the-art magnet-activated cell sorting systems currently used in clinical settings. Experimental validation of the presented model illustrates that a device designed according to the derived rational optimization can effectively isolate (∼100%) a magnetic-particle-tagged cell population from a homogeneous suspension even in a low abundance. Overall, this design analysis provides a rational basis to select the operating conditions, including chamber and wire geometry, flow rates, and applied currents, for a magnetic-microfluidic cell separation device. PMID:21526007

Divertor target shape optimization in realistic edge plasma geometry

NASA Astrophysics Data System (ADS)

Dekeyser, W.; Reiter, D.; Baelmans, M.

2014-07-01

Tokamak divertor design for next-step fusion reactors heavily relies on numerical simulations of the plasma edge. Currently, the design process is mainly done in a forward approach, where the designer is strongly guided by his experience and physical intuition in proposing divertor shapes, which are then thoroughly assessed by numerical computations. On the other hand, automated design methods based on optimization have proven very successful in the related field of aerodynamic design. By recasting design objectives and constraints into the framework of a mathematical optimization problem, efficient forward-adjoint based algorithms can be used to automatically compute the divertor shape which performs the best with respect to the selected edge plasma model and design criteria. In the past years, we have extended these methods to automated divertor target shape design, using somewhat simplified edge plasma models and geometries. In this paper, we build on and extend previous work to apply these shape optimization methods for the first time in more realistic, single null edge plasma and divertor geometry, as commonly used in current divertor design studies. In a case study with JET-like parameters, we show that the so-called one-shot method is very effective is solving divertor target design problems. Furthermore, by detailed shape sensitivity analysis we demonstrate that the development of the method already at the present state provides physically plausible trends, allowing to achieve a divertor design with an almost perfectly uniform power load for our particular choice of edge plasma model and design criteria.

Small-Tip-Angle Spokes Pulse Design Using Interleaved Greedy and Local Optimization Methods

PubMed Central

Grissom, William A.; Khalighi, Mohammad-Mehdi; Sacolick, Laura I.; Rutt, Brian K.; Vogel, Mika W.

2013-01-01

Current spokes pulse design methods can be grouped into methods based either on sparse approximation or on iterative local (gradient descent-based) optimization of the transverse-plane spatial frequency locations visited by the spokes. These two classes of methods have complementary strengths and weaknesses: sparse approximation-based methods perform an efficient search over a large swath of candidate spatial frequency locations but most are incompatible with off-resonance compensation, multifrequency designs, and target phase relaxation, while local methods can accommodate off-resonance and target phase relaxation but are sensitive to initialization and suboptimal local cost function minima. This article introduces a method that interleaves local iterations, which optimize the radiofrequency pulses, target phase patterns, and spatial frequency locations, with a greedy method to choose new locations. Simulations and experiments at 3 and 7 T show that the method consistently produces single- and multifrequency spokes pulses with lower flip angle inhomogeneity compared to current methods. PMID:22392822

Design of a Low-Energy FARAD Thruster

NASA Technical Reports Server (NTRS)

Polzin, K. A.; Rose, M. F.; Miller, R.; Best, S.; Owens, T.; Dankanich, J.

2007-01-01

The design of an electrodeless thruster that relies on a pulsed, rf-assisted discharge and electromagnetic acceleration using an inductive coil is presented. The thruster design is optimized using known performance,scaling parameters, and experimentally-determined design rules, with design targets for discharge energy, plasma exhaust velocity; and thrust efficiency of 100 J/pulse, 25 km/s, and 50%, respectively. Propellant is injected using a high-speed gas valve and preionized by a pulsed-RF signal supplied by a vector inversion generator, allowing for current sheet formation at lower discharge voltages and energies relative to pulsed inductive accelerators that do not employ preionization. The acceleration coil is designed to possess an inductance of at least 700 nH while the target stray (non-coil) inductance in the circuit is 70 nH. A Bernardes and Merryman pulsed power train or a pulse compression power train provide current to the acceleration coil and solid-state components are used to switch both powertrains.

Pressure control of a proton beam-irradiated water target through an internal flow channel-induced thermosyphon.

PubMed

Hong, Bong Hwan; Jung, In Su

2017-07-01

A water target was designed to enhance cooling efficiency using a thermosyphon, which is a system that uses natural convection to induce heat exchange. Two water targets were fabricated: a square target without any flow channel and a target with a flow channel design to induce a thermosyphon mechanism. These two targets had the same internal volume of 8 ml. First, visualization experiments were performed to observe the internal flow by natural convection. Subsequently, an experiment was conducted to compare the cooling performance of both water targets by measuring the temperature and pressure. A 30-MeV proton beam with a beam current of 20 μA was used to irradiate both targets. Consequently, the target with an internal flow channel had a lower mean temperature and a 50% pressure drop compared to the target without a flow channel during proton beam irradiation. Copyright © 2017 Elsevier Ltd. All rights reserved.

A Role for Fragment-Based Drug Design in Developing Novel Lead Compounds for Central Nervous System Targets.

PubMed

Wasko, Michael J; Pellegrene, Kendy A; Madura, Jeffry D; Surratt, Christopher K

2015-01-01

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 pharmacological screening, a costly method for assaying thousands of compounds. This approach has recently been augmented by virtual screening (VS), which employs computer models of the target protein to narrow the search for possible leads. A variant of VS is fragment-based drug design (FBDD), 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 FBDD 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 not only 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.

A Role for Fragment-Based Drug Design in Developing Novel Lead Compounds for Central Nervous System Targets

PubMed Central

Wasko, Michael J.; Pellegrene, Kendy A.; Madura, Jeffry D.; Surratt, Christopher K.

2015-01-01

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 pharmacological screening, a costly method for assaying thousands of compounds. This approach has recently been augmented by virtual screening (VS), which employs computer models of the target protein to narrow the search for possible leads. A variant of VS is fragment-based drug design (FBDD), 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 FBDD 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 not only 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. PMID:26441817

Effects of aggregate angularity on mix design characteristics and pavement performance.

DOT National Transportation Integrated Search

2009-12-01

This research targeted two primary purposes: to estimate current aggregate angularity test methods and to evaluate current : aggregate angularity requirements in the Nebraska asphalt mixture/pavement specification. To meet the first research : object...

Molecular Triage Trials in Colorectal Cancer.

PubMed

O'Hara, Mark H; Hamilton, Stanley R; O'Dwyer, Peter J

2016-01-01

Advances in the understanding of genomic alterations in cancer, and the various therapies targeted to these alterations have permitted the design of trials directed to bringing this science to the clinic, with the ultimate goal of tailoring therapy to the individual. There is a high need for advances in targeted therapy in colorectal cancer, a disease in which only 2 classes of targeted therapies are approved for use in colorectal cancer, despite the majority of colorectal cancers containing a potentially targetable mutation. Here we outline the key elements to the design of these clinical trials and summarize the current active molecular triage trials in colorectal cancer.

Designing multi-targeted agents: An emerging anticancer drug discovery paradigm.

PubMed

Fu, Rong-Geng; Sun, Yuan; Sheng, Wen-Bing; Liao, Duan-Fang

2017-08-18

The dominant paradigm in drug discovery is to design ligands with maximum selectivity to act on individual drug targets. With the target-based approach, many new chemical entities have been discovered, developed, and further approved as drugs. However, there are a large number of complex diseases such as cancer that cannot be effectively treated or cured only with one medicine to modulate the biological function of a single target. As simultaneous intervention of two (or multiple) cancer progression relevant targets has shown improved therapeutic efficacy, the innovation of multi-targeted drugs has become a promising and prevailing research topic and numerous multi-targeted anticancer agents are currently at various developmental stages. However, most multi-pharmacophore scaffolds are usually discovered by serendipity or screening, while rational design by combining existing pharmacophore scaffolds remains an enormous challenge. In this review, four types of multi-pharmacophore modes are discussed, and the examples from literature will be used to introduce attractive lead compounds with the capability of simultaneously interfering with different enzyme or signaling pathway of cancer progression, which will reveal the trends and insights to help the design of the next generation multi-targeted anticancer agents. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Design of photon converter and photoneutron target for High power electron accelerator based BNCT.

PubMed

Rahmani, Faezeh; Seifi, Samaneh; Anbaran, Hossein Tavakoli; Ghasemi, Farshad

2015-12-01

An electron accelerator, ILU-14, with current of 10 mA and 100 kW in power has been considered as one of the options for neutron source in Boron Neutron Capture Therapy (BNCT). The final design of neutron target has been obtained using MCNPX to optimize the neutron production. Tungsten in strip shape and D2O in cylindrical form have been proposed as the photon converter and the photoneutron target, respectively. In addition calculation of heat deposition in the photon target design has been considered to ensure mechanical stability of target. The results show that about 8.37×10(12) photoneutron/s with average energy of 615 keV can be produced by this neutron source design. In addition, using an appropriate beam shaping assembly an epithermal neutron flux of the order of 1.24×10(8) cm(-2) s(-1) can be obtained for BNCT applications. Copyright © 2015 Elsevier Ltd. All rights reserved.

Mo100 to Mo99 Target Cooling Enhancements Report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Woloshun, Keith Albert; Dale, Gregory E.; Olivas, Eric Richard

2016-02-16

Target design requirements changed significantly over the past year to a much higher beam current on larger diameter disks, and with a beam impingement on both ends of the target. Scaling from the previous design, that required significantly more mass flow rate of helium coolant, and also thinner disks. A new Aerzen GM12.4 blower was selected that can deliver up to 400 g/s at 400 psi, compared to about 100 g/s possible with the Tuthill blower previously selected.Further, to accommodate the 42 MeV, 2.7 mA beam on each side of the target, the disk thickness and the coolant gaps weremore » halved to create the current baseline design: 0.5 mm disk thickness (at 29 mm diameter) and 0.25 mm coolant gap. Thermal-hydraulic analysis of this target, presented below for reference, gave very good results, suggesting that the target could be improved with fewer, thicker disks and with disk thickness increasing toward the target center. The total thickness of Mo100 in the target remaining the same, that reduces the number of coolant gaps. This allows for the gap width to be increased, increasing the mass flow in each gap and consequently increasing heat transfer. A preliminary geometry was selected and analyzed with variable disk thickness and wider coolant gaps. The result of analysis of this target shows that disk thickness increase near the window was too aggressive and further resizing of the disks is necessary, but it does illustrate the potential improvements that are possible. Experimental and analytical study of diffusers on the target exit has been done. This shows modest improvement in requcing pressure drop, as will be summarized below. However, the benefit is not significant, and implementation becomes problematic when disk thickness is varying. A bull nose at the entrance does offer significant benefit and is relatively easy to incorporate. A bull nose on both ends is now a feature of the baseline design, and will be a feature of any redesign or enhanced designs that follow.« less

Oak Ridge Spallation Neutron Source (ORSNS) target station design integration

DOE Office of Scientific and Technical Information (OSTI.GOV)

McManamy, T.; Booth, R.; Cleaves, J.

1996-06-01

The conceptual design for a 1- to 3-MW short pulse spallation source with a liquid mercury target has been started recently. The design tools and methods being developed to define requirements, integrate the work, and provide early cost guidance will be presented with a summary of the current target station design status. The initial design point was selected with performance and cost estimate projections by a systems code. This code was developed recently using cost estimates from the Brookhaven Pulsed Spallation Neutron Source study and experience from the Advanced Neutron Source Project`s conceptual design. It will be updated and improvedmore » as the design develops. Performance was characterized by a simplified figure of merit based on a ratio of neutron production to costs. A work breakdown structure was developed, with simplified systems diagrams used to define interfaces and system responsibilities. A risk assessment method was used to identify potential problems, to identify required research and development (R&D), and to aid contingency development. Preliminary 3-D models of the target station are being used to develop remote maintenance concepts and to estimate costs.« less

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

PubMed

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.

How does the size and shape of local populations in China compare to general anthropometric surveys currently used for product design?

PubMed

Daniell, Nathan; Fraysse, François; Paul, Gunther

2012-01-01

Anthropometry has long been used for a range of ergonomic applications & product design. Although products are often designed for specific cohorts, anthropometric data are typically sourced from large scale surveys representative of the general population. Additionally, few data are available for emerging markets like China and India. This study measured 80 Chinese males that were representative of a specific cohort targeted for the design of a new product. Thirteen anthropometric measurements were recorded and compared to two large databases that represented a general population, a Chinese database and a Western database. Substantial differences were identified between the Chinese males measured in this study and both databases. The subjects were substantially taller, heavier and broader than subjects in the older Chinese database. However, they were still substantially smaller, lighter and thinner than Western males. Data from current Western anthropometric surveys are unlikely to accurately represent the target population for product designers and manufacturers in emerging markets like China.

Modifications to risk-targeted seismic design maps for subduction and near-fault hazards

USGS Publications Warehouse

Liel, Abbie B.; Luco, Nicolas; Raghunandan, Meera; Champion, C.; Haukaas, Terje

2015-01-01

ASCE 7-10 introduced new seismic design maps that define risk-targeted ground motions such that buildings designed according to these maps will have 1% chance of collapse in 50 years. These maps were developed by iterative risk calculation, wherein a generic building collapse fragility curve is convolved with the U.S. Geological Survey hazard curve until target risk criteria are met. Recent research shows that this current approach may be unconservative at locations where the tectonic environment is much different than that used to develop the generic fragility curve. This study illustrates how risk-targeted ground motions at selected sites would change if generic building fragility curve and hazard assessment were modified to account for seismic risk from subduction earthquakes and near-fault pulses. The paper also explores the difficulties in implementing these changes.

Compliant flow designs for optimum lift control of wind turbine rotors

NASA Astrophysics Data System (ADS)

Williams, Theodore J. H.

An optimization approach was formulated to determine geometric designs that are most compliant to flow control devices. Single dielectric barrier discharge (SDBD) plasma actuators are used in the flow control design optimization as they are able to be incorporated into CFD simulations. An adjoint formulation was derived in order to have a numerically efficient way of calculating the shape derivatives on the surface of the geometric design. The design of a wind turbine blade retrofit for the JIMP 25kW wind turbine at Notre Dame is used to motivate analyses that utilize the optimization approach. The CFD simulations of the existing wind turbine blade were validated against wind tunnel testing. A one-parameter optimization was performed in order to design a trailing edge addition for the current wind turbine blade. The trailing edge addition was designed to meet a desired lift target while maximizing the lift-to-drag ratio. This analysis was performed at seven radial locations on the wind turbine blade. The new trailing edge retrofits were able to achieve the lift target for the outboard radial locations. The designed geometry has been fabricated and is currently being validated on a full-scale turbine and it is predicted to have an increase in annual energy production of 4.30%. The design of a trailing edge retrofit that includes the use of a SDBD plasma actuator was performed using a two-parameter optimization. The objective of this analysis was to meet the lift target and maximize the controllability of the design. The controllability is defined as the difference in lift between plasma on and plasma off cases. A trailing edge retrofit with the plasma actuator located on the pressure side was able to achieve the target passive lift increase while using plasma flow control to reduce the lift to below the original design. This design resulted in a highly compliant flow.

Current target acquisition methodology in force on force simulations

NASA Astrophysics Data System (ADS)

Hixson, Jonathan G.; Miller, Brian; Mazz, John P.

2017-05-01

The U.S. Army RDECOM CERDEC NVESD MSD's target acquisition models have been used for many years by the military community in force on force simulations for training, testing, and analysis. There have been significant improvements to these models over the past few years. The significant improvements are the transition of ACQUIRE TTP-TAS (ACQUIRE Targeting Task Performance Target Angular Size) methodology for all imaging sensors and the development of new discrimination criteria for urban environments and humans. This paper is intended to provide an overview of the current target acquisition modeling approach and provide data for the new discrimination tasks. This paper will discuss advances and changes to the models and methodologies used to: (1) design and compare sensors' performance, (2) predict expected target acquisition performance in the field, (3) predict target acquisition performance for combat simulations, and (4) how to conduct model data validation for combat simulations.

SINQ layout, operation, applications and R&D to high power

NASA Astrophysics Data System (ADS)

Bauer, G. S.; Dai, Y.; Wagner, W.

2002-09-01

Since 1997, the Paul Scherrer Institut (PSI) is operating a 1 MW class research spallation neutron source, named SINQ. SINQ is driven by a cascade of three accelerators, the final stage being a 590 MeV isochronous ring cyclotron which delivers a beam current of 1.8 mA at an rf-frequency of 51 MHz. Since for neutron production this is essentially a dc-device, SINQ is a continuous neutron source and is optimized in its design for high time average neutron flux. This makes the facility similar to a research reactor in terms of utilization, but, in terms of beam power, it is, by a large margin, the most powerful spallation neutron source currently in operation world wide. As a consequence, target load levels prevail in SINQ which are beyond the realm of existing experience, demanding a careful approach to the design and operation of a high power target. While the best neutronic performance of the source is expected for a liquid lead-bismuth eutectic target, no experience with such systems exists. For this reason a staged approach has been embarked upon, starting with a heavy water cooled rod target of Zircaloy-2 and proceeding via steel clad lead rods towards the final goal of a target optimised in both, neutronic performance and service life time. Experience currently accruing with a test target containing sample rods with different materials specimens will help to select the proper structural material and make dependable life time estimates accounting for the real operating conditions that prevail in the facility. In parallel, both theoretical and experimental work is going on within the MEGAPIE (MEGAwatt Pilot Experiment) project, a joint initiative by six European research institutions and JAERI (Japan), DOE (USA) and KAERI (Korea), to design, build, operate and explore a liquid lead-bismuth spallation target for 1MW of beam power, taking advantage of the existing spallation neutron facility SINQ.

Experimental clean combustor program, phase 1

NASA Technical Reports Server (NTRS)

Bahr, D. W.; Gleason, C. C.

1975-01-01

Full annular versions of advanced combustor designs, sized to fit within the CF6-50 engine, were defined, manufactured, and tested at high pressure conditions. Configurations were screened, and significant reductions in CO, HC, and NOx emissions levels were achieved with two of these advanced combustor design concepts. Emissions and performance data at a typical AST cruise condition were also obtained along with combustor noise data as a part of an addendum to the basic program. The two promising combustor design approaches evolved in these efforts were the Double Annular Combustor and the Radial/Axial Combustor. With versions of these two basic combustor designs, CO and HC emissions levels at or near the target levels were obtained. Although the low target NOx emissions level was not obtained with these two advanced combustor designs, significant reductions were relative to the NOx levels of current technology combustors. Smoke emission levels below the target value were obtained.

Development of Water Target for Radioisotope Production

NASA Astrophysics Data System (ADS)

Tripp, Nathan

2011-10-01

Ongoing studies of plant physiology at TUNL require a supply of nitrogen-13 for use as a radiotracer. Production of nitrogen-13 using a water target and a proton beam follows the nuclear reaction 16-O(p,a)13-N. Unfortunately the irradiation of trace amounts of oxygen-18 within a natural water target produces fluorine-18 by the reaction 18-O(p, n)18-F. The presence of this second radioisotope reduces the efficacy of nitrogen-13 as a radiotracer. Designing a natural water target for nitrogen-13 production at TUNL required the design of several new systems to address the problems inherent in nitrogen-13 production. A heat exchanger cools the target water after irradiation within the target cell. The resulting improved thermal regulation of the target water prevents the system from overheating and minimizes the effect of the cavitations occurring within the target. Alumina pellets within a scrubbing unit remove the fluorine-18 contamination from the irradiated water. The modular design of the water target apparatus makes the system highly adaptable, allowing for easy reuse and adaptation of the different components into future projects. The newly designed and constructed water target should meet the current and future needs of TUNL researchers in the production of nitrogen-13. This TUNL REU project was funded in part by a grant from the National Science Foundation (NSF) NSF-PHY-08-51813.

Transport Simulations for Fast Ignition on NIF

DOE Office of Scientific and Technical Information (OSTI.GOV)

Strozzi, D J; Tabak, M; Grote, D P

2009-10-26

We are designing a full hydro-scale cone-guided, indirect-drive FI coupling experiment, for NIF, with the ARC-FIDO short-pulse laser. Current rad-hydro designs with limited fuel jetting into cone tip are not yet adequate for ignition. Designs are improving. Electron beam transport simulations (implicit-PIC LSP) show: (1) Magnetic fields and smaller angular spreads increase coupling to ignition-relevant 'hot spot' (20 um radius); (2) Plastic CD (for a warm target) produces somewhat better coupling than pure D (cryogenic target) due to enhanced resistive B fields; and (3) The optimal T{sub hot} for this target is {approx} 1 MeV; coupling falls by 3x asmore » T{sub hot} rises to 4 MeV.« less

The light ion pulsed power induction accelerator for ETF

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mazarakis, M.G.; Olson, R.E.; Olson, C.L.

1994-12-31

Our Engineering Test Facility (ETF) driver concept is based on HERMES III and RHEPP technologies. Actually, it is a scaled-down version of the LMF design incorporating repetition rate capabilities of up to 10 Hz CW. The preconceptual design presented here provides 200-TW peak power to the ETF target during 10 ns, equal to 2-MJ total ion beam energy. Linear inductive voltage addition driving a self-magnetically insulated transmission line (MITL) is utilized to generate the 36-MV peak voltage needed for lithium ion beams. The {approximately} 3-MA ion current is achieved by utilizing many accelerating modules in parallel. Since the current permore » module is relatively modest ({approximately}300 kA), two-stage or one-stage extraction diodes can be utilized for the generation of singly charged lithium ions. The accelerating modules are arranged symmetrically around the fusion chamber in order to provide uniform irradiation onto the ETF target. In addition, the modules are fired in a programmed sequence in order to generate the optimum power pulse shape onto the target. This design utilizes RHEPP accelerator modules as the principal power source.« less

Integrating modeling and surveys for more effective assessments

EPA Science Inventory

A false dichotomy currently exists in monitoring that pits sample surveys based on probability designs against targeted monitoring of hand-picked sites. We maintain that judicious use of both, when designed to be integrated, produces assessments of greater value than either inde...

Planar LTCC transformers for high voltage flyback converters: Part II.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schofield, Daryl; Schare, Joshua M., Ph.D.; Slama, George

This paper is a continuation of the work presented in SAND2007-2591 'Planar LTCC Transformers for High Voltage Flyback Converters'. The designs in that SAND report were all based on a ferrite tape/dielectric paste system originally developed by NASCENTechnoloy, Inc, who collaborated in the design and manufacturing of the planar LTCC flyback converters. The output/volume requirements were targeted to DoD application for hard target/mini fuzing at around 1500 V for reasonable primary peak currents. High voltages could be obtained but with considerable higher current. Work had begun on higher voltage systems and is where this report begins. Limits in material propertiesmore » and processing capabilities show that the state-of-the-art has limited our practical output voltage from such a small part volume. In other words, the technology is currently limited within the allowable funding and interest.« less

Methamphetamine Vaccines: Improvement through Hapten Design.

PubMed

Collins, Karen C; Schlosburg, Joel E; Bremer, Paul T; Janda, Kim D

2016-04-28

Methamphetamine (MA) addiction is a serious public health problem, and current methods to abate addiction and relapse are currently ineffective for mitigating this growing global epidemic. Development of a vaccine targeting MA would provide a complementary strategy to existing behavioral therapies, but this has proven challenging. Herein, we describe optimization of both hapten design and formulation, identifying a vaccine that elicited a robust anti-MA immune response in mice, decreasing methamphetamine-induced locomotor activity.

Designing multiple ligands - medicinal chemistry strategies and challenges.

PubMed

Morphy, Richard; Rankovic, Zoran

2009-01-01

It has been widely recognised over the recent years that parallel modulation of multiple biological targets can be beneficial for treatment of diseases with complex etiologies such as cancer asthma, and psychiatric disease. In this article, current strategies for the generation of ligands with a specific multi-target profile (designed multiple ligands or DMLs) are described and a number of illustrative example are given. Designing multiple ligands is frequently a challenging endeavour for medicinal chemists, with the need to appropriately balance affinity for 2 or more targets whilst obtaining physicochemical and pharmacokinetic properties that are consistent with the administration of an oral drug. Given that the properties of DMLs are influenced to a large extent by the proteomic superfamily to which the targets belong and the lead generation strategy that is pursued, an early assessment of the feasibility of any given DML project is essential.

Quantum control of coherent π -electron ring currents in polycyclic aromatic hydrocarbons

NASA Astrophysics Data System (ADS)

Mineo, Hirobumi; Fujimura, Yuichi

2017-12-01

We present results for quantum optimal control (QOC) of the coherent π electron ring currents in polycyclic aromatic hydrocarbons (PAHs). Since PAHs consist of a number of condensed benzene rings, in principle, there exist various coherent ring patterns. These include the ring current localized to a designated benzene ring, the perimeter ring current that flows along the edge of the PAH, and the middle ring current of PAHs having an odd number of benzene rings such as anthracene. In the present QOC treatment, the best target wavefunction for generation of the ring current through a designated path is determined by a Lagrange multiplier method. The target function is integrated into the ordinary QOC theory. To demonstrate the applicability of the QOC procedure, we took naphthalene and anthracene as the simplest examples of linear PAHs. The mechanisms of ring current generation were clarified by analyzing the temporal evolutions of the electronic excited states after coherent excitation by UV pulses or (UV+IR) pulses as well as those of electric fields of the optimal laser pulses. Time-dependent simulations of the perimeter ring current and middle ring current of anthracene, which are induced by analytical electric fields of UV pulsed lasers, were performed to reproduce the QOC results.

Adding Selectivity to Antimicrobial Peptides: Rational Design of a Multidomain Peptide against Pseudomonas spp.

PubMed Central

Eckert, Randal; Qi, Fengxia; Yarbrough, Daniel K.; He, Jian; Anderson, Maxwell H.; Shi, Wenyuan

2006-01-01

Currently available antimicrobials exhibit broad killing with regard to bacterial genera and species. Indiscriminate killing of microbes by these conventional antibiotics can disrupt the ecological balance of the indigenous microbial flora, often resulting in negative clinical consequences. Species-specific antimicrobials capable of precisely targeting pathogenic bacteria without damaging benign microorganisms provide a means of avoiding this problem. In this communication, we report the successful creation of the first synthetic, target-specific antimicrobial peptide, G10KHc, via addition of a rationally designed Pseudomonas-specific targeting moiety (KH) to a generally killing peptide (novispirin G10). The resulting chimeric peptide showed enhanced bactericidal activity and faster killing kinetics against Pseudomonas spp. than G10 alone. The enhanced killing activities are due to increased binding and penetration of the outer membrane of Pseudomonas sp. cells. These properties were not observed in tests of untargeted bacterial species, and this specificity allowed G10KHc to selectively eliminate Pseudomonas spp. from mixed cultures. This work lays a foundation for generating target-specific “smart” antimicrobials to complement currently available conventional antibiotics. PMID:16569868

Antares Reference Telescopes System

NASA Astrophysics Data System (ADS)

Viswanathan, V. K.; Kaprelian, E.; Swann, T.; Parker, J.; Wolfe, P.; Woodfin, G.; Knight, D.

1983-11-01

Antares is a 24-beam, 40-TW carbon-dioxide laser fusion system currently nearing completion at the Los Alamos National Laboratory. The 24 beams will be focused onto a tiny target (typically 300-1000 pm in diameter) located approximately at the center of a 7.3-m diameter by 9.3-m long vacuum (10-6 torr) chamber. The design goal is to position the targets to within 10 μm of a selected nominal position, which may be anywhere within a fixed spherical region 1 cm in diameter. The Antares Reference Telescope System is intended to help achieve this goal for alignment and viewing of the various targets used in the laser system. The Antares Reference Telescope System consists of two similar electro-optical systems positioned in a near orthogonal manner in the target chamber area of the laser. Each of these consists of four subsystems: 1) a fixed 9X optical imaging subsystem which produces an image of the target at the vidicon; 2) a reticle projection subsystem which superimposes an image of the reticle pattern at the vidicon; 3) an adjustable front-lighting subsystem which illuminates tne target; and 4) an adjustable back-lighting subsystem which also can be used to illuminate the target. The various optical, mechanical, and vidicon design considerations and trade-offs are discussed. The final system chosen (which is being built) and its current status are described in detail.

Balancing focused combinatorial libraries based on multiple GPCR ligands

NASA Astrophysics Data System (ADS)

Soltanshahi, Farhad; Mansley, Tamsin E.; Choi, Sun; Clark, Robert D.

2006-08-01

G-Protein coupled receptors (GPCRs) are important targets for drug discovery, and combinatorial chemistry is an important tool for pharmaceutical development. The absence of detailed structural information, however, limits the kinds of combinatorial design techniques that can be applied to GPCR targets. This is particularly problematic given the current emphasis on focused combinatorial libraries. By linking an incremental construction method (OptDesign) to the very fast shape-matching capability of ChemSpace, we have created an efficient method for designing targeted sublibraries that are topomerically similar to known actives. Multi-objective scoring allows consideration of multiple queries (actives) simultaneously. This can lead to a distribution of products skewed towards one particular query structure, however, particularly when the ligands of interest are quite dissimilar to one another. A novel pivoting technique is described which makes it possible to generate promising designs even under those circumstances. The approach is illustrated by application to some serotonergic agonists and chemokine antagonists.

Design and evaluation of 66 kV-class HTS power cable using REBCO wires

NASA Astrophysics Data System (ADS)

Ohya, M.; Yumura, H.; Masuda, T.; Amemiya, N.; Ishiyama, A.; Ohkuma, T.

2011-11-01

Sumitomo Electric (SEI) has been involved in the development of 66 kV-class HTS cables using REBCO wires. One of the technical targets in this project is to reduce the AC loss to less than 2 W/m/phase at 5 kA. SEI has developed a clad-type of textured metal substrate with lower magnetization loss compared with a conventional NiW substrate. In addition, 30 mm-wide REBCO tapes were slit into 4 mm-wide strips, and these strips were wound spirally on a former with small gaps. The AC loss of a manufactured 4-layer cable conductor was 1.5 W/m at 5 kA at 64 K. Given that the AC loss in a shield layer is supposed to be one-fourth of a whole cable core loss, our cables are expected to achieve the AC loss target of less than 2 W/m/phase at 5 kA. Another important target is to manage a fault current. A cable core was designed and fabricated based on the simulation findings, and over-current tests (max. 31.5 kA, 2 s) were conducted to check its performance. The critical current value of the cable cores were measured before and after the over-current tests and verified its soundness. A 5 kA-class current lead for the cable terminations was also developed. The current loading tests were conducted for the developed current leads. The temperature distribution of the current leads reached to the steady-state within less than 12 h, and it was confirmed that the developed current lead has enough capacity of 5 kA loading.

Comparing Pedagogies for Plastic Waste Management at University Level

ERIC Educational Resources Information Center

Yeung, Siu-Kit; So, Wing-Mui Winnie; Cheng, Nga-Yee Irene; Cheung, Tsz-Yan; Chow, Cheuk-Fai

2017-01-01

Purpose: This paper aims to compare the learning outcomes of gaming simulation and guided inquiry in sustainability education on plastic waste management. The current study targets the identification of success factors in these teaching approaches. Design/methodology/approach: This study used a quasi-experimental design with undergraduate…

Navigating School Safety Law and Policy

ERIC Educational Resources Information Center

Vaillancourt, Kelly; Rossen, Eric

2012-01-01

Initiatives designed to improve school safety and conditions for learning have become central to education reform efforts at the local, state, and national levels. These efforts often target the reduction and prevention of bullying, discrimination, and harassment in schools. While most states currently have some form of law or policy designed to…

Nanotechnology-based drug delivery treatments and specific targeting therapy for age-related macular degeneration.

PubMed

Lin, Tai-Chi; Hung, Kuo-Hsuan; Peng, Chi-Hsien; Liu, Jorn-Hon; Woung, Lin-Chung; Tsai, Ching-Yao; Chen, Shih-Jen; Chen, Yan-Ting; Hsu, Chih-Chien

2015-11-01

Nanoparticles combined with cells, drugs, and specially designed genes provide improved therapeutic efficacy in studies and clinical setting, demonstrating a new era of treatment strategy, especially in retinal diseases. Nanotechnology-based drugs can provide an essential platform for sustaining, releasing and a specific targeting design to treat retinal diseases. Poly-lactic-co-glycolic acid is the most widely used biocompatible and biodegradable polymer approved by the Food and Drug Administration. Many studies have attempted to develop special devices for delivering small-molecule drugs, proteins, and other macromolecules consistently and slowly. In this article, we first review current progress in the treatment of age-related macular degeneration. Then, we discuss the function of vascular endothelial growth factor (VEGF) and the pharmacological effects of anti-VEGF-A antibodies and soluble or modified VEGF receptors. Lastly, we summarize the combination of antiangiogenic therapy and nanomedicines, and review current potential targeting therapy in age-related macular degeneration. Copyright © 2015. Published by Elsevier Taiwan.

What Can Crystal Structures of Aminergic Receptors Tell Us about Designing Subtype-Selective Ligands?

PubMed Central

Michino, Mayako; Beuming, Thijs; Donthamsetti, Prashant; Newman, Amy Hauck; Javitch, Jonathan A.

2015-01-01

G protein–coupled receptors (GPCRs) are integral membrane proteins that represent an important class of drug targets. In particular, aminergic GPCRs interact with a significant portion of drugs currently on the market. However, most drugs that target these receptors are associated with undesirable side effects, which are due in part to promiscuous interactions with close homologs of the intended target receptors. Here, based on a systematic analysis of all 37 of the currently available high-resolution crystal structures of aminergic GPCRs, we review structural elements that contribute to and can be exploited for designing subtype-selective compounds. We describe the roles of secondary binding pockets (SBPs), as well as differences in ligand entry pathways to the orthosteric binding site, in determining selectivity. In addition, using the available crystal structures, we have identified conformational changes in the SBPs that are associated with receptor activation and explore the implications of these changes for the rational development of selective ligands with tailored efficacy. PMID:25527701

Modulation of Epigenetic Targets for Anticancer Therapy: Clinicopathological Relevance, Structural Data and Drug Discovery Perspectives

PubMed Central

Andreol, Federico; Barbosa, Arménio Jorge Moura; Daniele Parenti, Marco; Rio, Alberto Del

2013-01-01

Research on cancer epigenetics has flourished in the last decade. Nevertheless growing evidence point on the importance to understand the mechanisms by which epigenetic changes regulate the genesis and progression of cancer growth. Several epigenetic targets have been discovered and are currently under validation for new anticancer therapies. Drug discovery approaches aiming to target these epigenetic enzymes with small-molecules inhibitors have produced the first pre-clinical and clinical outcomes and many other compounds are now entering the pipeline as new candidate epidrugs. The most studied targets can be ascribed to histone deacetylases and DNA methyltransferases, although several other classes of enzymes are able to operate post-translational modifications to histone tails are also likely to represent new frontiers for therapeutic interventions. By acknowledging that the field of cancer epigenetics is evolving with an impressive rate of new findings, with this review we aim to provide a current overview of pre-clinical applications of small-molecules for cancer pathologies, combining them with the current knowledge of epigenetic targets in terms of available structural data and drug design perspectives. PMID:23016851

Inorganic chemistry in nuclear imaging and radiotherapy: current and future directions

PubMed Central

Carroll, Valerie; Demoin, Dustin W.; Hoffman, Timothy J; Jurisson, Silvia S

2013-01-01

Summary Radiometals play an important role in diagnostic and therapeutic radiopharmaceuticals. This field of radiochemistry is multidisciplinary, involving radiometal production, separation of the radiometal from its target, chelate design for complexing the radiometal in a biologically stable environment, specific targeting of the radiometal to its in vivo site, and nuclear imaging and/or radiotherapy applications of the resultant radiopharmaceutical. The critical importance of inorganic chemistry in the design and application of radiometal-containing imaging and therapy agents is described from a historical perspective to future directions. PMID:25382874

Designing Isoform-selective Inhibitors Against Classical HDACs for Effective Anticancer Therapy: Insight and Perspectives from In Silico.

PubMed

Ganai, Shabir Ahmad

2018-01-01

Histone deacetylase inhibitors, the small molecules modulating the biological activity of histone deacetylases are emerging as potent chemotherapeutic agents. Despite their considerable therapeutic benefits in disease models, the lack of isoform specificity culminates in debilitating off target effects, raising serious concerns regarding their applicability. This emphasizes the pressing and unmet medical need of designing isoform selective inhibitors for safe and effective anticancer therapy. Keeping these grim facts in view, the current article sheds light on structural basis of off-targeting. Furthermore, the article discusses extensively the role of in silico strategies such as Molecular Docking, Molecular Dynamics Simulation and Energetically-optimized structure based pharmacophore approach in designing on-target inhibitors against classical HDACs. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

29 mm Diameter Target Test Report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Woloshun, Keith Albert; Olivas, Eric Richard; Dale, Gregory E.

After numerous delays, the test of the 29 mm diameter target was conducted on 8/18/2017. The complete target design report, dated 8/15/2016, is reproduced below for completeness. This describes in detail the 10 disk target with varying thickness disks. The report presents and discusses the test results. In brief summary, there appears to have been multiple instrumentation errors. Measured temperatures, pressures and IR camera window temperature measurement are all suspect. All tests were done at 35 MeV, with 171 μA current, or 6 kW of beam power.

A pulsed supersonic gas jet target for precision spectroscopy at the HITRAP facility at GSI

NASA Astrophysics Data System (ADS)

Tiedemann, D.; Stiebing, K. E.; Winters, D. F. A.; Quint, W.; Varentsov, V.; Warczak, A.; Malarz, A.; Stöhlker, Th.

2014-11-01

A pulsed supersonic gas jet target for experiments at the HITRAP facility at the GSI Helmholtzzentrum für Schwerionenforschung in Darmstadt has been designed and built as a multi-purpose installation for key experiments on fundamental atomic physics in strong fields. This setup is currently installed at the Institut für Kernphysik of Goethe-University, Frankfurt am Main (IKF), in order to explore its operation prior to its installation at the HITRAP facility. Design and performance of the target are described. The measured target densities of 5.9×1012 atoms/cm3 for helium and 8.1×1012 atoms/cm³ for argon at the stagnation pressure of 30 bar match the required values. The target-beam diameter of 0.9 mm and the pulsed operation mode (jet built-up-time ≤15 ms) are well suited for the use at HITRAP.

Battlespace Representation for Air, Space, and Cyber

DTIC Science & Technology

2012-07-17

they were cardboard models of targets carried in the bombers to allow bombardiers to see how the target would look with current shadows. See Figure ...1 for an example. Command and control has changed as well as targeting. Figure 2 illustrates a WW II-era command center built in tunnels near...invariants that can be used to shape or guide designs. Figure 1. A cardboard model used by bombers. Command and control has changed as well as

Demonstration of a high-intensity neutron source based on a liquid-lithium target for Accelerator based Boron Neutron Capture Therapy.

PubMed

Halfon, S; Arenshtam, A; Kijel, D; Paul, M; Weissman, L; Berkovits, D; Eliyahu, I; Feinberg, G; Kreisel, A; Mardor, I; Shimel, G; Shor, A; Silverman, I; Tessler, M

2015-12-01

A free surface liquid-lithium jet target is operating routinely at Soreq Applied Research Accelerator Facility (SARAF), bombarded with a ~1.91 MeV, ~1.2 mA continuous-wave narrow proton beam. The experiments demonstrate the liquid lithium target (LiLiT) capability to constitute an intense source of epithermal neutrons, for Accelerator based Boron Neutron Capture Therapy (BNCT). The target dissipates extremely high ion beam power densities (>3 kW/cm(2), >0.5 MW/cm(3)) for long periods of time, while maintaining stable conditions and localized residual activity. LiLiT generates ~3×10(10) n/s, which is more than one order of magnitude larger than conventional (7)Li(p,n)-based near threshold neutron sources. A shield and moderator assembly for BNCT, with LiLiT irradiated with protons at 1.91 MeV, was designed based on Monte Carlo (MCNP) simulations of BNCT-doses produced in a phantom. According to these simulations it was found that a ~15 mA near threshold proton current will apply the therapeutic doses in ~1h treatment duration. According to our present results, such high current beams can be dissipated in a liquid-lithium target, hence the target design is readily applicable for accelerator-based BNCT. Copyright © 2015 Elsevier Ltd. All rights reserved.

Fuel Injector Design Optimization for an Annular Scramjet Geometry

NASA Technical Reports Server (NTRS)

Steffen, Christopher J., Jr.

2003-01-01

A four-parameter, three-level, central composite experiment design has been used to optimize the configuration of an annular scramjet injector geometry using computational fluid dynamics. The computational fluid dynamic solutions played the role of computer experiments, and response surface methodology was used to capture the simulation results for mixing efficiency and total pressure recovery within the scramjet flowpath. An optimization procedure, based upon the response surface results of mixing efficiency, was used to compare the optimal design configuration against the target efficiency value of 92.5%. The results of three different optimization procedures are presented and all point to the need to look outside the current design space for different injector geometries that can meet or exceed the stated mixing efficiency target.

PEG Enhancement for EM1 and EM2+ Missions

NASA Technical Reports Server (NTRS)

Von der Porten, Paul; Ahmad, Naeem; Hawkins, Matt

2018-01-01

NASA is currently building the Space Launch System (SLS) Block-1 launch vehicle for the Exploration Mission 1 (EM-1) test flight. The next evolution of SLS, the Block-1B Exploration Mission 2 (EM-2), is currently being designed. The Block-1 and Block-1B vehicles will use the Powered Explicit Guidance (PEG) algorithm. Due to the relatively low thrust-to-weight ratio of the Exploration Upper Stage (EUS), certain enhancements to the Block-1 PEG algorithm are needed to perform Block-1B missions. In order to accommodate mission design for EM-2 and beyond, PEG has been significantly improved since its use on the Space Shuttle program. The current version of PEG has the ability to switch to different targets during Core Stage (CS) or EUS flight, and can automatically reconfigure for a single Engine Out (EO) scenario, loss of communication with the Launch Abort System (LAS), and Inertial Navigation System (INS) failure. The Thrust Factor (TF) algorithm uses measured state information in addition to a priori parameters, providing PEG with an improved estimate of propulsion information. This provides robustness against unknown or undetected engine failures. A loft parameter input allows LAS jettison while maximizing payload mass. The current PEG algorithm is now able to handle various classes of missions with burn arcs much longer than were seen in the shuttle program. These missions include targeting a circular LEO orbit with a low-thrust, long-burn-duration upper stage, targeting a highly eccentric Trans-Lunar Injection (TLI) orbit, targeting a disposal orbit using the low-thrust Reaction Control System (RCS), and targeting a hyperbolic orbit. This paper will describe the design and implementation of the TF algorithm, the strategy to handle EO in various flight regimes, algorithms to cover off-nominal conditions, and other enhancements to the Block-1 PEG algorithm. This paper illustrates challenges posed by the Block-1B vehicle, and results show that the improved PEG algorithm is capable for use on the SLS Block 1-B vehicle as part of the Guidance, Navigation, and Control System.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Batchelor, D.B.; Carreras, B.A.; Hirshman, S.P.

Significant progress has been made in the development of new modest-size compact stellarator devices that could test optimization principles for the design of a more attractive reactor. These are 3 and 4 field period low-aspect-ratio quasi-omnigenous (QO) stellarators based on an optimization method that targets improved confinement, stability, ease of coil design, low-aspect-ratio, and low bootstrap current.

Beyond the Basics: Award-Winning Scholastic Newspapers Define Excellence.

ERIC Educational Resources Information Center

Konkle, Bruce E.

2001-01-01

Considers how a scholastic newspaper staff becomes "Award-Winning." Notes that it is important to consider developing effective and functional infographic formats; editing type and page designs with an eye for consistency; writing stories that are all targeted to their teen audience; or modernizing design to keep pace with current publication…

Using the Personal Competence Manager as a Complementary Approach to IMS Learning Design Authoring

ERIC Educational Resources Information Center

Vogten, Hubert; Koper, Rob; Martens, Harrie; van Bruggen, Jan

2008-01-01

In this article TENCompetence will be presented as a framework for lifelong competence development. More specifically, the relationship between the TENCompetence framework and the IMS Learning Design (LD) specification is explored. LD authoring has proven to be challenging and the toolset currently available is targeting expert users mostly…

Impact of tDCS on Performance and Learning of Target Detection: Interaction with Stimulus Characteristics and Experimental Design

ERIC Educational Resources Information Center

Coffman, B. A.; Trumbo, M. C.; Flores, R. A.; Garcia, C. M.; van der Merwe, A. J.; Wassermann, E. M.; Weisend, M. P.; Clark, V. P.

2012-01-01

We have previously found that transcranial direct current stimulation (tDCS) over right inferior frontal cortex (RIFC) enhances performance during learning of a difficult visual target detection task (Clark et al., 2012). In order to examine the cognitive mechanisms of tDCS that lead to enhanced performance, here we analyzed its differential…

Development of Liver-Targeting Insulin

DTIC Science & Technology

2017-08-01

decision unless so designated by other documentation. REPORT DOCUMENTATION PAGE Form Approved OMB No. 0704-0188 Public reporting burden for this...have been done in the design of better insulin, problems still exist with the current therapies. For example, frequent subcutaneous injections are always...ligands will be designed and synthesized. The ligands molecular weight is a fraction of insulin, and therefore should result in an insulin analog with

Injector design for liner-on-target gas-puff experiments

NASA Astrophysics Data System (ADS)

Valenzuela, J. C.; Krasheninnikov, I.; Conti, F.; Wessel, F.; Fadeev, V.; Narkis, J.; Ross, M. P.; Rahman, H. U.; Ruskov, E.; Beg, F. N.

2017-11-01

We present the design of a gas-puff injector for liner-on-target experiments. The injector is composed of an annular high atomic number (e.g., Ar and Kr) gas and an on-axis plasma gun that delivers an ionized deuterium target. The annular supersonic nozzle injector has been studied using Computational Fluid Dynamics (CFD) simulations to produce a highly collimated (M > 5), ˜1 cm radius gas profile that satisfies the theoretical requirement for best performance on ˜1-MA current generators. The CFD simulations allowed us to study output density profiles as a function of the nozzle shape, gas pressure, and gas composition. We have performed line-integrated density measurements using a continuous wave (CW) He-Ne laser to characterize the liner gas density. The measurements agree well with the CFD values. We have used a simple snowplow model to study the plasma sheath acceleration in a coaxial plasma gun to help us properly design the target injector.

Injector design for liner-on-target gas-puff experiments.

PubMed

Valenzuela, J C; Krasheninnikov, I; Conti, F; Wessel, F; Fadeev, V; Narkis, J; Ross, M P; Rahman, H U; Ruskov, E; Beg, F N

2017-11-01

We present the design of a gas-puff injector for liner-on-target experiments. The injector is composed of an annular high atomic number (e.g., Ar and Kr) gas and an on-axis plasma gun that delivers an ionized deuterium target. The annular supersonic nozzle injector has been studied using Computational Fluid Dynamics (CFD) simulations to produce a highly collimated (M > 5), ∼1 cm radius gas profile that satisfies the theoretical requirement for best performance on ∼1-MA current generators. The CFD simulations allowed us to study output density profiles as a function of the nozzle shape, gas pressure, and gas composition. We have performed line-integrated density measurements using a continuous wave (CW) He-Ne laser to characterize the liner gas density. The measurements agree well with the CFD values. We have used a simple snowplow model to study the plasma sheath acceleration in a coaxial plasma gun to help us properly design the target injector.

Design specification for the European Spallation Source neutron generating target element

NASA Astrophysics Data System (ADS)

Aguilar, A.; Sordo, F.; Mora, T.; Mena, L.; Mancisidor, M.; Aguilar, J.; Bakedano, G.; Herranz, I.; Luna, P.; Magan, M.; Vivanco, R.; Jimenez-Villacorta, F.; Sjogreen, K.; Oden, U.; Perlado, J. M.; Martinez, J. L.; Bermejo, F. J.

2017-06-01

The paper addresses some of the most relevant issues concerning the thermal hydraulics and radiation damage of the neutron generation target to be built at the European Spallation Source as recently approved after a critical design review. The target unit consists of a set of Tungsten blocks placed inside a wheel of 2.5 m diameter which rotates at some 0.5 Hz in order to distribute the heat generated from incoming protons which reach the target in the radial direction. The spallation material elements are composed of an array of Tungsten pieces which rest on a rotating steel support (the cassette) and are distributed in a cross-flow configuration. The thermal, mechanical and radiation effects resulting from the impact of a 2 GeV proton pulse are analysed in detail as well as an evaluation of the inventory of spallation products. The current design is found to conform to specifications and found to be robust enough to deal with several accident scenarios.

Large-scale production of diesel-like biofuels - process design as an inherent part of microorganism development.

PubMed

Cuellar, Maria C; Heijnen, Joseph J; van der Wielen, Luuk A M

2013-06-01

Industrial biotechnology is playing an important role in the transition to a bio-based economy. Currently, however, industrial implementation is still modest, despite the advances made in microorganism development. Given that the fuels and commodity chemicals sectors are characterized by tight economic margins, we propose to address overall process design and efficiency at the start of bioprocess development. While current microorganism development is targeted at product formation and product yield, addressing process design at the start of bioprocess development means that microorganism selection can also be extended to other critical targets for process technology and process scale implementation, such as enhancing cell separation or increasing cell robustness at operating conditions that favor the overall process. In this paper we follow this approach for the microbial production of diesel-like biofuels. We review current microbial routes with both oleaginous and engineered microorganisms. For the routes leading to extracellular production, we identify the process conditions for large scale operation. The process conditions identified are finally translated to microorganism development targets. We show that microorganism development should be directed at anaerobic production, increasing robustness at extreme process conditions and tailoring cell surface properties. All the same time, novel process configurations integrating fermentation and product recovery, cell reuse and low-cost technologies for product separation are mandatory. This review provides a state-of-the-art summary of the latest challenges in large-scale production of diesel-like biofuels. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Feedstock Supply System Design and Economics for Conversion of Lignocellulosic Biomass to Hydrocarbon Fuels: Conversion Pathway: Biological Conversion of Sugars to Hydrocarbons The 2017 Design Case

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kevin Kenney; Kara G. Cafferty; Jacob J. Jacobson

The U.S. Department of Energy promotes the production of a range of liquid fuels and fuel blendstocks from lignocellulosic biomass feedstocks by funding fundamental and applied research that advances the state of technology in biomass collection, conversion, and sustainability. As part of its involvement in this program, the Idaho National Laboratory (INL) investigates the feedstock logistics economics and sustainability of these fuels. Between 2000 and 2012, INL conducted a campaign to quantify the economics and sustainability of moving biomass from standing in the field or stand to the throat of the biomass conversion process. The goal of this program wasmore » to establish the current costs based on conventional equipment and processes, design improvements to the current system, and to mark annual improvements based on higher efficiencies or better designs. The 2012 programmatic target was to demonstrate a delivered biomass logistics cost of $35/dry ton. This goal was successfully achieved in 2012 by implementing field and process demonstration unit-scale data from harvest, collection, storage, preprocessing, handling, and transportation operations into INL’s biomass logistics model. Looking forward to 2017, the programmatic target is to supply biomass to the conversion facilities at a total cost of $80/dry ton and on specification with in-feed requirements. The goal of the 2017 Design Case is to enable expansion of biofuels production beyond highly productive resource areas by breaking the reliance of cost-competitive biofuel production on a single, abundant, low-cost feedstock. If this goal is not achieved, biofuel plants are destined to be small and/or clustered in select regions of the country that have a lock on low-cost feedstock. To put the 2017 cost target into perspective of past accomplishments of the cellulosic ethanol pathway, the $80 target encompasses total delivered feedstock cost, including both grower payment and logistics costs, while meeting all conversion in-feed quality targets. The 2012 $35 programmatic target included only logistics costs with a limited focus on biomass quality« less

76 FR 6598 - Notice of Intent To Request Revision and Extension of a Currently Approved Information Collection

Federal Register 2010, 2011, 2012, 2013, 2014

2011-02-07

... Clearance for Survey Research Studies. Revision to burden hours may be needed due to changes in the size of the target population, sampling design, and/or questionnaire length. DATES: Comments on this notice... Survey Research Studies. OMB Control Number: 0535-0248. Type of Request: To revise and extend a currently...

77 FR 75120 - Notice of Intent To Request Revision and Extension of a Currently Approved Information Collection

Federal Register 2010, 2011, 2012, 2013, 2014

2012-12-19

... Clearance for Survey Research Studies. Revision to burden hours will be needed due to changes in the size of the target population, sampling design, and/or questionnaire length. DATES: Comments on this notice... Survey Research Studies. OMB Control Number: 0535-0248. Type of Request: To revise and extend a currently...

Antares reference telescope system

NASA Astrophysics Data System (ADS)

Viswanathan, V. K.; Kaprelian, E.; Swann, T.; Parker, J.; Wolfe, P.; Woodfin, G.; Knight, D.

Antares is a 24 beam, 40 TW carbon dioxide laser fusion system currently nearing completion. The 24 beams will be focused onto a tiny target. It is to position the targets to within 10 (SIGMA)m of a selected nominal position, which may be anywhere within a fixed spherical region 1 cm in diameter. The Antares reference telescope system is intended to help achieve this goal for alignment and viewing of the various targets used in the laser system. The Antares reference telescope system consists of two similar electrooptical systems positioned in a near orthogonal manner in the target chamber area of the laser. Each of these consists of four subsystems: (1) a fixed 9% optical imaging subsystem which produces an image of the target at the vidicon; (2) a reticle projection subsystem which superimposes an image of the reticle pattern at the vidicon; (3) an adjustable front lighting subsystem which illuminates the target; and (4) an adjustable back lighting subsystem which also can be used to illuminate the target. The various optical, mechanical, and vidicon design considerations and tradeoffs are discussed. The final system chosen and its current status are described.

Optimization of 3D Field Design

NASA Astrophysics Data System (ADS)

Logan, Nikolas; Zhu, Caoxiang

2017-10-01

Recent progress in 3D tokamak modeling is now leveraged to create a conceptual design of new external 3D field coils for the DIII-D tokamak. Using the IPEC dominant mode as a target spectrum, the Finding Optimized Coils Using Space-curves (FOCUS) code optimizes the currents and 3D geometry of multiple coils to maximize the total set's resonant coupling. The optimized coils are individually distorted in space, creating toroidal ``arrays'' containing a variety of shapes that often wrap around a significant poloidal extent of the machine. The generalized perturbed equilibrium code (GPEC) is used to determine optimally efficient spectra for driving total, core, and edge neoclassical toroidal viscosity (NTV) torque and these too provide targets for the optimization of 3D coil designs. These conceptual designs represent a fundamentally new approach to 3D coil design for tokamaks targeting desired plasma physics phenomena. Optimized coil sets based on plasma response theory will be relevant to designs for future reactors or on any active machine. External coils, in particular, must be optimized for reliable and efficient fusion reactor designs. Work supported by the US Department of Energy under DE-AC02-09CH11466.

Design of a line-VISAR interferometer system for the Sandia Z Machine

NASA Astrophysics Data System (ADS)

Galbraith, J.; Austin, K.; Baker, J.; Bettencourt, R.; Bliss, E.; Celeste, J.; Clancy, T.; Cohen, S.; Crosley, M.; Datte, P.; Fratanduono, D.; Frieders, G.; Hammer, J.; Jackson, J.; Johnson, D.; Jones, M.; Koen, D.; Lusk, J.; Martinez, A.; Massey, W.; McCarville, T.; McLean, H.; Raman, K.; Rodriguez, S.; Spencer, D.; Springer, P.; Wong, J.

2017-08-01

A joint team comprised of Lawrence Livermore National Laboratory (LLNL) and Sandia National Laboratory (SNL) personnel is designing a line-VISAR (Velocity Interferometer System for Any Reflector) for the Sandia Z Machine, Z Line-VISAR. The diagnostic utilizes interferometry to assess current delivery as a function of radius during a magnetically-driven implosion. The Z Line-VISAR system is comprised of the following: a two-leg line-VISAR interferometer, an eight-channel Gated Optical Imager (GOI), and a fifty-meter transport beampath to/from the target of interest. The Z Machine presents unique optomechanical design challenges. The machine utilizes magnetically driven pulsed power to drive a target to elevated temperatures and pressures useful for high energy density science. Shock accelerations exceeding 30g and a strong electromagnetic pulse (EMP) are generated during the shot event as the machine discharges currents of over 25 million amps. Sensitive optical components must be protected from shock loading, and electrical equipment must be adequately shielded from the EMP. The optical design must accommodate temperature and humidity fluctuations in the facility as well as airborne hydrocarbons from the pulsed power components. We will describe the engineering design and concept of operations of the Z Line-VISAR system. Focus will be on optomechanical design.

Research on the optimization of quota design in real estate

NASA Astrophysics Data System (ADS)

Sun, Chunling; Ma, Susu; Zhong, Weichao

2017-11-01

Quota design is one of the effective methods of cost control in real estate development project and widely used in the current real estate development project to control the engineering construction cost, but quota design have many deficiencies in design process. For this purpose, this paper put forward a method to achieve investment control of real estate development project, which combine quota design and value engineering(VE) at the stage of design. Specifically, it’s an optimizing for the structure of quota design. At first, determine the design limits by investment estimate value, then using VE to carry on initial allocation of design limits and gain the functional target cost, finally, consider the whole life cycle cost (LCC) and operational problem in practical application to finish complex correction for the functional target cost. The improved process can control the project cost more effectively. It not only can control investment in a certain range, but also make the project realize maximum value within investment.

Pilots' Attention Distributions Between Chasing a Moving Target and a Stationary Target.

PubMed

Li, Wen-Chin; Yu, Chung-San; Braithwaite, Graham; Greaves, Matthew

2016-12-01

Attention plays a central role in cognitive processing; ineffective attention may induce accidents in flight operations. The objective of the current research was to examine military pilots' attention distributions between chasing a moving target and a stationary target. In the current research, 37 mission-ready F-16 pilots participated. Subjects' eye movements were collected by a portable head-mounted eye-tracker during tactical training in a flight simulator. The scenarios of chasing a moving target (air-to-air) and a stationary target (air-to-surface) consist of three operational phases: searching, aiming, and lock-on to the targets. The findings demonstrated significant differences in pilots' percentage of fixation during the searching phase between air-to-air (M = 37.57, SD = 5.72) and air-to-surface (M = 33.54, SD = 4.68). Fixation duration can indicate pilots' sustained attention to the trajectory of a dynamic target during air combat maneuvers. Aiming at the stationary target resulted in larger pupil size (M = 27,105, SD = 6565), reflecting higher cognitive loading than aiming at the dynamic target (M = 23,864, SD = 8762). Pilots' visual behavior is not only closely related to attention distribution, but also significantly associated with task characteristics. Military pilots demonstrated various visual scan patterns for searching and aiming at different types of targets based on the research settings of a flight simulator. The findings will facilitate system designers' understanding of military pilots' cognitive processes during tactical operations. They will assist human-centered interface design to improve pilots' situational awareness. The application of an eye-tracking device integrated with a flight simulator is a feasible and cost-effective intervention to improve the efficiency and safety of tactical training.Li W-C, Yu C-S, Braithwaite G, Greaves M. Pilots' attention distributions between chasing a moving target and a stationary target. Aerosp Med Hum Perform. 2016; 87(12):989-995.

Analytic Guided-Search Model of Human Performance Accuracy in Target- Localization Search Tasks

NASA Technical Reports Server (NTRS)

Eckstein, Miguel P.; Beutter, Brent R.; Stone, Leland S.

2000-01-01

Current models of human visual search have extended the traditional serial/parallel search dichotomy. Two successful models for predicting human visual search are the Guided Search model and the Signal Detection Theory model. Although these models are inherently different, it has been difficult to compare them because the Guided Search model is designed to predict response time, while Signal Detection Theory models are designed to predict performance accuracy. Moreover, current implementations of the Guided Search model require the use of Monte-Carlo simulations, a method that makes fitting the model's performance quantitatively to human data more computationally time consuming. We have extended the Guided Search model to predict human accuracy in target-localization search tasks. We have also developed analytic expressions that simplify simulation of the model to the evaluation of a small set of equations using only three free parameters. This new implementation and extension of the Guided Search model will enable direct quantitative comparisons with human performance in target-localization search experiments and with the predictions of Signal Detection Theory and other search accuracy models.

Multi-Step Usage of in Vivo Models During Rational Drug Design and Discovery

PubMed Central

Williams, Charles H.; Hong, Charles C.

2011-01-01

In this article we propose a systematic development method for rational drug design while reviewing paradigms in industry, emerging techniques and technologies in the field. Although the process of drug development today has been accelerated by emergence of computational methodologies, it is a herculean challenge requiring exorbitant resources; and often fails to yield clinically viable results. The current paradigm of target based drug design is often misguided and tends to yield compounds that have poor absorption, distribution, metabolism, and excretion, toxicology (ADMET) properties. Therefore, an in vivo organism based approach allowing for a multidisciplinary inquiry into potent and selective molecules is an excellent place to begin rational drug design. We will review how organisms like the zebrafish and Caenorhabditis elegans can not only be starting points, but can be used at various steps of the drug development process from target identification to pre-clinical trial models. This systems biology based approach paired with the power of computational biology; genetics and developmental biology provide a methodological framework to avoid the pitfalls of traditional target based drug design. PMID:21731440

Development of Bone Targeting Drugs.

PubMed

Stapleton, Molly; Sawamoto, Kazuki; Alméciga-Díaz, Carlos J; Mackenzie, William G; Mason, Robert W; Orii, Tadao; Tomatsu, Shunji

2017-06-23

The skeletal system, comprising bones, ligaments, cartilage and their connective tissues, is critical for the structure and support of the body. Diseases that affect the skeletal system can be difficult to treat, mainly because of the avascular cartilage region. Targeting drugs to the site of action can not only increase efficacy but also reduce toxicity. Bone-targeting drugs are designed with either of two general targeting moieties, aimed at the entire skeletal system or a specific cell type. Most bone-targeting drugs utilize an affinity to hydroxyapatite, a major component of the bone matrix that includes a high concentration of positively-charged Ca 2+ . The strategies for designing such targeting moieties can involve synthetic and/or biological components including negatively-charged amino acid peptides or bisphosphonates. Efficient delivery of bone-specific drugs provides significant impact in the treatment of skeletal related disorders including infectious diseases (osteoarthritis, osteomyelitis, etc.), osteoporosis, and metabolic skeletal dysplasia. Despite recent advances, however, both delivering the drug to its target without losing activity and avoiding adverse local effects remain a challenge. In this review, we investigate the current development of bone-targeting moieties, their efficacy and limitations, and discuss future directions for the development of these specific targeted treatments.

Development of Bone Targeting Drugs

PubMed Central

Stapleton, Molly; Sawamoto, Kazuki; Alméciga-Díaz, Carlos J.; Mackenzie, William G.; Mason, Robert W.; Orii, Tadao; Tomatsu, Shunji

2017-01-01

The skeletal system, comprising bones, ligaments, cartilage and their connective tissues, is critical for the structure and support of the body. Diseases that affect the skeletal system can be difficult to treat, mainly because of the avascular cartilage region. Targeting drugs to the site of action can not only increase efficacy but also reduce toxicity. Bone-targeting drugs are designed with either of two general targeting moieties, aimed at the entire skeletal system or a specific cell type. Most bone-targeting drugs utilize an affinity to hydroxyapatite, a major component of the bone matrix that includes a high concentration of positively-charged Ca2+. The strategies for designing such targeting moieties can involve synthetic and/or biological components including negatively-charged amino acid peptides or bisphosphonates. Efficient delivery of bone-specific drugs provides significant impact in the treatment of skeletal related disorders including infectious diseases (osteoarthritis, osteomyelitis, etc.), osteoporosis, and metabolic skeletal dysplasia. Despite recent advances, however, both delivering the drug to its target without losing activity and avoiding adverse local effects remain a challenge. In this review, we investigate the current development of bone-targeting moieties, their efficacy and limitations, and discuss future directions for the development of these specific targeted treatments. PMID:28644392

Countering MANPADS: study of new concepts and applications: part two

NASA Astrophysics Data System (ADS)

Maltese, Dominique; Vergnolle, Jean-François; Aragones, Julien; Renaudat, Mathieu

2007-04-01

The latest events of ground-to-air Man Portable Air Defense (MANPAD) attacks against aircraft have revealed a new threat both for military and civilian aircraft. Consequently, the implementation of protecting systems (i.e. Directed Infra Red Counter Measure - DIRCM) in order to face IR guided missiles turns out to be now inevitable. In a near future, aircraft will have to possess detection, tracking, identification, targeting and jamming capabilities to face MANPAD threats. Besides, Multiple Missiles attacks become more and more current scenarios to deal with. In this paper, a practical example of DIRCM systems under study at SAGEM DEFENSE & SECURITY Company is presented. The article is the continuation of a previous SPIE one. Self-protection solutions include built-in and automatic locking-on, tracking, identification and laser jamming capabilities, including defeat assessment. Target Designations are provided by a Missile Warning System. Targets scenarios including multiple threats are considered to design systems architectures. In a first step, the article reminds the context, current and future threats (IR seekers of different generations...), and scenarios for system definition. Then, it focuses on potential self-protection systems under study at SAGEM DEFENSE & SECURITY Company. Different strategies including target identification, multi band laser and active imagery have been previously studied in order to design DIRCM System solutions. Thus, results of self-protection scenarios are provided for different MANPAD scenarios to highlight key problems to solve. Data have been obtained from simulation software modeling full DIRCM systems architectures on technical and operational scenarios (parametric studies).

Comparison of current ATDs with Chinese adults in anthropometry.

PubMed

Cao, Libo; Zhang, Kai; Lv, Xin; Yan, Lingbo

2016-05-18

Crash test dummies are full-scale anthropomorphic test devices (ATDs) that simulate the dimensions, weight proportions, and articulation of the human body and are used to measure human injury potential in vehicle crashes. The Hybrid III dummy family, which is widely used currently, takes selected percentiles of anthropometry dimensions of U.S. adults as design references. The objective of this study was to assess the difference in anthropometry between Chinese adults and the currently used dummy. Based on the Chinese National Physical Fitness Surveillance of the year 2000, 2005, 2010 and National Standard of China GB/T 10000-1988, a series of anthropometric parameters for Chinese adults were obtained, and data analysis was conducted between Chinese adults and ATDs that are currently used. The comparison revealed distinct anthropometric difference between ATDs and Chinese adults. Based on the latest data, median Chinese females were about 2.6% lower in stature and about 8.03% lower in body weight than the ATD design targets. Similarly, median Chinese males were about 3.48% shorter and weighed 11.89% less than the ATD design targets. Although the anthropometric differences between Chinese adults and the Hybrid III ATD specifications were modest and growing smaller, it is advisable to take the differences in anthropometry between ATDs and Chinese adults into consideration when developing new vehicles in China to provide effective protection specifically for Chinese occupants.

Advances in oral nano-delivery systems for colon targeted drug delivery in inflammatory bowel disease: selective targeting to diseased versus healthy tissue.

PubMed

Hua, Susan; Marks, Ellen; Schneider, Jennifer J; Keely, Simon

2015-07-01

Colon targeted drug delivery is an active area of research for local diseases affecting the colon, as it improves the efficacy of therapeutics and enables localized treatment, which reduces systemic toxicity. Targeted delivery of therapeutics to the colon is particularly advantageous for the treatment of inflammatory bowel disease (IBD), which includes ulcerative colitis and Crohn's disease. Advances in oral drug delivery design have significantly improved the bioavailability of drugs to the colon; however in order for a drug to have therapeutic efficacy during disease, considerations must be made for the altered physiology of the gastrointestinal (GI) tract that is associated with GI inflammation. Nanotechnology has been used in oral dosage formulation design as strategies to further enhance uptake into diseased tissue within the colon. This review will describe some of the physiological challenges faced by orally administered delivery systems in IBD, the important developments in orally administered nano-delivery systems for colon targeting, and the future advances of this research. Inflammatory Bowel Disease (IBD) poses a significant problem for a large number of patients worldwide. Current medical therapy mostly aims at suppressing the active inflammatory episodes. In this review article, the authors described and discussed the various approaches current nano-delivery systems can offer in overcoming the limitations of conventional drug formulations. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Design of Diaphragm and Coil for Stable Performance of an Eddy Current Type Pressure Sensor.

PubMed

Lee, Hyo Ryeol; Lee, Gil Seung; Kim, Hwa Young; Ahn, Jung Hwan

2016-07-01

The aim of this work was to develop an eddy current type pressure sensor and investigate its fundamental characteristics affected by the mechanical and electrical design parameters of sensor. The sensor has two key components, i.e., diaphragm and coil. On the condition that the outer diameter of sensor is 10 mm, two key parts should be designed so as to keep a good linearity and sensitivity. Experiments showed that aluminum is the best target material for eddy current detection. A round-grooved diaphragm is suggested in order to measure more precisely its deflection caused by applied pressures. The design parameters of a round-grooved diaphragm can be selected depending on the measuring requirements. A developed pressure sensor with diaphragm of t = 0.2 mm and w = 1.05 mm was verified to measure pressure up to 10 MPa with very good linearity and errors of less than 0.16%.

Alzheimer’s Disease Drug Development in 2008 and Beyond: Problems and Opportunities

PubMed Central

Becker, Robert E.; Greig, Nigel H.

2008-01-01

Recently, a number of Alzheimer’s disease (AD) multi-center clinical trials (CT) have failed to provide statistically significant evidence of drug efficacy. To test for possible design or execution flaws we analyzed in detail CTs for two failed drugs that were strongly supported by preclinical evidence and by proven CT AD efficacy for other drugs in their class. Studies of the failed commercial trials suggest that methodological flaws may contribute to the failures and that these flaws lurk within current drug development practices ready to impact other AD drug development [1]. To identify and counter risks we considered the relevance to AD drug development of the following factors: (1) effective dosing of the drug product, (2) reliable evaluations of research subjects, (3) effective implementation of quality controls over data at research sites, (4) resources for practitioners to effectively use CT results in patient care, (5) effective disease modeling, (6) effective research designs. New drugs currently under development for AD address a variety of specific mechanistic targets. Mechanistic targets provide AD drug development opportunities to escape from many of the factors that currently undermine AD clinical pharmacology, especially the problems of inaccuracy and imprecision associated with using rated outcomes. In this paper we conclude that many of the current problems encountered in AD drug development can be avoided by changing practices. Current problems with human errors in clinical trials make it difficult to differentiate drugs that fail to evidence efficacy from apparent failures due to Type II errors. This uncertainty and the lack of publication of negative data impede researchers’ abilities to improve methodologies in clinical pharmacology and to develop a sound body of knowledge about drug actions. We consider the identification of molecular targets as offering further opportunities for overcoming current failures in drug development. PMID:18690832

Thiazolidine-2,4-dione derivatives: programmed chemical weapons for key protein targets of various pathological conditions.

PubMed

Chadha, Navriti; Bahia, Malkeet Singh; Kaur, Maninder; Silakari, Om

2015-07-01

Thiazolidine-2,4-dione is an extensively explored heterocyclic nucleus for designing of novel agents implicated for a wide variety of pathophysiological conditions, that is, diabetes, diabetic complications, cancer, arthritis, inflammation, microbial infection, and melanoma, etc. The current paradigm of drug development has shifted to the structure-based drug design, since high-throughput screenings have continued to generate disappointing results. The gap between hit generation and drug establishment can be narrowed down by investigation of ligand interactions with its receptor protein. Therefore, it would always be highly beneficial to gain knowledge of molecular level interactions between specific protein target and developed ligands; since this information can be maneuvered to design new molecules with improved protein fitting. Thus, considering this aspect, we have corroborated the information about molecular (target) level implementations of thiazolidine-2,4-diones (TZD) derivatives having therapeutic implementations such as, but not limited to, anti-diabetic (glitazones), anti-cancer, anti-arthritic, anti-inflammatory, anti-oxidant and anti-microbial, etc. The structure based SAR of TZD derivatives for various protein targets would serve as a benchmark for the alteration of existing ligands to design new ones with better binding interactions. Copyright © 2015 Elsevier Ltd. All rights reserved.

A review on current status of antiviral siRNA.

PubMed

Qureshi, Abid; Tantray, Vaqar Gani; Kirmani, Altaf Rehman; Ahangar, Abdul Ghani

2018-04-15

Viral diseases like influenza, AIDS, hepatitis, and Ebola cause severe epidemics worldwide. Along with their resistant strains, new pathogenic viruses continue to be discovered so creating an ongoing need for new antiviral treatments. RNA interference is a cellular gene-silencing phenomenon in which sequence-specific degradation of target mRNA is achieved by means of complementary short interfering RNA (siRNA) molecules. Short interfering RNA technology affords a potential tractable strategy to combat viral pathogenesis because siRNAs are specific, easy to design, and can be directed against multiple strains of a virus by targeting their conserved gene regions. In this review, we briefly summarize the current status of siRNA therapy for representative examples from different virus families. In addition, other aspects like their design, delivery, medical significance, bioinformatics resources, and limitations are also discussed. Copyright © 2018 John Wiley & Sons, Ltd.

Prototyping the HPDP Chip on STM 65 NM Process

NASA Astrophysics Data System (ADS)

Papadas, C.; Dramitinos, G.; Syed, M.; Helfers, T.; Dedes, G.; Schoellkopf, J.-P.; Dugoujon, L.

2011-08-01

Currently Astrium GmbH is involved in the of the High Performance Data Processor (HPDP) development programme for telecommunication applications under a DLR contract. The HPDP project targets the implementation of the commercially available reconfigurable array processor IP (XPP from the company PACT XPP Technologies) in a radiation hardened technology.In the current complementary development phase funded under the Greek Industry Incentive scheme, it is planned to prototype the HPDP chip in commercial STM 65 nm technology. In addition it is also planned to utilise the preliminary radiation hardened components of this library wherever possible.This abstract gives an overview of the HPDP chip architecture, the basic details of the STM 65 nm process and the design flow foreseen for the prototyping. The paper will discuss the development and integration issues involved in using the STM 65 nm process (also including the available preliminary radiation hardened components) for designs targeted to be used in space applications.

Clearance Pathways and Tumor Targeting of Imaging Nanoparticles

PubMed Central

Yu, Mengxiao; Zheng, Jie

2016-01-01

A basic understanding of how imaging nanoparticles are removed from the normal organs/tissues but retained in the tumors is important for their future clinical applications in early cancer diagnosis and therapy. In this review, we discuss current understandings of clearance pathways and tumor targeting of small-molecule- and inorganic-nanoparticle-based imaging probes with an emphasis on molecular nanoprobes, a class of inorganic nanoprobes that can escape reticuloendothelial system (RES) uptake and be rapidly eliminated from the normal tissues/organs via kidneys but can still passively target the tumor with high efficiency through the enhanced permeability permeability and retention (EPR) effect. The impact of nanoparticle design (size, shape, and surface chemistry) on their excretion, pharmacokinetics, and passive tumor targeting were quantitatively discussed. Synergetic integration of effective renal clearance and EPR effect offers a promising pathway to design low-toxicity and high-contrast-enhancement imaging nanoparticles that could meet with the clinical translational requirements of regulatory agencies. PMID:26149184

Anticancer molecules targeting fibroblast growth factor receptors.

PubMed

Liang, Guang; Liu, Zhiguo; Wu, Jianzhang; Cai, Yuepiao; Li, Xiaokun

2012-10-01

The fibroblast growth factor receptor (FGFR) family includes four highly conserved receptor tyrosine kinases: FGFR1-4. Upon ligand binding, FGFRs activate an array of downstream signaling pathways, such as the mitogen activated protein kinase (MAPK) and the phosphoinositide-3-kinase (PI3K)/Akt pathways. These FGFR cascades play crucial roles in tumor cell proliferation, angiogenesis, migration, and survival. The combination of knockdown studies and pharmaceutical inhibition in preclinical models demonstrates that FGFRs are attractive targets for therapeutic intervention in cancer. Multiple FGFR inhibitors with various structural skeletons have been designed, synthesized, and evaluated. Reviews on FGFRs have recently focused on FGFR signaling, pathophysiology, and functions in cancer or other diseases. In this article, we review recent advances in structure-activity relationships (SAR) of FGFR inhibitors, as well as the FGFR-targeting drug design strategies currently employed in targeting deregulated FGFRs by antibodies and small molecule inhibitors. Copyright © 2012 Elsevier Ltd. All rights reserved.

1L Mark-IV Target Design Review

DOE Office of Scientific and Technical Information (OSTI.GOV)

Koehler, Paul E.

This presentation includes General Design Considerations; Current (Mark-III) Lower Tier; Mark-III Upper Tier; Performance Metrics; General Improvements for Material Science; General Improvements for Nuclear Science; Improving FOM for Nuclear Science; General Design Considerations Summary; Design Optimization Studies; Expected Mark-IV Performance: Material Science; Expected Mark-IV Performance: Nuclear Science (Disk); Mark IV Enables Much Wider Range of Nuclear-Science FOM Gains than Mark III; Mark-IV Performance Summary; Rod or Disk? Center or Real FOV?; and Project Cost and Schedule.

Constraints in distortion-invariant target recognition system simulation

NASA Astrophysics Data System (ADS)

Iftekharuddin, Khan M.; Razzaque, Md A.

2000-11-01

Automatic target recognition (ATR) is a mature but active research area. In an earlier paper, we proposed a novel ATR approach for recognition of targets varying in fine details, rotation, and translation using a Learning Vector Quantization (LVQ) Neural Network (NN). The proposed approach performed segmentation of multiple objects and the identification of the objects using LVQNN. In this current paper, we extend the previous approach for recognition of targets varying in rotation, translation, scale, and combination of all three distortions. We obtain the analytical results of the system level design to show that the approach performs well with some constraints. The first constraint determines the size of the input images and input filters. The second constraint shows the limits on amount of rotation, translation, and scale of input objects. We present the simulation verification of the constraints using DARPA's Moving and Stationary Target Recognition (MSTAR) images with different depression and pose angles. The simulation results using MSTAR images verify the analytical constraints of the system level design.

Effects of Base Cavity Depth on a Free Spinning Wrap-Around Fin Missile Configuration

DTIC Science & Technology

1995-12-01

packaging problem. Current missile systems which possess wrap-around fin designs are the Army’s Multiple Launch Rocket System (MLRS) and the Hard Target...aerodynamic irregularities (2). Of particular importance to projectile designers is the side force/moment inherent to wrap-around fin configurations. During...virtual instrument programs integrated to perform all necessary aspects of calibration, data collection, and reduction. The details surrounding the design

Integrated cockpit design for the Army helicopter improvement program

NASA Technical Reports Server (NTRS)

Drennen, T.; Bowen, B.

1984-01-01

The main Army Helicopter Improvement Program (AHIP) mission is to navigate precisely, locate targets accurately, communicate their position to other battlefield elements, and to designate them for laser guided weapons. The onboard navigation and mast-mounted sight (MMS) avionics enable accurate tracking of current aircraft position and subsequent target location. The AHIP crewstation development was based on extensive mission/task analysis, function allocation, total system design, and test and verification. The avionics requirements to meet the mission was limited by the existing aircraft structural and performance characteristics and resultant space, weight, and power restrictions. These limitations and night operations requirement led to the use of night vision goggles. The combination of these requirements and limitations dictated an integrated control/display approach using multifunction displays and controls.

Optimal Incentives for Public Sector Workers: The Case of Teacher-Designed Incentive Pay in Texas. Working Paper 2009-05

ERIC Educational Resources Information Center

Taylor, Lori L.; Springer, Matthew G.

2009-01-01

Pay for performance is a popular public education reform, and millions of dollars are currently being targeted for pay for performance programs. These reforms are popular because economic and management theories suggest that well-designed incentive pay programs could improve teacher effectiveness. There is little evidence about the characteristics…

An infrastructure for accurate characterization of single-event transients in digital circuits.

PubMed

Savulimedu Veeravalli, Varadan; Polzer, Thomas; Schmid, Ulrich; Steininger, Andreas; Hofbauer, Michael; Schweiger, Kurt; Dietrich, Horst; Schneider-Hornstein, Kerstin; Zimmermann, Horst; Voss, Kay-Obbe; Merk, Bruno; Hajek, Michael

2013-11-01

We present the architecture and a detailed pre-fabrication analysis of a digital measurement ASIC facilitating long-term irradiation experiments of basic asynchronous circuits, which also demonstrates the suitability of the general approach for obtaining accurate radiation failure models developed in our FATAL project. Our ASIC design combines radiation targets like Muller C-elements and elastic pipelines as well as standard combinational gates and flip-flops with an elaborate on-chip measurement infrastructure. Major architectural challenges result from the fact that the latter must operate reliably under the same radiation conditions the target circuits are exposed to, without wasting precious die area for a rad-hard design. A measurement architecture based on multiple non-rad-hard counters is used, which we show to be resilient against double faults, as well as many triple and even higher-multiplicity faults. The design evaluation is done by means of comprehensive fault injection experiments, which are based on detailed Spice models of the target circuits in conjunction with a standard double-exponential current injection model for single-event transients (SET). To be as accurate as possible, the parameters of this current model have been aligned with results obtained from 3D device simulation models, which have in turn been validated and calibrated using micro-beam radiation experiments at the GSI in Darmstadt, Germany. For the latter, target circuits instrumented with high-speed sense amplifiers have been used for analog SET recording. Together with a probabilistic analysis of the sustainable particle flow rates, based on a detailed area analysis and experimental cross-section data, we can conclude that the proposed architecture will indeed sustain significant target hit rates, without exceeding the resilience bound of the measurement infrastructure.

An infrastructure for accurate characterization of single-event transients in digital circuits☆

PubMed Central

Savulimedu Veeravalli, Varadan; Polzer, Thomas; Schmid, Ulrich; Steininger, Andreas; Hofbauer, Michael; Schweiger, Kurt; Dietrich, Horst; Schneider-Hornstein, Kerstin; Zimmermann, Horst; Voss, Kay-Obbe; Merk, Bruno; Hajek, Michael

2013-01-01

We present the architecture and a detailed pre-fabrication analysis of a digital measurement ASIC facilitating long-term irradiation experiments of basic asynchronous circuits, which also demonstrates the suitability of the general approach for obtaining accurate radiation failure models developed in our FATAL project. Our ASIC design combines radiation targets like Muller C-elements and elastic pipelines as well as standard combinational gates and flip-flops with an elaborate on-chip measurement infrastructure. Major architectural challenges result from the fact that the latter must operate reliably under the same radiation conditions the target circuits are exposed to, without wasting precious die area for a rad-hard design. A measurement architecture based on multiple non-rad-hard counters is used, which we show to be resilient against double faults, as well as many triple and even higher-multiplicity faults. The design evaluation is done by means of comprehensive fault injection experiments, which are based on detailed Spice models of the target circuits in conjunction with a standard double-exponential current injection model for single-event transients (SET). To be as accurate as possible, the parameters of this current model have been aligned with results obtained from 3D device simulation models, which have in turn been validated and calibrated using micro-beam radiation experiments at the GSI in Darmstadt, Germany. For the latter, target circuits instrumented with high-speed sense amplifiers have been used for analog SET recording. Together with a probabilistic analysis of the sustainable particle flow rates, based on a detailed area analysis and experimental cross-section data, we can conclude that the proposed architecture will indeed sustain significant target hit rates, without exceeding the resilience bound of the measurement infrastructure. PMID:24748694

A Multidimensional Strategy to Detect Polypharmacological Targets in the Absence of Structural and Sequence Homology

PubMed Central

Durrant, Jacob D.; Amaro, Rommie E.; Xie, Lei; Urbaniak, Michael D.; Ferguson, Michael A. J.; Haapalainen, Antti; Chen, Zhijun; Di Guilmi, Anne Marie; Wunder, Frank; Bourne, Philip E.; McCammon, J. Andrew

2010-01-01

Conventional drug design embraces the “one gene, one drug, one disease” philosophy. Polypharmacology, which focuses on multi-target drugs, has emerged as a new paradigm in drug discovery. The rational design of drugs that act via polypharmacological mechanisms can produce compounds that exhibit increased therapeutic potency and against which resistance is less likely to develop. Additionally, identifying multiple protein targets is also critical for side-effect prediction. One third of potential therapeutic compounds fail in clinical trials or are later removed from the market due to unacceptable side effects often caused by off-target binding. In the current work, we introduce a multidimensional strategy for the identification of secondary targets of known small-molecule inhibitors in the absence of global structural and sequence homology with the primary target protein. To demonstrate the utility of the strategy, we identify several targets of 4,5-dihydroxy-3-(1-naphthyldiazenyl)-2,7-naphthalenedisulfonic acid, a known micromolar inhibitor of Trypanosoma brucei RNA editing ligase 1. As it is capable of identifying potential secondary targets, the strategy described here may play a useful role in future efforts to reduce drug side effects and/or to increase polypharmacology. PMID:20098496

A multidimensional strategy to detect polypharmacological targets in the absence of structural and sequence homology.

PubMed

Durrant, Jacob D; Amaro, Rommie E; Xie, Lei; Urbaniak, Michael D; Ferguson, Michael A J; Haapalainen, Antti; Chen, Zhijun; Di Guilmi, Anne Marie; Wunder, Frank; Bourne, Philip E; McCammon, J Andrew

2010-01-22

Conventional drug design embraces the "one gene, one drug, one disease" philosophy. Polypharmacology, which focuses on multi-target drugs, has emerged as a new paradigm in drug discovery. The rational design of drugs that act via polypharmacological mechanisms can produce compounds that exhibit increased therapeutic potency and against which resistance is less likely to develop. Additionally, identifying multiple protein targets is also critical for side-effect prediction. One third of potential therapeutic compounds fail in clinical trials or are later removed from the market due to unacceptable side effects often caused by off-target binding. In the current work, we introduce a multidimensional strategy for the identification of secondary targets of known small-molecule inhibitors in the absence of global structural and sequence homology with the primary target protein. To demonstrate the utility of the strategy, we identify several targets of 4,5-dihydroxy-3-(1-naphthyldiazenyl)-2,7-naphthalenedisulfonic acid, a known micromolar inhibitor of Trypanosoma brucei RNA editing ligase 1. As it is capable of identifying potential secondary targets, the strategy described here may play a useful role in future efforts to reduce drug side effects and/or to increase polypharmacology.

Functionalization of reduced graphene oxide by electroactive polymer for biosensing applications

NASA Astrophysics Data System (ADS)

Nguyen, Le Huy; Dzung Nguyen, Tuan; Hoang Tran, Vinh; Thu Huyen Dang, Thi; Tran, Dai Lam

2014-09-01

A novel biosensing platform was designed by the functionalizing reduced graphene oxide sheets (rGO) with electroactive copolymer juglone. The composite film showed well-defined, stable electroactivity in a biocompatible buffer medium. Square wave voltammetry is used to record the redox signal for DNA hybridization. Current increase upon hybridization (signal-on) evidenced that short DNA target as well as polymerase chain reaction (PCR), so called ‘real sample’ products, related to different lineages of Mycobacterium tuberculosis strain. The signal-on reached ∼40% with 1 nM of short DNA (25 mer) target, while PCR product (Africanum, EAI and Beijing strains) produced a current change of ∼20%.

New Developments in Vaccines, Inhibitors of Anthrax Toxins, and Antibiotic Therapeutics for Bacillus anthracis

PubMed Central

Beierlein, J.M.; Anderson, A.C.

2013-01-01

Bacillus anthracis, the causative agent responsible for anthrax infections, poses a significant biodefense threat. There is a high mortality rate associated with untreated anthrax infections; specifically, inhalation anthrax is a particularly virulent form of infection with mortality rates close to 100%, even with aggressive treatment. Currently, a vaccine is not available to the general public and few antibiotics have been approved by the FDA for the treatment of inhalation anthrax. With the threat of natural or engineered bacterial resistance to antibiotics and the limited population for whom the current drugs are approved, there is a clear need for more effective treatments against this deadly infection. A comprehensive review of current research in drug discovery is presented in this article, including efforts to improve the purity and stability of vaccines, design inhibitors targeting the anthrax toxins, and identify inhibitors of novel enzyme targets. High resolution structural information for the anthrax toxins and several essential metabolic enzymes has played a significant role in aiding the structure-based design of potent and selective antibiotics. PMID:22050756

Versatile Stimulation Back-End With Programmable Exponential Current Pulse Shapes for a Retinal Visual Prosthesis.

PubMed

Maghami, Mohammad Hossein; Sodagar, Amir M; Sawan, Mohamad

2016-11-01

This paper reports on the design, implementation, and test of a stimulation back-end, for an implantable retinal prosthesis. In addition to traditional rectangular pulse shapes, the circuit features biphasic stimulation pulses with both rising and falling exponential shapes, whose time constants are digitally programmable. A class-B second generation current conveyor is used as a wide-swing, high-output-resistance stimulation current driver, delivering stimulation current pulses of up to ±96 μA to the target tissue. Duration of the generated current pulses is programmable within the range of 100 μs to 3 ms. Current-mode digital-to-analog converters (DACs) are used to program the amplitudes of the stimulation pulses. Fabricated using the IBM 130 nm process, the circuit consumes 1.5×1.5 mm 2 of silicon area. According to the measurements, the DACs exhibit DNL and INL of 0.23 LSB and 0.364 LSB, respectively. Experimental results indicate that the stimuli generator meets expected requirements when connected to electrode-tissue impedance of as high as 25 k Ω. Maximum power consumption of the proposed design is 3.4 mW when delivering biphasic rectangular pulses to the target load. A charge pump block is in charge of the upconversion of the standard 1.2-V supply voltage to ±3.3V.

Screening for small molecule inhibitors of Toxoplasma gondii.

PubMed

Kortagere, Sandhya

2012-12-01

Toxoplasma gondii, the agent that causes toxoplasmosis, is an opportunistic parasite that infects many mammalian species. It is an obligate intracellular parasite that causes severe congenital neurological and ocular disease mostly in immunocompromised humans. The current regimen of therapy includes only a few medications that often lead to hypersensitivity and toxicity. In addition, there are no vaccines available to prevent the transmission of this agent. Therefore, safer and more effective medicines to treat toxoplasmosis are urgently needed. The author presents in silico and in vitro strategies that are currently used to screen for novel targets and unique chemotypes against T. gondii. Furthermore, this review highlights the screening technologies and characterization of some novel targets and new chemical entities that could be developed into highly efficacious treatments for toxoplasmosis. A number of diverse methods are being used to design inhibitors against T. gondii. These include ligand-based methods, in which drugs that have been shown to be efficacious against other Apicomplexa parasites can be repurposed to identify lead molecules against T. gondii. In addition, structure-based methods use currently available repertoire of structural information in various databases to rationally design small-molecule inhibitors of T. gondii. Whereas the screening methods have their advantages and limitations, a combination of methods is ideally suited to design small-molecule inhibitors of complex parasites such as T. gondii.

Ion Source Development at the SNS

NASA Astrophysics Data System (ADS)

Welton, R. F.; Stockli, M. P.; Murray, S. N.; Carr, J.; Carmichael, J.; Goulding, R. H.; Baity, F. W.

2007-08-01

The US Spallation Neutron Source (SNS) has recently begun producing neutrons and is currently on track to becoming a world-leading facility for material science based on neutron scattering. The facility is comprised of an H- ion source, a linear accelerator, an accumulator ring, a liquid-Hg target and a suite of neutron scattering instruments. Over the next several years the average H- current from the ion source will be increased in order to meet the baseline facility requirement of providing 1.4 MW of beam-power to the target and the SNS power upgrade power requirement of 2+ MW on target. Meeting the latter goal will require H- currents of 70-100 mA with an RMS emittance of 0.20-0.35 π mm mrad and a ˜7% duty-factor. To date, the RF-driven-multicusp SNS ion source has only been able to demonstrate sustained operation at 33 mA of beam current at a ˜7% duty-factor. This report details our efforts to develop variations of the current ion source which can meet these requirements. Designs and experimental results are presented for helicon plasma drivers, high-power external antennas, glow-discharge plasma guns and advanced Cs systems.

[Computational chemistry in structure-based drug design].

PubMed

Cao, Ran; Li, Wei; Sun, Han-Zi; Zhou, Yu; Huang, Niu

2013-07-01

Today, the understanding of the sequence and structure of biologically relevant targets is growing rapidly and researchers from many disciplines, physics and computational science in particular, are making significant contributions to modern biology and drug discovery. However, it remains challenging to rationally design small molecular ligands with desired biological characteristics based on the structural information of the drug targets, which demands more accurate calculation of ligand binding free-energy. With the rapid advances in computer power and extensive efforts in algorithm development, physics-based computational chemistry approaches have played more important roles in structure-based drug design. Here we reviewed the newly developed computational chemistry methods in structure-based drug design as well as the elegant applications, including binding-site druggability assessment, large scale virtual screening of chemical database, and lead compound optimization. Importantly, here we address the current bottlenecks and propose practical solutions.

Programmable high-output-impedance, large-voltage compliance, microstimulator for low-voltage biomedical applications.

PubMed

Farahmand, Sina; Maghami, Mohammad Hossein; Sodagar, Amir M

2012-01-01

This paper reports on the design of a programmable, high output impedance, large voltage compliance microstimulator for low-voltage biomedical applications. A 6-bit binary-weighted digital to analog converter (DAC) is used to generate biphasic stimulus current pulses. A compact current mirror with large output voltage compliance and high output resistance conveys the current pulses to the target tissue. Designed and simulated in a standard 0.18µm CMOS process, the microstimulator circuit is capable of delivering a maximum stimulation current of 160µA to a 10-kΩ resistive load. Operated at a 1.8-V supply voltage, the output stage exhibits a voltage compliance of 1.69V and output resistance of 160MΩ at full scale stimulus current. Layout of the core microelectrode circuit measures 25.5µm×31.5µm.

A simulator for airborne laser swath mapping via photon counting

NASA Astrophysics Data System (ADS)

Slatton, K. C.; Carter, W. E.; Shrestha, R.

2005-06-01

Commercially marketed airborne laser swath mapping (ALSM) instruments currently use laser rangers with sufficient energy per pulse to work with return signals of thousands of photons per shot. The resulting high signal to noise level virtually eliminates spurious range values caused by noise, such as background solar radiation and sensor thermal noise. However, the high signal level approach requires laser repetition rates of hundreds of thousands of pulses per second to obtain contiguous coverage of the terrain at sub-meter spatial resolution, and with currently available technology, affords little scalability for significantly downsizing the hardware, or reducing the costs. A photon-counting ALSM sensor has been designed by the University of Florida and Sigma Space, Inc. for improved topographic mapping with lower power requirements and weight than traditional ALSM sensors. Major elements of the sensor design are presented along with preliminary simulation results. The simulator is being developed so that data phenomenology and target detection potential can be investigated before the system is completed. Early simulations suggest that precise estimates of terrain elevation and target detection will be possible with the sensor design.

Front End and HFOFO Snake for a Muon Facility

DOE Office of Scientific and Technical Information (OSTI.GOV)

Neuffer, D.; Alexahin, Y.

2015-09-01

A neutrino factory or muon collider requires the capture and cooling of a large number of muons. Scenarios for capture, bunching, phase-energy rotation and initial cooling of μ’s produced from a proton source target have been developed, for neutrino factory and muon collider scenarios. They require a drift section from the target, a bunching section and amore » $$\\phi-\\delta E$$ rotation section leading into the cooling channel. The currently preferred cooling channel design is an “HFOFO Snake” configuration that cools both $$\\mu^+$$ and $$\\mu^-$$ transversely and longitudinally. The status of the design is presented and variations are discussed.« less

Attentional Blink Impairment in Social Anxiety Disorder: Depression Comorbidity Matters

PubMed Central

Morrison, Amanda S.; Brozovich, Faith A.; Lakhan-Pal, Shreya; Jazaieri, Hooria; Goldin, Philippe R.; Heimberg, Richard G.; Gross, James J.

2015-01-01

Background and Objectives Difficulties with attentional control have long been thought to play a key role in anxiety and depressive disorders. However, the nature and extent of attentional control difficulties in social anxiety disorder (SAD) are not yet well understood. The current study was designed to assess whether attentional control for non-emotional information is impaired in SAD when taking comorbid depression into account. Methods Individuals with SAD and healthy controls (HCs) were administered an attentional blink (AB) task in which they identified number targets in a rapid serial visual presentation stream of letters. Results Individuals with SAD and current comorbid depression exhibited reduced accuracy to identify a target that fell within the AB window after the presentation of a first target compared to individuals with SAD without current comorbid depression, as well as to HCs. The latter two groups did not differ from each other, and the three groups did not differ in accuracy for the second target when it was presented after the AB window. Limitations Although we included two clinical groups and the sample size for the noncomorbid SAD group was large, the comorbid SAD group was relatively small. Conclusions These results suggest that impaired attentional control among individuals with SAD may be limited to those suffering from current comorbid depression. PMID:26370394

Obesity Pharmacotherapy: Current Perspectives and Future Directions

PubMed Central

Misra, Monika

2013-01-01

The rising tide of obesity and its related disorders is one of the most pressing health concerns worldwide, yet existing medicines to combat the problem are disappointingly limited in number and effectiveness. Recent advances in mechanistic insights into the neuroendocrine regulation of body weight have revealed an expanding list of molecular targets for novel, rationally designed antiobesity pharmaceutical agents. Antiobesity drugs act via any of four mechanisms: 1) decreasing energy intake, 2) increasing energy expenditure or modulating lipid metabolism, 3) modulating fat stores or adipocyte differentiation, and 4) mimicking caloric restriction. Various novel drug candidates and targets directed against obesity are currently being explored. A few of them are also in the later phases of clinical trials. This review discusses the development of novel antiobesity drugs based on current understanding of energy homeostasis PMID:23092275

Dengue Virus NS2B/NS3 Protease Inhibitors Exploiting the Prime Side.

PubMed

Lin, Kuan-Hung; Ali, Akbar; Rusere, Linah; Soumana, Djade I; Kurt Yilmaz, Nese; Schiffer, Celia A

2017-05-15

The mosquito-transmitted dengue virus (DENV) infects millions of people in tropical and subtropical regions. Maturation of DENV particles requires proper cleavage of the viral polyprotein, including processing of 8 of the 13 substrate cleavage sites by dengue virus NS2B/NS3 protease. With no available direct-acting antiviral targeting DENV, NS2/NS3 protease is a promising target for inhibitor design. Current design efforts focus on the nonprime side of the DENV protease active site, resulting in highly hydrophilic and nonspecific scaffolds. However, the prime side also significantly modulates DENV protease binding affinity, as revealed by engineering the binding loop of aprotinin, a small protein with high affinity for DENV protease. In this study, we designed a series of cyclic peptides interacting with both sides of the active site as inhibitors of dengue virus protease. The design was based on two aprotinin loops and aimed to leverage both key specific interactions of substrate sequences and the entropic advantage driving aprotinin's high affinity. By optimizing the cyclization linker, length, and amino acid sequence, the tightest cyclic peptide achieved a K i value of 2.9 μM against DENV3 wild-type (WT) protease. These inhibitors provide proof of concept that both sides of DENV protease active site can be exploited to potentially achieve specificity and lower hydrophilicity in the design of inhibitors targeting DENV. IMPORTANCE Viruses of the flaviviral family, including DENV and Zika virus transmitted by Aedes aegypti , continue to be a threat to global health by causing major outbreaks in tropical and subtropical regions, with no available direct-acting antivirals for treatment. A better understanding of the molecular requirements for the design of potent and specific inhibitors against flaviviral proteins will contribute to the development of targeted therapies for infections by these viruses. The cyclic peptides reported here as DENV protease inhibitors provide novel scaffolds that enable exploiting the prime side of the protease active site, with the aim of achieving better specificity and lower hydrophilicity than those of current scaffolds in the design of antiflaviviral inhibitors. Copyright © 2017 American Society for Microbiology.

Effects of HIV-1 protease on cellular functions and their potential applications in antiretroviral therapy

PubMed Central

2012-01-01

Human Immunodeficiency Virus Type 1 (HIV-1) protease inhibitors (PIs) are the most potent class of drugs in antiretroviral therapies. However, viral drug resistance to PIs could emerge rapidly thus reducing the effectiveness of those drugs. Of note, all current FDA-approved PIs are competitive inhibitors, i.e., inhibitors that compete with substrates for the active enzymatic site. This common inhibitory approach increases the likelihood of developing drug resistant HIV-1 strains that are resistant to many or all current PIs. Hence, new PIs that move away from the current target of the active enzymatic site are needed. Specifically, allosteric inhibitors, inhibitors that prohibit PR enzymatic activities through non-competitive binding to PR, should be sought. Another common feature of current PIs is they were all developed based on the structure-based design. Drugs derived from a structure-based strategy may generate target specific and potent inhibitors. However, this type of drug design can only target one site at a time and drugs discovered by this method are often associated with strong side effects such as cellular toxicity, limiting its number of target choices, efficacy, and applicability. In contrast, a cell-based system may provide a useful alternative strategy that can overcome many of the inherited shortcomings associated with structure-based drug designs. For example, allosteric PIs can be sought using a cell-based system without considering the site or mechanism of inhibition. In addition, a cell-based system can eliminate those PIs that have strong cytotoxic effect. Most importantly, a simple, economical, and easy-to-maintained eukaryotic cellular system such as yeast will allow us to search for potential PIs in a large-scaled high throughput screening (HTS) system, thus increasing the chances of success. Based on our many years of experience in using fission yeast as a model system to study HIV-1 Vpr, we propose the use of fission yeast as a possible surrogate system to study the effects of HIV-1 protease on cellular functions and to explore its utility as a HTS system to search for new PIs to battle HIV-1 resistant strains. PMID:22971934

Optimization study on structural analyses for the J-PARC mercury target vessel

NASA Astrophysics Data System (ADS)

Guan, Wenhai; Wakai, Eiichi; Naoe, Takashi; Kogawa, Hiroyuki; Wakui, Takashi; Haga, Katsuhiro; Takada, Hiroshi; Futakawa, Masatoshi

2018-06-01

The spallation neutron source at the Japan Proton Accelerator Research Complex (J-PARC) mercury target vessel is used for various materials science studies, work is underway to achieve stable operation at 1 MW. This is very important for enhancing the structural integrity and durability of the target vessel, which is being developed for 1 MW operation. In the present study, to reduce thermal stress and relax stress concentrations more effectively in the existing target vessel in J-PARC, an optimization approach called the Taguchi method (TM) is applied to thermo-mechanical analysis. The ribs and their relative parameters, as well as the thickness of the mercury vessel and shrouds, were selected as important design parameters for this investigation. According to the analytical results of 18 model types designed using the TM, the optimal design was determined. It is characterized by discrete ribs and a thicker vessel wall than the current design. The maximum thermal stresses in the mercury vessel and the outer shroud were reduced by 14% and 15%, respectively. Furthermore, it was indicated that variations in rib width, left/right rib intervals, and shroud thickness could influence the maximum thermal stress performance. It is therefore concluded that the TM was useful for optimizing the structure of the target vessel and to reduce the thermal stress in a small number of calculation cases.

Lactate biosensors: current status and outlook.

PubMed

Rassaei, Liza; Olthuis, Wouter; Tsujimura, Seiya; Sudhölter, Ernst J R; van den Berg, Albert

2014-01-01

Many research efforts over the last few decades have been devoted to sensing lactate as an important analytical target in clinical care, sport medicine, and food processing. Therefore, research in designing lactate sensors is no longer in its infancy and now is more directed toward viable sensors for direct applications. In this review, we provide an overview of the most immediate and relevant developments toward this end, and we discuss and assess common transduction approaches. Further, we critically describe the pros and cons of current commercial lactate sensors and envision how future sensing design may benefit from emerging new technologies.

HIV protease drug resistance and its impact on inhibitor design.

PubMed

Ala, P J; Rodgers, J D; Chang, C H

1999-07-01

The primary cause of resistance to the currently available HIV protease inhibitors is the accumulation of multiple mutations in the viral protease. So far more than 20 substitutions have been observed in the active site, dimer interface, surface loops and flaps of the homodimer. While many mutations reduce the protease's affinity for inhibitors, others appear to enhance its catalytic efficiency. This high degree of genetic flexibility has made the protease an elusive drug target. The design of the next generation of HIV protease inhibitors will be discussed in light of the current structural information.

Breast cancer: the role of angiogenesis and antiangiogenic therapy.

PubMed

Miller, Kathy D; Dul, Carrie L

2004-10-01

Angiogenesis plays a role in breast cancer development. Preclinical and clinical evidence is reviewed. Development of targeted antiangiogenic agents provides new challenges to clinical trial design. Current antiangiogenic therapy with traditional agents and novel agents are classified and reviewed.

Combined Heat and Power Systems Technology Development and Demonstration 370 kW High Efficiency Microturbine

DOE Office of Scientific and Technical Information (OSTI.GOV)

none,

The C370 Program was awarded in October 2010 with the ambitious goal of designing and testing the most electrically efficient recuperated microturbine engine at a rated power of less than 500 kW. The aggressive targets for electrical efficiency, emission regulatory compliance, and the estimated price point make the system state-of-the-art for microturbine engine systems. These goals will be met by designing a two stage microturbine engine identified as the low pressure spool and high pressure spool that are based on derivative hardware of Capstone’s current commercially available engines. The development and testing of the engine occurred in two phases. Phasemore » I focused on developing a higher power and more efficient engine, that would become the low pressure spool which is based on Capstone’s C200 (200kW) engine architecture. Phase II integrated the low pressure spool created in Phase I with the high pressure spool, which is based on Capstone’s C65 (65 kW) commercially available engine. Integration of the engines, based on preliminary research, would allow the dual spool engine to provide electrical power in excess of 370 kW, with electrical efficiency approaching 42%. If both of these targets were met coupled with the overall CHP target of 85% total combined heating and electrical efficiency California Air Resources Board (CARB) level emissions, and a price target of $600 per kW, the system would represent a step change in the currently available commercial generation technology. Phase I of the C370 program required the development of the C370 low pressure spool. The goal was to increase the C200 engine power by a minimum of 25% — 250 kW — and efficiency from 32% to 37%. These increases in the C200 engine output were imperative to meet the power requirements of the engine when both spools were integrated. An additional benefit of designing and testing the C370 low pressure spool was the possibility of developing a stand-alone product for possible commercialization. The low pressure spool design activity focused on an aeropath derivative of the current C200 engine. The aeropath derivative included changes to the compressor section —compressor and inducer — and to the turbine nozzle. The increased power also necessitated a larger, more powerful generator and generator controller to support the increased power requirements. These two major design changes were completed by utilizing both advanced 3D modeling and computational fluid dynamics modelling. After design, modeling, and analysis, the decision was made to acquire and integrate the components for testing. The second task of Phase I was to integrate and test the components of the low pressure spool to validate power and efficiency. Acquisition of the components for the low pressure spool was completed utilizing Capstone’s current supplier base. Utilization of Capstone’s supply base for integration of the test article would allow — if the decision was made —expedited commercialization of the product. After integration of the engine components, the engine was tested and evaluated for performance and emissions. Test data analysis confirmed that the engine met all power and efficiency requirements and did so while maintaining CARB level emissions. The emissions were met without the use of any post processing or catalyst. After testing was completed, the DOE authorized — via a milestone review — proceeding to Phase II: the development of the integrated C370 engine. The C370 high pressure spool design activity required significant changes to the C65 engine architecture. The engine required a high power density generator, completely redesigned compressor stage, turbine section, recuperator, controls architecture, and intercooler stage asThe two most critical design challenges were the turbine section (the nozzle and turbine) and the controls architecture. The design and analysis of all of the components was completed and integrated into a system model. The system model — after numerous iterations — indicated that, once integrated, the engine will meet or exceed all system requirements. Unfortunately, the turbine section’s life requirements remain a technical challenge and will require continued refinement of the bi-metallic turbine wheel design and manufacturing approach to meet the life requirement at theses high temperatures. The current controls architecture requires substantial effort to develop a system capable of handling the high-speed, near real-time controls requirement, but it was determined not to be a technical roadblock for the project. The C370 Program has been a significant effort with state-of-the-art technical targets. The targets have pushed Capstone’s designers to the limits of current technology. The program has been fortunate to see many successes: the successful testing of the low pressure spool (C250), the development of new material processes, and the implementation of new design practices. The technology and practices learned during the program will be utilized in Capstone’s current product lines and future products. The C370 Program has been a resounding success on many fronts for the DOE and for Capstone.« less

Pinch current limitation effect in plasma focus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, S.; Saw, S. H.; INTI International University College, 71800 Nilai

The Lee model couples the electrical circuit with plasma focus dynamics, thermodynamics, and radiation. It is used to design and simulate experiments. A beam-target mechanism is incorporated, resulting in realistic neutron yield scaling with pinch current and increasing its versatility for investigating all Mather-type machines. Recent runs indicate a previously unsuspected 'pinch current limitation' effect. The pinch current does not increase beyond a certain value however low the static inductance is reduced to. The results indicate that decreasing the present static inductance of the PF1000 machine will neither increase the pinch current nor the neutron yield, contrary to expectations.

Alternating magnetic field optimization for IONP hyperthermia cancer treatment

NASA Astrophysics Data System (ADS)

Kastner, Elliot J.; Reeves, Russell; Bennett, William; Misra, Aditi; Petryk, Jim D.; Petryk, Alicia A.; Hoopes, P. Jack

2015-03-01

Iron oxide nanoparticles (IONP) have therapeutic potential to deliver a thermal dose to tumors when activated in an alternating magnetic field (AMF). Through various targeting methods such as antibody labeling or injection site choice, delivery of IONPs to tumors yields enhanced treatment accuracy and efficacy. Despite this advantage, delivery an AMF, which is sufficient to result in clinically relevant IONP heating, can result in nonspecific tissue heating via the generation of eddy currents and tissue permeated by local electric fields (joule heating). The production of eddy current heating is a function of tissue size, geometry and composition as well as coil design and operation. The purpose of this research is to increase the level of energy deposited into the IONPs versus the non-target tissue (power ratio/PR)1 in order to improve target heating and reduce nonspecific tissue damage. We propose to improve the PR using two primary concepts: (1) reduce power deposition into non-target tissue by manipulating the fields and eddy current flow and (2) enhance heat removal from non-target tissue. We have shown that controlling tissue placement within the AMF field, accounting for tissue geometry, utilizing external cooling devices, and modifying the field properties can decrease non-target heating by more than 50%, at clinically relevant AMF levels, thereby allowing for an increase in thermal dose to the tumor and increasing the therapeutic ratio.

Measuring the Effects of an On-Line Training Module for School Psychologists Working with Traumatized Children: A Pilot Study

ERIC Educational Resources Information Center

Dezen, Kristin

2012-01-01

The present study was designed to address the current lack of trauma training provided to school psychologists. Specifically, this study employed a randomized, controlled design to test the efficacy of an on-line training targeting school psychology graduate student trainees' awareness of the signs and symptoms of child abuse as well as their…

Software Design for Real-Time Systems on Parallel Computers: Formal Specifications.

DTIC Science & Technology

1996-04-01

This research investigated the important issues related to the analysis and design of real - time systems targeted to parallel architectures. In...particular, the software specification models for real - time systems on parallel architectures were evaluated. A survey of current formal methods for...uniprocessor real - time systems specifications was conducted to determine their extensibility in specifying real - time systems on parallel architectures. In

The Designing and Development of a Program to Prepare Inactive Registered Nurses for Reentry into Practice. Curriculum Development.

ERIC Educational Resources Information Center

Belock, Shirley

The planning and design of a course for the inactive registered nurse desiring to return to active practice is reported in this practicum paper. Current literature was reviewed with emphasis on the needs in rural states, such as Vermont, and characteristics of the target group. The first three modules of the course were developed, entitled: The…

Target-cancer-cell-specific activatable fluorescence imaging probes: rational design and in vivo applications.

PubMed

Kobayashi, Hisataka; Choyke, Peter L

2011-02-15

Conventional imaging methods, such as angiography, computed tomography (CT), magnetic resonance imaging (MRI), and radionuclide imaging, rely on contrast agents (iodine, gadolinium, and radioisotopes, for example) that are "always on." Although these indicators have proven clinically useful, their sensitivity is lacking because of inadequate target-to-background signal ratio. A unique aspect of optical imaging is that fluorescence probes can be designed to be activatable, that is, only "turned on" under certain conditions. These probes are engineered to emit signal only after binding a target tissue; this design greatly increases sensitivity and specificity in the detection of disease. Current research focuses on two basic types of activatable fluorescence probes. The first developed were conventional enzymatically activatable probes. These fluorescent molecules exist in the quenched state until activated by enzymatic cleavage, which occurs mostly outside of the cells. However, more recently, researchers have begun designing target-cell-specific activatable probes. These fluorophores exist in the quenched state until activated within targeted cells by endolysosomal processing, which results when the probe binds specific receptors on the cell surface and is subsequently internalized. In this Account, we present a review of the rational design and in vivo applications of target-cell-specific activatable probes. In engineering these probes, researchers have asserted control over a variety of factors, including photochemistry, pharmacological profile, and biological properties. Their progress has recently allowed the rational design and synthesis of target-cell-specific activatable fluorescence imaging probes, which can be conjugated to a wide variety of targeting molecules. Several different photochemical mechanisms have been utilized, each of which offers a unique capability for probe design. These include self-quenching, homo- and hetero-fluorescence resonance energy transfer (FRET), H-dimer formation, and photon-induced electron transfer (PeT). In addition, the repertoire is further expanded by the option for reversibility or irreversibility of the signal emitted through these mechanisms. Given the wide range of photochemical mechanisms and properties, target-cell-specific activatable probes have considerable flexibility and can be adapted to specific diagnostic needs. A multitude of cell surface molecules, such as overexpressed growth factor receptors, are directly related to carcinogenesis and thus provide numerous targets highly specific for cancer. This discussion of the chemical, pharmacological, and biological basis of target-cell-specific activatable imaging probes, and methods for successfully designing them, underscores the systematic, rational basis for further developing in vivo cancer imaging.

New compact hohlraum configuration research at the 1.7 MA Z-pinch generator

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kantsyrev, V. L., E-mail: victor@unr.edu; Shrestha, I. K.; Esaulov, A. A.

A new compact Z-pinch x-ray hohlraum design with parallel-driven x-ray sources was experimentally demonstrated in a full configuration with a central target and tailored shine shields (to provide a symmetric temperature distribution on the target) at the 1.7 MA Zebra generator. This presentation reports on the joint success of two independent lines of research. One of these was the development of new sources – planar wire arrays (PWAs). PWAs turned out to be a prolific radiator. Another success was the drastic improvement in energy efficiency of pulsed-power systems, such as the Load Current Multiplier (LCM). The Zebra/LCM generator almost doubledmore » the plasma load current to 1.7 MA. The two above-mentioned innovative approaches were used in combination to produce a new compact hohlraum design for ICF, as jointly proposed by SNL and UNR. Good agreement between simulated and measured radiation temperature of the central target is shown. Experimental comparison of PWAs with planar foil liners (PFL) - another viable alternative to wire array loads at multi-MA generators show promising data. Results of research at the University of Nevada Reno allowed for the study of hohlraum coupling physics at University-scale generators. The advantages of new hohlraum design applications for multi-MA facilities with W or Au double PWAs or PFL x-ray sources are discussed.« less

Multisource inverse-geometry CT. Part II. X-ray source design and prototype

PubMed Central

Neculaes, V. Bogdan; Caiafa, Antonio; Cao, Yang; De Man, Bruno; Edic, Peter M.; Frutschy, Kristopher; Gunturi, Satish; Inzinna, Lou; Reynolds, Joseph; Vermilyea, Mark; Wagner, David; Zhang, Xi; Zou, Yun; Pelc, Norbert J.; Lounsberry, Brian

2016-01-01

Purpose: This paper summarizes the development of a high-power distributed x-ray source, or “multisource,” designed for inverse-geometry computed tomography (CT) applications [see B. De Man et al., “Multisource inverse-geometry CT. Part I. System concept and development,” Med. Phys. 43, 4607–4616 (2016)]. The paper presents the evolution of the source architecture, component design (anode, emitter, beam optics, control electronics, high voltage insulator), and experimental validation. Methods: Dispenser cathode emitters were chosen as electron sources. A modular design was adopted, with eight electron emitters (two rows of four emitters) per module, wherein tungsten targets were brazed onto copper anode blocks—one anode block per module. A specialized ceramic connector provided high voltage standoff capability and cooling oil flow to the anode. A matrix topology and low-noise electronic controls provided switching of the emitters. Results: Four modules (32 x-ray sources in two rows of 16) have been successfully integrated into a single vacuum vessel and operated on an inverse-geometry computed tomography system. Dispenser cathodes provided high beam current (>1000 mA) in pulse mode, and the electrostatic lenses focused the current beam to a small optical focal spot size (0.5 × 1.4 mm). Controlled emitter grid voltage allowed the beam current to be varied for each source, providing the ability to modulate beam current across the fan of the x-ray beam, denoted as a virtual bowtie filter. The custom designed controls achieved x-ray source switching in <1 μs. The cathode-grounded source was operated successfully up to 120 kV. Conclusions: A high-power, distributed x-ray source for inverse-geometry CT applications was successfully designed, fabricated, and operated. Future embodiments may increase the number of spots and utilize fast read out detectors to increase the x-ray flux magnitude further, while still staying within the stationary target inherent thermal limitations. PMID:27487878

Multisource inverse-geometry CT. Part II. X-ray source design and prototype

DOE Office of Scientific and Technical Information (OSTI.GOV)

Neculaes, V. Bogdan, E-mail: neculaes@ge.com; Caia

2016-08-15

Purpose: This paper summarizes the development of a high-power distributed x-ray source, or “multisource,” designed for inverse-geometry computed tomography (CT) applications [see B. De Man et al., “Multisource inverse-geometry CT. Part I. System concept and development,” Med. Phys. 43, 4607–4616 (2016)]. The paper presents the evolution of the source architecture, component design (anode, emitter, beam optics, control electronics, high voltage insulator), and experimental validation. Methods: Dispenser cathode emitters were chosen as electron sources. A modular design was adopted, with eight electron emitters (two rows of four emitters) per module, wherein tungsten targets were brazed onto copper anode blocks—one anode blockmore » per module. A specialized ceramic connector provided high voltage standoff capability and cooling oil flow to the anode. A matrix topology and low-noise electronic controls provided switching of the emitters. Results: Four modules (32 x-ray sources in two rows of 16) have been successfully integrated into a single vacuum vessel and operated on an inverse-geometry computed tomography system. Dispenser cathodes provided high beam current (>1000 mA) in pulse mode, and the electrostatic lenses focused the current beam to a small optical focal spot size (0.5 × 1.4 mm). Controlled emitter grid voltage allowed the beam current to be varied for each source, providing the ability to modulate beam current across the fan of the x-ray beam, denoted as a virtual bowtie filter. The custom designed controls achieved x-ray source switching in <1 μs. The cathode-grounded source was operated successfully up to 120 kV. Conclusions: A high-power, distributed x-ray source for inverse-geometry CT applications was successfully designed, fabricated, and operated. Future embodiments may increase the number of spots and utilize fast read out detectors to increase the x-ray flux magnitude further, while still staying within the stationary target inherent thermal limitations.« less

Mock Target Window OTR and IR Design and Testing

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wass, Alexander Joseph

In order to fully verify temperature measurements made on the target window using infrared (IR) optical non-contact methods, actual comparative measurements are made with a real beam distribution as the heat source using Argonne National Laboratory’s (ANL) 35 MeV electron accelerator. Using Monte Carlo N-Particle (MCNP) simulations and thermal Finite Element Analysis (FEA), a cooled mock target window with thermocouple implants is designed to be used in such a test to achieve window temperatures up to 700°C. An uncoated and blackcoated mock window is designed to enhance the IR temperature measurements and verify optical transmitted radiation (OTR) imagery. This allowsmore » us to fully verify and characterize our temperature accuracy with our current IR camera method and any future method we may wish to explore using actual production conditions. This test also provides us with valuable conclusions/concerns regarding the calibration method we developed using our IR test stand at TA-53 in MPF-14.« less

Computational and Pharmacological Target of Neurovascular Unit for Drug Design and Delivery

PubMed Central

2015-01-01

The blood-brain barrier (BBB) is a dynamic and highly selective permeable interface between central nervous system (CNS) and periphery that regulates the brain homeostasis. Increasing evidences of neurological disorders and restricted drug delivery process in brain make BBB as special target for further study. At present, neurovascular unit (NVU) is a great interest and highlighted topic of pharmaceutical companies for CNS drug design and delivery approaches. Some recent advancement of pharmacology and computational biology makes it convenient to develop drugs within limited time and affordable cost. In this review, we briefly introduce current understanding of the NVU, including molecular and cellular composition, physiology, and regulatory function. We also discuss the recent technology and interaction of pharmacogenomics and bioinformatics for drug design and step towards personalized medicine. Additionally, we develop gene network due to understand NVU associated transporter proteins interactions that might be effective for understanding aetiology of neurological disorders and new target base protective therapies development and delivery. PMID:26579539

Inhibitor designing, virtual screening, and docking studies for methyltransferase: A potential target against dengue virus

PubMed Central

Singh, Jagbir; Kumar, Mahesh; Mansuri, Rani; Sahoo, Ganesh Chandra; Deep, Aakash

2016-01-01

Aim: Aim of this work was to design and identify some S-adenosyl-L-homocysteine (SAH) analogs as inhibitors of S-adenosyl-L-methionine-dependent methyltransferase (MTase) protein using computational approaches. Introduction: According to the current scenario the dengue has been a global burden. The people are being killed by dengue virus in an abundant number. Despite of lot of research being going on dengue worldwide, there is no single drug which can kill its virus. This creates an urge for new drug target identification and designing. MTase has been reported as an effective target against dengue virus as it catalyzes an essential step in methylation and capping of viral RNA for viral replication. Materials and Methods: The crystal structure of MTase in complex with SAH was used for designing new analogs of SAH. SAH analogs designed were analyzed on the basis of docking, ADMET, and toxicity analysis done using Discovery Studio 3.5. Results: Seventeen analogs found noncarcinogenic, nonmutagenic, as well as good ADMET properties and good drug-like profile. Conclusion: These SAH analogs, inhibitors of MTase may act as drugs against dengue virus. Further synthesis and biological testing against dengue virus is under observation. PMID:27413346

Tailoring the charged particle fluxes across the target surface of Magnum-PSI

NASA Astrophysics Data System (ADS)

Costin, C.; Anita, V.; Popa, G.; Scholten, J.; De Temmerman, G.

2016-04-01

Linear plasma generators are plasma devices designed to study fusion-relevant plasma-surface interactions. The first requirement for such devices is to operate with adjustable and well characterized plasma parameters. In the linear plasma device Magnum-PSI, the distribution of the charged particle flux across the target surface can be tailored by the target bias. The process is based on the radial inhomogeneity of the plasma column and it is evidenced by electrical measurements via a 2D multi-probe system installed as target. Typical results are reported for a hydrogen discharge operated at 125 A and confined by a magnetic field strength of 0.95 T in the middle of the coils. The probes were biased in the range of  -80 to  -25 V, while the floating potential of the target was about  -35 V. The results were obtained in steady-state regime of Magnum-PSI, being time-averaged over any type of fluctuations. Depending on the relative value of the target bias voltage with respect to the local floating potential in the plasma column, the entire target surface can be exposed to ion or electron dominated flux, respectively, or it can be divided into two adjacent zones: one exposed to electron flux and the other to ion flux. As a consequence of this effect, a floating conductive surface that interacts with an inhomogeneous plasma is exposed to non-zero local currents despite its overall null current and it is subjected to internal current flows.

New method to design stellarator coils without the winding surface

NASA Astrophysics Data System (ADS)

Zhu, Caoxiang; Hudson, Stuart R.; Song, Yuntao; Wan, Yuanxi

2018-01-01

Finding an easy-to-build coils set has been a critical issue for stellarator design for decades. Conventional approaches assume a toroidal ‘winding’ surface, but a poorly chosen winding surface can unnecessarily constrain the coil optimization algorithm, This article presents a new method to design coils for stellarators. Each discrete coil is represented as an arbitrary, closed, one-dimensional curve embedded in three-dimensional space. A target function to be minimized that includes both physical requirements and engineering constraints is constructed. The derivatives of the target function with respect to the parameters describing the coil geometries and currents are calculated analytically. A numerical code, named flexible optimized coils using space curves (FOCUS), has been developed. Applications to a simple stellarator configuration, W7-X and LHD vacuum fields are presented.

New Molecular Targets of Anticancer Therapy - Current Status and Perspectives.

PubMed

Zajac, Marianna; Muszalska, Izabela; Jelinska, Anna

2016-01-01

Molecularly targeted anticancer therapy involves the use of drugs or other substances affecting specific molecular targets that play a part in the development, progression and spread of a given neoplasm. By contrast, the majority of classical chemotherapeutics act on all rapidly proliferating cells, both healthy and cancerous ones. Target anticancer drugs are designed to achieve a particular aim and they usually act cytostatically, not cytotoxically like classical chemotherapeutics. At present, more than 300 biological molecular targets have been identified. The proteins involved in cellular metabolism include (among others) receptor proteins, signal transduction proteins, mRNA thread matrix synthesis proteins participating in neoplastic transformation, cell cycle control proteins, functional and structural proteins. The receptor proteins that are targeted by currently used anticancer drugs comprise the epithelial growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor(VEGFR). Target anticancer drugs may affect extracellular receptor domains (antibodies) or intracellular receptor domains (tyrosine kinase inhibitors). The blocking of the mRNA thread containing information about the structure of oncogenes (signal transduction proteins) is another molecular target of anticancer drugs. That type of treatment, referred to as antisense therapy, is in clinical trials. When the synthesis of genetic material is disturbed, in most cases the passage to the next cycle phase is blocked. The key proteins responsible for the blockage are cyclines and cycline- dependent kinases (CDK). Clinical trials are focused on natural and synthetic substances capable of blocking various CDKs. The paper discusses the molecular targets and chemical structure of target anticancer drugs that have been approved for and currently applied in antineoplastic therapy together with indications and contraindications for their application.

Emerging therapeutic targets currently under investigation for the treatment of systemic amyloidosis.

PubMed

Nuvolone, Mario; Merlini, Giampaolo

2017-12-01

Systemic amyloidosis occurs when one of a growing list of circulating proteins acquires an abnormal fold, aggregates and gives rise to extracellular amyloid deposits in different body sites, leading to organ dysfunction and eventually death. Current approaches are mainly aimed at lowering the supply of the amyloidogenic precursor or at stabilizing it in a non-amyloidogenic state, thus interfering with the initial phases of amyloid formation and toxicity. Areas covered: Improved understanding of the pathophysiology is indicating novel steps and molecules that could be therapeutically targeted. Here, we will review emerging molecular targets and therapeutic approaches against the main forms of systemic amyloidosis at the early preclinical level. Expert opinion: Conspicuous efforts in drug design and drug discovery have provided an unprecedented list of potential new drugs or therapeutic strategies, from gene-based therapies to small molecules and peptides, from novel monoclonal antibodies to engineered cell-based therapies. The challenge will now be to validate and optimize the most promising candidates, cross the bridge from the preclinical phase to the clinics and identify, through innovative trials design, the safest and most effective combination therapies, striving for a better care, possibly a definitive cure for these diseases.

Selection and trajectory design to mission secondary targets

NASA Astrophysics Data System (ADS)

Victorino Sarli, Bruno; Kawakatsu, Yasuhiro

2017-02-01

Recently, with new trajectory design techniques and use of low-thrust propulsion systems, missions have become more efficient and cheaper with respect to propellant. As a way to increase the mission's value and scientific return, secondary targets close to the main trajectory are often added with a small change in the transfer trajectory. As a result of their large number, importance and facility to perform a flyby, asteroids are commonly used as such targets. This work uses the Primer Vector theory to define the direction and magnitude of the thrust for a minimum fuel consumption problem. The design of a low-thrust trajectory with a midcourse asteroid flyby is not only challenging for the low-thrust problem solution, but also with respect to the selection of a target and its flyby point. Currently more than 700,000 minor bodies have been identified, which generates a very large number of possible flyby points. This work uses a combination of reachability, reference orbit, and linear theory to select appropriate candidates, drastically reducing the simulation time, to be later included in the main trajectory and optimized. Two test cases are presented using the aforementioned selection process and optimization to add and design a secondary flyby to a mission with the primary objective of 3200 Phaethon flyby and 25143 Itokawa rendezvous.

The MiniCLEAN Dark Matter Experiment

NASA Astrophysics Data System (ADS)

Schnee, Richard; Deap/Clean Collaboration

2011-10-01

The MiniCLEAN dark matter experiment exploits a single-phase liquid argon (LAr) detector, instrumented with photomultiplier tubes submerged in the cryogen with nearly 4 π coverage of a 500 kg target (150 kg fiducial) mass. The high light yield and large difference in singlet/triplet scintillation time-profiles in LAr provide effective defense against radioactive backgrounds through pulse-shape discrimination and event position reconstruction. The detector is also designed for a liquid neon target which, in the event of a positive signal in LAr, will enable an independent verification of backgrounds and provide a unique test of the expected A2 dependence of the WIMP interaction rate. The conceptually simple design can be scaled to target masses in excess of 10 tons in a relatively straightforward and economic manner. The experimental technique and current status of MiniCLEAN will be summarized.

Volatile organic compounds discrimination based on dual mode detection

NASA Astrophysics Data System (ADS)

Yu, Yuanyuan; Wu, Enxiu; Chen, Yan; Feng, Zhihong; Zheng, Shijun; Zhang, Hao; Pang, Wei; Liu, Jing; Zhang, Daihua

2018-06-01

We report on a volatile organic compound (VOC) sensor that can provide concentration-independent signals toward target gases. The device is based on a dual-mode detection mechanism that can simultaneously record the mechanical (resonant frequency, f r) and electrical (current, I) responses of the same gas adsorption event. The two independent signals form a unique I–f r trace for each target VOC as the concentration varies. The mechanical response (frequency shift, Δf r) resulting from mass load on the device is directly related to the amount of surface adsorptions, while the electrical response (current variation, ΔI) is associated with charge transfer across the sensing interface and changes in carrier mobility. The two responses resulting from independent physical processes reflect intrinsic physical properties of each target gas. The ΔI–Δf r trace combined with the concentration dependent frequency (or current) signals can therefore be used to achieve target both recognition and quantification. The dual-mode device is designed and fabricated using standard complementary metal oxide semiconductor (CMOS) compatible processes. It exhibits consistent and stable performance in our tests with six different VOCs including ethanol, methanol, acetone, formaldehyde, benzene and hexane.

Volatile organic compounds discrimination based on dual mode detection.

PubMed

Yu, Yuanyuan; Wu, Enxiu; Chen, Yan; Feng, Zhihong; Zheng, Shijun; Zhang, Hao; Pang, Wei; Liu, Jing; Zhang, Daihua

2018-06-15

We report on a volatile organic compound (VOC) sensor that can provide concentration-independent signals toward target gases. The device is based on a dual-mode detection mechanism that can simultaneously record the mechanical (resonant frequency, f r ) and electrical (current, I) responses of the same gas adsorption event. The two independent signals form a unique I-f r trace for each target VOC as the concentration varies. The mechanical response (frequency shift, Δf r ) resulting from mass load on the device is directly related to the amount of surface adsorptions, while the electrical response (current variation, ΔI) is associated with charge transfer across the sensing interface and changes in carrier mobility. The two responses resulting from independent physical processes reflect intrinsic physical properties of each target gas. The ΔI-Δf r trace combined with the concentration dependent frequency (or current) signals can therefore be used to achieve target both recognition and quantification. The dual-mode device is designed and fabricated using standard complementary metal oxide semiconductor (CMOS) compatible processes. It exhibits consistent and stable performance in our tests with six different VOCs including ethanol, methanol, acetone, formaldehyde, benzene and hexane.

The Role of Exposure Science in Air Quality Management

EPA Science Inventory

Air quality standards and regulations are designed to protect public health and the environment. However, there are issues regarding whether the current standards and regulations should be adjusted to be more protective or to more effectively target air quality management activi...

Cancer Nanotheranostics: Improving Imaging and Therapy by Targeted Delivery across Biological Barriers

PubMed Central

Kievit, Forrest M.; Zhang, Miqin

2012-01-01

Cancer nanotheranostics aims to combine imaging and therapy of cancer through use of nanotechnology. The ability to engineer nanomaterials to interact with cancer cells at the molecular level can significantly improve the effectiveness and specificity of therapy to cancers that are currently difficult to treat. In particular, metastatic cancers, drug-resistant cancers, and cancer stem cells impose the greatest therapeutic challenge that requires targeted therapy to treat effectively. Targeted therapy can be achieved with appropriate designed drug delivery vehicles such as nanoparticles, adult stem cells, or T cells in immunotherapy. In this article, we first review the different types of materials commonly used to synthesize nanotheranostic particles and their use in imaging. We then discuss biological barriers that these nanoparticles encounter and must bypass to reach the target cancer cells, including the blood, liver, kidneys, spleen, and particularly the blood-brain barrier. We then review how nanotheranostics can be used to improve targeted delivery and treatment of cancer cells using nanoparticles, adult stem cells, and T cells in immunotherapy. Finally, we discuss development of nanoparticles to overcome current limitations in cancer therapy. PMID:21842473

Water Cooled Mirror Design

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dale, Gregory E.; Holloway, Michael Andrew; Pulliam, Elias Noel

2015-03-30

This design is intended to replace the current mirror setup being used for the NorthStar Moly 99 project in order to monitor the target coupon. The existing setup has limited movement for camera alignment and is difficult to align properly. This proposed conceptual design for a water cooled mirror will allow for greater thermal transfer between the mirror and the water block. It will also improve positioning of the mirror by using flexible vacuum hosing and a ball head joint capable of a wide range of motion. Incorporating this design into the target monitoring system will provide more efficient coolingmore » of the mirror which will improve the amount of diffraction caused by the heating of the mirror. The process of aligning the mirror for accurate position will be greatly improved by increasing the range of motion by offering six degrees of freedom.« less

Ethical considerations of neuro-oncology trial design in the era of precision medicine.

PubMed

Gupta, Saksham; Smith, Timothy R; Broekman, Marike L

2017-08-01

The field of oncology is currently undergoing a paradigm shift. Advances in the understanding of tumor biology and in tumor sequencing technology have contributed to the shift towards precision medicine, the therapeutic framework of targeting the individual oncogenic changes each tumor harbors. The success of precision medicine therapies, such as targeted kinase inhibitors and immunotherapies, in other cancers have motivated studies in brain cancers. The high specificity and cost of these therapies also encourage a shift in clinical trial design away from randomized control trials towards smaller, more exclusive early phase clinical trials. While these new trials advance the clinical application of increasingly precise and individualized therapies, their design brings ethical challenges . We review the pertinent ethical considerations for clinical trials of precision medicine in neuro-oncology and discuss methods to protect patients in this new era of trial design.

Beyond cysteine: recent developments in the area of targeted covalent inhibition.

PubMed

Mukherjee, Herschel; Grimster, Neil P

2018-05-29

Over the past decade targeted covalent inhibitors have undergone a renaissance due to the clinical validation and regulatory approval of several small molecule therapeutics that are designed to irreversibly modify their target protein. Invariably, these compounds rely on the serendipitous placement of a cysteine residue proximal to the small molecule binding site; while this strategy has afforded numerous successes, it necessarily limits the number of proteins that can be targeted by this approach. This drawback has led several research groups to develop novel methodologies that target non-cysteine residues for covalent modification. Herein, we survey the current literature of warheads that covalently modify non-cysteine amino acids in proteins. Copyright © 2018 Elsevier Ltd. All rights reserved.

Novel Cyclotron-Based Radiometal Production

DOE Office of Scientific and Technical Information (OSTI.GOV)

DeGrado, Timothy R.

2013-10-31

Accomplishments: (1) Construction of prototype solution target for radiometal production; (2) Testing of prototype target for production of following isotopes: a. Zr-89. Investigation of Zr-89 production from Y-89 nitrate solution. i. Defined problems of gas evolution and salt precipitation. ii. Solved problem of precipitation by addition of nitric acid. iii. Solved gas evolution problem with addition of backpressure regulator and constant degassing of target during irradiations. iv. Investigated effects of Y-89 nitrate concentration and beam current. v. Published abstracts at SNM and ISRS meetings; (3) Design of 2nd generation radiometal solution target. a. Included reflux chamber and smaller target volumemore » to conserve precious target materials. b. Included aluminum for prototype and tantalum for working model. c. Included greater varicosities for improved heat transfer; and, (4) Construction of 2nd generation radiometal solution target started.« less

The Influence of the September 11, 2001 Attacks and Related Events Years Later on the Expectations and Experiences of Saudi Undergraduate Students Studying in the United States

ERIC Educational Resources Information Center

Ghaleb, Sarah Mohammad

2013-01-01

This study was designed to determine whether or not undergraduate Saudi Arabian students currently studying in the United States still expect and experience negativity more than a decade after the events related to September 11, 2001. The study target population is all undergraduate Saudi students currently studying through the Saudi Arabian…

Fast Fourier Transform algorithm design and tradeoffs

NASA Technical Reports Server (NTRS)

Kamin, Ray A., III; Adams, George B., III

1988-01-01

The Fast Fourier Transform (FFT) is a mainstay of certain numerical techniques for solving fluid dynamics problems. The Connection Machine CM-2 is the target for an investigation into the design of multidimensional Single Instruction Stream/Multiple Data (SIMD) parallel FFT algorithms for high performance. Critical algorithm design issues are discussed, necessary machine performance measurements are identified and made, and the performance of the developed FFT programs are measured. Fast Fourier Transform programs are compared to the currently best Cray-2 FFT program.

Application of a Design Space Exploration Tool to Enhance Interleaver Generation

DTIC Science & Technology

2009-06-24

2], originally dedicated to channel coding, are being currently reused in a large set of the whole digital communication systems (e.g. equalization... originally target interface synthesis, is shown to be also suited to the interleaver design space exploration. Our design flow can take as input...slice turbo codes,” in Proc. 3rd Int. Symp. Turbo Codes, Related Topics, Brest , 2003, pp. 343–346. [11] IEEE 802.15.3a, WPAN High Rate Alternative [12

LH2 Target Design & Position Survey Techniques for the MUSE experiment for Precise Proton Radius Measurement

NASA Astrophysics Data System (ADS)

Le Pottier, Luc; Roy, Pryiashee; Lorenzon, Wolfgang; Raymond, Richard; Steinberg, Noah; Rossi de La Fuente, Erick; MUSE (MUon proton Scattering Experiment) Collaboration

2017-09-01

The proton radius puzzle is a currently unresolved problem which has intrigued the scientific community, dealing with a 7 σ discrepancy between the proton radii determined from muonic hydrogen spectroscopy and electron scattering measurements. The MUon Scattering Experiment (MUSE) aims to resolve this puzzle by performing the first simultaneous elastic scattering measurements of both electrons and muons on the proton, which will allow the comparison of the radii from the two interactions with reduced systematic uncertainties. The data from this experiment is expected to provide the best test of lepton universality to date. The experiment will take place at the Paul Scherrer Institute in Switzerland in 2018. An essential component of the experiment is a liquid hydrogen (LH2) cryotarget system. Our group at the University of Michigan is responsible for the design, fabrication and installation of this system. Here we present our LH2 target cell design and fabrication techniques for successful operation at 20 K and 1 atm, and our computer vision-based target position survey system which will determine the position of the target, installed inside a vacuum chamber, with 0.01 mm or better precision at the height of the liquid hydrogen target and along the beam direction during the experiment.

Solution to the satisfiability problem using a complete Grover search with trapped ions

NASA Astrophysics Data System (ADS)

Yang, Wan-Li; Wei, Hua; Zhou, Fei; Chang, Weng-Long; Feng, Mang

2009-07-01

The main idea in the original Grover search (1997 Phys. Rev. Lett. 79 325) is to single out a target state containing the solution to a search problem by amplifying the amplitude of the state, following the Oracle's job, i.e., a black box giving us information about the target state. We design quantum circuits to accomplish a complete Grover search involving both the Oracle's job and the amplification of the target state, which are employed to solve satisfiability (SAT) problems. We explore how to carry out the quantum circuits with currently available ion-trap quantum computing technology.

150 {mu}A 18F{sup -} target and beam port upgrade for the IBA 18/9 cyclotron

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stokely, M. H.; Peeples, J. L.; Poorman, M. C.

2012-12-19

A high power ({approx}3 kW) target platform has been developed for the IBA 18/9 cyclotron. New designs for the airlock, collimator and target subsystems have been fabricated and deployed. The primary project goal is reliable commercial production of 18F{sup -} at 150 {mu}A or greater, while secondary goals include improving serviceability and extending service intervals relative to OEM systems. Reliable operation in a production environment has been observed at beam currents up to 140 {mu}A. Challenges include ion source lifetime and localized peaking in the beam intensity distribution.

Targeting Key Transporters in Tumor Glycolysis as a Novel Anticancer Strategy.

PubMed

Shi, Yunli; Liu, Shengnan; Ahmad, Shabir; Gao, Qingzhi

2018-05-22

Increased glycolysis has been one of the metabolic characteristics known as the Warburg effect. The functional and therapeutic importance of the Warburg effect in targeted therapy is scientifically recognized and the glucose metabolic pathway has become a desirable target of anticancer strategies. Glucose transporters (GLUTs) play an important role in cancer glycolysis to sustain cancer cell proliferation, metastasis and survival. Utilizing the knowledge of differential expression and biological functions of GLUTs offers us the possibility of designing and delivering chemotherapeutics toward targeted tumor tissues for improved cancer selectivity. Inhibition of glucose uptake or glycolysis may effectively kill hypoxic cancer cells. Facilitative drug uptake via active transportation provides the potential opportunity to circumvent the drug resistance in chemotherapy. GLUTs as the hallmarks and biotargets of cancer metabolism enable the design and development of novel targeted theranostic agents. In this updated review, we examine the current scenario of the GLUTs as strategic targets in cancer and the unique concepts for discovery and development of GLUTs-targeted anticancer agents. We highlight the recent progresses on structural biology and underlying mechanism studies of GLUTs, with a brief introduction to the computational approaches in GLUT-mediated drug transport and tumor targeting. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

An advanced wide area chemical sensor testbed

NASA Astrophysics Data System (ADS)

Seeley, Juliette A.; Kelly, Michael; Wack, Edward; Ryan-Howard, Danette; Weidler, Darryl; O'Brien, Peter; Colonero, Curtis; Lakness, John; Patel, Paras

2005-11-01

In order to meet current and emerging needs for remote passive standoff detection of chemical agent threats, MIT Lincoln Laboratory has developed a Wide Area Chemical Sensor (WACS) testbed. A design study helped define the initial concept, guided by current standoff sensor mission requirements. Several variants of this initial design have since been proposed to target other applications within the defense community. The design relies on several enabling technologies required for successful implementation. The primary spectral component is a Wedged Interferometric Spectrometer (WIS) capable of imaging in the LWIR with spectral resolutions as narrow as 4 cm-1. A novel scanning optic will enhance the ability of this sensor to scan over large areas of concern with a compact, rugged design. In this paper, we shall discuss our design, development, and calibration process for this system as well as recent testbed measurements that validate the sensor concept.

Small Molecule Docking from Theoretical Structural Models

NASA Astrophysics Data System (ADS)

Novoa, Eva Maria; de Pouplana, Lluis Ribas; Orozco, Modesto

Structural approaches to rational drug design rely on the basic assumption that pharmacological activity requires, as necessary but not sufficient condition, the binding of a drug to one or several cellular targets, proteins in most cases. The traditional paradigm assumes that drugs that interact only with a single cellular target are specific and accordingly have little secondary effects, while promiscuous molecules are more likely to generate undesirable side effects. However, current examples indicate that often efficient drugs are able to interact with several biological targets [1] and in fact some dirty drugs, such as chlorpromazine, dextromethorphan, and ibogaine exhibit desired pharmacological properties [2]. These considerations highlight the tremendous difficulty of designing small molecules that both have satisfactory ADME properties and the ability of interacting with a limited set of target proteins with a high affinity, avoiding at the same time undesirable interactions with other proteins. In this complex and challenging scenario, computer simulations emerge as the basic tool to guide medicinal chemists during the drug discovery process.

Characterization of Deuteron-Deuteron Neutron Generators

NASA Astrophysics Data System (ADS)

Waltz, Cory Scott

A facility based on a next-generation, high-flux D-D neutron generator (HFNG) was commissioned at the University of California Berkeley. The characterization of the HFNG is presented in the following study. The current generator design produces near mono-energetic 2.45 MeV neutrons at outputs of 108 n/s. Calculations provided show that future conditioning at higher currents and voltages will allow for a production rate over 1010 n/s. Characteristics that effect the operational stability include the suppression of the target-emitted back streaming electrons, target sputtering and cooling, and ion beam optics. Suppression of secondary electrons resulting from the deuterium beam striking the target was achieved via the implementation of an electrostatic shroud with a voltage offset of greater than -400 V relative to the target. Ion beam optics analysis resulted in the creation of a defocussing extraction nozzle, allowing for cooler target temperatures and a more compact design. To calculate the target temperatures, a finite difference method (FDM) solver incorporating the additional heat removal effects of subcooled boiling was developed. Validation of the energy balance results from the finite difference method calculations showed the iterative solver converged to heat removal results within about 3% of the expected value. Testing of the extraction nozzle at 1.43 mA and 100 kV determined that overheating of the target did not occur as the measured neutron flux of the generator was near predicted values. Many factors, including the target stopping power, deuterium atomic species, and target loading ratio, affect the flux distribution of the HFNG neutron generator. A detailed analysis to understand these factors effects is presented. Comparison of the calculated flux of the neutron generator using deuteron depth implantation data, neutron flux distribution data, and deuterium atomic species data matched the experimentally calculated flux determined from indium foil irradiations. An overview of experiments using the HFNG, including medical isotope cross section measurements, geochronology, delayed gamma measurements from uranium fission, and single event upset of cpu's is discussed. Future work should focus on the reduction of beam induced arcing between the shroud and the vacuum chamber. Investigation of insulator charge build-up, as well as electrical ash-over of insulators should be explored. The reduction of beam induced arcing will allow for larger beam currents and acceleration voltages, therefore increasing the neutron flux.

Advances in chemical labeling of proteins in living cells.

PubMed

Yan, Qi; Bruchez, Marcel P

2015-04-01

The pursuit of quantitative biological information via imaging requires robust labeling approaches that can be used in multiple applications and with a variety of detectable colors and properties. In addition to conventional fluorescent proteins, chemists and biologists have come together to provide a range of approaches that combine dye chemistry with the convenience of genetic targeting. This hybrid-tagging approach amalgamates the rational design of properties available through synthetic dye chemistry with the robust biological targeting available with genetic encoding. In this review, we discuss the current range of approaches that have been exploited for dye targeting or for targeting and activation and some of the recent applications that are uniquely permitted by these hybrid-tagging approaches.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Neuffer, David; Snopok, Pavel; Alexahin, Yuri

A neutrino factory or muon collider requires the capture and cooling of a large number of muons. Scenarios for capture, bunching, phase-energy rotation and initial cooling of μ’s produced from a proton source target have been developed, initially for neutrino factory scenarios. They require a drift section from the target, a bunching section and a Φ-δE rotation section leading into the cooling channel. Important concerns are rf limitations within the focusing magnetic fields and large losses in the transport. The currently preferred cooling channel design is an “HFOFO Snake” configuration that cools both μ + and μ - transversely andmore » longitudinally. Finally, the status of the design is presented and variations are discussed.« less

Direct measurements of anode/cathode gap plasma in cylindrically imploding loads on the Z machine

NASA Astrophysics Data System (ADS)

Porwitzky, A.; Dolan, D. H.; Martin, M. R.; Laity, G.; Lemke, R. W.; Mattsson, T. R.

2018-06-01

By deploying a photon Doppler velocimetry based plasma diagnostic, we have directly observed low density plasma in the load anode/cathode gap of cylindrically converging pulsed power targets. The arrival of this plasma is temporally correlated with gross current loss and subtle power flow differences between the anode and the cathode. The density is in the range where Hall terms in the electromagnetic equations are relevant, but this physics is lacking in the magnetohydrodynamics codes commonly used to design, analyze, and optimize pulsed power experiments. The present work presents evidence of the importance of physics beyond traditional resistive magnetohydrodynamics for the design of pulsed power targets and drivers.

Front End for a neutrino factory or muon collider

NASA Astrophysics Data System (ADS)

Neuffer, D.; Snopok, P.; Alexahin, Y.

2017-11-01

A neutrino factory or muon collider requires the capture and cooling of a large number of muons. Scenarios for capture, bunching, phase-energy rotation and initial cooling of μ 's produced from a proton source target have been developed, initially for neutrino factory scenarios. They require a drift section from the target, a bunching section and a varphi -δ E rotation section leading into the cooling channel. Important concerns are rf limitations within the focusing magnetic fields and large losses in the transport. The currently preferred cooling channel design is an "HFOFO Snake" configuration that cools both μ+ and μ- transversely and longitudinally. The status of the design is presented and variations are discussed.

Portraiture lens concept in a mobile phone camera

NASA Astrophysics Data System (ADS)

Sheil, Conor J.; Goncharov, Alexander V.

2017-11-01

A small form-factor lens was designed for the purpose of portraiture photography, the size of which allows use within smartphone casing. The current general requirement of mobile cameras having good all-round performance results in a typical, familiar, many-element design. Such designs have little room for improvement, in terms of the available degrees of freedom and highly-demanding target metrics such as low f-number and wide field of view. However, the specific application of the current portraiture lens relaxed the requirement of an all-round high-performing lens, allowing improvement of certain aspects at the expense of others. With a main emphasis on reducing depth of field (DoF), the current design takes advantage of the simple geometrical relationship between DoF and pupil diameter. The system has a large aperture, while a reasonable f-number gives a relatively large focal length, requiring a catadioptric lens design with double ray path; hence, field of view is reduced. Compared to typical mobile lenses, the large diameter reduces depth of field by a factor of four.

Current progress of immunoinformatics approach harnessed for cellular- and antibody-dependent vaccine design.

PubMed

Kazi, Ada; Chuah, Candy; Majeed, Abu Bakar Abdul; Leow, Chiuan Herng; Lim, Boon Huat; Leow, Chiuan Yee

2018-03-12

Immunoinformatics plays a pivotal role in vaccine design, immunodiagnostic development, and antibody production. In the past, antibody design and vaccine development depended exclusively on immunological experiments which are relatively expensive and time-consuming. However, recent advances in the field of immunological bioinformatics have provided feasible tools which can be used to lessen the time and cost required for vaccine and antibody development. This approach allows the selection of immunogenic regions from the pathogen genomes. The ideal regions could be developed as potential vaccine candidates to trigger protective immune responses in the hosts. At present, epitope-based vaccines are attractive concepts which have been successfully trailed to develop vaccines which target rapidly mutating pathogens. In this article, we provide an overview of the current progress of immunoinformatics and their applications in the vaccine design, immune system modeling and therapeutics.

CD28z CARs and Armored CARs

PubMed Central

Pegram, Hollie J.; Park, Jae H.; Brentjens, Renier J.

2015-01-01

CD19-targeted chimeric antigen receptor (CAR) T cells are currently being tested in the clinic with very promising outcomes. However, limitations to CAR T cell therapy exist. These include lack of efficacy against some tumors, specific targeting of tumor cells without affecting normal tissue and retaining activity within the suppressive tumor microenvironment. Whilst promising clinical trials are in progress, preclinical development is focused on optimizing CAR design, to generate “armored CAR T cells” which are protected from the inhibitory tumor microenvironment. Studies investigating the expression of cytokine transgenes, combination therapy with small molecule inhibitors or monoclonal antibodies are aimed at improving the anti-tumor efficacy of CAR T cell therapy. Other strategies aimed at improving CAR T cell therapy include utilizing dual CARs and chemokine receptors to more specifically target tumor cells. This review will describe the current clinical data and some novel “armored CAR T cell” approaches for improving anti-tumor efficacy therapy. PMID:24667958

CD28z CARs and armored CARs.

PubMed

Pegram, Hollie J; Park, Jae H; Brentjens, Renier J

2014-01-01

CD19-targeted chimeric antigen receptor (CAR) T cells are currently being tested in the clinic with very promising outcomes. However, limitations to CAR T cell therapy exist. These include lack of efficacy against some tumors, specific targeting of tumor cells without affecting normal tissue and retaining activity within the suppressive tumor microenvironment. Whereas promising clinical trials are in progress, preclinical development is focused on optimizing CAR design, to generate "armored CAR T cells," which are protected from the inhibitory tumor microenvironment. Studies investigating the expression of cytokine transgenes, combination therapy with small molecule inhibitors, or monoclonal antibodies, are aimed at improving the antitumor efficacy of CAR T cell therapy. Other strategies aimed at improving CAR T cell therapy include using dual CARs and chemokine receptors to more specifically target tumor cells. This review will describe the current clinical data and some novel armored CAR T cell approaches for improving antitumor efficacy therapy.

Targeted polymeric therapeutic nanoparticles: design, development and clinical translation†

PubMed Central

Kamaly, Nazila; Xiao, Zeyu; Valencia, Pedro M.; Radovic-Moreno, Aleksandar F.; Farokhzad, Omid C.

2013-01-01

Polymeric materials have been used in a range of pharmaceutical and biotechnology products for more than 40 years. These materials have evolved from their earlier use as biodegradable products such as resorbable sutures, orthopaedic implants, macroscale and microscale drug delivery systems such as microparticles and wafers used as controlled drug release depots, to multifunctional nanoparticles (NPs) capable of targeting, and controlled release of therapeutic and diagnostic agents. These newer generations of targeted and controlled release polymeric NPs are now engineered to navigate the complex in vivo environment, and incorporate functionalities for achieving target specificity, control of drug concentration and exposure kinetics at the tissue, cell, and subcellular levels. Indeed this optimization of drug pharmacology as aided by careful design of multifunctional NPs can lead to improved drug safety and efficacy, and may be complimentary to drug enhancements that are traditionally achieved by medicinal chemistry. In this regard, polymeric NPs have the potential to result in a highly differentiated new class of therapeutics, distinct from the original active drugs used in their composition, and distinct from first generation NPs that largely facilitated drug formulation. A greater flexibility in the design of drug molecules themselves may also be facilitated following their incorporation into NPs, as drug properties (solubility, metabolism, plasma binding, biodistribution, target tissue accumulation) will no longer be constrained to the same extent by drug chemical composition, but also become in-part the function of the physicochemical properties of the NP. The combination of optimally designed drugs with optimally engineered polymeric NPs opens up the possibility of improved clinical outcomes that may not be achievable with the administration of drugs in their conventional form. In this critical review, we aim to provide insights into the design and development of targeted polymeric NPs and to highlight the challenges associated with the engineering of this novel class of therapeutics, including considerations of NP design optimization, development and biophysicochemical properties. Additionally, we highlight some recent examples from the literature, which demonstrate current trends and novel concepts in both the design and utility of targeted polymeric NPs (444 references). PMID:22388185

Using computer-aided drug design and medicinal chemistry strategies in the fight against diabetes.

PubMed

Semighini, Evandro P; Resende, Jonathan A; de Andrade, Peterson; Morais, Pedro A B; Carvalho, Ivone; Taft, Carlton A; Silva, Carlos H T P

2011-04-01

The aim of this work is to present a simple, practical and efficient protocol for drug design, in particular Diabetes, which includes selection of the illness, good choice of a target as well as a bioactive ligand and then usage of various computer aided drug design and medicinal chemistry tools to design novel potential drug candidates in different diseases. We have selected the validated target dipeptidyl peptidase IV (DPP-IV), whose inhibition contributes to reduce glucose levels in type 2 diabetes patients. The most active inhibitor with complex X-ray structure reported was initially extracted from the BindingDB database. By using molecular modification strategies widely used in medicinal chemistry, besides current state-of-the-art tools in drug design (including flexible docking, virtual screening, molecular interaction fields, molecular dynamics, ADME and toxicity predictions), we have proposed 4 novel potential DPP-IV inhibitors with drug properties for Diabetes control, which have been supported and validated by all the computational tools used herewith.

Thin film surface treatments for lowering dust adhesion on Mars Rover calibration targets

NASA Astrophysics Data System (ADS)

Sabri, F.; Werhner, T.; Hoskins, J.; Schuerger, A. C.; Hobbs, A. M.; Barreto, J. A.; Britt, D.; Duran, R. A.

The current generation of calibration targets on Mars Rover serve as a color and radiometric reference for the panoramic camera. They consist of a transparent silicon-based polymer tinted with either color or grey-scale pigments and cast with a microscopically rough Lambertian surface for a diffuse reflectance pattern. This material has successfully withstood the harsh conditions existent on Mars. However, the inherent roughness of the Lambertian surface (relative to the particle size of the Martian airborne dust) and the tackiness of the polymer in the calibration targets has led to a serious dust accumulation problem. In this work, non-invasive thin film technology was successfully implemented in the design of future generation calibration targets leading to significant reduction of dust adhesion and capture. The new design consists of a μm-thick interfacial layer capped with a nm-thick optically transparent layer of pure metal. The combination of these two additional layers is effective in burying the relatively rough Lambertian surface while maintaining diffuse properties of the samples which is central to the correct operation as calibration targets. A set of these targets are scheduled for flight on the Mars Phoenix mission.

Development of pharmacophore models for small molecules targeting RNA: Application to the RNA repeat expansion in myotonic dystrophy type 1.

PubMed

Angelbello, Alicia J; González, Àlex L; Rzuczek, Suzanne G; Disney, Matthew D

2016-12-01

RNA is an important drug target, but current approaches to identify bioactive small molecules have been engineered primarily for protein targets. Moreover, the identification of small molecules that bind a specific RNA target with sufficient potency remains a challenge. Computer-aided drug design (CADD) and, in particular, ligand-based drug design provide a myriad of tools to identify rapidly new chemical entities for modulating a target based on previous knowledge of active compounds without relying on a ligand complex. Herein we describe pharmacophore virtual screening based on previously reported active molecules that target the toxic RNA that causes myotonic dystrophy type 1 (DM1). DM1-associated defects are caused by sequestration of muscleblind-like 1 protein (MBNL1), an alternative splicing regulator, by expanded CUG repeats (r(CUG) exp ). Several small molecules have been found to disrupt the MBNL1-r(CUG) exp complex, ameliorating DM1 defects. Our pharmacophore model identified a number of potential lead compounds from which we selected 11 compounds to evaluate. Of the 11 compounds, several improved DM1 defects both in vitro and in cells. Copyright © 2016 Elsevier Ltd. All rights reserved.

Rare isotope accelerator project in Korea and its application to high energy density sciences

NASA Astrophysics Data System (ADS)

Chung, M.; Chung, Y. S.; Kim, S. K.; Lee, B. J.; Hoffmann, D. H. H.

2014-01-01

As a national science project, the Korean government has recently established the Institute for Basic Science (IBS) with the goal of conducting world-class research in basic sciences. One of the core facilities for the IBS will be the rare isotope accelerator which can produce high-intensity rare isotope beams to investigate the fundamental properties of nature, and also to support a broad research program in material sciences, medical and biosciences, and future nuclear energy technologies. The construction of the accelerator is scheduled to be completed by approximately 2017. The design of the accelerator complex is optimized to deliver high average beam current on targets, and to maximize the production of rare isotope beams through the simultaneous use of Isotope Separation On-Line (ISOL) and In-Flight Fragmentation (IFF) methods. The proposed accelerator is, however, not optimal for high energy density science, which usually requires very high peak currents on the target. In this study, we present possible beam-plasma experiments that can be done within the scope of the current accelerator design, and we also investigate possible future extension paths that may enable high energy density science with intense pulsed heavy ion beams.

Design of a New Acceleration System for High-Current Pulsed Proton Beams from an ECR Source

NASA Astrophysics Data System (ADS)

Cooper, Andrew L.; Pogrebnyak, Ivan; Surbrook, Jason T.; Kelly, Keegan J.; Carlin, Bret P.; Champagne, Arthur E.; Clegg, Thomas B.

2014-03-01

A primary objective for accelerators at TUNL's Laboratory for Experimental Nuclear Astrophysics (LENA) is to maximize target beam intensity to ensure a high rate of nuclear events during each experiment. Average proton target currents of several mA are needed from LENA's electron cyclotron resonance (ECR) ion source because nuclear cross sections decrease substantially at energies of interest <200 keV. We seek to suppress undesired continuous environmental background by pulsing the beam and detecting events only during beam pulses. To improve beam intensity and transport, we installed a more powerful, stable microwave system for the ECR plasma, and will install a new acceleration system. This system will: reduce defocusing effects of the beam's internal space charge; provide better vacuum with a high gas conductance accelerating column; suppress bremsstrahlung X-rays produced when backstreaming electrons strike internal acceleration tube structures; and provide better heat dissipation by using deionized water to provide the current drain needed to establish the accelerating tube's voltage gradient. Details of beam optical modeling calculations, proposed accelerating tube design, and initial beam pulsing tests will be described. Work supported in part by USDOE Office of HE and Nuclear Physics.

Precision Medicine in Gastrointestinal Pathology.

PubMed

Wang, David H; Park, Jason Y

2016-05-01

-Precision medicine is the promise of individualized therapy and management of patients based on their personal biology. There are now multiple global initiatives to perform whole-genome sequencing on millions of individuals. In the United States, an early program was the Million Veteran Program, and a more recent proposal in 2015 by the president of the United States is the Precision Medicine Initiative. To implement precision medicine in routine oncology care, genetic variants present in tumors need to be matched with effective clinical therapeutics. When we focus on the current state of precision medicine for gastrointestinal malignancies, it becomes apparent that there is a mixed history of success and failure. -To present the current state of precision medicine using gastrointestinal oncology as a model. We will present currently available targeted therapeutics, promising new findings in clinical genomic oncology, remaining quality issues in genomic testing, and emerging oncology clinical trial designs. -Review of the literature including clinical genomic studies on gastrointestinal malignancies, clinical oncology trials on therapeutics targeted to molecular alterations, and emerging clinical oncology study designs. -Translating our ability to sequence thousands of genes into meaningful improvements in patient survival will be the challenge for the next decade.

Molecular genetics and targeted therapeutics in biliary tract carcinoma.

PubMed

Marks, Eric I; Yee, Nelson S

2016-01-28

The primary malignancies of the biliary tract, cholangiocarcinoma and gallbladder cancer, often present at an advanced stage and are marginally sensitive to radiation and chemotherapy. Accumulating evidence indicates that molecularly targeted agents may provide new hope for improving treatment response in biliary tract carcinoma (BTC). In this article, we provide a critical review of the pathogenesis and genetic abnormalities of biliary tract neoplasms, in addition to discussing the current and emerging targeted therapeutics in BTC. Genetic studies of biliary tumors have identified the growth factors and receptors as well as their downstream signaling pathways that control the growth and survival of biliary epithelia. Target-specific monoclonal antibodies and small molecules inhibitors directed against the signaling pathways that drive BTC growth and invasion have been developed. Numerous clinical trials designed to test these agents as either monotherapy or in combination with conventional chemotherapy have been completed or are currently underway. Research focusing on understanding the molecular basis of biliary tumorigenesis will continue to identify for targeted therapy the key mutations that drive growth and invasion of biliary neoplasms. Additional strategies that have emerged for treating this malignant disease include targeting the epigenetic alterations of BTC and immunotherapy. By integrating targeted therapy with molecular profiles of biliary tumor, we hope to provide precision treatment for patients with malignant diseases of the biliary tract.

Revisiting nanoparticle technology for blood-brain barrier transport: Unfolding at the endothelial gate improves the fate of transferrin receptor-targeted liposomes.

PubMed

Johnsen, Kasper Bendix; Moos, Torben

2016-01-28

An unmet need exists for therapeutic compounds to traverse the brain capillary endothelial cells that denote the blood-brain barrier (BBB) to deliver effective treatment to the diseased brain. The use of nanoparticle technology for targeted delivery to the brain implies that targeted liposomes encapsulating a drug of interest will undergo receptor-mediated uptake and transport through the BBB with a subsequent unfolding of the liposomal content inside the brain, hence revealing drug release to adjacent drug-demanding neurons. As transferrin receptors (TfRs) are present on brain capillary endothelial, but not on endothelial cells elsewhere in the body, the use of TfR-targeted liposomes - colloidal particulates with a phospholipid bilayer membrane - remains the most relevant strategy to obtain efficient drug delivery to the brain. However, many studies have failed to provide sufficient quantitative data to proof passage of the BBB and significant appearance of drugs inside the brain parenchyma. Here, we critically evaluate the current evidence on the use of TfR-targeted liposomes for brain drug delivery based on a thorough investigation of all available studies within this research field. We focus on issues with respect to experimental design and data analysis that may provide an explanation to conflicting reports, and we discuss possible explanations for the current lack of sufficient transcytosis across the BBB for implementation in the design of TfR-targeted liposomes. We finally provide a list of suggestions for strategies to obtain substantial uptake and transport of drug carriers at the BBB with a concomitant transport of therapeutics into the brain. Copyright © 2015 Elsevier B.V. All rights reserved.

Design and testing of a magnetically driven implosion peak current diagnostic

NASA Astrophysics Data System (ADS)

Hess, M. H.; Peterson, K. J.; Ampleford, D. J.; Hutsel, B. T.; Jennings, C. A.; Gomez, M. R.; Dolan, D. H.; Robertson, G. K.; Payne, S. L.; Stygar, W. A.; Martin, M. R.; Sinars, D. B.

2018-04-01

A critical component of the magnetically driven implosion experiments at Sandia National Laboratories is the delivery of high-current, 10s of MA, from the Z pulsed power facility to a target. In order to assess the performance of the experiment, it is necessary to measure the current delivered to the target. Recent Magnetized Liner Inertial Fusion (MagLIF) experiments have included velocimetry diagnostics, such as PDV (Photonic Doppler Velocimetry) or Velocity Interferometer System for Any Reflector, in the final power feed section in order to infer the load current as a function of time. However, due to the nonlinear volumetrically distributed magnetic force within a velocimetry flyer, a complete time-dependent load current unfold is typically a time-intensive process and the uncertainties in the unfold can be difficult to assess. In this paper, we discuss how a PDV diagnostic can be simplified to obtain a peak current by sufficiently increasing the thickness of the flyer. This effectively keeps the magnetic force localized to the flyer surface, resulting in fast and highly accurate measurements of the peak load current. In addition, we show the results of experimental peak load current measurements from the PDV diagnostic in recent MagLIF experiments.

New method to design stellarator coils without the winding surface

DOE PAGES

Zhu, Caoxiang; Hudson, Stuart R.; Song, Yuntao; ...

2017-11-06

Finding an easy-to-build coils set has been a critical issue for stellarator design for decades. Conventional approaches assume a toroidal 'winding' surface, but a poorly chosen winding surface can unnecessarily constrain the coil optimization algorithm, This article presents a new method to design coils for stellarators. Each discrete coil is represented as an arbitrary, closed, one-dimensional curve embedded in three-dimensional space. A target function to be minimized that includes both physical requirements and engineering constraints is constructed. The derivatives of the target function with respect to the parameters describing the coil geometries and currents are calculated analytically. A numerical code,more » named flexible optimized coils using space curves (FOCUS), has been developed. Furthermore, applications to a simple stellarator configuration, W7-X and LHD vacuum fields are presented.« less

New method to design stellarator coils without the winding surface

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhu, Caoxiang; Hudson, Stuart R.; Song, Yuntao

Finding an easy-to-build coils set has been a critical issue for stellarator design for decades. Conventional approaches assume a toroidal 'winding' surface, but a poorly chosen winding surface can unnecessarily constrain the coil optimization algorithm, This article presents a new method to design coils for stellarators. Each discrete coil is represented as an arbitrary, closed, one-dimensional curve embedded in three-dimensional space. A target function to be minimized that includes both physical requirements and engineering constraints is constructed. The derivatives of the target function with respect to the parameters describing the coil geometries and currents are calculated analytically. A numerical code,more » named flexible optimized coils using space curves (FOCUS), has been developed. Furthermore, applications to a simple stellarator configuration, W7-X and LHD vacuum fields are presented.« less

Current applications and future potential for bioinorganic chemistry in the development of anticancer drugs

PubMed Central

van Rijt, Sabine H.; Sadler, Peter J.

2010-01-01

This review illustrates notable recent progress in the field of medicinal bioinorganic chemistry with many new approaches to the design of innovative metal-based anticancer drugs emerging. Current research addressing the problems associated with platinum drugs has focused on other metal-based therapeutics that have different modes of action, and on prodrug and targeting strategies in an effort to diminish the side-effects of cisplatin chemotherapy. PMID:19782150

Everyday Inclusive Web Design: An Activity Perspective

ERIC Educational Resources Information Center

Kane, Shaun K.

2007-01-01

Introduction: Website accessibility is a problem that affects millions of people with disabilities. While most current accessibility initiatives target government or commercial sites, a growing segment of online content is being created by non-professionals. This content is often inaccessible to users with disabilities. Everyday inclusive Web…

Targeting the Binding Interface on a Shared Receptor Subunit of a Cytokine Family Enables the Inhibition of Multiple Member Cytokines with Selectable Target Spectrum*

PubMed Central

Nata, Toshie; Basheer, Asjad; Cocchi, Fiorenza; van Besien, Richard; Massoud, Raya; Jacobson, Steven; Azimi, Nazli; Tagaya, Yutaka

2015-01-01

The common γ molecule (γc) is a shared signaling receptor subunit used by six γc-cytokines. These cytokines play crucial roles in the differentiation of the mature immune system and are involved in many human diseases. Moreover, recent studies suggest that multiple γc-cytokines are pathogenically involved in a single disease, thus making the shared γc-molecule a logical target for therapeutic intervention. However, the current therapeutic strategies seem to lack options to treat such cases, partly because of the lack of appropriate neutralizing antibodies recognizing the γc and, more importantly, because of the inherent and practical limitations in the use of monoclonal antibodies. By targeting the binding interface of the γc and cytokines, we successfully designed peptides that not only inhibit multiple γc-cytokines but with a selectable target spectrum. Notably, the lead peptide inhibited three γc-cytokines without affecting the other three or non-γc-cytokines. Biological and mutational analyses of our peptide provide new insights to our current understanding on the structural aspect of the binding of γc-cytokines the γc-molecule. Furthermore, we provide evidence that our peptide, when conjugated to polyethylene glycol to gain stability in vivo, efficiently blocks the action of one of the target cytokines in animal models. Collectively, our technology can be expanded to target various combinations of γc-cytokines and thereby will provide a novel strategy to the current anti-cytokine therapies against immune, inflammatory, and malignant diseases. PMID:26183780

Target charging in short-pulse-laser-plasma experiments.

PubMed

Dubois, J-L; Lubrano-Lavaderci, F; Raffestin, D; Ribolzi, J; Gazave, J; Compant La Fontaine, A; d'Humières, E; Hulin, S; Nicolaï, Ph; Poyé, A; Tikhonchuk, V T

2014-01-01

Interaction of high-intensity laser pulses with solid targets results in generation of large quantities of energetic electrons that are the origin of various effects such as intense x-ray emission, ion acceleration, and so on. Some of these electrons are escaping the target, leaving behind a significant positive electric charge and creating a strong electromagnetic pulse long after the end of the laser pulse. We propose here a detailed model of the target electric polarization induced by a short and intense laser pulse and an escaping electron bunch. A specially designed experiment provides direct measurements of the target polarization and the discharge current in the function of the laser energy, pulse duration, and target size. Large-scale numerical simulations describe the energetic electron generation and their emission from the target. The model, experiment, and numerical simulations demonstrate that the hot-electron ejection may continue long after the laser pulse ends, enhancing significantly the polarization charge.

Targeted endothelial nanomedicine for common acute pathological conditions

PubMed Central

Shuvaev, Vladimir V.; Brenner, Jacob S.; Muzykantov, Vladimir R.

2017-01-01

Endothelium, a thin monolayer of specialized cells lining the lumen of blood vessels is the key regulatory interface between blood and tissues. Endothelial abnormalities are implicated in many diseases, including common acute conditions with high morbidity and mortality lacking therapy, in part because drugs and drug carriers have no natural endothelial affinity. Precise endothelial drug delivery may improve management of these conditions. Using ligands of molecules exposed to the bloodstream on the endothelial surface enables design of diverse targeted endothelial nanomedicine agents. Target molecules and binding epitopes must be accessible to drug carriers, carriers must be free of harmful effects, and targeting should provide desirable sub-cellular addressing of the drug cargo. The roster of current candidate target molecules for endothelial nanomedicine includes peptidases and other enzymes, cell adhesion molecules and integrins, localized in different domains of the endothelial plasmalemma and differentially distributed throughout the vasculature. Endowing carriers with an affinity to specific endothelial epitopes enables an unprecedented level of precision of control of drug delivery: binding to selected endothelial cell phenotypes, cellular addressing and duration of therapeutic effects. Features of nanocarrier design such as choice of epitope and ligand control delivery and effect of targeted endothelial nanomedicine agents. Pathological factors modulate endothelial targeting and uptake of nanocarriers. Selection of optimal binding sites and design features of nanocarriers are key controllable factors that can be iteratively engineered based on their performance from in vitro to pre-clinical in vivo experimental models. Targeted endothelial nanomedicine agents provide antioxidant, anti-inflammatory and other therapeutic effects unattainable by non-targeted counterparts in animal models of common acute severe human disease conditions. The results of animal studies provide the basis for the challenging translation endothelial nanomedicine into the clinical domain. PMID:26435455

Flow and Heat Transfer Tests in New Loop at 2757 kPa (400 psi)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Woloshun, Keith Albert

2016-06-13

A helium flow and heat transfer experiment has been designed for the new helium flow loop facility at LANL. This new facility is centered on an Aerzen GM 12.4 Root’s blower, selected for operation at higher pressure, up to 2757 kPa, and mass flow rate, up to 400 g/s. This replaces the previous Tuthill PD plus 3206 blower and loop limited to 2067 kPa (300 psi) and 100 g/s. The resistively heated test piece is comprised of 7 electric heaters with embedded thermocouples. The plant design for the Mo100 to Mo99 targets requires sharp bends and geometry changes in themore » helium flow tube immediately before and after the target. An idealized fully developed flow configuration with straight entry and exit will be tested and compared with an option that employs rectangular tubing to make the bend at a radius consistent with and practical for the actual plant design. The current plant design, with circular tubing and a sudden contraction to rectangular just prior to target entrance, will also be tested. This requires some modification of the test piece, as described in the report.« less

Package design and nutritional profile of foods targeted at children in supermarkets in Montevideo, Uruguay.

PubMed

Giménez, Ana; Saldamando, Luis de; Curutchet, María Rosa; Ares, Gastón

2017-06-12

Marketing of unhealthy products has been identified as one of the main characteristics of the food environment that negatively affects children's eating patterns. Restrictions on advertising of unhealthy foods to children have already been imposed in different countries. However, marketing strategies are not limited to broadcast and digital advertising, but also include package design. In this context, the current study aimed to describe the food products targeted at children and sold in supermarkets in Montevideo, Uruguay, in terms of package design and nutrient profile. Two supermarkets in Montevideo were selected for data collection. In each supermarket, all products targeted at children were identified. Products were analyzed in terms of package design and nutritional profile, considering the Pan American Health Organization Nutrient Profile Model. A total of 180 unique products were identified, which included a wide range of product categories. The great majority of the products corresponded to ultra-processed products with excessive amounts of sodium, free sugars, total fat, saturated fat, and/or trans fat, which are not recommended for frequent consumption. Several marketing strategies were identified in the design of packages to attract children's attention and drive their preferences. The most common strategies were the inclusion of cartoon characters, bright colors, childish lettering, and a wide range of claims related to health and nutrition, as well as the products' sensory and hedonic characteristics. The study's findings provide additional evidence on the need to regulate packaging of products targeted at children.

Research of vibration control based on current mode piezoelectric shunt damping circuit

NASA Astrophysics Data System (ADS)

Liu, Weiwei; Mao, Qibo

2017-12-01

The piezoelectric shunt damping circuit using current mode approach is imposed to control the vibration of a cantilever beam. Firstly, the simulated inductance with large values are designed for the corresponding RL series shunt circuits. Moreover, with an example of cantilever beam, the second natural frequency of the beam is targeted to control for experiment. By adjusting the values of the equivalent inductance and equivalent resistance of the shunt circuit, the optimal damping of the shunt circuit is obtained. Meanwhile, the designed piezoelectric shunt damping circuit stability is experimental verified. Experimental results show that the proposed piezoelectric shunt damping circuit based on current mode circuit has good vibration control performance. However, the control performance will be reduced if equivalent inductance and equivalent resistance values deviate from optimal values.

Value-based design for the elderly: An application in the field of mobility aids.

PubMed

Boerema, Simone T; van Velsen, Lex; Vollenbroek-Hutten, Miriam M R; Hermens, Hermie J

2017-01-01

In the aging society, the need for the elderly to remain mobile and independent is higher than ever. However, many aids supporting mobility often fail to target real needs and lack acceptance. The aim of this study is to demonstrate how value-based design can contribute to the design of mobility aids that address real needs and thus, lead to high acceptance. We elicited values, facilitators, and barriers of mobility of older adults via ten in-depth interviews. Next, we held co-creation sessions, resulting in several designs of innovative mobility aids, which were evaluated for acceptance via nine in-depth interviews. The interviews resulted in a myriad of key values, such as "independence from family" and "doing their own groceries." Design sessions resulted in three designs for a wheeled walker. Their acceptance was rather low. Current mobility device users were more eager to accept the designs than non-users. The value-based approach offers designers a close look into the lives of the elderly, thereby opening up a wide range of innovation possibilities that better fit their actual needs. Product service systems seem to be a promising focus for targeting human needs in mobility device design.

Where microbiology meets microengineering: design and applications of reporter bacteria.

PubMed

van der Meer, Jan Roelof; Belkin, Shimshon

2010-07-01

Bacteria have long been the targets for genetic manipulation, but more recently they have been synthetically designed to carry out specific tasks. Among the simplest of these tasks is chemical compound and toxicity detection coupled to the production of a quantifiable reporter signal. In this Review, we describe the current design of bacterial bioreporters and their use in a range of assays to measure the presence of harmful chemicals in water, air, soil, food or biological specimens. New trends for integrating synthetic biology and microengineering into the design of bacterial bioreporter platforms are also highlighted.

Compact, diode-pumped, solid-state lasers for next generation defence and security sensors

NASA Astrophysics Data System (ADS)

Silver, M.; Lee, S. T.; Borthwick, A.; McRae, I.; Jackson, D.; Alexander, W.

2015-06-01

Low-cost semiconductor laser diode pump sources have made a dramatic impact in sectors such as advanced manufacturing. They are now disrupting other sectors, such as defence and security (D&S), where Thales UK is a manufacturer of sensor systems for application on land, sea, air and man portable. In this talk, we will first give an overview of the market trends and challenges in the D&S sector. Then we will illustrate how low cost pump diodes are enabling new directions in D&S sensors, by describing two diode pumped, solid- state laser products currently under development at Thales UK. The first is a new generation of Laser Target Designators (LTD) that are used to identify targets for the secure guiding of munitions. Current systems are bulky, expensive and require large battery packs to operate. The advent of low cost diode technology, merged with our novel solid-state laser design, has created a designator that will be the smallest, lowest cost, STANAG compatible laser designator on the market. The LTD delivers greater that 50mJ per pulse up to 20Hz, and has compact dimensions of 125×70×55mm. Secondly, we describe an ultra-compact, eye-safe, solid-state laser rangefinder (LRF) with reduced size, weight and power consumption compared to existing products. The LRF measures 100×55×34mm, weighs 200g, and can range to greater than 10km with a single laser shot and at a reprate of 1Hz. This also leverages off advances in laser pump diodes, but also utilises low cost, high reliability, packaging technology commonly found in the telecoms sector. As is common in the D&S sector, the products are designed to work in extreme environments, such as wide temperature range (-40 to +71°C) and high levels of shock and vibration. These disruptive products enable next- generation laser sensors such as rangefinders, target designators and active illuminated imagers.

Benchmarking for the Effective Use of Student Evaluation Data

ERIC Educational Resources Information Center

Smithson, John; Birks, Melanie; Harrison, Glenn; Nair, Chenicheri Sid; Hitchins, Marnie

2015-01-01

Purpose: The purpose of this paper is to examine current approaches to interpretation of student evaluation data and present an innovative approach to developing benchmark targets for the effective and efficient use of these data. Design/Methodology/Approach: This article discusses traditional approaches to gathering and using student feedback…

Prenatal diagnosis of chromosomal abnormalities using array-based comparative genomic hybridization

USDA-ARS?s Scientific Manuscript database

This study was designed to evaluate the feasibility of using a targeted array-CGH strategy for prenatal diagnosis of genomic imbalances in a clinical setting of current pregnancies. Women undergoing prenatal diagnosis were counseled and offered array-CGH (BCM V4.0) in addition to routine chromosome ...

Improving Approximate Number Sense Abilities in Preschoolers: PLUS Games

ERIC Educational Resources Information Center

Van Herwegen, Jo; Costa, Hiwet Mariam; Passolunghi, Maria Chiara

2017-01-01

Previous studies in both typically and atypically developing children have shown that approximate number system (ANS) abilities predict formal mathematical knowledge later on in life. The current study investigated whether playing specially designed training games that targets the ANS system using nonsymbolic stimuli only would improve preschool…

QSAR studies in the discovery of novel type-II diabetic therapies.

PubMed

Abuhammad, Areej; Taha, Mutasem O

2016-01-01

Type-II diabetes mellitus (T2DM) is a complex chronic disease that represents a major therapeutic challenge. Despite extensive efforts in T2DM drug development, therapies remain unsatisfactory. Currently, there are many novel and important antidiabetic drug targets under investigation by many research groups worldwide. One of the main challenges to develop effective orally active hypoglycemic agents is off-target effects. Computational tools have impacted drug discovery at many levels. One of the earliest methods is quantitative structure-activity relationship (QSAR) studies. QSAR strategies help medicinal chemists understand the relationship between hypoglycemic activity and molecular properties. Hence, QSAR may hold promise in guiding the synthesis of specifically designed novel ligands that demonstrate high potency and target selectivity. This review aims to provide an overview of the QSAR strategies used to model antidiabetic agents. In particular, this review focuses on drug targets that raised recent scientific interest and/or led to successful antidiabetic agents in the market. Special emphasis has been made on studies that led to the identification of novel antidiabetic scaffolds. Computer-aided molecular design and discovery techniques like QSAR have a great potential in designing leads against complex diseases such as T2DM. Combined with other in silico techniques, QSAR can provide more useful and rational insights to facilitate the discovery of novel compounds. However, since T2DM is a complex disease that includes several faulty biological targets, multi-target QSAR studies are recommended in the future to achieve efficient antidiabetic therapies.

Controlling gene networks and cell fate with precision-targeted DNA-binding proteins and small-molecule-based genome readers

PubMed Central

Eguchi, Asuka; Lee, Garrett O.; Wan, Fang; Erwin, Graham S.; Ansari, Aseem Z.

2014-01-01

Transcription factors control the fate of a cell by regulating the expression of genes and regulatory networks. Recent successes in inducing pluripotency in terminally differentiated cells as well as directing differentiation with natural transcription factors has lent credence to the efforts that aim to direct cell fate with rationally designed transcription factors. Because DNA-binding factors are modular in design, they can be engineered to target specific genomic sequences and perform pre-programmed regulatory functions upon binding. Such precision-tailored factors can serve as molecular tools to reprogramme or differentiate cells in a targeted manner. Using different types of engineered DNA binders, both regulatory transcriptional controls of gene networks, as well as permanent alteration of genomic content, can be implemented to study cell fate decisions. In the present review, we describe the current state of the art in artificial transcription factor design and the exciting prospect of employing artificial DNA-binding factors to manipulate the transcriptional networks as well as epigenetic landscapes that govern cell fate. PMID:25145439

The MROI fast tip-tilt correction and target acquisition system

NASA Astrophysics Data System (ADS)

Young, John; Buscher, David; Fisher, Martin; Haniff, Christopher; Rea, Alexander; Seneta, Eugene B.; Sun, Xiaowei; Wilson, Donald; Farris, Allen; Olivares, Andres; Selina, Robert

2012-07-01

The fast tip-tilt correction system for the Magdalena Ridge Observatory Interferometer (MROI) is being designed and fabricated by the University of Cambridge. The design of the system is currently at an advanced stage and the performance of its critical subsystems has been verified in the laboratory. The system has been designed to meet a demanding set of specifications including satisfying all performance requirements in ambient temperatures down to -5 °C, maintaining the stability of the tip-tilt fiducial over a 5 °C temperature change without recourse to an optical reference, and a target acquisition mode with a 60” field-of-view. We describe the important technical features of the system, which uses an Andor electron-multiplying CCD camera protected by a thermal enclosure, a transmissive optical system with mounts incorporating passive thermal compensation, and custom control software running under Xenomai real-time Linux. We also report results from laboratory tests that demonstrate (a) the high stability of the custom optic mounts and (b) the low readout and compute latencies that will allow us to achieve a 40 Hz closed-loop bandwidth on bright targets.

Young drivers' engagement with social interactive technology on their smartphone: Critical beliefs to target in public education messages.

PubMed

Gauld, Cassandra S; Lewis, Ioni M; White, Katherine M; Watson, Barry

2016-11-01

The current study forms part of a larger study based on the Step Approach to Message Design and Testing (SatMDT), a new and innovative framework designed to guide the development and evaluation of health communication messages, including road safety messages. This four step framework is based on several theories, including the Theory of Planned Behaviour. The current study followed steps one and two of the SatMDT framework and utilised a quantitative survey to validate salient beliefs (behavioural, normative, and control) about initiating, monitoring/reading, and responding to social interactive technology on smartphones by N=114 (88F, 26M) young drivers aged 17-25 years. These beliefs had been elicited in a prior in-depth qualitative study. A subsequent critical beliefs analysis identified seven beliefs as potential targets for public education messages, including, 'slow-moving traffic' (control belief - facilitator) for both monitoring/reading and responding behaviours; 'feeling at ease that you had received an expected communication' (behavioural belief -advantage) for monitoring/reading behaviour; and 'friends/peers more likely to approve' (normative belief) for responding behaviour. Potential message content targeting these seven critical beliefs is discussed in accordance with the SatMDT. Copyright © 2016 Elsevier Ltd. All rights reserved.

Epithermal neutron formation for boron neutron capture therapy by adiabatic resonance crossing concept

NASA Astrophysics Data System (ADS)

Khorshidi, A.; Ghafoori-Fard, H.; Sadeghi, M.

2014-05-01

Low-energy protons from the cyclotron in the range of 15-30 MeV and low current have been simulated on beryllium (Be) target with a lead moderator around the target. This research was accomplished to design an epithermal neutron beam for Boron Neutron Capture Therapy (BNCT) using the moderated neutron on the average produced from 9Be target via (p, xn) reaction in Adiabatic Resonance Crossing (ARC) concept. Generation of neutron to proton ratio, energy distribution, flux and dose components in head phantom have been simulated by MCNP5 code. The reflector and collimator were designed in prevention and collimation of derivation neutrons from proton bombarding. The scalp-skull-brain phantom consisting of bone and brain equivalent material has been simulated in order to evaluate the dosimetric effect on the brain. Results of this analysis demonstrated while the proton energy decreased, the dose factor altered according to filters thickness. The maximum epithermal flux revealed using fluental, Fe and bismuth (Bi) filters with thicknesses of 9.4, 3 and 2 cm, respectively and also the epithermal to thermal neutron flux ratio was 103.85. The potential of the ARC method to replace or complement the current reactor-based supply sources of BNCT purposes.

Design studies on the 4π γ-ray calorimeter for the ETF experiment at HIRFL-CSR

NASA Astrophysics Data System (ADS)

Yue, Ke; Xu, Hu-Shan; Sun, Zhi-Yu; Su, Guang-Hui; Wang, Jian-Song; Zheng, Chuan; Li, Song-Lin; Hu, Zheng-Guo; Chen, Rou-Fu; Xiao, Zhi-Gang; Hu, Qiang; Zhang, Xue-Ying; Yu, Yu-Hong; Chen, Jun-Ling

2011-01-01

A high detection efficiency calorimeter which is used to detect γ-rays with energies from 1 MeV up to 10 MeV as well as light charged particles has been proposed. Design of the geometry, results of the crystal tests and Monte Carlo simulations are presented in this paper. The simulation results confirm that the calorimeter can obtain high detection efficiency and good energy resolution with the current designed geometry. And the calorimeter is competent for the future External Target Facility (ETF) experiments.

Editorial: Current status and perspective on drug targets in tubercle bacilli and drug design of antituberculous agents based on structure-activity relationship.

PubMed

Tomioka, Haruaki

2014-01-01

Worldwide, tuberculosis (TB) remains the most frequent and important infectious disease causing morbidity and death. However, the development of new drugs for the treatment and prophylaxis of TB, particularly those truly active against dormant and persistent types of tubercle bacilli, has been slow, although some promising drugs, such as diarylquinoline TMC207, nitroimidazopyran PA-824, nitroimidazo-oxazole Delamanid (OPC-67683), oxazolidinone PNU-100480, ethylene diamine SQ-109, and pyrrole derivative LL3858, are currently under phase 1 to 3 clinical trials. Therefore, novel types of antituberculous drug, which act on unique drug targets in Mycobacterium tuberculosis (MTB) pathogens, particularly drug targets related to the establishment of mycobacterial dormancy in the host's macrophages, are urgently needed. In this context, it should be noted that current anti-TB drugs mostly target the metabolic reactions and proteins which are essential for the growth of MTB in extracellular milieus. It may also be promising to develop another type of drug that exerts an inhibitory action against bacterial virulence factors which cross-talk and interfere with signaling pathways of MTB-infected immunocompetent host cells, such as lymphocytes, macrophages, and NK cells, thereby changing the intracellular milieus that are favorable to intramacrophage survival and the growth of infected bacilli. This special issue contains ten review articles, dealing with recent approaches to identify and establish novel drug targets in MTB for the development of new and unique antitubercular drugs, including those related to mycobacterial dormancy and crosstalk with cellular signaling pathways. In addition, this special issue contains some review papers with special reference to the drug design based on quantitative structure-activity relationship (QSAR) analysis, especially three-dimensional (3D)-QSAR. New, critical information on the entire genome of MTB and mycobacterial virulence genes is promoting the elucidation of the molecular structures of drug targets in MTB, and are consequently markedly useful for the design of new, promising antituberculous drugs using QSAR techniques. In this issue, we review the following areas. Firstly, Dr. Li M. Fu reviews the perspective that combines machine learning and genomics for drug discovery in tuberculosis, in relation to the problem that the exhaustive search for useful drug targets over the entire MTB genome would not be as productive as expected in practice [1]. Secondly, the review article by Drs. R. S. Chauhan. S. K. Chanumolu, C. Rout, and R. Shrivastava focuses on analysis of the current state of MTB genomic resources, host-pathogen interaction studies in the context of mycobacterial persistence, and drug target discovery based on the utilization of computational tools and metabolic network analyses [2]. Thirdly, Drs. Daria Bottai, Agnese Serafini, Alessandro Cascioferro, Roland Brosch, and Riccardo Manganelli review the current knowledge on MTB T7SS/ESX secretion systems and their impact on MTB physiology and virulence, and the possible approaches to develop T7SS/ESX inhibitors [3]. Fourthly, Drs. E. Jeffrey North, Mary Jackson, and Richard E. Lee review and analyze new and emerging inhibitors of the mycolic acid biosynthetic pathway, including mycobacterial enzymes for fatty acid synthesis, mycolic acid-modifying enzymes, fatty acid-activating and -condensing enzymes, transporters, and transferases, that have been discovered in the post-genomic era of tuberculosis drug discovery [4]. Fifthly, Drs. Katarina Mikusova, Vadim Makarov, and Joao Neres review the mycobacterial enzyme DprE1, which catalyzes a unique epimerization reaction in the biosynthesis of decaprenylphosphoryl arabinose, a single donor of the arabinosyl residue for the build-up of arabinans, one of the mycobacterial cell wall components, as an important drug target especially for the development of benzothiazinones [5]. Sixthly, I review the present status of global research on novel drug targets related to the Toll-like receptor in the MTB pathogen, with special reference to mycobacterial virulence factors that cross-talk and interfere with signaling pathways of host macrophages [6]. The following four review articles deal with drug design of novel anti-TB agents employing QSAR techniques. Firstly, Drs. Nidhi and Mohammad Imran Siddiqi review 2D and 3D QSAR approaches and the recent trends of these methods integrated with virtual screening using the 3D pharmacophore and molecular docking approaches for the identification and design of novel antituberculous agents, by presenting a comprehensive overview of QSAR studies reported for newer antituberculous agents [7]. Secondly, Drs. Filomena Martins, Cristina Ventura, Susana Santos, and Miguel Viveiros review the current status of different QSAR-based strategies for the design of novel anti-TB drugs based upon the most active anti-TB agent, isoniazid, from the viewpoint of the development of promising derivatives that are active against isoniazid- resistant strains with katG mutations [8]. Thirdly, Drs. Sanchaita Rajkhowa and Ramesh C. Deka review current studies concerning 2D and 3D QSAR models that contain density-functional theory (DFT)-based descriptors as their parameters [9]. Notably, DFT-based descriptors such as atomic charges, molecular orbital energies, frontier orbital densities, and atom-atom polarizabilities are very useful in predicting the reactivity of atoms in molecules. Fourthly, Drs. Renata V. Bueno, Rodolpho C. Braga, Natanael D. Segretti, Elizabeth I. Ferreira, Gustavo H. G. Trossini, and Carolina H. Andrade review the current progress and applications of QSAR analysis for the discovery of innovative tuberculostatic agents as inhibitors of ribonucleotide reductase, DNA gyrase, ATP synthase, and thymidylate kinase enzymes, highlighting present challenges and new opportunities in TB drug design [10]. The aim of this issue is to address the future prospects for the development of new antituberculous drugs. There are a number of difficulties in computational drug-design for the development of new drug formulations with potential antimycobacterial effects, especially therapeutic and prophylactic efficacy against infection due to dormant-type MTB pathogens. In addition, it should be emphasized that the most urgent goal of TB chemotherapy is develop highly active, low-cost drugs which can be used not only in industrialized but also in developing countries, because most global TB incidence occurs in the latter. I am sincerely grateful to the individuals who contributed to this work. All authors are experts in their fields and they made earnest efforts to perform these in-depth reviews. I thank them all.

Approach and Instrument Placement Validation

NASA Technical Reports Server (NTRS)

Ator, Danielle

2005-01-01

The Mars Exploration Rovers (MER) from the 2003 flight mission represents the state of the art technology for target approach and instrument placement on Mars. It currently takes 3 sols (Martian days) for the rover to place an instrument on a designated rock target that is about 10 to 20 m away. The objective of this project is to provide an experimentally validated single-sol instrument placement capability to future Mars missions. After completing numerous test runs on the Rocky8 rover under various test conditions, it has been observed that lighting conditions, shadow effects, target features and the initial target distance have an effect on the performance and reliability of the tracking software. Additional software validation testing will be conducted in the months to come.

Additive manufacturing capabilities applied to inertial confinement confusion at Los Alamos National Laboratory

DOE PAGES

Cardenas, Tana; Schmidt, Derek William; Peterson, Dominic S.

2016-08-01

We describe the use at Los Alamos National Laboratory of additive manufacturing (AM) for a variety of jigs and coating, assembly, and radiography fixtures. Additive manufacturing has also been used to produce shipping containers of complex design that would be too costly to have fabricated using traditional techniques. The current goal for AM use in target fabrication is to increase target accuracy and rigidity. This has been realized by implementing AM into target stalk fabrication, allowing increased complexity to address target strength and the addition of features for alignment at facilities. As a result, we will describe the fabrication ofmore » these components and our plans to utilize AM in the future.« less

Thermal limits on MV x-ray production by bremsstrahlung targets in the context of novel linear accelerators.

PubMed

Wang, Jinghui; Trovati, Stefania; Borchard, Philipp M; Loo, Billy W; Maxim, Peter G; Fahrig, Rebecca

2017-12-01

To study the impact of target geometrical and linac operational parameters, such as target material and thickness, electron beam size, repetition rate, and mean current on the ability of the radiotherapy treatment head to deliver high-dose-rate x-ray irradiation in the context of novel linear accelerators capable of higher repetition rates/duty cycle than conventional clinical linacs. The depth dose in a water phantom without a flattening filter and heat deposition in an x-ray target by 10 MeV pulsed electron beams were calculated using the Monte-Carlo code MCNPX, and the transient temperature behavior of the target was simulated by ANSYS. Several parameters that affect both the dose distribution and temperature behavior were investigated. The target was tungsten with a thickness ranging from 0 to 3 mm and a copper heat remover layer. An electron beam with full width at half maximum (FWHM) between 0 and3 mm and mean current of 0.05-2 mA was used as the primary beam at repetition rates of 100, 200, 400, and 800 Hz. For a 10 MeV electron beam with FWHM of 1 mm, pulse length of 5 μs, by using a thin tungsten target with thickness of 0.2 mm instead of 1 mm, and by employing a high repetition rate of 800 Hz instead of 100 Hz, the maximum dose rate delivered can increase two times from 0.57 to 1.16 Gy/s. In this simple model, the limiting factor on dose rate is the copper heat remover's softening temperature, which was considered to be 500°C in our study. A high dose rate can be obtained by employing thin targets together with high repetition rate electron beams enabled by novel linac designs, whereas the benefit of thin targets is marginal at conventional repetition rates. Next generation linacs used to increase dose rate need different target designs compared to conventional linacs. © 2017 American Association of Physicists in Medicine.

Optimization of the dissolution of molybdenum disks. FY-16 results

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tkac, Peter; Rotsch, David A.; Chemerisov, Sergey D.

2016-09-01

Argonne National Laboratory is providing technical development assistance to NorthStar Medical Technologies LLC in its pursuit of two pathways for production of molybdenum-99: the 98Mo(n,γ) 99Mo reaction and the photonuclear reaction, 100Mo(γ,n) 99Mo. Processing of irradiated targets, from either production mode, requires dissolution of the target material in H 2O 2 followed by a concentration step, addition of ferric ion to precipitate impurities, and conversion of the final solution to 5M potassium hydroxide solution of potassium molybdate. Currently, NorthStar is using pressed and sintered Mo disks as targets. Several options are being considered for the design of Mo targets formore » the production of 99Mo using the (γ,n) reaction. In the current design, the target holder contains a series of sintered Mo disks lined up perpendicular to two incident electron beams, one entering from each side of the target stack. In this configuration, the front-most disks absorb most of the heat from the electron beam and need to be thinner to allow for better cooling, while the middle of the target can be thicker. Distribution of the total mass of Mo allows for larger masses of Mo material and thus larger production batches of 99Mo. A limitation of the sintering approach is the production of very thin disks. Recent advances in 3D printing allow for much thinner target components can be achieved than when the traditional press-and-sinter approach is used. We have demonstrated that several factors can play important roles in dissolution behavior: particle size of Mo metal used for production of targets, sintering conditions, degree of open porosity, and thickness of the sintered Mo targets. Here we report experimental results from studies of small-scale dissolution of sintered Mo disks fabricated from various recycled and commercial Mo materials, and dissolution of 3D-printed Mo disks that were fabricated by Oak Ridge National Laboratory (ORNL). We also report on large-scale dissolution studies with 600 g batches of sintered Mo disks.« less

A rail system for circular synthetic aperture sonar imaging and acoustic target strength measurements: design/operation/preliminary results.

PubMed

Kennedy, J L; Marston, T M; Lee, K; Lopes, J L; Lim, R

2014-01-01

A 22 m diameter circular rail, outfitted with a mobile sonar tower trolley, was designed, fabricated, instrumented with underwater acoustic transducers, and assembled on a 1.5 m thick sand layer at the bottom of a large freshwater pool to carry out sonar design and target scattering response studies. The mobile sonar tower translates along the rail via a drive motor controlled by customized LabVIEW software. The rail system is modular and assembly consists of separately deploying eight circular arc sections, measuring a nominal center radius of 11 m and 8.64 m arc length each, and having divers connect them together in the underwater environment. The system enables full scale measurements on targets of interest with 0.1° angular resolution over a complete 360° aperture, without disrupting target setup, and affording a level of control over target environment conditions and noise sources unachievable in standard field measurements. In recent use, the mobile cart carrying an instrumented sonar tower was translated along the rail in 720 equal position increments and acoustic backscatter data were acquired at each position. In addition, this system can accommodate both broadband monostatic and bistatic scattering measurements on targets of interest, allowing capture of target signature phenomena under diverse configurations to address current scientific and technical issues encountered in mine countermeasure and unexploded ordnance applications. In the work discussed here, the circular rail apparatus is used for acoustic backscatter testing, but this system also has the capacity to facilitate the acquisition of magnetic and optical sensor data from targets of interest. A brief description of the system design and operation will be presented along with preliminary processed results for data acquired from acoustic measurements conducted at the Naval Surface Warfare Center, Panama City Division Test Pond Facility. [Work Supported by the U.S. Office of Naval Research and The Strategic Environmental Research and Development Program.].

A rail system for circular synthetic aperture sonar imaging and acoustic target strength measurements: Design/operation/preliminary results

NASA Astrophysics Data System (ADS)

Kennedy, J. L.; Marston, T. M.; Lee, K.; Lopes, J. L.; Lim, R.

2014-01-01

A 22 m diameter circular rail, outfitted with a mobile sonar tower trolley, was designed, fabricated, instrumented with underwater acoustic transducers, and assembled on a 1.5 m thick sand layer at the bottom of a large freshwater pool to carry out sonar design and target scattering response studies. The mobile sonar tower translates along the rail via a drive motor controlled by customized LabVIEW software. The rail system is modular and assembly consists of separately deploying eight circular arc sections, measuring a nominal center radius of 11 m and 8.64 m arc length each, and having divers connect them together in the underwater environment. The system enables full scale measurements on targets of interest with 0.1° angular resolution over a complete 360° aperture, without disrupting target setup, and affording a level of control over target environment conditions and noise sources unachievable in standard field measurements. In recent use, the mobile cart carrying an instrumented sonar tower was translated along the rail in 720 equal position increments and acoustic backscatter data were acquired at each position. In addition, this system can accommodate both broadband monostatic and bistatic scattering measurements on targets of interest, allowing capture of target signature phenomena under diverse configurations to address current scientific and technical issues encountered in mine countermeasure and unexploded ordnance applications. In the work discussed here, the circular rail apparatus is used for acoustic backscatter testing, but this system also has the capacity to facilitate the acquisition of magnetic and optical sensor data from targets of interest. A brief description of the system design and operation will be presented along with preliminary processed results for data acquired from acoustic measurements conducted at the Naval Surface Warfare Center, Panama City Division Test Pond Facility. [Work Supported by the U.S. Office of Naval Research and The Strategic Environmental Research and Development Program.

Real-time classification of vehicles by type within infrared imagery

NASA Astrophysics Data System (ADS)

Kundegorski, Mikolaj E.; Akçay, Samet; Payen de La Garanderie, Grégoire; Breckon, Toby P.

2016-10-01

Real-time classification of vehicles into sub-category types poses a significant challenge within infra-red imagery due to the high levels of intra-class variation in thermal vehicle signatures caused by aspects of design, current operating duration and ambient thermal conditions. Despite these challenges, infra-red sensing offers significant generalized target object detection advantages in terms of all-weather operation and invariance to visual camouflage techniques. This work investigates the accuracy of a number of real-time object classification approaches for this task within the wider context of an existing initial object detection and tracking framework. Specifically we evaluate the use of traditional feature-driven bag of visual words and histogram of oriented gradient classification approaches against modern convolutional neural network architectures. Furthermore, we use classical photogrammetry, within the context of current target detection and classification techniques, as a means of approximating 3D target position within the scene based on this vehicle type classification. Based on photogrammetric estimation of target position, we then illustrate the use of regular Kalman filter based tracking operating on actual 3D vehicle trajectories. Results are presented using a conventional thermal-band infra-red (IR) sensor arrangement where targets are tracked over a range of evaluation scenarios.

Molecular Targeted Intervention for Pancreatic Cancer

PubMed Central

Mohammed, Altaf; Janakiram, Naveena B.; Pant, Shubham; Rao, Chinthalapally V.

2015-01-01

Pancreatic cancer (PC) remains one of the worst cancers, with almost uniform lethality. PC risk is associated with westernized diet, tobacco, alcohol, obesity, chronic pancreatitis, and family history of pancreatic cancer. New targeted agents and the use of various therapeutic combinations have yet to provide adequate treatments for patients with advanced cancer. To design better preventive and/or treatment strategies against PC, knowledge of PC pathogenesis at the molecular level is vital. With the advent of genetically modified animals, significant advances have been made in understanding the molecular biology and pathogenesis of PC. Currently, several clinical trials and preclinical evaluations are underway to investigate novel agents that target signaling defects in PC. An important consideration in evaluating novel drugs is determining whether an agent can reach the target in concentrations effective to treat the disease. Recently, we have reported evidence for chemoprevention of PC. Here, we provide a comprehensive review of current updates on molecularly targeted interventions, as well as dietary, phytochemical, immunoregulatory, and microenvironment-based approaches for the development of novel therapeutic and preventive regimens. Special attention is given to prevention and treatment in preclinical genetically engineered mouse studies and human clinical studies. PMID:26266422

Front End for a neutrino factory or muon collider

DOE PAGES

Neuffer, David; Snopok, Pavel; Alexahin, Yuri

2017-11-30

A neutrino factory or muon collider requires the capture and cooling of a large number of muons. Scenarios for capture, bunching, phase-energy rotation and initial cooling of μ’s produced from a proton source target have been developed, initially for neutrino factory scenarios. They require a drift section from the target, a bunching section and a Φ-δE rotation section leading into the cooling channel. Important concerns are rf limitations within the focusing magnetic fields and large losses in the transport. The currently preferred cooling channel design is an “HFOFO Snake” configuration that cools both μ + and μ - transversely andmore » longitudinally. Finally, the status of the design is presented and variations are discussed.« less

Enhancing Readiness-to-Change Substance Abuse in Persons with Schizophrenia

PubMed Central

Carey, Kate B.; Purnine, Daniel M.; Maisto, Stephen A.; Carey, Michael P.

2008-01-01

This article describes a four-session intervention designed for persons with co-occurring substance abuse and schizophrenia-spectrum disorders, to be administered as an add-on module to supplement ongoing mental health treatment in an outpatient setting. The intervention targets those dually diagnosed individuals with low readiness-to-change as indicated by current use, and/or low level of engagement in treatment for substance abuse. The intervention is designed to increase problem recognition, to enhance motivation to change maladaptive patterns of substance use, and to facilitate engagement in substance abuse. To achieve these goals, we have adopted constructs from the Transtheoretical Model of Change and utilize principles of motivational and harm reduction interventions, and tailored them to the target population. PMID:11428245

United States Air and Space Power in the 21st Century: Strategic Appraisal

DTIC Science & Technology

2002-01-01

changes in current U.S. nuclear operational practice. It would require at the very least • suitable planning systems (e.g., near- real - time target...to increase real - time visibility into demands, inventories, and flows will likely be very valuable in this regard. Robust, well-stocked FSLs will...of the type of wholesale shift required. The current system is designed for heavy deployments with fairly long lead times . To sup- port Air

MAGID-II: a next-generation magnetic unattended ground sensor (UGS)

NASA Astrophysics Data System (ADS)

Walter, Paul A.; Mauriello, Fred; Huber, Philip

2012-06-01

A next generation magnetic sensor is being developed at L-3 Communications, Communication Systems East to enhance the ability of Army and Marine Corps unattended ground sensor (UGS) systems to detect and track targets on the battlefield. This paper describes a magnetic sensor that provides superior detection range for both armed personnel and vehicle targets, at a reduced size, weight, and level of power consumption (SWAP) over currently available magnetic sensors. The design integrates the proven technology of a flux gate magnetometer combined with advanced digital signal processing algorithms to provide the warfighter with a rapidly deployable, extremely low false-alarm-rate sensor. This new sensor improves on currently available magnetic UGS systems by providing not only target detection and direction information, but also a magnetic disturbance readout, indicating the size of the target. The sensor integrates with Government Off-the-Shelf (GOTS) systems such as the United States Army's Battlefield Anti-Intrusion System (BAIS) and the United States Marine Corps Tactical Remote Sensor System (TRSS). The system has undergone testing by the US Marine Corps, as well as extensive company testing. Results from these field tests are given.

Dengue virus NS2 and NS4: Minor proteins, mammoth roles.

PubMed

Gopala Reddy, Sindhoora Bhargavi; Chin, Wei-Xin; Shivananju, Nanjunda Swamy

2018-04-17

Despite the ever-increasing global incidence of dengue fever, there are no specific chemotherapy regimens for its treatment. Structural studies on dengue virus (DENV) proteins have revealed potential drug targets. Major DENV proteins such as the envelope protein and non-structural (NS) proteins 3 and 5 have been extensively investigated in antiviral studies, but with limited success in vitro. However, the minor NS proteins NS2 and NS4 have remained relatively underreported. Emerging evidence indicating their indispensable roles in virus propagation and host immunomodulation should encourage us to target these proteins for drug discovery. This review covers current knowledge on DENV NS2 and NS4 proteins from structural and functional perspectives and assesses their potential as targets for antiviral design. Antiviral targets in NS2A include surface-exposed transmembrane regions involved in pathogenesis, while those in NS2B include protease-binding sites in a conserved hydrophilic domain. Ideal drug targets in NS4A include helix α4 and the PEPEKQR sequence, which are essential for NS4A-2K cleavage and NS4A-NS4B association, respectively. In NS4B, the cytoplasmic loop connecting helices α5 and α7 is an attractive target for antiviral design owing to its role in dimerization and NS4B-NS3 interaction. Findings implicating NS2A, NS2B, and NS4A in membrane-modulation and viroporin-like activities indicate an opportunity to target these proteins by disrupting their association with membrane lipids. Despite the lack of 3D structural data, recent topological findings and progress in structure-prediction methods should be sufficient impetus for targeting NS2 and NS4 for drug design. Copyright © 2018 Elsevier Inc. All rights reserved.

Design Principles of Nanoparticles as Contrast Agents for Magnetic Resonance Imaging

NASA Astrophysics Data System (ADS)

Shan, Liang; Gu, Xinbin; Wang, Paul

2013-09-01

Molecular imaging is an emerging field that introduces molecular agents into traditional imaging techniques, enabling visualization, characterization and measurement of biological processes at the molecular and cellular levels in humans and other living systems. The promise of molecular imaging lies in its potential for selective potency by targeting biomarkers or molecular targets and the imaging agents serve as reporters for the selectivity of targeting. Development of an efficient molecular imaging agent depends on well-controlled high-quality experiment design involving target selection, agent synthesis, in vitro characterization, and in vivo animal characterization before it is applied in humans. According to the analysis from the Molecular Imaging and Contrast Agent Database (MICAD, ), more than 6000 molecular imaging agents with sufficient preclinical evaluation have been reported to date in the literature and this number increases by 250-300 novel agents each year. The majority of these agents are radionuclides, which are developed for positron emission tomography (PET) and single photon emission computed tomography (SPECT). Contrast agents for magnetic resonance imaging (MRI) account for only a small part. This is largely due to the fact that MRI is currently not a fully quantitative imaging technique and is less sensitive than PET and SPECT. However, because of the superior ability to simultaneously extract molecular and anatomic information, molecular MRI is attracting significant interest and various targeted nanoparticle contrast agents have been synthesized for MRI. The first and one of the most critical steps in developing a targeted nanoparticle contrast agent is target selection, which plays the central role and forms the basis for success of molecular imaging. This chapter discusses the design principles of targeted contrast agents in the emerging frontiers of molecular MRI.

Engineered Peptides for Applications in Cancer-Targeted Drug Delivery and Tumor Detection.

PubMed

Soudy, R; Byeon, N; Raghuwanshi, Y; Ahmed, S; Lavasanifar, A; Kaur, K

2017-01-01

Cancer-targeting peptides as ligands for targeted delivery of anticancer drugs or drug carriers have the potential to significantly enhance the selectivity and the therapeutic benefit of current chemotherapeutic agents. Identification of tumor-specific biomarkers like integrins, aminopeptidase N, and epidermal growth factor receptor as well as the popularity of phage display techniques along with synthetic combinatorial methods used for peptide design and structure optimization have fueled the advancement and application of peptide ligands for targeted drug delivery and tumor detection in cancer treatment, detection and guided therapy. Although considerable preclinical data have shown remarkable success in the use of tumor targeting peptides, peptides generally suffer from poor pharmacokinetics, enzymatic instability, and weak receptor affinity, and they need further structural modification before successful translation to clinics is possible. The current review gives an overview of the different engineering strategies that have been developed for peptide structure optimization to confer selectivity and stability. We also provide an update on the methods used for peptide ligand identification, and peptide- receptor interactions. Additionally, some applications for the use of peptides in targeted delivery of chemotherapeutics and diagnostics over the past 5 years are summarized. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Carlson, Thomas J.; Myjak, Mitchell J.

At the request of the U.S. Army Corps of Engineers, Portland District, researchers from Pacific Northwest National Laboratory investigated the use of an application-specific integrated circuit (ASIC) to reduce the weight and volume of Juvenile Salmon Acoustic Telemetry System (JSATS) transmitters while retaining current functionality. Review of the design of current JSATS transmitters identified components that could be replaced by an ASIC while retaining the function of the current transmitter and offering opportunities to extend function if desired. ASIC design alternatives were identified that could meet transmitter weight and volume targets of 200 mg and 100 mm3. If alternatives tomore » the cylindrical batteries used in current JSATS transmitters can be identified, it could be possible to implant ASIC-based JSATS transmitters by injection rather than surgery. Using criteria for the size of fish suitable for surgical implantation of current JSATS transmitters, it was concluded that fish as small as 70 mm in length could be implanted with an ASIC-based transmitter, particularly if implantation by injection became feasible.« less

The RTL-46: A simulated commercial air transportation study

NASA Technical Reports Server (NTRS)

Dunbar, Christian; Prette, John; Andersen, Gerald; Sprunck, Martin; Vogel, Christine; Rivera, Francisco

1993-01-01

The RTL-46 provides an aircraft which utilizes advanced technology within the fictional Aeroworld market to better service the air travel customers and airlines of Aeroworld. The RTL-46 is designed to serve the portion of the travel market which flies less than 10,000 feet per flight. The design cruise velocity for the aircraft is 35 ft/sec, which rapidly expedites travel through Aeroworld. The major focus of the endeavor was to design an aircraft which would serve the Aeroworld market better than the existing aircraft, the HB-40. This could have been done through targeting another portion of the Aeroworld market or through serving the current HB-40 market more effectively. Due to the fact that approximately 70 percent of the potential Aeroworld passengers desired flights of 10,000 ft or less, this range became the target market for the RTL-46.

CodeSlinger: a case study in domain-driven interactive tool design for biomedical coding scheme exploration and use.

PubMed

Flowers, Natalie L

2010-01-01

CodeSlinger is a desktop application that was developed to aid medical professionals in the intertranslation, exploration, and use of biomedical coding schemes. The application was designed to provide a highly intuitive, easy-to-use interface that simplifies a complex business problem: a set of time-consuming, laborious tasks that were regularly performed by a group of medical professionals involving manually searching coding books, searching the Internet, and checking documentation references. A workplace observation session with a target user revealed the details of the current process and a clear understanding of the business goals of the target user group. These goals drove the design of the application's interface, which centers on searches for medical conditions and displays the codes found in the application's database that represent those conditions. The interface also allows the exploration of complex conceptual relationships across multiple coding schemes.

Low-energy ion beamline scattering apparatus for surface science investigations

NASA Astrophysics Data System (ADS)

Gordon, M. J.; Giapis, K. P.

2005-08-01

We report on the design, construction, and performance of a high current (monolayers/s), mass-filtered ion beamline system for surface scattering studies using inert and reactive species at collision energies below 1500 eV. The system combines a high-density inductively coupled plasma ion source, high-voltage floating beam transport line with magnet mass-filter and neutral stripping, decelerator, and broad based detection capabilities (ions and neutrals in both mass and energy) for products leaving the target surface. The entire system was designed from the ground up to be a robust platform to study ion-surface interactions from a more global perspective, i.e., high fluxes (>100μA/cm2) of a single ion species at low, tunable energy (50-1400±5eV full width half maximum) can be delivered to a grounded target under ultrahigh vacuum conditions. The high current at low energy problem is solved using an accel-decel transport scheme where ions are created at the desired collision energy in the plasma source, extracted and accelerated to high transport energy (20 keV to fight space charge repulsion), and then decelerated back down to their original creation potential right before impacting the grounded target. Scattered species and those originating from the surface are directly analyzed in energy and mass using a triply pumped, hybrid detector composed of an electron impact ionizer, hemispherical electrostatic sector, and rf/dc quadrupole in series. With such a system, the collision kinematics, charge exchange, and chemistry occurring on the target surface can be separated by fully analyzing the scattered product flux. Key design aspects of the plasma source, beamline, and detection system are emphasized here to highlight how to work around physical limitations associated with high beam flux at low energy, pumping requirements, beam focusing, and scattered product analysis. Operational details of the beamline are discussed from the perspective of available beam current, mass resolution, projectile energy spread, and energy tunability. As well, performance of the overall system is demonstrated through three proof-of-concept examples: (1) elastic binary collisions at low energy, (2) core-level charge exchange reactions involving Ne+20 with Mg /Al/Si/P targets, and (3) reactive scattering of CF2+/CF3+ off Si. These studies clearly demonstrate why low, tunable incident energy, as well as mass and energy filtering of products leaving the target surface is advantageous and often essential for studies of inelastic energy losses, hard-collision charge exchange, and chemical reactions that occur during ion-surface scattering.

Application of three-dimensional printing for colon targeted drug delivery systems

PubMed Central

Charbe, Nitin B.; McCarron, Paul A.; Lane, Majella E.; Tambuwala, Murtaza M.

2017-01-01

Orally administered solid dosage forms currently dominate over all other dosage forms and routes of administrations. However, human gastrointestinal tract (GIT) poses a number of obstacles to delivery of the drugs to the site of interest and absorption in the GIT. Pharmaceutical scientists worldwide have been interested in colon drug delivery for several decades, not only for the delivery of the drugs for the treatment of colonic diseases such as ulcerative colitis and colon cancer but also for delivery of therapeutic proteins and peptides for systemic absorption. Despite extensive research in the area of colon targeted drug delivery, we have not been able to come up with an effective way of delivering drugs to the colon. The current tablets designed for colon drug release depend on either pH-dependent or time-delayed release formulations. During ulcerative colitis the gastric transit time and colon pH-levels is constantly changing depending on whether the patient is having a relapse or under remission. Hence, the current drug delivery system to the colon is based on one-size-fits-all. Fails to effectively deliver the drugs locally to the colon for colonic diseases and delivery of therapeutic proteins and peptides for systemic absorption from the colon. Hence, to overcome the current issues associated with colon drug delivery, we need to provide the patients with personalized tablets which are specifically designed to match the individual's gastric transit time depending on the disease state. Three-dimensional (3D) printing (3DP) technology is getting cheaper by the day and bespoke manufacturing of 3D-printed tablets could provide the solutions in the form of personalized colon drug delivery system. This review provides a bird's eye view of applications and current advances in pharmaceutical 3DP with emphasis on the development of colon targeted drug delivery systems. PMID:28929046

Application of three-dimensional printing for colon targeted drug delivery systems.

PubMed

Charbe, Nitin B; McCarron, Paul A; Lane, Majella E; Tambuwala, Murtaza M

2017-01-01

Orally administered solid dosage forms currently dominate over all other dosage forms and routes of administrations. However, human gastrointestinal tract (GIT) poses a number of obstacles to delivery of the drugs to the site of interest and absorption in the GIT. Pharmaceutical scientists worldwide have been interested in colon drug delivery for several decades, not only for the delivery of the drugs for the treatment of colonic diseases such as ulcerative colitis and colon cancer but also for delivery of therapeutic proteins and peptides for systemic absorption. Despite extensive research in the area of colon targeted drug delivery, we have not been able to come up with an effective way of delivering drugs to the colon. The current tablets designed for colon drug release depend on either pH-dependent or time-delayed release formulations. During ulcerative colitis the gastric transit time and colon pH-levels is constantly changing depending on whether the patient is having a relapse or under remission. Hence, the current drug delivery system to the colon is based on one-size-fits-all. Fails to effectively deliver the drugs locally to the colon for colonic diseases and delivery of therapeutic proteins and peptides for systemic absorption from the colon. Hence, to overcome the current issues associated with colon drug delivery, we need to provide the patients with personalized tablets which are specifically designed to match the individual's gastric transit time depending on the disease state. Three-dimensional (3D) printing (3DP) technology is getting cheaper by the day and bespoke manufacturing of 3D-printed tablets could provide the solutions in the form of personalized colon drug delivery system. This review provides a bird's eye view of applications and current advances in pharmaceutical 3DP with emphasis on the development of colon targeted drug delivery systems.

A COL11A1-correlated pan-cancer gene signature of activated fibroblasts for the prioritization of therapeutic targets

PubMed Central

Jia, Dongyu; Liu, Zhenqiu; Deng, Nan; Tan, Tuan Zea; Huang, Ruby Yun-Ju; Taylor-Harding, Barbie; Cheon, Dong-Joo; Lawrenson, Kate; Wiedemeyer, Wolf R.; Walts, Ann E.; Karlan, Beth Y.; Orsulic, Sandra

2016-01-01

Although cancer-associated fibroblasts (CAFs) are viewed as a promising therapeutic target, the design of rational therapy has been hampered by two key obstacles. First, attempts to ablate CAFs have resulted in significant toxicity because currently used biomarkers cannot effectively distinguish activated CAFs from non-cancer associated fibroblasts and mesenchymal progenitor cells. Second, it is unclear whether CAFs in different organs have different molecular and functional properties that necessitate organ-specific therapeutic designs. Our analyses uncovered COL11A1 as a highly specific biomarker of activated CAFs. Using COL11A1 as a ‘seed’, we identified co-expressed genes in 13 types of primary carcinoma in The Cancer Genome Atlas. We demonstrated that a molecular signature of activated CAFs is conserved in epithelial cancers regardless of organ site and transforming events within cancer cells, suggesting that targeting fibroblast activation should be effective in multiple cancers. We prioritized several potential pan-cancer therapeutic targets that are likely to have high specificity for activated CAFs and minimal toxicity in normal tissues. PMID:27609069

Development and in vivo Quantitative Magnetic Resonance Imaging of Polymer Micelles Targeted to the Melanocortin 1 Receptor

PubMed Central

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.

2013-01-01

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) crosslinking 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 and/or uncrosslinked 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. PMID:23863078

Achieving optimum diffraction based overlay performance

NASA Astrophysics Data System (ADS)

Leray, Philippe; Laidler, David; Cheng, Shaunee; Coogans, Martyn; Fuchs, Andreas; Ponomarenko, Mariya; van der Schaar, Maurits; Vanoppen, Peter

2010-03-01

Diffraction Based Overlay (DBO) metrology has been shown to have significantly reduced Total Measurement Uncertainty (TMU) compared to Image Based Overlay (IBO), primarily due to having no measurable Tool Induced Shift (TIS). However, the advantages of having no measurable TIS can be outweighed by increased susceptibility to WIS (Wafer Induced Shift) caused by target damage, process non-uniformities and variations. The path to optimum DBO performance lies in having well characterized metrology targets, which are insensitive to process non-uniformities and variations, in combination with optimized recipes which take advantage of advanced DBO designs. In this work we examine the impact of different degrees of process non-uniformity and target damage on DBO measurement gratings and study their impact on overlay measurement accuracy and precision. Multiple wavelength and dual polarization scatterometry are used to characterize the DBO design performance over the range of process variation. In conclusion, we describe the robustness of DBO metrology to target damage and show how to exploit the measurement capability of a multiple wavelength, dual polarization scatterometry tool to ensure the required measurement accuracy for current and future technology nodes.

Molecular genetics and targeted therapeutics in biliary tract carcinoma

PubMed Central

Marks, Eric I; Yee, Nelson S

2016-01-01

The primary malignancies of the biliary tract, cholangiocarcinoma and gallbladder cancer, often present at an advanced stage and are marginally sensitive to radiation and chemotherapy. Accumulating evidence indicates that molecularly targeted agents may provide new hope for improving treatment response in biliary tract carcinoma (BTC). In this article, we provide a critical review of the pathogenesis and genetic abnormalities of biliary tract neoplasms, in addition to discussing the current and emerging targeted therapeutics in BTC. Genetic studies of biliary tumors have identified the growth factors and receptors as well as their downstream signaling pathways that control the growth and survival of biliary epithelia. Target-specific monoclonal antibodies and small molecules inhibitors directed against the signaling pathways that drive BTC growth and invasion have been developed. Numerous clinical trials designed to test these agents as either monotherapy or in combination with conventional chemotherapy have been completed or are currently underway. Research focusing on understanding the molecular basis of biliary tumorigenesis will continue to identify for targeted therapy the key mutations that drive growth and invasion of biliary neoplasms. Additional strategies that have emerged for treating this malignant disease include targeting the epigenetic alterations of BTC and immunotherapy. By integrating targeted therapy with molecular profiles of biliary tumor, we hope to provide precision treatment for patients with malignant diseases of the biliary tract. PMID:26819503

Designing oral vaccines targeting intestinal dendritic cells.

PubMed

Devriendt, Bert; De Geest, Bruno G; Cox, Eric

2011-04-01

Most pathogens colonize and invade the host at mucosal surfaces, such as the lung and the intestine. To combat intestinal pathogens the induction of local adaptive immune responses is required, which is mainly achieved through oral vaccination. However, most vaccines are ineffective when given orally owing to the hostile environment in the gastrointestinal tract. The encapsulation of antigens in biodegradable microparticulate delivery systems enhances their immunogenicity; however, the uptake of these delivery systems by intestinal immune cells is rather poor. Surface decoration of the particulates with targeting ligands could increase the uptake and mediate the selective targeting of the vaccine to intestinal antigen-presenting cells, including dendritic cells. In this review, current knowledge on dendritic cell subsets is discussed, along with progress in the development of selective antigen targeting to these cells, in addition to focusing on data obtained in mice and, where possible, the pig, as a non-rodent animal model for humans. Moreover, the potential use and benefits of Fcγ receptor-mediated targeting of antigen delivery systems are highlighted. In conclusion, dendritic cell targeting ligands grafted on antigen carrier systems should preferably bind to a conserved endocytotic receptor, facilitating the design of a multispecies vaccine platform, which could elicit robust protective immune responses against enteric pathogens.

Anti-ship missile tracking with a chirped amplitude modulation ladar

NASA Astrophysics Data System (ADS)

Redman, Brian C.; Stann, Barry L.; Ruff, William C.; Giza, Mark M.; Aliberti, Keith; Lawler, William B.

2004-09-01

Shipboard infrared search and track (IRST) systems can detect sea-skimming anti-ship missiles at long ranges. Since IRST systems cannot measure range and velocity, they have difficulty distinguishing missiles from slowly moving false targets and clutter. ARL is developing a ladar based on its patented chirped amplitude modulation (AM) technique to provide unambiguous range and velocity measurements of targets handed over to it by the IRST. Using the ladar's range and velocity data, false alarms and clutter objects will be distinguished from valid targets. If the target is valid, it's angular location, range, and velocity, will be used to update the target track until remediation has been effected. By using an array receiver, ARL's ladar can also provide 3D imagery of potential threats in support of force protection. The ladar development program will be accomplished in two phases. In Phase I, currently in progress, ARL is designing and building a breadboard ladar test system for proof-of-principle static platform field tests. In Phase II, ARL will build a brassboard ladar test system that will meet operational goals in shipboard testing against realistic targets. The principles of operation for the chirped AM ladar for range and velocity measurements, the ladar performance model, and the top-level design for the Phase I breadboard are presented in this paper.

Engineering synthetic TAL effectors with orthogonal target sites

PubMed Central

Garg, Abhishek; Lohmueller, Jason J.; Silver, Pamela A.; Armel, Thomas Z.

2012-01-01

The ability to engineer biological circuits that process and respond to complex cellular signals has the potential to impact many areas of biology and medicine. Transcriptional activator-like effectors (TALEs) have emerged as an attractive component for engineering these circuits, as TALEs can be designed de novo to target a given DNA sequence. Currently, however, the use of TALEs is limited by degeneracy in the site-specific manner by which they recognize DNA. Here, we propose an algorithm to computationally address this problem. We apply our algorithm to design 180 TALEs targeting 20 bp cognate binding sites that are at least 3 nt mismatches away from all 20 bp sequences in putative 2 kb human promoter regions. We generated eight of these synthetic TALE activators and showed that each is able to activate transcription from a targeted reporter. Importantly, we show that these proteins do not activate synthetic reporters containing mismatches similar to those present in the genome nor a set of endogenous genes predicted to be the most likely targets in vivo. Finally, we generated and characterized TALE repressors comprised of our orthogonal DNA binding domains and further combined them with shRNAs to accomplish near complete repression of target gene expression. PMID:22581776

A System for Multiplexed Direct Electrical Detection of DNA Synthesis.

PubMed

Anderson, Erik P; Daniels, Jonathan S; Yu, Heng; Karhanek, Miloslav; Lee, Thomas H; Davis, Ronald W; Pourmand, Nader

2008-01-29

An electronic system for the multiplexed detection of DNA polymerization is designed and characterized. DNA polymerization is detected by the measurement of small transient currents arising from ion diffusion during polymerization. A transimpedance amplifier is used to detect these small currents; we implemented a twenty-four channel recording system on a single printed circuit board. Various contributions to the input-referred current noise are analyzed and characterized, as it limits the minimum detectable current and thus the biological limit of detection. We obtained 8.5 pA RMS mean noise current (averaged over all 24 channels) over the recording bandwidth (DC to 2 kHz). With digital filtering, the input-referred current noise of the acquisition system is reduced to 2.4 pA, which is much lower than the biological noise. Electrical crosstalk between channels is measured, and a model for the crosstalk is presented. Minimizing the crosstalk is critical because it can lead to erroneous microarray data. With proper precautions, crosstalk is reduced to a negligible value (less than 1.4%). Using a micro-fabricated array of 24 gold electrodes, we demonstrated system functionality by detecting the presence of a target DNA oligonucleotide which hybridized onto its corresponding target.

77 FR 60671 - Notice of Intent To Request Revision and Extension of a Currently Approved Information Collection

Federal Register 2010, 2011, 2012, 2013, 2014

2012-10-04

... approved information collection, the List Sampling Frame Surveys. Revision to burden hours will be needed due to changes in the size of the target population, sampling design, and/or questionnaire length... Agriculture, (202) 720-4333. SUPPLEMENTARY INFORMATION: Title: List Sampling Frame Surveys. OMB Control Number...

Investigating the Use of an Enterotropic Newcastle Disease Virus as a Recombinant Vaccine Platform Targeting Poultry Enteric Viruses

USDA-ARS?s Scientific Manuscript database

Control strategies for poultry viral enteric disease must include vaccine platforms that have been specifically designed to improve flock performance, lessen disease severity, and reduce viral transmission. With the exception of certain autogenous vaccines, no vaccines currently exist to aid in the ...

Project Target: Criterion-Referenced Physical Fitness Standards for Adolescents with Disabilities. Final Report.

ERIC Educational Resources Information Center

Winnick, Joseph P.; Short, Francis X.

This final report discusses the outcomes of a project designed to extend the nation's current emphasis on health-related, criterion-referenced fitness testing and programming to children and adolescents with disabilities. It summarizes project activities leading up to the Brockport Physical Fitness Test and related measures. Activities included:…

Promoting Hong Kong's Higher Education to Asian Markets: Market Segmentations and Strategies

ERIC Educational Resources Information Center

Cheung, Alan C. K.; Yuen, Timothy W. W.; Yuen, Celeste Y. M.; Cheng, Yin Cheong

2010-01-01

Purpose: The main purpose of this study is threefold: to analyze the current conditions of higher education services offered in the three target markets; to conduct market segmentation analysis of these markets; and to recommend the most appropriate market entry strategies for Hong Kong's education service providers. Design/methodology/approach:…

Powder River lures contractors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stremel, K.

1984-10-01

Drilling successes are stimulating a high level of geophysical activity in the Powder River Basin. Focused in areas of concentrated exploration, a majority of speculative surveys are specifically designed to delineate target formations. Several contractors credit available data with an increased amount of current and proposed exploration. Geophysical surveying operations in the northern Rockies are discussed.

Managing Information and Communication Technology in Sudanese Secondary School

ERIC Educational Resources Information Center

Ahmed, Abdelrahman

2015-01-01

This research article is based on a larger study whose purpose was to investigate the current status and implementation of ICT in Khartoum State secondary schools. The study, adopted a descriptive survey design. Two instruments questionnaires and a structured interview schedule were used to collect data. The target population comprised of 320…

77 FR 54887 - Proposed Information Collection; Comment Request; 2013 Census Test

Federal Register 2010, 2011, 2012, 2013, 2014

2012-09-06

... Test will inform Census Bureau planners who are guiding the design of additional 2020 Decennial Census.... Current plans do not target Tribal sites and group quarters addresses for this test due to limitations of... Test AGENCY: U.S. Census Bureau, Commerce. ACTION: Notice. SUMMARY: The Department of Commerce, as part...

HCN Channels Modulators: The Need for Selectivity

PubMed Central

Romanelli, Maria Novella; Sartiani, Laura; Masi, Alessio; Mannaioni, Guido; Manetti, Dina; Mugelli, Alessandro; Cerbai, Elisabetta

2016-01-01

Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels, the molecular correlate of the hyperpolarization-activated current (If/Ih), are membrane proteins which play an important role in several physiological processes and various pathological conditions. In the Sino Atrial Node (SAN) HCN4 is the target of ivabradine, a bradycardic agent that is, at the moment, the only drug which specifically blocks If. Nevertheless, several other pharmacological agents have been shown to modulate HCN channels, a property that may contribute to their therapeutic activity and/or to their side effects. HCN channels are considered potential targets for developing drugs to treat several important pathologies, but a major issue in this field is the discovery of isoform-selective compounds, owing to the wide distribution of these proteins into the central and peripheral nervous systems, heart and other peripheral tissues. This survey is focused on the compounds that have been shown, or have been designed, to interact with HCN channels and on their binding sites, with the aim to summarize current knowledge and possibly to unveil useful information to design new potent and selective modulators. PMID:26975509

Development of 66 kV class REBCO superconducting cable

NASA Astrophysics Data System (ADS)

Ohya, M.; Masuda, T.; Amemiya, N.; Ishiyama, A.; Ohkuma, T.

Sumitomo Electric Industries (SEI) has been involved in the development of 66 kV/5 kA-class HTS cables using REBCO wires. One of the technical targets was to reduce the AC loss to less than 2 W/m/phase at 5 kA. SEI developed a clad-type textured metal substrate with lower magnetization loss than NiW substrates. REBCO wires of 30 mm wide were slit into 4 mm-wide strips, and these strips were wound spirally on a former with small gaps. The measured AC loss of the manufactured cable was 1.8 W/m/phase at 5 kA, achieving the AC loss goal. Another important target was to manage fault current. The copper protection layers were designed based on simulation findings. Fault current tests (max. 31.5 kA, 2 sec) showed that the designed HTS cable has the required withstanding performance. The development of the elemental technologies was finished on schedule, and a 15 m-long HTS cable system will be constructed to demonstrate that it meets all the required specifications.

Determining Acceptable Limits of Fast-Electron Preheat in Polar-Drive-Ignition Designs

NASA Astrophysics Data System (ADS)

Delettrez, J. A.; Collins, T. J. B.; Ye, C.

2014-10-01

In direct-drive-ignition designs, preheat by fast electrons created by the two-plasmon-decay instability at the quarter-critical density surface can increase the adiabat in the fuel layer and prevent ignition. Since eliminating the preheat entirely is not possible, it is necessary to understand the levels of preheat our targets can withstand before ignition is precluded. The current polar-drive point design is used as the basis for examining the effects of increasing the levels of fast electrons using the one-dimensional, radiation-hydrodynamics code LILAC. Once ignition failure is obtained, the design is then reoptimized using Telios, a downhill simplex method program, to recover ignition. This cycle is repeated until the design can no longer be reoptimized to produce ignition. Mappings of these final results provide insight into ignition failure caused by preheat and what specific target parameters serve to best stave off the effects of the preheat. This material is based upon work supported by the Department of Energy National Nuclear Security Administration under Award Number DE-NA0001944.

Rigor and reproducibility in research with transcranial electrical stimulation: An NIMH-sponsored workshop.

PubMed

Bikson, Marom; Brunoni, Andre R; Charvet, Leigh E; Clark, Vincent P; Cohen, Leonardo G; Deng, Zhi-De; Dmochowski, Jacek; Edwards, Dylan J; Frohlich, Flavio; Kappenman, Emily S; Lim, Kelvin O; Loo, Colleen; Mantovani, Antonio; McMullen, David P; Parra, Lucas C; Pearson, Michele; Richardson, Jessica D; Rumsey, Judith M; Sehatpour, Pejman; Sommers, David; Unal, Gozde; Wassermann, Eric M; Woods, Adam J; Lisanby, Sarah H

Neuropsychiatric disorders are a leading source of disability and require novel treatments that target mechanisms of disease. As such disorders are thought to result from aberrant neuronal circuit activity, neuromodulation approaches are of increasing interest given their potential for manipulating circuits directly. Low intensity transcranial electrical stimulation (tES) with direct currents (transcranial direct current stimulation, tDCS) or alternating currents (transcranial alternating current stimulation, tACS) represent novel, safe, well-tolerated, and relatively inexpensive putative treatment modalities. This report seeks to promote the science, technology and effective clinical applications of these modalities, identify research challenges, and suggest approaches for addressing these needs in order to achieve rigorous, reproducible findings that can advance clinical treatment. The National Institute of Mental Health (NIMH) convened a workshop in September 2016 that brought together experts in basic and human neuroscience, electrical stimulation biophysics and devices, and clinical trial methods to examine the physiological mechanisms underlying tDCS/tACS, technologies and technical strategies for optimizing stimulation protocols, and the state of the science with respect to therapeutic applications and trial designs. Advances in understanding mechanisms, methodological and technological improvements (e.g., electronics, computational models to facilitate proper dosing), and improved clinical trial designs are poised to advance rigorous, reproducible therapeutic applications of these techniques. A number of challenges were identified and meeting participants made recommendations made to address them. These recommendations align with requirements in NIMH funding opportunity announcements to, among other needs, define dosimetry, demonstrate dose/response relationships, implement rigorous blinded trial designs, employ computational modeling, and demonstrate target engagement when testing stimulation-based interventions for the treatment of mental disorders. Published by Elsevier Inc.

Rigor and reproducibility in research with transcranial electrical stimulation: An NIMH-sponsored workshop

PubMed Central

Bikson, Marom; Brunoni, Andre R.; Charvet, Leigh E.; Clark, Vincent P.; Cohen, Leonardo G.; Deng, Zhi-De; Dmochowski, Jacek; Edwards, Dylan J.; Frohlich, Flavio; Kappenman, Emily S.; Lim, Kelvin O.; Loo, Colleen; Mantovani, Antonio; McMullen, David P.; Parra, Lucas C.; Pearson, Michele; Richardson, Jessica D.; Rumsey, Judith M.; Sehatpour, Pejman; Sommers, David; Unal, Gozde; Wassermann, Eric M.; Woods, Adam J.; Lisanby, Sarah H.

2018-01-01

Background Neuropsychiatric disorders are a leading source of disability and require novel treatments that target mechanisms of disease. As such disorders are thought to result from aberrant neuronal circuit activity, neuromodulation approaches are of increasing interest given their potential for manipulating circuits directly. Low intensity transcranial electrical stimulation (tES) with direct currents (transcranial direct current stimulation, tDCS) or alternating currents (transcranial alternating current stimulation, tACS) represent novel, safe, well-tolerated, and relatively inexpensive putative treatment modalities. Objective This report seeks to promote the science, technology and effective clinical applications of these modalities, identify research challenges, and suggest approaches for addressing these needs in order to achieve rigorous, reproducible findings that can advance clinical treatment. Methods The National Institute of Mental Health (NIMH) convened a workshop in September 2016 that brought together experts in basic and human neuroscience, electrical stimulation biophysics and devices, and clinical trial methods to examine the physiological mechanisms underlying tDCS/tACS, technologies and technical strategies for optimizing stimulation protocols, and the state of the science with respect to therapeutic applications and trial designs. Results Advances in understanding mechanisms, methodological and technological improvements (e.g., electronics, computational models to facilitate proper dosing), and improved clinical trial designs are poised to advance rigorous, reproducible therapeutic applications of these techniques. A number of challenges were identified and meeting participants made recommendations made to address them. Conclusions These recommendations align with requirements in NIMH funding opportunity announcements to, among other needs, define dosimetry, demonstrate dose/response relationships, implement rigorous blinded trial designs, employ computational modeling, and demonstrate target engagement when testing stimulation-based interventions for the treatment of mental disorders. PMID:29398575

Eyesafe laser cloud mapper

NASA Astrophysics Data System (ADS)

Woodall, Milton A., II; Minch, J. R.; Nunez, J.; Keeter, Howard S.; Johnson, Anthony M.

1990-07-01

The performance of eyesafe erbium:glass lasers operating at a wavelength of 1. 54 urn has been tested under various natural and manmade obscurants. To obtain the maximum amount of information two distinct system configurations were employed. The first a laser cloud mapper was designed to provide a direct depth profile of smoke density and reflectivity as well as target position. The second configuration was a production military laser rangefinder. It is representative of systems currently incorporated in tactical armored vehicles and was used to provide a direct indication of target range. 1.

Structure-based drug design: aiming for a perfect fit

PubMed Central

van Montfort, Rob L.M.; Workman, Paul

2017-01-01

Knowledge of the three-dimensional structure of therapeutically relevant targets has informed drug discovery since the first protein structures were determined using X-ray crystallography in the 1950s and 1960s. In this editorial we provide a brief overview of the powerful impact of structure-based drug design (SBDD), which has its roots in computational and structural biology, with major contributions from both academia and industry. We describe advances in the application of SBDD for integral membrane protein targets that have traditionally proved very challenging. We emphasize the major progress made in fragment-based approaches for which success has been exemplified by over 30 clinical drug candidates and importantly three FDA-approved drugs in oncology. We summarize the articles in this issue that provide an excellent snapshot of the current state of the field of SBDD and fragment-based drug design and which offer key insights into exciting new developments, such as the X-ray free-electron laser technology, cryo-electron microscopy, open science approaches and targeted protein degradation. We stress the value of SBDD in the design of high-quality chemical tools that are used to interrogate biology and disease pathology, and to inform target validation. We emphasize the need to maintain the scientific rigour that has been traditionally associated with structural biology and extend this to other methods used in drug discovery. This is particularly important because the quality and robustness of any form of contributory data determines its usefulness in accelerating drug design, and therefore ultimately in providing patient benefit. PMID:29118091

The cytoskeleton as a novel therapeutic target for old neurodegenerative disorders.

PubMed

Eira, Jessica; Silva, Catarina Santos; Sousa, Mónica Mendes; Liz, Márcia Almeida

2016-06-01

Cytoskeleton defects, including alterations in microtubule stability, in axonal transport as well as in actin dynamics, have been characterized in several unrelated neurodegenerative conditions. These observations suggest that defects of cytoskeleton organization may be a common feature contributing to neurodegeneration. In line with this hypothesis, drugs targeting the cytoskeleton are currently being tested in animal models and in human clinical trials, showing promising effects. Drugs that modulate microtubule stability, inhibitors of posttranslational modifications of cytoskeletal components, specifically compounds affecting the levels of tubulin acetylation, and compounds targeting signaling molecules which regulate cytoskeleton dynamics, constitute the mostly addressed therapeutic interventions aiming at preventing cytoskeleton damage in neurodegenerative disorders. In this review, we will discuss in a critical perspective the current knowledge on cytoskeleton damage pathways as well as therapeutic strategies designed to revert cytoskeleton-related defects mainly focusing on the following neurodegenerative disorders: Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Amyotrophic Lateral Sclerosis and Charcot-Marie-Tooth Disease. Copyright © 2016 Elsevier Ltd. All rights reserved.

Current scenario of peptide-based drugs: the key roles of cationic antitumor and antiviral peptides

PubMed Central

Mulder, Kelly C. L.; Lima, Loiane A.; Miranda, Vivian J.; Dias, Simoni C.; Franco, Octávio L.

2013-01-01

Cationic antimicrobial peptides (AMPs) and host defense peptides (HDPs) show vast potential as peptide-based drugs. Great effort has been made in order to exploit their mechanisms of action, aiming to identify their targets as well as to enhance their activity and bioavailability. In this review, we will focus on both naturally occurring and designed antiviral and antitumor cationic peptides, including those here called promiscuous, in which multiple targets are associated with a single peptide structure. Emphasis will be given to their biochemical features, selectivity against extra targets, and molecular mechanisms. Peptides which possess antitumor activity against different cancer cell lines will be discussed, as well as peptides which inhibit virus replication, focusing on their applications for human health, animal health and agriculture, and their potential as new therapeutic drugs. Moreover, the current scenario for production and the use of nanotechnology as delivery tool for both classes of cationic peptides, as well as the perspectives on improving them is considered. PMID:24198814

Performance Characterization of the Production Facility Prototype Helium Flow System

DOE Office of Scientific and Technical Information (OSTI.GOV)

Woloshun, Keith Albert; Dale, Gregory E.; Dalmas, Dale Allen

2015-12-16

The roots blower in use at ANL for in-beam experiments and also at LANL for flow tests was sized for 12 mm diameter disks and significantly less beam heating. Currently, the disks are 29 mm in diameter, with a 12 mm FWHM Gaussian beam spot at 42 MeV and 2.86 μA on each side of the target, 5.72 μA total. The target design itself is reported elsewhere. With the increased beam heating, the helium flow requirement increased so that a larger blower was need for a mass flow rate of 400 g/s at 2.76 MPa (400 psig). An Aerzen GMmore » 12.4 blower was selected, and is currently being installed at the LANL facility for target and component flow testing. This report describes this blower/motor/pressure vessel package and the status of the facility preparations. Blower performance (mass flow rate as a function of loop pressure drop) was measured at 4 blower speeds. Results are reported below.« less

The GENCODE exome: sequencing the complete human exome

PubMed Central

Coffey, Alison J; Kokocinski, Felix; Calafato, Maria S; Scott, Carol E; Palta, Priit; Drury, Eleanor; Joyce, Christopher J; LeProust, Emily M; Harrow, Jen; Hunt, Sarah; Lehesjoki, Anna-Elina; Turner, Daniel J; Hubbard, Tim J; Palotie, Aarno

2011-01-01

Sequencing the coding regions, the exome, of the human genome is one of the major current strategies to identify low frequency and rare variants associated with human disease traits. So far, the most widely used commercial exome capture reagents have mainly targeted the consensus coding sequence (CCDS) database. We report the design of an extended set of targets for capturing the complete human exome, based on annotation from the GENCODE consortium. The extended set covers an additional 5594 genes and 10.3 Mb compared with the current CCDS-based sets. The additional regions include potential disease genes previously inaccessible to exome resequencing studies, such as 43 genes linked to ion channel activity and 70 genes linked to protein kinase activity. In total, the new GENCODE exome set developed here covers 47.9 Mb and performed well in sequence capture experiments. In the sample set used in this study, we identified over 5000 SNP variants more in the GENCODE exome target (24%) than in the CCDS-based exome sequencing. PMID:21364695

CRISPRdirect: software for designing CRISPR/Cas guide RNA with reduced off-target sites

PubMed Central

Naito, Yuki; Hino, Kimihiro; Bono, Hidemasa; Ui-Tei, Kumiko

2015-01-01

Summary: CRISPRdirect is a simple and functional web server for selecting rational CRISPR/Cas targets from an input sequence. The CRISPR/Cas system is a promising technique for genome engineering which allows target-specific cleavage of genomic DNA guided by Cas9 nuclease in complex with a guide RNA (gRNA), that complementarily binds to a ∼20 nt targeted sequence. The target sequence requirements are twofold. First, the 5′-NGG protospacer adjacent motif (PAM) sequence must be located adjacent to the target sequence. Second, the target sequence should be specific within the entire genome in order to avoid off-target editing. CRISPRdirect enables users to easily select rational target sequences with minimized off-target sites by performing exhaustive searches against genomic sequences. The server currently incorporates the genomic sequences of human, mouse, rat, marmoset, pig, chicken, frog, zebrafish, Ciona, fruit fly, silkworm, Caenorhabditis elegans, Arabidopsis, rice, Sorghum and budding yeast. Availability: Freely available at http://crispr.dbcls.jp/. Contact: y-naito@dbcls.rois.ac.jp Supplementary information: Supplementary data are available at Bioinformatics online. PMID:25414360

Beryllium Ignition Targets for Indirect Drive NIF Experiments

NASA Astrophysics Data System (ADS)

Simakov, A. N.; Wilson, D. C.; Yi, S. A.; Kline, J. L.; Salmonson, J. D.; Clark, D. S.; Milovich, J. L.; Marinak, M. M.; Callahan, D. A.

2013-10-01

Current NIF plastic capsules are under-performing, and alternate ablators are being investigated. Beryllium presents an attractive option, since it has lower opacity and therefore higher ablation rate, pressure, and velocity. Previous NIF Be designs assumed significantly better hohlraum performance than recently observed (e.g., 7.5 vs. 15-17% of back-scattered power and 1.0 vs. 0.85 main pulse's power multipliers) and employed less accurate atomic configuration models than currently used (XSN vs. DCA), and thus an updated design is required. We present a new, Rev. 6 Be ignition target design that employs the full NIF capacity (1.8 MJ, 520 TW) and uses a standard 5.75 mm gold hohlraum with 1.5 mg/cm3 of helium gas fill. The 1051 μm capsule features 180 μm of layered copper-doped (with the maximum of 3 atom-%) Be ablator and 90 μm of cryogenic deuterium-tritium fuel. The peak implosion velocity of 367 μm/ns results in 4.1 keV of no-burn ion temperature, 1.6 and 1.9 g/cm2 of fuel and total areal densities, respectively, and 20.6 MJ of fusion yield. The capsule demonstrates robust performance with surface/interface roughnesses up to 1.6 times larger that Rev. 3 specs. Work supported by the US Department of Energy.

Targeting cancer with kinase inhibitors

PubMed Central

Gross, Stefan; Rahal, Rami; Stransky, Nicolas; Lengauer, Christoph; Hoeflich, Klaus P.

2015-01-01

Kinase inhibitors have played an increasingly prominent role in the treatment of cancer and other diseases. Currently, more than 25 oncology drugs that target kinases have been approved, and numerous additional therapeutics are in various stages of clinical evaluation. In this Review, we provide an in-depth analysis of activation mechanisms for kinases in cancer, highlight recent successes in drug discovery, and demonstrate the clinical impact of selective kinase inhibitors. We also describe the substantial progress that has been made in designing next-generation inhibitors to circumvent on-target resistance mechanisms, as well as ongoing strategies for combining kinase inhibitors in the clinic. Last, there are numerous prospects for the discovery of novel kinase targets, and we explore cancer immunotherapy as a new and promising research area for studying kinase biology. PMID:25932675

The TESS Input Catalog and Selection of Targets for the TESS Transit Search

NASA Astrophysics Data System (ADS)

Pepper, Joshua; Stassun, Keivan G.; Paegert, Martin; Oelkers, Ryan; De Lee, Nathan Michael; Torres, Guillermo; TESS Target Selection Working Group

2018-01-01

The TESS mission will photometrically survey millions of the brightest stars over almost the entire the sky to detect transiting exoplanets. A key step to enable that search is the creation of the TESS Input Catalog (TIC), a compiled catalog of 700 million stars and galaxies with observed and calculated parameters. From the TIC we derive the Candidate Target List (CTL) to identify target stars for the 2-minute TESS postage stamps. The CTL is designed to identify the best stars for the detection of small planets, which includes all bright cool dwarf stars in the sky. I will describe the target selection strategy, the distribution of stars in the current CTL, and how both the TIC and CTL will expand and improve going forward.

Systems biology-embedded target validation: improving efficacy in drug discovery.

PubMed

Vandamme, Drieke; Minke, Benedikt A; Fitzmaurice, William; Kholodenko, Boris N; Kolch, Walter

2014-01-01

The pharmaceutical industry is faced with a range of challenges with the ever-escalating costs of drug development and a drying out of drug pipelines. By harnessing advances in -omics technologies and moving away from the standard, reductionist model of drug discovery, there is significant potential to reduce costs and improve efficacy. Embedding systems biology approaches in drug discovery, which seek to investigate underlying molecular mechanisms of potential drug targets in a network context, will reduce attrition rates by earlier target validation and the introduction of novel targets into the currently stagnant market. Systems biology approaches also have the potential to assist in the design of multidrug treatments and repositioning of existing drugs, while stratifying patients to give a greater personalization of medical treatment. © 2013 Wiley Periodicals, Inc.

Prioritizing bird conservation actions in the Prairie Hardwood transition of the Midwestern United States

USGS Publications Warehouse

Thogmartin, Wayne E.; Crimmins, Shawn M.; Pearce, Jennie

2014-01-01

Large-scale planning for the conservation of species is often hindered by a poor understanding of factors limiting populations. In regions with declining wildlife populations, it is critical that objective metrics of conservation success are developed to ensure that conservation actions achieve desired results. Using spatially explicit estimates of bird abundance, we evaluated several management alternatives for conserving bird populations in the Prairie Hardwood Transition of the United States. We designed landscapes conserving species at 50% of their current predicted abundance as well as landscapes attempting to achieve species population targets (which often required the doubling of current abundance). Conserving species at reduced (half of current) abundance led to few conservation conflicts. However, because of extensive modification of the landscape to suit human use, strategies for achieving regional population targets for forest bird species would be difficult under even ideal circumstances, and even more so if maintenance of grassland bird populations is also desired. Our results indicated that large-scale restoration of agricultural lands to native grassland and forest habitats may be the most productive conservation action for increasing bird population sizes but the level of landscape transition required to approach target bird population sizes may be societally unacceptable.

Multi-targetable chalcone analogs to treat deadly Alzheimer's disease: Current view and upcoming advice.

PubMed

Zhang, Xu; Rakesh, K P; Bukhari, S N A; Balakrishna, Moku; Manukumar, H M; Qin, Hua-Li

2018-06-05

The complications of Alzheimer's disease AD were deadly dangerous cause of neurodegenerative disorders connected with the decline of the cognitive functions and loss of memory. The common form of dementia is accounted as the sixth leading cause of the death affecting any stage of people in a lifetime. Synthetic natural chalcone analogs were currently a hot research topic for the treatment of (AD) which has affected millions of peoples throughout the world. The present aim was set to understand the important problems of the AD and its treatment based on natural derivatives of novel chalcones. One interesting strategy currently of searching for the treatment of AD is to find inhibitors for acetylcholinesterase (AChE) and using metal chelators to target amyloid-β (Aβ) peptides, and then metal-Aβ complexes for the AD pathogenesis. The present compressed review focuses and highlights the design and synthesis of new approaches for the construction of important chalcones playing multiple beneficiary roles in the AD treatments. These hallmarks of concurred research represent the immediate needs of development of novel therapeutic drugs for effective treatment of ADs by understanding the specific pharmacology targets. Copyright © 2018 Elsevier Inc. All rights reserved.

MicroRNAs and other non-coding RNAs as targets for anticancer drug development

PubMed Central

Ling, Hui; Fabbri, Muller; Calin, George A.

2015-01-01

With the first cancer-targeted microRNA drug, MRX34, a liposome-based miR-34 mimic, entering phase I clinical trial in patients with advanced hepatocellular carcinoma in April 2013, miRNA therapeutics are attracting special attention from both academia and biotechnology companies. Although to date the most studied non-coding RNAs (ncRNAs) are miRNAs, the importance of long non-coding RNAs (lncRNAs) is increasingly being recognized. Here we summarize the roles of miRNAs and lncRNAs in cancer, with a focus on the recently identified novel mechanisms of action, and discuss the current strategies in designing ncRNA-targeting therapeutics, as well as the associated challenges. PMID:24172333

Guilty Feelings, Targeted Actions

PubMed Central

Cryder, Cynthia E.; Springer, Stephen; Morewedge, Carey K.

2014-01-01

Early investigations of guilt cast it as an emotion that prompts broad reparative behaviors that help guilty individuals feel better about themselves or about their transgressions. The current investigation found support for a more recent representation of guilt as an emotion designed to identify and correct specific social offenses. Across five experiments, guilt influenced behavior in a targeted and strategic way. Guilt prompted participants to share resources more generously with others, but only did so when those others were persons whom the participant had wronged and only when those wronged individuals could notice the gesture. Rather than trigger broad reparative behaviors that remediate one’s general reputation or self-perception, guilt triggers targeted behaviors intended to remediate specific social transgressions. PMID:22337764

Guilty feelings, targeted actions.

PubMed

Cryder, Cynthia E; Springer, Stephen; Morewedge, Carey K

2012-05-01

Early investigations of guilt cast it as an emotion that prompts broad reparative behaviors that help guilty individuals feel better about themselves or about their transgressions. The current investigation found support for a more recent representation of guilt as an emotion designed to identify and correct specific social offenses. Across five experiments, guilt influenced behavior in a targeted and strategic way. Guilt prompted participants to share resources more generously with others, but only did so when those others were persons whom the participant had wronged and only when those wronged individuals could notice the gesture. Rather than trigger broad reparative behaviors that remediate one's general reputation or self-perception, guilt triggers targeted behaviors intended to remediate specific social transgressions.

Exploration of the medical periodic table: towards new targets.

PubMed

Barry, Nicolas P E; Sadler, Peter J

2013-06-07

Metallodrugs offer potential for unique mechanisms of drug action based on the choice of the metal, its oxidation state, the types and number of coordinated ligands and the coordination geometry. We discuss recent progress in identifying new target sites and elucidating the mechanisms of action of anti-cancer, anti-bacterial, anti-viral, anti-parasitic, anti-inflammatory, and anti-neurodegenerative agents, as well as in the design of metal-based diagnostic agents. Progress in identifying and defining target sites has been accelerated recently by advances in proteomics, genomics and metal speciation analysis. Examples of metal compounds and chelating agents (enzyme inhibitors) currently in clinical use, clinical trials or preclinical development are highlighted.

Experiments with radioactive target samples at FRANZ

NASA Astrophysics Data System (ADS)

Sonnabend, K.; Altstadt, S.; Beinrucker, C.; Berger, M.; Endres, A.; Fiebiger, S.; Gerbig, J.; Glorius, J.; Göbel, K.; Heftrich, T.; Hinrichs, O.; Koloczek, A.; Lazarus, A.; Lederer, C.; Lier, A.; Mei, B.; Meusel, O.; Mevius, E.; Ostermöller, J.; Plag, R.; Pohl, M.; Reifarth, R.; Schmidt, S.; Slavkovská, Z.; Thomas, B.; Thomas, T.; Weigand, M.; Wolf, C.

2016-01-01

The FRANZ facility is currently under construction at Goethe Universität Frankfurt a.M., Germany. It is designed to produce the world's highest neutron intensities in the astrophysically relevant energy range between 10 keV and 1 MeV and consists of a high-intensity proton linac providing energies close to the threshold of the 7Li(p,n) reaction at Ep = 1880 keV. The high intensities of both the proton and the neutron beam allow the investigation of reactions of unstable target isotopes since the needed amount of target material is significantly reduced. We will present two examplary reactions relevant for the s process and the nucleosynthesis of p nuclei, respectively.

Using cheminformatics to predict cross reactivity of “designer drugs” to their currently available immunoassays

PubMed Central

2014-01-01

Background A challenge for drug of abuse testing is presented by ‘designer drugs’, compounds typically discovered by modifications of existing clinical drug classes such as amphetamines and cannabinoids. Drug of abuse screening immunoassays directed at amphetamine or methamphetamine only detect a small subset of designer amphetamine-like drugs, and those immunoassays designed for tetrahydrocannabinol metabolites generally do not cross-react with synthetic cannabinoids lacking the classic cannabinoid chemical backbone. This suggests complexity in understanding how to detect and identify whether a patient has taken a molecule of one class or another, impacting clinical care. Methods Cross-reactivity data from immunoassays specifically targeting designer amphetamine-like and synthetic cannabinoid drugs was collected from multiple published sources, and virtual chemical libraries for molecular similarity analysis were built. The virtual library for synthetic cannabinoid analysis contained a total of 169 structures, while the virtual library for amphetamine-type stimulants contained 288 compounds. Two-dimensional (2D) similarity for each test compound was compared to the target molecule of the immunoassay undergoing analysis. Results 2D similarity differentiated between cross-reactive and non-cross-reactive compounds for immunoassays targeting mephedrone/methcathinone, 3,4-methylenedioxypyrovalerone, benzylpiperazine, mephentermine, and synthetic cannabinoids. Conclusions In this study, we applied 2D molecular similarity analysis to the designer amphetamine-type stimulants and synthetic cannabinoids. Similarity calculations can be used to more efficiently decide which drugs and metabolites should be tested in cross-reactivity studies, as well as to design experiments and potentially predict antigens that would lead to immunoassays with cross reactivity for a broader array of designer drugs. PMID:24851137

Crysalis: an integrated server for computational analysis and design of protein crystallization.

PubMed

Wang, Huilin; Feng, Liubin; Zhang, Ziding; Webb, Geoffrey I; Lin, Donghai; Song, Jiangning

2016-02-24

The failure of multi-step experimental procedures to yield diffraction-quality crystals is a major bottleneck in protein structure determination. Accordingly, several bioinformatics methods have been successfully developed and employed to select crystallizable proteins. Unfortunately, the majority of existing in silico methods only allow the prediction of crystallization propensity, seldom enabling computational design of protein mutants that can be targeted for enhancing protein crystallizability. Here, we present Crysalis, an integrated crystallization analysis tool that builds on support-vector regression (SVR) models to facilitate computational protein crystallization prediction, analysis, and design. More specifically, the functionality of this new tool includes: (1) rapid selection of target crystallizable proteins at the proteome level, (2) identification of site non-optimality for protein crystallization and systematic analysis of all potential single-point mutations that might enhance protein crystallization propensity, and (3) annotation of target protein based on predicted structural properties. We applied the design mode of Crysalis to identify site non-optimality for protein crystallization on a proteome-scale, focusing on proteins currently classified as non-crystallizable. Our results revealed that site non-optimality is based on biases related to residues, predicted structures, physicochemical properties, and sequence loci, which provides in-depth understanding of the features influencing protein crystallization. Crysalis is freely available at http://nmrcen.xmu.edu.cn/crysalis/.

Crysalis: an integrated server for computational analysis and design of protein crystallization

PubMed Central

Wang, Huilin; Feng, Liubin; Zhang, Ziding; Webb, Geoffrey I.; Lin, Donghai; Song, Jiangning

2016-01-01

The failure of multi-step experimental procedures to yield diffraction-quality crystals is a major bottleneck in protein structure determination. Accordingly, several bioinformatics methods have been successfully developed and employed to select crystallizable proteins. Unfortunately, the majority of existing in silico methods only allow the prediction of crystallization propensity, seldom enabling computational design of protein mutants that can be targeted for enhancing protein crystallizability. Here, we present Crysalis, an integrated crystallization analysis tool that builds on support-vector regression (SVR) models to facilitate computational protein crystallization prediction, analysis, and design. More specifically, the functionality of this new tool includes: (1) rapid selection of target crystallizable proteins at the proteome level, (2) identification of site non-optimality for protein crystallization and systematic analysis of all potential single-point mutations that might enhance protein crystallization propensity, and (3) annotation of target protein based on predicted structural properties. We applied the design mode of Crysalis to identify site non-optimality for protein crystallization on a proteome-scale, focusing on proteins currently classified as non-crystallizable. Our results revealed that site non-optimality is based on biases related to residues, predicted structures, physicochemical properties, and sequence loci, which provides in-depth understanding of the features influencing protein crystallization. Crysalis is freely available at http://nmrcen.xmu.edu.cn/crysalis/. PMID:26906024

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bieniosek, F.M.; Anders, A.; Barnard, J.J.

This effort contains two main components: The new induction-bunching module is expected to deliver higher fluence in the bunched beam, and the new target positioner will enable a significantly enhanced target physics repetition rate. The velocity ramp that bunches the K{sup +} beam in the neutralized drift compression section is established with a bipolar voltage ramp applied to an acceleration gap. An induction acceleration module creates this voltage waveform. The new bunching module (IBM) specially built for NDCX has approximately twice the capability (volt-seconds) as our original IBM. We reported on the beam line design for the best use ofmore » the bunching module in our FY08 Q2 report. Based on simulations and theoretical work, we chose to extend the drift compression section and use the additional volt-seconds to extend the pulse duration and keep the peak voltage swing (and velocity excursions) similar to the present module. Simulations showed that this approach, which extends the drift section, to be advantageous because it limits the chromatic aberrations in the beam spot on target. To this end, colleagues at PPPL have fabricated the meter-long extension to the ferroelectric plasma source and it was installed on the beam line with the new IBM in January 2009. Simulation results suggest a factor of two increase in energy deposition from the bunched beam. In the first WDM target run (August-November 2008) the target handling setup required opening the vacuum system to manually replace the target after each shot (which destroys the target). Because of the requirement for careful alignment of each individual target, the target shot repetition rate was no greater than 1 shot per day. Initial results of this run are reported in our FY08 4th Quarter Milestone Report. Based on the valuable experience gained in the initial run, we have designed and installed an improved target alignment and positioning system with the capability to reposition targets remotely. This capability allows us to significantly increase our shot repetition rate, and to take greater advantage of the pinhole/cone arrangement we have developed to localize the beam at final focus. In addition we have improved the capability of the optical diagnostic systems, and we have installed a new beam current transformer downstream of the target to monitor beam current transmitted through the target during an experiment. These improvements will allow us to better exploit the inherent capability of the NDCX facility for high repetition rate and thus to provide more detailed experimental data to assess WDM physics models of target behavior. This milestone has been met by demonstrating highly compressed beams with the new bunching module, which are neutralized in the longer drift compression section by the new ferro-electric plasma sources. The peak uncompressed beam intensity ({approx}600 kW/cm{sup 2}) is higher than in previous measurements, and the bunched beam current profiles are {approx}2ns. We have also demonstrated a large increase in the experimental data acquisition rate for target heating experiments. In the first test of the new remote-controlled target positioning system, we completed three successful target physics shots in less than two hours. Further improvements are expected.« less

Off-target model based OPC

NASA Astrophysics Data System (ADS)

Lu, Mark; Liang, Curtis; King, Dion; Melvin, Lawrence S., III

2005-11-01

Model-based Optical Proximity correction has become an indispensable tool for achieving wafer pattern to design fidelity at current manufacturing process nodes. Most model-based OPC is performed considering the nominal process condition, with limited consideration of through process manufacturing robustness. This study examines the use of off-target process models - models that represent non-nominal process states such as would occur with a dose or focus variation - to understands and manipulate the final pattern correction to a more process robust configuration. The study will first examine and validate the process of generating an off-target model, then examine the quality of the off-target model. Once the off-target model is proven, it will be used to demonstrate methods of generating process robust corrections. The concepts are demonstrated using a 0.13 μm logic gate process. Preliminary indications show success in both off-target model production and process robust corrections. With these off-target models as tools, mask production cycle times can be reduced.

Segmented beryllium target for a 2 MW super beam facility

DOE PAGES

Davenne, T.; Caretta, O.; Densham, C.; ...

2015-09-14

The Long Baseline Neutrino Facility (LBNF, formerly the Long Baseline Neutrino Experiment) is under design as a next generation neutrino oscillation experiment, with primary objectives to search for CP violation in the leptonic sector, to determine the neutrino mass hierarchy and to provide a precise measurement of θ 23. The facility will generate a neutrino beam at Fermilab by the interaction of a proton beam with a target material. At the ultimate anticipated proton beam power of 2.3 MW the target material must dissipate a heat load of between 10 and 25 kW depending on the target size. This paper presents amore » target concept based on an array of spheres and compares it to a cylindrical monolithic target such as that which currently operates at the T2K facility. Thus simulation results show that the proposed technology offers efficient cooling and lower stresses whilst delivering a neutrino production comparable with that of a conventional solid cylindrical target.« less

The SPES High Power ISOL production target

NASA Astrophysics Data System (ADS)

Andrighetto, A.; Corradetti, S.; Ballan, M.; Borgna, F.; Manzolaro, M.; Scarpa, D.; Monetti, A.; Rossignoli, M.; Silingardi, R.; Mozzi, A.; Vivian, G.; Boratto, E.; De Ruvo, L.; Sattin, N.; Meneghetti, G.; Oboe, R.; Guerzoni, M.; Margotti, A.; Ferrari, M.; Zenoni, A.; Prete, G.

2016-11-01

SPES (Selective Production of Exotic Species) is a facility under construction at INFN-LNL (Istituto Nazionale di Fisica Nucleare - Laboratori Nazionali di Legnaro), aimed to produce intense neutron-rich radioactive ion beams (RIBs). These will be obtained using the ISOL (Isotope Separation On-Line) method, bombarding a uranium carbide target with a proton beam of 40MeV energy and currents up to 200μA. The target configuration was designed to obtain a high number of fissions, up to 1013 per second, low power deposition and fast release of the produced isotopes. The exotic isotopes generated in the target are ionized, mass separated and re-accelerated by the ALPI superconducting LINAC at energies of 10AMeV and higher, for masses in the region of A = 130 amu , with an expected rate on the secondary target up to 109 particles per second. In this work, recent results on the R&D activities regarding the SPES RIB production target-ion source system are reported.

Model MTF for the mosaic window

NASA Astrophysics Data System (ADS)

Xing, Zhenchong; Hong, Yongfeng; Zhang, Bao

2017-10-01

An electro-optical targeting system mounted either within an airframe or housed in separate pods requires a window to form an environmental barrier to the outside world. In current practice, such windows usually use a mosaic or segmented window. When scanning the target, internally gimbaled systems sweep over the window, which can affect the modulation transfer function (MTF) due to wave-front division and optical path differences arising from the thickness/wedge differences between panes. In this paper, a mathematical model of the MTF of the mosaic window is presented that allows an analysis of influencing factors; we show how the model may be integrated into ZEMAX® software for optical design. The model can be used to guide both the design and the tolerance analysis of optical systems that employ a mosaic window.

Natural language processing: an introduction

PubMed Central

Ohno-Machado, Lucila; Chapman, Wendy W

2011-01-01

Objectives To provide an overview and tutorial of natural language processing (NLP) and modern NLP-system design. Target audience This tutorial targets the medical informatics generalist who has limited acquaintance with the principles behind NLP and/or limited knowledge of the current state of the art. Scope We describe the historical evolution of NLP, and summarize common NLP sub-problems in this extensive field. We then provide a synopsis of selected highlights of medical NLP efforts. After providing a brief description of common machine-learning approaches that are being used for diverse NLP sub-problems, we discuss how modern NLP architectures are designed, with a summary of the Apache Foundation's Unstructured Information Management Architecture. We finally consider possible future directions for NLP, and reflect on the possible impact of IBM Watson on the medical field. PMID:21846786

Quantitative Comparison of Minimum Inductance and Minimum Power Algorithms for the Design of Shim Coils for Small Animal Imaging

PubMed Central

HUDSON, PARISA; HUDSON, STEPHEN D.; HANDLER, WILLIAM B.; SCHOLL, TIMOTHY J.; CHRONIK, BLAINE A.

2010-01-01

High-performance shim coils are required for high-field magnetic resonance imaging and spectroscopy. Complete sets of high-power and high-performance shim coils were designed using two different methods: the minimum inductance and the minimum power target field methods. A quantitative comparison of shim performance in terms of merit of inductance (ML) and merit of resistance (MR) was made for shim coils designed using the minimum inductance and the minimum power design algorithms. In each design case, the difference in ML and the difference in MR given by the two design methods was <15%. Comparison of wire patterns obtained using the two design algorithms show that minimum inductance designs tend to feature oscillations within the current density; while minimum power designs tend to feature less rapidly varying current densities and lower power dissipation. Overall, the differences in coil performance obtained by the two methods are relatively small. For the specific case of shim systems customized for small animal imaging, the reduced power dissipation obtained when using the minimum power method is judged to be more significant than the improvements in switching speed obtained from the minimum inductance method. PMID:20411157

Designing patient-centric applications for chronic disease management.

PubMed

Tsalatsanis, Athanasios; Gil-Herrera, Eleazar; Yalcin, Ali; Djulbegovic, Benjamin; Barnes, Laura

2011-01-01

Chronic diseases such as diabetes and heart disease are the leading causes of disability and death in the developed world. Technological interventions such as mobile applications have the ability to facilitate and motivate patients in chronic disease management, but these types of interventions present considerable design challenges. The primary objective of this paper is to present the challenges arising from the design and implementation of software applications aiming to assist patients in chronic disease management. We also outline preliminary results regarding a self-management application currently under development targeting young adults suffering from type 1 diabetes.

Designing a connectionist network supercomputer.

PubMed

Asanović, K; Beck, J; Feldman, J; Morgan, N; Wawrzynek, J

1993-12-01

This paper describes an effort at UC Berkeley and the International Computer Science Institute to develop a supercomputer for artificial neural network applications. Our perspective has been strongly influenced by earlier experiences with the construction and use of a simpler machine. In particular, we have observed Amdahl's Law in action in our designs and those of others. These observations inspire attention to many factors beyond fast multiply-accumulate arithmetic. We describe a number of these factors along with rough expressions for their influence and then give the applications targets, machine goals and the system architecture for the machine we are currently designing.

Identification of Critical Design Points for the EAP of a Space-based Doppler Lidar Wind Sounder

NASA Technical Reports Server (NTRS)

Emmitt, G. D.; Wood, S. A.

1992-01-01

The feasibility of making tropospheric wind measurements with a space-based Doppler lidar was studied by a number of agencies over the past 10-15 years. Currently NASA has a plan to launch such an instrument, the Laser Atmospheric Wind Sounder (LAWS), within the next decade. The design of the LAWS continues to undergo a series of iterations common to most instruments targeted for a space platform. In general, the constraints of available platform power, weight allowance, and project funds continue to change. With these changes the performance and design specifications also must change.

The impact of nurse-driven targeted HIV screening in 8 emergency departments: study protocol for the DICI-VIH cluster-randomized two-period crossover trial.

PubMed

Leblanc, Judith; Rousseau, Alexandra; Hejblum, Gilles; Durand-Zaleski, Isabelle; de Truchis, Pierre; Lert, France; Costagliola, Dominique; Simon, Tabassome; Crémieux, Anne-Claude

2016-02-01

In 2010, to reduce late HIV diagnosis, the French national health agency endorsed non-targeted HIV screening in health care settings. Despite these recommendations, non-targeted screening has not been implemented and only physician-directed diagnostic testing is currently performed. A survey conducted in 2010 in 29 French Emergency Departments (EDs) showed that non-targeted nurse-driven screening was feasible though only a few new HIV diagnoses were identified, predominantly among high-risk groups. A strategy targeting high-risk groups combined with current practice could be shown to be feasible, more efficient and cost-effective than current practice alone. DICI-VIH (acronym for nurse-driven targeted HIV screening) is a multicentre, cluster-randomized, two-period crossover trial. The primary objective is to compare the effectiveness of 2 strategies for diagnosing HIV among adult patients visiting EDs: nurse-driven targeted HIV screening combined with current practice (physician-directed diagnostic testing) versus current practice alone. Main secondary objectives are to compare access to specialist consultation and how early HIV diagnosis occurs in the course of the disease between the 2 groups, and to evaluate the implementation, acceptability and cost-effectiveness of nurse-driven targeted screening. The 2 strategies take place during 2 randomly assigned periods in 8 EDs of metropolitan Paris, where 42 % of France's new HIV patients are diagnosed every year. All patients aged 18 to 64, not presenting secondary to HIV exposure are included. During the intervention period, patients are invited to fill a 7-item questionnaire (country of birth, sexual partners and injection drug use) in order to select individuals who are offered a rapid test. If the rapid test is reactive, a follow-up visit with an infectious disease specialist is scheduled within 72 h. Assuming an 80 % statistical power and a 5 % type 1 error, with 1.04 and 3.38 new diagnoses per 10,000 patients in the control and targeted groups respectively, a sample size of 140,000 patients was estimated corresponding to 8,750 patients per ED and per period. Inclusions started in June 2014. Results are expected by mid-2016. The DICI-VIH study is the first large randomized controlled trial designed to assess nurse-driven targeted HIV screening. This study can provide valuable information on HIV screening in health care settings. ClinicalTrials.gov: NCT02127424 (29 April 2014).

Acid-mediated Lipinski's second rule: application to drug design and targeting in cancer.

PubMed

Omran, Ziad; Rauch, Cyril

2014-05-01

With a predicted 382.4 per 100,000 people expected to suffer from some form of malignant neoplasm by 2015, and a current death toll of 1 out of 8 deaths worldwide, improving treatment and/or drug design is an essential focus of cancer research. Multi-drug resistance is the leading cause of chemotherapeutic failure, and delivery of anticancer drugs to the inside of cancerous cells is another major challenge. Fifteen years ago, in a completely different field in which improving drug delivery is the objective, the bioavailability of oral compounds, Christopher Lipinski formulated some rules that are still used by the pharmaceutical industry as rules of thumb to improve drug delivery to their target. Although Lipinski's rules were not formulated to improve delivery of antineoplastic drugs to the inside of cancer cells, it is interesting to note that the problems are similar. On the basis of the strong similarity between the fields, we discuss how they can be connected and how new drug targets can be defined in cancer.

Electromagnetic Pulses Generated From Laser Target Interactions at Shenguang II Laser Facility

NASA Astrophysics Data System (ADS)

Yang, Jinwen; Li, Tingshuai; Yi, Tao; Wang, Chuanke; Yang, Ming; Yang, Weiming; Liu, Shenye; Jiang, Shaoen; Ding, Yongkun

2016-10-01

Significant electromagnetic pulses (EMP) can be generated by the intensive laser irradiating solid targets in inertial confinement fusion (ICF). To evaluate the EMP intensity and distribution in and outside the laser chamber, we designed and fabricated a discone antenna with ultra-wide bands of over 10 GHz. The return loss (S11 parameter) of this antenna was below -10 dB and could even achieve under -30 dB at 3.1 GHz. The EMP intensity in this study at 80 cm and 40 cm away from the target chamber center (TCC) reached 400 kV/m and 2000 kV/m. The current results are expected to offer preliminary information to study physics regarding laser plasma interactions and will also lay experimental foundation for EMI shielding design to protect various diagnostics. supported by the Fundamental Research Funds for the Central Universities of China (No. ZYGX2015J108) and National Natural Science Foundation of China (Nos. 11575166 and 51581140)

The Design of New HIV-IN Tethered Bifunctional Inhibitors using Multiple Microdomain Targeted Docking.

PubMed

Ciubotaru, Mihai; Musat, Mihaela Georgiana; Surleac, Marius; Ionita, Elena; Petrescu, Andrei Jose; Abele, Edgars; Abele, Ramona

2018-04-05

Currently used antiretroviral HIV therapy drugs exclusively target critical groups in the enzymes essential for the viral life cycle. Increased mutagenesis of their genes, changes these viral enzymes which once mutated can evade therapeutic targeting, effects which confer drug resistance. To circumvent this, our review addresses a strategy to design and derive HIV-Integrase (HIV-IN) inhibitors which simultaneously target two IN functional domains, rendering it inactive even if the enzyme accumulates many mutations. First we review the enzymatic role of IN to insert the copied viral DNA into a chromosome of the host T lymphocyte, highlighting its main functional and structural features to be subjected to inhibitory action. From a functional and structural perspective we present all classes of HIV-IN inhibitors with their most representative candidates. For each chosen compound we also explain its mechanism of IN inhibition. We use the recently resolved cryo EM IN tetramer intasome DNA complex [1] onto which we dock various reference IN inhibitory chemical scaffolds such as to target adjacent functional IN domains. Pairing compounds with complementary activity, which dock in the vicinity of a IN structural microdomain, we design bifunctional new drugs which may not only be more resilient to IN mutations but also may be more potent inhibitors than their original counterparts. In the end of our review we propose synthesis pathways to link such paired compounds with enhanced synergistic IN inhibitory effects. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Design of the Blood Pressure Goals in Dialysis pilot study.

PubMed

Gul, Ambreen; Miskulin, Dana; Gassman, Jennifer; Harford, Antonia; Horowitz, Bruce; Chen, Joline; Paine, Susan; Bedrick, Edward; Kusek, John W; Unruh, Mark; Zager, Philip

2014-02-01

Cardiovascular disease (CVD) is markedly increased among hemodialysis (HD) patients. Optimizing blood pressure (BP) among HD patients may present an important opportunity to reduce the disparity in CVD rates between HD patients and the general population. The optimal target predialysis systolic BP (SBP) among HD patients is unknown. Current international guidelines, calling for a predialysis SBP < 140 mm Hg, are based on the opinion and extrapolation from the general population. Existing randomized controlled trials (RCTs) were small and did not include prespecified BP targets. The authors described the design of the Blood Pressure in Dialysis (BID) Study, a pilot, multicenter RCT where HD patients are randomized to either a target-standardized predialysis SBP of 110 to 140 mm Hg or 155 to 165 mm Hg. This is the first study to randomize HD patients to 2 different SBP targets. Primary outcomes are feasibility and safety. Feasibility parameters include recruitment and retention rates, adherence with prescribed BP measurements and achievement and maintenance of selected BP targets. Safety parameters include rates of hypotension and other adverse and serious adverse events. The authors obtained preliminary data on changes in left ventricular mass, aortic pulse wave velocity, vascular access thromboses and health-related quality of life across study arms, which may be the secondary outcomes in the full-scale study. The data acquired in the pilot RCT will determine the feasibility and safety and inform the design of a full-scale trial, powered for hard outcomes, which may require 2000 participants.

Improved InGaN LED System Efficacy and Cost via Droop Reduction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wildeson, Isaac

Efficiency droop is a non-thermal process intrinsic to indium gallium nitride light emitting diodes (LEDs) in which the external quantum efficiency (EQE) decreases with increasing drive current density. Mitigating droop would allow one to reduce the size of LEDs driven at a given current or to drive LEDs of given size at higher current while maintaining high efficiencies. In other words, droop mitigation can lead to significant gains in light output per dollar and/or light output per watt of input power. This project set an EQE improvement goal at high drive current density which was to be attained by improvingmore » the LED active region design and growth process following a droop mitigation strategy. The interactions between LED active region design parameters and efficiency droop were studied by modeling and experiments. The crystal defects that tend to form in more complex LED designs intended to mitigate droop were studied with advanced characterization methods that provided insight into the structural and electronic properties of the material. This insight was applied to improve the epitaxy process both in terms of active region design and optimization of growth parameters. The final project goals were achieved on schedule and an epitaxy process leading to LEDs with EQE exceeding the project target was demonstrated.« less

A biosensor generated via high throughput screening quantifies cell edge Src dynamics

PubMed Central

Gulyani, Akash; Vitriol, Eric; Allen, Richard; Wu, Jianrong; Gremyachinskiy, Dmitriy; Lewis, Steven; Dewar, Brian; Graves, Lee M.; Kay, Brian K.; Kuhlman, Brian; Elston, Tim; Hahn, Klaus M.

2011-01-01

Fluorescent biosensors for living cells currently require laborious optimization and a unique design for each target. They are limited by the availability of naturally occurring ligands with appropriate target specificity. Here we describe a biosensor based on an engineered fibronectin monobody scaffold that can be tailored to bind different targets via high throughput screening. This Src family kinase (SFK) biosensor was made by derivatizing a monobody specific for activated SFK with a bright dye whose fluorescence increases upon target binding. We identified sites for dye attachment and alterations to eliminate vesiculation in living cells, providing a generalizable scaffold for biosensor production. This approach minimizes cell perturbation because it senses endogenous, unmodified target, and because sensitivity is enhanced by direct dye excitation. Automated correlation of cell velocities and SFK activity revealed that SFK are activated specifically during protrusion. Activity correlates with velocity, and peaks 1–2 microns from the leading edge. PMID:21666688

megaTALs: a rare-cleaving nuclease architecture for therapeutic genome engineering.

PubMed

Boissel, Sandrine; Jarjour, Jordan; Astrakhan, Alexander; Adey, Andrew; Gouble, Agnès; Duchateau, Philippe; Shendure, Jay; Stoddard, Barry L; Certo, Michael T; Baker, David; Scharenberg, Andrew M

2014-02-01

Rare-cleaving endonucleases have emerged as important tools for making targeted genome modifications. While multiple platforms are now available to generate reagents for research applications, each existing platform has significant limitations in one or more of three key properties necessary for therapeutic application: efficiency of cleavage at the desired target site, specificity of cleavage (i.e. rate of cleavage at 'off-target' sites), and efficient/facile means for delivery to desired target cells. Here, we describe the development of a single-chain rare-cleaving nuclease architecture, which we designate 'megaTAL', in which the DNA binding region of a transcription activator-like (TAL) effector is used to 'address' a site-specific meganuclease adjacent to a single desired genomic target site. This architecture allows the generation of extremely active and hyper-specific compact nucleases that are compatible with all current viral and nonviral cell delivery methods.

Targeting cancer’s weaknesses (not its strengths): Therapeutic strategies suggested by the atavistic model

PubMed Central

Lineweaver, Charles H.; Davies, Paul C.W.; Vincent, Mark D.

2014-01-01

In the atavistic model of cancer progression, tumor cell dedifferentiation is interpreted as a reversion to phylogenetically earlier capabilities. The more recently evolved capabilities are compromised first during cancer progression. This suggests a therapeutic strategy for targeting cancer: design challenges to cancer that can only be met by the recently evolved capabilities no longer functional in cancer cells. We describe several examples of this target-the-weakness strategy. Our most detailed example involves the immune system. The absence of adaptive immunity in immunosuppressed tumor environments is an irreversible weakness of cancer that can be exploited by creating a challenge that only the presence of adaptive immunity can meet. This leaves tumor cells more vulnerable than healthy tissue to pathogenic attack. Such a target-the-weakness therapeutic strategy has broad applications, and contrasts with current therapies that target the main strength of cancer: cell proliferation. PMID:25043755

Bacterial Transcription as a Target for Antibacterial Drug Development

PubMed Central

Ma, Cong; Yang, Xiao

2016-01-01

SUMMARY Transcription, the first step of gene expression, is carried out by the enzyme RNA polymerase (RNAP) and is regulated through interaction with a series of protein transcription factors. RNAP and its associated transcription factors are highly conserved across the bacterial domain and represent excellent targets for broad-spectrum antibacterial agent discovery. Despite the numerous antibiotics on the market, there are only two series currently approved that target transcription. The determination of the three-dimensional structures of RNAP and transcription complexes at high resolution over the last 15 years has led to renewed interest in targeting this essential process for antibiotic development by utilizing rational structure-based approaches. In this review, we describe the inhibition of the bacterial transcription process with respect to structural studies of RNAP, highlight recent progress toward the discovery of novel transcription inhibitors, and suggest additional potential antibacterial targets for rational drug design. PMID:26764017

Measurement of the target current by inductive probe during laser interaction on terawatt laser system PALS.

PubMed

Cikhardt, J; Krása, J; De Marco, M; Pfeifer, M; Velyhan, A; Krouský, E; Cikhardtová, B; Klír, D; Rezáč, K; Ullschmied, J; Skála, J; Kubeš, P; Kravárik, J

2014-10-01

Measurements of the return-current flowing through a solid target irradiated with the sub-nanosecond kJ-class Prague Asterix Laser System is reported. A new inductive target probe was developed which allows us measuring the target current derivative in a kA/ns range. The dependences of the target current on the laser pulse energy for cooper, graphite, and polyethylene targets are reported. The experiment shows that the target current is proportional to the deposited laser energy and is strongly affected by the shot-to-shot fluctuations. The corresponding maximum target charge exceeded a value of 10 μC. A return-current dependence of the electromagnetic pulse produced by the laser-target interaction is presented.

FINAL TECHNICAL REPORT: Underwater Active Acoustic Monitoring Network For Marine And Hydrokinetic Energy Projects

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stein, Peter J.; Edson, Patrick L.

2013-12-20

This project saw the completion of the design and development of a second generation, high frequency (90-120 kHz) Subsurface-Threat Detection Sonar Network (SDSN). The system was deployed, operated, and tested in Cobscook Bay, Maine near the site the Ocean Renewable Power Company TidGen™ power unit. This effort resulted in a very successful demonstration of the SDSN detection, tracking, localization, and classification capabilities in a high current, MHK environment as measured by results from the detection and tracking trials in Cobscook Bay. The new high frequency node, designed to operate outside the hearing range of a subset of marine mammals, wasmore » shown to detect and track objects of marine mammal-like target strength to ranges of approximately 500 meters. This performance range results in the SDSN system tracking objects for a significant duration - on the order of minutes - even in a tidal flow of 5-7 knots, potentially allowing time for MHK system or operator decision-making if marine mammals are present. Having demonstrated detection and tracking of synthetic targets with target strengths similar to some marine mammals, the primary hurdle to eventual automated monitoring is a dataset of actual marine mammal kinematic behavior and modifying the tracking algorithms and parameters which are currently tuned to human diver kinematics and classification.« less

Considerations for biomarker-targeted intervention strategies for tuberculosis disease prevention.

PubMed

Fiore-Gartland, Andrew; Carpp, Lindsay N; Naidoo, Kogieleum; Thompson, Ethan; Zak, Daniel E; Self, Steve; Churchyard, Gavin; Walzl, Gerhard; Penn-Nicholson, Adam; Scriba, Thomas J; Hatherill, Mark

2018-03-01

Current diagnostic tests for Mycobacterium tuberculosis (MTB) infection have low prognostic specificity for identifying individuals who will develop tuberculosis (TB) disease, making mass preventive therapy strategies targeting all MTB-infected individuals impractical in high-burden TB countries. Here we discuss general considerations for a risk-targeted test-and-treat strategy based on a highly specific transcriptomic biomarker that can identify individuals who are most likely to progress to active TB disease as well as individuals with TB disease who have not yet presented for medical care. Such risk-targeted strategies may offer a rapid, ethical and cost-effective path towards decreasing the burden of TB disease and interrupting transmission and would also be critical to achieving TB elimination in countries nearing elimination. We also discuss design considerations for a Correlate of Risk Targeted Intervention Study (CORTIS), which could provide proof-of-concept for the strategy. One such study in South Africa is currently enrolling 1500 high-risk and 1700 low-risk individuals, as defined by biomarker status, and is randomizing high-risk participants to TB preventive therapy or standard of care treatment. All participants are monitored for progression to active TB with primary objectives to assess efficacy of the treatment and performance of the biomarker. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Receptor-mediated gene transfer vectors: progress towards genetic pharmaceuticals.

PubMed

Molas, M; Gómez-Valadés, A G; Vidal-Alabró, A; Miguel-Turu, M; Bermudez, J; Bartrons, R; Perales, J C

2003-10-01

Although specific delivery to tissues and unique cell types in vivo has been demonstrated for many non-viral vectors, current methods are still inadequate for human applications, mainly because of limitations on their efficiencies. All the steps required for an efficient receptor-mediated gene transfer process may in principle be exploited to enhance targeted gene delivery. These steps are: DNA/vector binding, internalization, subcellular trafficking, vesicular escape, nuclear import, and unpacking either for transcription or other functions (i.e., antisense, RNA interference, etc.). The large variety of vector designs that are currently available, usually aimed at improving the efficiency of these steps, has complicated the evaluation of data obtained from specific derivatives of such vectors. The importance of the structure of the final vector and the consequences of design decisions at specific steps on the overall efficiency of the vector will be discussed in detail. We emphasize in this review that stability in serum and thus, proper bioavailability of vectors to their specific receptors may be the single greatest limiting factor on the overall gene transfer efficiency in vivo. We discuss current approaches to overcome the intrinsic instability of synthetic vectors in the blood. In this regard, a summary of the structural features of the vectors obtained from current protocols will be presented and their functional characteristics evaluated. Dissecting information on molecular conjugates obtained by such methodologies, when carefully evaluated, should provide important guidelines for the creation of effective, targeted and safe DNA therapeutics.

Transcranial current stimulation focality using disc and ring electrode configurations: FEM analysis

NASA Astrophysics Data System (ADS)

Datta, Abhishek; Elwassif, Maged; Battaglia, Fortunato; Bikson, Marom

2008-06-01

We calculated the electric fields induced in the brain during transcranial current stimulation (TCS) using a finite-element concentric spheres human head model. A range of disc electrode configurations were simulated: (1) distant-bipolar; (2) adjacent-bipolar; (3) tripolar; and three ring designs, (4) belt, (5) concentric ring, and (6) double concentric ring. We compared the focality of each configuration targeting cortical structures oriented normal to the surface ('surface-radial' and 'cross-section radial'), cortical structures oriented along the brain surface ('surface-tangential' and 'cross-section tangential') and non-oriented cortical surface structures ('surface-magnitude' and 'cross-section magnitude'). For surface-radial fields, we further considered the 'polarity' of modulation (e.g. superficial cortical neuron soma hyper/depolarizing). The distant-bipolar configuration, which is comparable with commonly used TCS protocols, resulted in diffuse (un-focal) modulation with bi-directional radial modulation under each electrode and tangential modulation between electrodes. Increasing the proximity of the two electrodes (adjacent-bipolar electrode configuration) increased focality, at the cost of more surface current. At similar electrode distances, the tripolar-electrodes configuration produced comparable peak focality, but reduced radial bi-directionality. The concentric-ring configuration resulted in the highest spatial focality and uni-directional radial modulation, at the expense of increased total surface current. Changing ring dimensions, or use of two concentric rings, allow titration of this balance. The concentric-ring design may thus provide an optimized configuration for targeted modulation of superficial cortical neurons.

The genetics of age-related macular degeneration (AMD)--Novel targets for designing treatment options?

PubMed

Grassmann, Felix; Fauser, Sascha; Weber, Bernhard H F

2015-09-01

Age-related macular degeneration (AMD) is a progressive disease of the central retina and the main cause of legal blindness in industrialized countries. Risk to develop the disease is conferred by both individual as well as genetic factors with the latter being increasingly deciphered over the last decade. Therapeutically, striking advances have been made for the treatment of the neovascular form of late stage AMD while for the late stage atrophic form of the disease, which accounts for almost half of the visually impaired, there is currently no effective therapy on the market. This review highlights our current knowledge on the genetic architecture of early and late stage AMD and explores its potential for the discovery of novel, target-guided treatment options. We reflect on current clinical and experimental therapies for all forms of AMD and specifically note a persisting lack of efficacy for treatment in atrophic AMD. We further explore the current insight in AMD-associated genes and pathways and critically question whether this knowledge is suited to design novel treatment options. Specifically, we point out that known genetic factors associated with AMD govern the risk to develop disease and thus may not play a role in its severity or progression. Treatments based on such knowledge appear appropriate rather for prevention than treatment of manifest disease. As a consequence, future research in AMD needs to be greatly focused on approaches relevant to the patients and their medical needs. Copyright © 2015 Elsevier B.V. All rights reserved.

Seat Capacity Selection for an Advanced Short-Haul Aircraft Design

NASA Technical Reports Server (NTRS)

Marien, Ty V.

2016-01-01

A study was performed to determine the target seat capacity for a proposed advanced short-haul aircraft concept projected to enter the fleet by 2030. This analysis projected the potential demand in the U.S. for a short-haul aircraft using a transportation theory approach, rather than selecting a target seat capacity based on recent industry trends or current market demand. A transportation systems model was used to create a point-to-point network of short-haul trips and then predict the number of annual origin-destination trips on this network. Aircraft of varying seat capacities were used to meet the demand on this network, assuming a single aircraft type for the entire short-haul fleet. For each aircraft size, the ticket revenue and operational costs were used to calculate a total market profitability metric for all feasible flights. The different aircraft sizes were compared, based on this market profitability metric and also the total number of annual round trips and markets served. Sensitivity studies were also performed to determine the effect of changing the aircraft cruise speed and maximum trip length. Using this analysis, the advanced short-haul aircraft design team was able to select a target seat capacity for their design.

Modulation of Insulin-Like Growth Factor-1 Receptor and its Signaling Network for the Treatment of Cancer: Current Status and Future Perspectives

PubMed Central

Jin, Meizhong; Buck, Elizabeth; Mulvihill, Mark J.

2013-01-01

Based on over three decades of pre-clinical data, insulin-like growth factor-1 receptor (IGF-1R) signaling has gained recognition as a promoter of tumorogenesis, driving cell survival and proliferation in multiple human cancers. As a result, IGF-1R has been pursued as a target for cancer treatment. Early pioneering efforts targeting IGF-1R focused on highly selective monoclonal antibodies, with multiple agents advancing to clinical trials. However, despite some initial promising results, recent clinical disclosures have been less encouraging. Moreover, recent studies have revealed that IGF-1R participates in a dynamic and complex signaling network, interacting with additional targets and pathways thereof through various crosstalk and compensatory signaling mechanisms. Such mechanisms of bypass signaling help to shed some light on the decreased effectiveness of selective IGF-1R targeted therapies (e.g. monoclonal antibodies) and suggest that targeting multiple nodes within this signaling network might be necessary to produce a more effective therapeutic response. Additionally, such findings have led to the development of small molecule IGF-1R inhibitors which also co-inhibit additional targets such as insulin receptor and epidermal growth factor receptor. Such findings have helped to guide the design rationale of numerous drug combinations that are currently being evaluated in clinical trials. PMID:25992224

Electromagnetic characteristics of eccentric figure-eight coils for transcranial magnetic stimulation: A numerical study

NASA Astrophysics Data System (ADS)

Kato, Takuya; Sekino, Masaki; Matsuzaki, Taiga; Nishikawa, Atsushi; Saitoh, Youichi; Ohsaki, Hiroyuki

2012-04-01

Repetitive transcranial magnetic stimulation (rTMS) is effective for treatment of several neurological and psychiatric diseases. We proposed an eccentric figure-eight coil, which induces strong eddy currents in the target brain tissue. In this study, numerical analyses were carried out to obtain magnetic field distribution of the eccentric figure-eight coil and eddy current in the brain. The analyses were performed with various coil design parameters, such as the outer and inner diameters and number of turns, to investigate the influence of these parameters on the coil characteristics. Increases in the inner diameter, outer diameter, and number of turns caused increases in the maximum eddy current densities. Coil inductance, working voltage, and heat generation also became higher with the increases in these design parameters. In order to develop a compact stimulator system for use at home, we need to obtain strong eddy current density, keeping the working voltage as low as possible. Our results show that it is effective to enlarge the outer diameter.

The British National Formulary: Checking, medicines and clinicians.

PubMed

Dickson, Jane

2015-01-01

The British National Formulary underpins the way medical practice is made safe in the UK. Its move from book to digital product has been identified as welcome but with problematic aspects. This chapter describes and investigates the current use of the formulary in order to examine how a rapid, well-targeted project is designed and executed.

Focus Framework: A New Guideline for Presenting and Evaluating Lexical Contents in ELT Materials

ERIC Educational Resources Information Center

Zarifi, Abdolvahed

2015-01-01

Despite the not-so-distant negligence of lexicon in language instruction, it is currently taking on a core role in designing ELT materials. Selection of the lexical content is usually informed by a set of pedagogical and non-pedagogical factors like learnability, usefulness, the level of proficiency targeted, frequency, range, coverage, etc. With…

Emotional and Narrative Responses of Students to Targeted Educational Experiences: An Exploratory Study Employing the Use of Emotional Measurement

ERIC Educational Resources Information Center

Mudge, Suzanne D.; Grinnan, Cullen T.; Priesmeyer, H. Richard

2006-01-01

Current educational research suggests that emotions can either enhance or inhibit the ability to learn, with social and cultural influences causing changes in behavior and altering biological processes. In this exploratory study researchers utilized a qualitative design to seek insight into student emotions associated with school attitude and…

Influence of Conduct Problems and Depressive Symptomatology on Adolescent Substance Use: Developmentally Proximal versus Distal Effects

ERIC Educational Resources Information Center

Maslowsky, Julie; Schulenberg, John E.; Zucker, Robert A.

2014-01-01

The identification of developmentally specific windows at which key predictors of adolescent substance use are most influential is a crucial task for informing the design of appropriately targeted substance use prevention and intervention programs. The current study examined effects of conduct problems and depressive symptomatology on changes in…

Cell cycle-tailored targeting of metastatic melanoma: Challenges and opportunities.

PubMed

Haass, Nikolas K; Gabrielli, Brian

2017-07-01

The advent of targeted therapies of metastatic melanoma, such as MAPK pathway inhibitors and immune checkpoint antagonists, has turned dermato-oncology from the "bad guy" to the "poster child" in oncology. Current targeted therapies are effective, although here is a clear need to develop combination therapies to delay the onset of resistance. Many antimelanoma drugs impact on the cell cycle but are also dependent on certain cell cycle phases resulting in cell cycle phase-specific drug insensitivity. Here, we raise the question: Have combination trials been abandoned prematurely as ineffective possibly only because drug scheduling was not optimized? Firstly, if both drugs of a combination hit targets in the same melanoma cell, cell cycle-mediated drug insensitivity should be taken into account when planning combination therapies, timing of dosing schedules and choice of drug therapies in solid tumors. Secondly, if the combination is designed to target different tumor cell subpopulations of a heterogeneous tumor, one drug effective in a particular subpopulation should not negatively impact on the other drug targeting another subpopulation. In addition to the role of cell cycle stage and progression on standard chemotherapeutics and targeted drugs, we discuss the utilization of cell cycle checkpoint control defects to enhance chemotherapeutic responses or as targets themselves. We propose that cell cycle-tailored targeting of metastatic melanoma could further improve therapy outcomes and that our real-time cell cycle imaging 3D melanoma spheroid model could be utilized as a tool to measure and design drug scheduling approaches. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

A Research Agenda for Malaria Eradication: Vaccines

PubMed Central

2011-01-01

Vaccines could be a crucial component of efforts to eradicate malaria. Current attempts to develop malaria vaccines are primarily focused on Plasmodium falciparum and are directed towards reducing morbidity and mortality. Continued support for these efforts is essential, but if malaria vaccines are to be used as part of a repertoire of tools for elimination or eradication of malaria, they will need to have an impact on malaria transmission. We introduce the concept of “vaccines that interrupt malaria transmission” (VIMT), which includes not only “classical” transmission-blocking vaccines that target the sexual and mosquito stages but also pre-erythrocytic and asexual stage vaccines that have an effect on transmission. VIMT may also include vaccines that target the vector to disrupt parasite development in the mosquito. Importantly, if eradication is to be achieved, malaria vaccine development efforts will need to target other malaria parasite species, especially Plasmodium vivax, where novel therapeutic vaccines against hypnozoites or preventive vaccines with effect against multiple stages could have enormous impact. A target product profile (TPP) for VIMT is proposed and a research agenda to address current knowledge gaps and develop tools necessary for design and development of VIMT is presented. PMID:21311586

A research agenda for malaria eradication: vaccines.

PubMed

2011-01-25

Vaccines could be a crucial component of efforts to eradicate malaria. Current attempts to develop malaria vaccines are primarily focused on Plasmodium falciparum and are directed towards reducing morbidity and mortality. Continued support for these efforts is essential, but if malaria vaccines are to be used as part of a repertoire of tools for elimination or eradication of malaria, they will need to have an impact on malaria transmission. We introduce the concept of "vaccines that interrupt malaria transmission" (VIMT), which includes not only "classical" transmission-blocking vaccines that target the sexual and mosquito stages but also pre-erythrocytic and asexual stage vaccines that have an effect on transmission. VIMT may also include vaccines that target the vector to disrupt parasite development in the mosquito. Importantly, if eradication is to be achieved, malaria vaccine development efforts will need to target other malaria parasite species, especially Plasmodium vivax, where novel therapeutic vaccines against hypnozoites or preventive vaccines with effect against multiple stages could have enormous impact. A target product profile (TPP) for VIMT is proposed and a research agenda to address current knowledge gaps and develop tools necessary for design and development of VIMT is presented.

TARGETED SEQUENTIAL DESIGN FOR TARGETED LEARNING INFERENCE OF THE OPTIMAL TREATMENT RULE AND ITS MEAN REWARD.

PubMed

Chambaz, Antoine; Zheng, Wenjing; van der Laan, Mark J

2017-01-01

This article studies the targeted sequential inference of an optimal treatment rule (TR) and its mean reward in the non-exceptional case, i.e. , assuming that there is no stratum of the baseline covariates where treatment is neither beneficial nor harmful, and under a companion margin assumption. Our pivotal estimator, whose definition hinges on the targeted minimum loss estimation (TMLE) principle, actually infers the mean reward under the current estimate of the optimal TR. This data-adaptive statistical parameter is worthy of interest on its own. Our main result is a central limit theorem which enables the construction of confidence intervals on both mean rewards under the current estimate of the optimal TR and under the optimal TR itself. The asymptotic variance of the estimator takes the form of the variance of an efficient influence curve at a limiting distribution, allowing to discuss the efficiency of inference. As a by product, we also derive confidence intervals on two cumulated pseudo-regrets, a key notion in the study of bandits problems. A simulation study illustrates the procedure. One of the corner-stones of the theoretical study is a new maximal inequality for martingales with respect to the uniform entropy integral.

Guidance and Navigation for Rendezvous and Proximity Operations with a Non-Cooperative Spacecraft at Geosynchronous Orbit

NASA Technical Reports Server (NTRS)

Barbee, Brent William; Carpenter, J. Russell; Heatwole, Scott; Markley, F. Landis; Moreau, Michael; Naasz, Bo J.; VanEepoel, John

2010-01-01

The feasibility and benefits of various spacecraft servicing concepts are currently being assessed, and all require that the servicer spacecraft perform rendezvous, proximity, and capture operations with the target spacecraft to be serviced. Many high-value spacecraft, which would be logical targets for servicing from an economic point of view, are located in geosynchronous orbit, a regime in which autonomous rendezvous and capture operations are not commonplace. Furthermore, existing GEO spacecraft were not designed to be serviced. Most do not have cooperative relative navigation sensors or docking features, and some servicing applications, such as de-orbiting of a non-functional spacecraft, entail rendezvous and capture with a spacecraft that may be non-functional or un-controlled. Several of these challenges have been explored via the design of a notional mission in which a nonfunctional satellite in geosynchronous orbit is captured by a servicer spacecraft and boosted into super-synchronous orbit for safe disposal. A strategy for autonomous rendezvous, proximity operations, and capture is developed, and the Orbit Determination Toolbox (ODTBX) is used to perform a relative navigation simulation to assess the feasibility of performing the rendezvous using a combination of angles-only and range measurements. Additionally, a method for designing efficient orbital rendezvous sequences for multiple target spacecraft is utilized to examine the capabilities of a servicer spacecraft to service multiple targets during the course of a single mission.

ATR architecture for multisensor fusion

NASA Astrophysics Data System (ADS)

Hamilton, Mark K.; Kipp, Teresa A.

1996-06-01

The work of the U.S. Army Research Laboratory (ARL) in the area of algorithms for the identification of static military targets in single-frame electro-optical (EO) imagery has demonstrated great potential in platform-based automatic target identification (ATI). In this case, the term identification is used to mean being able to tell the difference between two military vehicles -- e.g., the M60 from the T72. ARL's work includes not only single-sensor forward-looking infrared (FLIR) ATI algorithms, but also multi-sensor ATI algorithms. We briefly discuss ARL's hybrid model-based/data-learning strategy for ATI, which represents a significant step forward in ATI algorithm design. For example, in the case of single sensor FLIR it allows the human algorithm designer to build directly into the algorithm knowledge that can be adequately modeled at this time, such as the target geometry which directly translates into the target silhouette in the FLIR realm. In addition, it allows structure that is not currently well understood (i.e., adequately modeled) to be incorporated through automated data-learning algorithms, which in a FLIR directly translates into an internal thermal target structure signature. This paper shows the direct applicability of this strategy to both the single-sensor FLIR as well as the multi-sensor FLIR and laser radar.

Optimal design of reflectometer density profile measurements using a radar systems approach (invited) (abstract)

NASA Astrophysics Data System (ADS)

Doyle, E. J.; Kim, K. W.; Peebles, W. A.; Rhodes, T. L.

1997-01-01

Reflectometry is an attractive and versatile diagnostic technique that can address a wide range of measurement needs on fusion devices. However, progress in the area of profile measurement has been hampered by the lack of a well-understood basis for the optimum design and implementation of such systems. Such a design basis is provided by the realization that reflectometer systems utilized for density profile measurements are in fact specialized forms of radar systems. In this article five criteria are introduced by which reflectometer systems can be systematically designed for optimal performance: range resolution, spatial sampling, turbulence immunity, bandwidth optimization, and the need for adaptive data processing. Many of these criteria are familiar from radar systems analysis, and are applicable to reflectometry after allowance is made for differences stemming from the nature of the plasma target. These criteria are utilized to critically evaluate current reflectometer density profile techniques and indicate improvements that can impact current and next step devices, such as ITER.

Applying visual attention theory to transportation safety research and design: evaluation of alternative automobile rear lighting systems.

PubMed

McIntyre, Scott E; Gugerty, Leo

2014-06-01

This field experiment takes a novel approach in applying methodologies and theories of visual search to the subject of conspicuity in automobile rear lighting. Traditional rear lighting research has not used the visual search paradigm in experimental design. It is our claim that the visual search design uniquely uncovers visual attention processes operating when drivers search the visual field that current designs fail to capture. This experiment is a validation and extension of previous simulator research on this same topic and demonstrates that detection of red automobile brake lamps will be improved if tail lamps are another color (in this test, amber) rather than the currently mandated red. Results indicate that when drivers miss brake lamp onset in low ambient light, RT and error are reduced in detecting the presence and absence of red brake lamps with multiple lead vehicles when tail lamps are not red compared to current rear lighting which mandates red tail lamps. This performance improvement is attributed to efficient visual processing that automatically segregates tail (amber) and brake (red) lamp colors into distractors and targets respectively. Copyright © 2014 Elsevier Ltd. All rights reserved.

Innovations in compact stellarator coil design

NASA Astrophysics Data System (ADS)

Pomphrey, N.; Berry, L.; Boozer, A.; Brooks, A.; Hatcher, R. E.; Hirshman, S. P.; Ku, L.-P.; Miner, W. H.; Mynick, H. E.; Reiersen, W.; Strickler, D. J.; Valanju, P. M.

2001-03-01

Experimental devices for the study of the physics of high beta (β gtrsim 4%), low aspect ratio (A lesssim 4.5) stellarator plasmas require coils that will produce plasmas satisfying a set of physics goals, provide experimental flexibility and be practical to construct. In the course of designing a flexible coil set for the National Compact Stellarator Experiment, several innovations have been made that may be useful in future stellarator design efforts. These include: the use of singular value decomposition methods for obtaining families of smooth current potentials on distant coil winding surfaces from which low current density solutions may be identified; the use of a control matrix method for identifying which few of the many detailed elements of a stellarator boundary must be targeted if a coil set is to provide fields to control the essential physics of the plasma; the use of a genetic algorithm for choosing an optimal set of discrete coils from a continuum of potential contours; the evaluation of alternate coil topologies for balancing the trade-off between physics objectives and engineering constraints; the development of a new coil optimization code for designing modular coils and the identification of a `natural' basis for describing current sheet distributions.

Targeted nanomedicine for cancer therapeutics: Towards precision medicine overcoming drug resistance.

PubMed

Bar-Zeev, Maya; Livney, Yoav D; Assaraf, Yehuda G

2017-03-01

Intrinsic anticancer drug resistance appearing prior to chemotherapy as well as acquired resistance due to drug treatment, remain the dominant impediments towards curative cancer therapy. Hence, novel targeted strategies to overcome cancer drug resistance constitute a key aim of cancer research. In this respect, targeted nanomedicine offers innovative therapeutic strategies to overcome the various limitations of conventional chemotherapy, enabling enhanced selectivity, early and more precise cancer diagnosis, individualized treatment as well as overcoming of drug resistance, including multidrug resistance (MDR). Delivery systems based on nanoparticles (NPs) include diverse platforms enabling a plethora of rationally designed therapeutic nanomedicines. Here we review NPs designed to enhance antitumor drug uptake and selective intracellular accumulation using strategies including passive and active targeting, stimuli-responsive drug activation or target-activated release, triggered solely in the cancer cell or in specific organelles, cutting edge theranostic multifunctional NPs delivering drug combinations for synergistic therapy, while facilitating diagnostics, and personalization of therapeutic regimens. In the current paper we review the recent findings of the past four years and discuss the advantages and limitations of the various novel NPs-based drug delivery systems. Special emphasis is put on in vivo study-based evidences supporting significant therapeutic impact in chemoresistant cancers. A future perspective is proposed for further research and development of complex targeted, multi-stage responsive nanomedical drug delivery systems for personalized cancer diagnosis and efficacious therapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Interception of LPI radar signals

NASA Astrophysics Data System (ADS)

Lee, Jim P.

1991-11-01

Most current radars are designed to transmit short duration pulses with relatively high peak power. These radars can be detected easily by the use of relatively modest EW intercept receivers. Three radar functions (search, anti-ship missile (ASM) seeker, and navigation) are examined to evaluate the effectiveness of potential low probability of intercept (LPI) techniques, such as waveform coding, antenna profile control, and power management that a radar may employ against current Electronic Warfare (EW) receivers. The general conclusion is that it is possible to design a LPI radar which is effective against current intercept EW receivers. LPI operation is most easily achieved at close ranges and against a target with a large radar cross section. The general system sensitivity requirement for the detection of current and projected LPI radars is found to be on the order of -100 dBmi which cannot be met by current EW receivers. Finally, three potential LPI receiver architectures, using channelized, superhet, and acousto-optic receivers with narrow RF and video bandwidths are discussed. They have shown some potential in terms of providing the sensitivity and capability in an environment where both conventional and LPI signals are present.

Studies of Short Time Response Options for Potentially Hazardous Objects: Current and Forthcoming Results

NASA Technical Reports Server (NTRS)

Barbee, Brent W.; Greenaugh, Kevin C.; Seery, Bernard D.; Bambacus, Myra; Leung, Ronald Y.; Finewood, Lee; Dearborn, David S. P.; Miller, Paul L.; Weaver, Robert P.; Plesko, Catherine;

Spatial and polarity precision of concentric high-definition transcranial direct current stimulation (HD-tDCS).

PubMed

Alam, Mahtab; Truong, Dennis Q; Khadka, Niranjan; Bikson, Marom

2016-06-21

Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique that applies low amplitude current via electrodes placed on the scalp. Rather than directly eliciting a neuronal response, tDCS is believed to modulate excitability-enhancing or suppressing neuronal activity in regions of the brain depending on the polarity of stimulation. The specificity of tDCS to any therapeutic application derives in part from how electrode configuration determines the brain regions that are stimulated. Conventional tDCS uses two relatively large pads (>25 cm(2)) whereas high-definition tDCS (HD-tDCS) uses arrays of smaller electrodes to enhance brain targeting. The 4  ×  1 concentric ring HD-tDCS (one center electrode surrounded by four returns) has been explored in application where focal targeting of cortex is desired. Here, we considered optimization of concentric ring HD-tDCS for targeting: the role of electrodes in the ring and the ring's diameter. Finite element models predicted cortical electric field generated during tDCS. High resolution MRIs were segmented into seven tissue/material masks of varying conductivities. Computer aided design (CAD) model of electrodes, gel, and sponge pads were incorporated into the segmentation. Volume meshes were generated and the Laplace equation ([Formula: see text] · (σ [Formula: see text] V)  =  0) was solved for cortical electric field, which was interpreted using physiological assumptions to correlate with stimulation and modulation. Cortical field intensity was predicted to increase with increasing ring diameter at the cost of focality while uni-directionality decreased. Additional surrounding ring electrodes increased uni-directionality while lowering cortical field intensity and increasing focality; though, this effect saturated and more than 4 surround electrode would not be justified. Using a range of concentric HD-tDCS montages, we showed that cortical region of influence can be controlled while balancing other design factors such as intensity at the target and uni-directionality. Furthermore, the evaluated concentric HD-tDCS approaches can provide categorical improvements in targeting compared to conventional tDCS. Hypothesis driven clinical trials, based on specific target engagement, would benefit by this more precise method of stimulation that could avoid potentially confounding brain regions.

Design challenges in nanoparticle-based platforms: Implications for targeted drug delivery systems

NASA Astrophysics Data System (ADS)

Mullen, Douglas Gurnett

Characterization and control of heterogeneous distributions of nanoparticle-ligand components are major design challenges for nanoparticle-based platforms. This dissertation begins with an examination of poly(amidoamine) (PAMAM) dendrimer-based targeted delivery platform. A folic acid targeted modular platform was developed to target human epithelial cancer cells. Although active targeting was observed in vitro, active targeting was not found in vivo using a mouse tumor model. A major flaw of this platform design was that it did not provide for characterization or control of the component distribution. Motivated by the problems experienced with the modular design, the actual composition of nanoparticle-ligand distributions were examined using a model dendrimer-ligand system. High Pressure Liquid Chromatography (HPLC) resolved the distribution of components in samples with mean ligand/dendrimer ratios ranging from 0.4 to 13. A peak fitting analysis enabled the quantification of the component distribution. Quantified distributions were found to be significantly more heterogeneous than commonly expected and standard analytical parameters, namely the mean ligand/nanoparticle ratio, failed to adequately represent the component heterogeneity. The distribution of components was also found to be sensitive to particle modifications that preceded the ligand conjugation. With the knowledge gained from this detailed distribution analysis, a new platform design was developed to provide a system with dramatically improved control over the number of components and with improved batch reproducibility. Using semi-preparative HPLC, individual dendrimer-ligand components were isolated. The isolated dendrimer with precise numbers of ligands were characterized by NMR and analytical HPLC. In total, nine different dendrimer-ligand components were obtained with degrees of purity ≥80%. This system has the potential to serve as a platform to which a precise number of functional molecules can be attached and has the potential to dramatically improve platform efficacy. An additional investigation of reproducibility challenges for current dendrimer-based platform designs is also described. The mass transport quality during the partial acetylation reaction of the dendrimer was found to have a major impact on subsequent dendrimer-ligand distributions that cannot be detected by standard analytical techniques. Consequently, this reaction should be eliminated from the platform design. Finally, optimized protocols for purification and characterization of PAMAM dendrimer were detailed.

Born approximation, multiple scattering, and butterfly algorithm

NASA Astrophysics Data System (ADS)

Martinez, Alex; Qiao, Zhijun

2014-06-01

Many imaging algorithms have been designed assuming the absence of multiple scattering. In the 2013 SPIE proceeding, we discussed an algorithm for removing high order scattering components from collected data. In this paper, our goal is to continue this work. First, we survey the current state of multiple scattering in SAR. Then, we revise our method and test it. Given an estimate of our target reflectivity, we compute the multi scattering effects in our target region for various frequencies. Furthermore, we propagate this energy through free space towards our antenna, and remove it from the collected data.

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

NASA Astrophysics Data System (ADS)

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.

Colon-targeted oral drug delivery systems: design trends and approaches.

PubMed

Amidon, Seth; Brown, Jack E; Dave, Vivek S

2015-08-01

Colon-specific drug delivery systems (CDDS) are desirable for the treatment of a range of local diseases such as ulcerative colitis, Crohn's disease, irritable bowel syndrome, chronic pancreatitis, and colonic cancer. In addition, the colon can be a potential site for the systemic absorption of several drugs to treat non-colonic conditions. Drugs such as proteins and peptides that are known to degrade in the extreme gastric pH, if delivered to the colon intact, can be systemically absorbed by colonic mucosa. In order to achieve effective therapeutic outcomes, it is imperative that the designed delivery system specifically targets the drugs into the colon. Several formulation approaches have been explored in the development colon-targeted drug delivery systems. These approaches involve the use of formulation components that interact with one or more aspects of gastrointestinal (GI) physiology, such as the difference in the pH along the GI tract, the presence of colonic microflora, and enzymes, to achieve colon targeting. This article highlights the factors influencing colon-specific drug delivery and colonic bioavailability, and the limitations associated with CDDS. Further, the review provides a systematic discussion of various conventional, as well as relatively newer formulation approaches/technologies currently being utilized for the development of CDDS.

Bioavailability and transport of peptides and peptide drugs into the brain.

PubMed

Egleton, R D; Davis, T P

1997-01-01

Rational drug design and the targeting of specific organs has become a reality in modern drug development, with the emergence of molecular biology and receptor chemistry as powerful tools for the pharmacologist. A greater understanding of peptide function as one of the major extracellular message systems has made neuropeptides an important target in neuropharmaceutical drug design. The major obstacle to targeting the brain with therapeutics is the presence of the blood-brain barrier (BBB), which controls the concentration and entry of solutes into the central nervous system. Peptides are generally polar in nature, do not easily cross the blood-brain barrier by diffusion, and except for a small number do not have specific transport systems. Peptides can also undergo metabolic deactivation by peptidases of the blood, brain and the endothelial cells that comprise the BBB. In this review, we discuss a number of the recent strategies which have been used to promote peptide stability and peptide entry into the brain. In addition, we approach the subject of targeting specific transport systems that can be found on the brain endothelial cells, and describe the limitations of the methodologies that are currently used to study brain entry of neuropharmaceuticals.

Computational investigation of reshock strength in hydrodynamic instability growth at the National Ignition Facility

NASA Astrophysics Data System (ADS)

Bender, Jason; Raman, Kumar; Huntington, Channing; Nagel, Sabrina; Morgan, Brandon; Prisbrey, Shon; MacLaren, Stephan

2017-10-01

Experiments at the National Ignition Facility (NIF) are studying Richtmyer-Meshkov and Rayleigh-Taylor hydrodynamic instabilities in multiply-shocked plasmas. Targets feature two different-density fluids with a multimode initial perturbation at the interface, which is struck by two X-ray-driven shock waves. Here we discuss computational hydrodynamics simulations investigating the effect of second-shock (``reshock'') strength on instability growth, and how these simulations are informing target design for the ongoing experimental campaign. A Reynolds-Averaged Navier Stokes (RANS) model was used to predict motion of the spike and bubble fronts and the mixing-layer width. In addition to reshock strength, the reshock ablator thickness and the total length of the target were varied; all three parameters were found to be important for target design, particularly for ameliorating undesirable reflected shocks. The RANS data are compared to theoretical models that predict multimode instability growth proportional to the shock-induced change in interface velocity, and to currently-available data from the NIF experiments. Work performed under the auspices of the U.S. D.O.E. by Lawrence Livermore National Laboratory under Contract No. DE-AC52-07NA27344. LLNL-ABS-734611.

Stable Gene Targeting in Human Cells Using Single-Strand Oligonucleotides with Modified Bases

PubMed Central

Rios, Xavier; Briggs, Adrian W.; Christodoulou, Danos; Gorham, Josh M.; Seidman, Jonathan G.; Church, George M.

2012-01-01

Recent advances allow multiplexed genome engineering in E. coli, employing easily designed oligonucleotides to edit multiple loci simultaneously. A similar technology in human cells would greatly expedite functional genomics, both by enhancing our ability to test how individual variants such as single nucleotide polymorphisms (SNPs) are related to specific phenotypes, and potentially allowing simultaneous mutation of multiple loci. However, oligo-mediated targeting of human cells is currently limited by low targeting efficiencies and low survival of modified cells. Using a HeLa-based EGFP-rescue reporter system we show that use of modified base analogs can increase targeting efficiency, in part by avoiding the mismatch repair machinery. We investigate the effects of oligonucleotide toxicity and find a strong correlation between the number of phosphorothioate bonds and toxicity. Stably EGFP-corrected cells were generated at a frequency of ~0.05% with an optimized oligonucleotide design combining modified bases and reduced number of phosphorothioate bonds. We provide evidence from comparative RNA-seq analysis suggesting cellular immunity induced by the oligonucleotides might contribute to the low viability of oligo-corrected cells. Further optimization of this method should allow rapid and scalable genome engineering in human cells. PMID:22615794

Towards a Chlamydia trachomatis vaccine: how close are we?

PubMed

Cochrane, Melanie; Armitage, Charles W; O'Meara, Connor P; Beagley, Kenneth W

2010-12-01

Chlamydia trachomatis is the leading cause of bacterial sexually transmitted infections and preventable blindness worldwide. The incidence of chlamydial sexually transmitted infections has increased rapidly and current antibiotic therapy has failed as an intervention strategy. The most accepted strategy for protection and/or control of chlamydial infections is a vaccine that induces both local neutralizing antibodies to prevent infections by the extracellular elementary bodies and a cell-mediated immune response to target the intracellular infection. This article will discuss the challenges in vaccine design for the prevention of chlamydial urogenital infection and/or disease, including selection of target antigens, discussion of effective delivery systems, immunization routes and adjuvants for induction of protective immunity at the targeted mucosal surface whilst minimizing severe inflammatory disease sequelae.

The interdependence between screening methods and screening libraries.

PubMed

Shelat, Anang A; Guy, R Kiplin

2007-06-01

The most common methods for discovery of chemical compounds capable of manipulating biological function involves some form of screening. The success of such screens is highly dependent on the chemical materials - commonly referred to as libraries - that are assayed. Classic methods for the design of screening libraries have depended on knowledge of target structure and relevant pharmacophores for target focus, and on simple count-based measures to assess other properties. The recent proliferation of two novel screening paradigms, structure-based screening and high-content screening, prompts a profound rethink about the ideal composition of small-molecule screening libraries. We suggest that currently utilized libraries are not optimal for addressing new targets by high-throughput screening, or complex phenotypes by high-content screening.

The prospect of gene therapy for prostate cancer: update on theory and status.

PubMed

Koeneman, K S; Hsieh, J T

2001-09-01

Molecularly based novel therapeutic agents are needed to address the problem of locally recurrent, or metastatic, advanced hormone-refractory prostate cancer. Recent basic science advances in mechanisms of gene expression, vector delivery, and targeting have rendered clinically relevant gene therapy to the prostatic fossa and distant sites feasible in the near future. Current research and clinical investigative efforts involving methods for more effective vector delivery and targeting, with enhanced gene expression to selected (specific) sites, are reviewed. These areas of research involve tissue-specific promoters, transgene exploration, vector design and delivery, and selective vector targeting. The 'vectorology' involved mainly addresses selective tissue homing with ligands, mechanisms of innate immune system evasion for durable transgene expression, and the possibility of repeat administration.

Design and synthetic considerations of matrix metalloproteinase inhibitors.

PubMed

Skotnicki, J S; Zask, A; Nelson, F C; Albright, J D; Levin, J I

1999-06-30

Experimental evidence confirms that the matrix metalloproteinases (MMPs) play a fundamental role in a wide variety of pathologic conditions that involve connective tissue destruction including osteoarthritis and rheumatoid arthritis, tumor metastasis and angiogenesis, corneal ulceration, multiple sclerosis, periodontal disease, and atherosclerosis. Modulation of MMP regulation is possible at several biochemical sites, but direct inhibition of enzyme action provides a particularly attractive target for therapeutic intervention. Hypotheses concerning inhibition of specific MMP(s) with respect to disease target and/or side-effect profile have emerged. Examples are presented of recent advances in medicinal chemistry approaches to the design of matrix metalloproteinase inhibitors (MMPIs), approaches that address structural requirements and that influence potency, selectivity, and bioavailability. Two important approaches to the design, synthesis, and biological evaluation of MMPIs are highlighted: (1) the invention of alternatives to hydroxamic acid zinc chelators and (2) the construction of nonpeptide scaffolds. One current example in each of these two approaches from our own work is described.

Label-Free Aptasensors for the Detection of Mycotoxins

PubMed Central

Rhouati, Amina; Catanante, Gaelle; Nunes, Gilvanda; Hayat, Akhtar; Marty, Jean-Louis

2016-01-01

Various methodologies have been reported in the literature for the qualitative and quantitative monitoring of mycotoxins in food and feed samples. Based on their enhanced specificity, selectivity and versatility, bio-affinity assays have inspired many researchers to develop sensors by exploring bio-recognition phenomena. However, a significant problem in the fabrication of these devices is that most of the biomolecules do not generate an easily measurable signal upon binding to the target analytes, and signal-generating labels are required to perform the measurements. In this context, aptamers have been emerged as a potential and attractive bio-recognition element to design label-free aptasensors for various target analytes. Contrary to other bioreceptor-based approaches, the aptamer-based assays rely on antigen binding-induced conformational changes or oligomerization states rather than binding-assisted changes in adsorbed mass or charge. This review will focus on current designs in label-free conformational switchable design strategies, with a particular focus on applications in the detection of mycotoxins. PMID:27999353

Computational Tools for Allosteric Drug Discovery: Site Identification and Focus Library Design.

PubMed

Huang, Wenkang; Nussinov, Ruth; Zhang, Jian

2017-01-01

Allostery is an intrinsic phenomenon of biological macromolecules involving regulation and/or signal transduction induced by a ligand binding to an allosteric site distinct from a molecule's active site. Allosteric drugs are currently receiving increased attention in drug discovery because drugs that target allosteric sites can provide important advantages over the corresponding orthosteric drugs including specific subtype selectivity within receptor families. Consequently, targeting allosteric sites, instead of orthosteric sites, can reduce drug-related side effects and toxicity. On the down side, allosteric drug discovery can be more challenging than traditional orthosteric drug discovery due to difficulties associated with determining the locations of allosteric sites and designing drugs based on these sites and the need for the allosteric effects to propagate through the structure, reach the ligand binding site and elicit a conformational change. In this study, we present computational tools ranging from the identification of potential allosteric sites to the design of "allosteric-like" modulator libraries. These tools may be particularly useful for allosteric drug discovery.

Rational design of inducible CRISPR guide RNAs for de novo assembly of transcriptional programs

PubMed Central

Ferry, Quentin R. V.; Lyutova, Radostina; Fulga, Tudor A.

2017-01-01

CRISPR-based transcription regulators (CRISPR-TRs) have transformed the current synthetic biology landscape by allowing specific activation or repression of any target gene. Here we report a modular and versatile framework enabling rapid implementation of inducible CRISPR-TRs in mammalian cells. This strategy relies on the design of a spacer-blocking hairpin (SBH) structure at the 5′ end of the single guide RNA (sgRNA), which abrogates the function of CRISPR-transcriptional activators. By replacing the SBH loop with ligand-controlled RNA-cleaving units, we demonstrate conditional activation of quiescent sgRNAs programmed to respond to genetically encoded or externally delivered triggers. We use this system to couple multiple synthetic and endogenous target genes with specific inducers, and assemble gene regulatory modules demonstrating parallel and orthogonal transcriptional programs. We anticipate that this ‘plug and play' approach will be a valuable addition to the synthetic biology toolkit, facilitating the understanding of natural gene circuits and the design of cell-based therapeutic strategies. PMID:28256578

Enabling Large-Scale Design, Synthesis and Validation of Small Molecule Protein-Protein Antagonists

PubMed Central

Koes, David; Khoury, Kareem; Huang, Yijun; Wang, Wei; Bista, Michal; Popowicz, Grzegorz M.; Wolf, Siglinde; Holak, Tad A.; Dömling, Alexander; Camacho, Carlos J.

2012-01-01

Although there is no shortage of potential drug targets, there are only a handful known low-molecular-weight inhibitors of protein-protein interactions (PPIs). One problem is that current efforts are dominated by low-yield high-throughput screening, whose rigid framework is not suitable for the diverse chemotypes present in PPIs. Here, we developed a novel pharmacophore-based interactive screening technology that builds on the role anchor residues, or deeply buried hot spots, have in PPIs, and redesigns these entry points with anchor-biased virtual multicomponent reactions, delivering tens of millions of readily synthesizable novel compounds. Application of this approach to the MDM2/p53 cancer target led to high hit rates, resulting in a large and diverse set of confirmed inhibitors, and co-crystal structures validate the designed compounds. Our unique open-access technology promises to expand chemical space and the exploration of the human interactome by leveraging in-house small-scale assays and user-friendly chemistry to rationally design ligands for PPIs with known structure. PMID:22427896

A computationally designed inhibitor of an Epstein-Barr viral Bcl-2 protein induces apoptosis in infected cells

PubMed Central

Shen, Betty W.; Song, Yifan; Frayo, Shani; Convertine, Anthony J.; Margineantu, Daciana; Booth, Garrett; Correia, Bruno E.; Cheng, Yuanhua; Schief, William R.; Hockenbery, David M.; Press, Oliver W.; Stoddard, Barry L.; Stayton, Patrick S.; Baker, David

2014-01-01

SUMMARY Since apoptosis of infected cells can limit virus production and spread, some viruses have co-opted prosurvival genes from the host. This includes the Epstein-Barr virus (EBV) gene BHRF1, a homologue of human Bcl-2 proteins that block apoptosis and are associated with cancer. Computational design and experimental optimization were used to generate a novel protein called BINDI that binds BHRF1 with picomolar affinity. BINDI recognizes the hydrophobic cleft of BHRF1 in a manner similar to other Bcl-2 protein interactions, but makes many additional contacts to achieve exceptional affinity and specificity. BINDI induces apoptosis in EBV-infected cancer lines, and when delivered with an antibody-targeted intracellular delivery carrier, BINDI suppressed tumor growth and extended survival in a xenograft disease model of EBV-positive human lymphoma. High specificity designed proteins that selectively kill target cells may provide an advantage over the toxic compounds used in current generation antibody-drug conjugates. PMID:24949974

Optical Alignment of the JWST ISIM to the OTE Simulator (OSIM): Current Concept and Design Studies

NASA Technical Reports Server (NTRS)

Frey, Bradley J.; Davila, Pamela S.; Marsh, James M.; Ohl, Raymond G.; Sullivan, Joseph

2007-01-01

The James Webb Space Telescope's (JWST) Integrated Science Instrument Module (ISIM) is the scientific payload of the observatory and contai ns four science instruments. During alignment and test of the integrated ISIM (i.e. ISIM + science instruments) at NASA's Goddard Space Fli ght Center (GSFC), the Optical telescope element SIMulator (OSIM) wil l be used to optically stimulate the science instruments to verify their operation and performance. In this paper we present the design of two cryogenic alignment fixtures that will be used to determine and verify the proper alignment of OSIM to ISIM during testing at GSFC. The se fixtures, the Master Alignment Target Fixture (MATF) and the ISIM Alignment Target Fixture (IATF), will provide continuous, 6 degree of freedom feedback to OSIM during initial ambient alignment as well as during cryogenic vacuum testing.

Crystal structure of Zika virus NS5 RNA-dependent RNA polymerase.

PubMed

Godoy, Andre S; Lima, Gustavo M A; Oliveira, Ketllyn I Z; Torres, Naiara U; Maluf, Fernando V; Guido, Rafael V C; Oliva, Glaucius

2017-03-27

The current Zika virus (ZIKV) outbreak became a global health threat of complex epidemiology and devastating neurological impacts, therefore requiring urgent efforts towards the development of novel efficacious and safe antiviral drugs. Due to its central role in RNA viral replication, the non-structural protein 5 (NS5) RNA-dependent RNA-polymerase (RdRp) is a prime target for drug discovery. Here we describe the crystal structure of the recombinant ZIKV NS5 RdRp domain at 1.9 Å resolution as a platform for structure-based drug design strategy. The overall structure is similar to other flaviviral homologues. However, the priming loop target site, which is suitable for non-nucleoside polymerase inhibitor design, shows significant differences in comparison with the dengue virus structures, including a tighter pocket and a modified local charge distribution.

"Slit Mask Design for the Giant Magellan Telescope Multi-object Astronomical and Cosmological Spectrograph"

NASA Astrophysics Data System (ADS)

Williams, Darius; Marshall, Jennifer L.; Schmidt, Luke M.; Prochaska, Travis; DePoy, Darren L.

2018-01-01

The Giant Magellan Telescope Multi-object Astronomical and Cosmological Spectrograph (GMACS) is currently in development for the Giant Magellan Telescope (GMT). GMACS will employ slit masks with a usable diameter of approximately 0.450 m for the purpose of multi-slit spectroscopy. Of significant importance are the design constraints and parameters of the multi-object slit masks themselves as well as the means for mapping astronomical targets to physical mask locations. Analytical methods are utilized to quantify deformation effects on a potential slit mask due to thermal expansion and vignetting of target light cones. Finite element analysis (FEA) is utilized to simulate mask flexure in changing gravity vectors. The alpha version of the mask creation program for GMACS, GMACS Mask Simulator (GMS), a derivative of the OSMOS Mask Simulator (OMS), is introduced.

CADD Modeling of Multi-Target Drugs Against Alzheimer's Disease.

PubMed

Ambure, Pravin; Roy, Kunal

2017-01-01

Alzheimer's disease (AD) is a neurodegenerative disorder that is described by multiple factors linked with the progression of the disease. The currently approved drugs in the market are not capable of curing AD; instead, they merely provide symptomatic relief. Development of multi-target directed ligands (MTDLs) is an emerging strategy for improving the quality of the treatment against complex diseases like AD. Polypharmacology is a branch of pharmaceutical sciences that deals with the MTDL development. In this mini-review, we have summarized and discussed different strategies that are reported in the literature to design MTDLs for AD. Further, we have discussed the role of different in silico techniques and online resources in computer-aided drug discovery (CADD), for designing or identifying MTDLs against AD. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Divertor Coil Design and Implementation on Pegasus

NASA Astrophysics Data System (ADS)

Shriwise, P. C.; Bongard, M. W.; Cole, J. A.; Fonck, R. J.; Kujak-Ford, B. A.; Lewicki, B. T.; Winz, G. R.

2012-10-01

An upgraded divertor coil system is being commissioned on the Pegasus Toroidal Experiment in conjunction with power system upgrades in order to achieve higher β plasmas, reduce impurities, and possibly achieve H-mode operation. Design points for the divertor coil locations and estimates of their necessary current ratings were found using predictive equilibrium modeling based upon a 300 kA target plasma. This modeling represented existing Pegasus coil locations and current drive limits. The resultant design calls for 125 kA-turns from the divertor system to support the creation of a double null magnetic topology in plasmas with Ip<=300 kA. Initial experiments using this system will employ 900 V IGBT power supply modules to provide IDIV<=4 kA. The resulting 20 kA-turn capability of the existing divertor coil will be augmented by a new coil providing additional A-turns in series. Induced vessel wall current modeling indicates the time response of a 28 turn augmentation coil remains fast compared to the poloidal field penetration rate through the vessel. First results operating the augmented system are shown.

Genome-scale model-driven strain design for dicarboxylic acid production in Yarrowia lipolytica.

PubMed

Mishra, Pranjul; Lee, Na-Rae; Lakshmanan, Meiyappan; Kim, Minsuk; Kim, Byung-Gee; Lee, Dong-Yup

2018-03-19

Recently, there have been several attempts to produce long-chain dicarboxylic acids (DCAs) in various microbial hosts. Of these, Yarrowia lipolytica has great potential due to its oleaginous characteristics and unique ability to utilize hydrophobic substrates. However, Y. lipolytica should be further engineered to make it more competitive: the current approaches are mostly intuitive and cumbersome, thus limiting its industrial application. In this study, we proposed model-guided metabolic engineering strategies for enhanced production of DCAs in Y. lipolytica. At the outset, we reconstructed genome-scale metabolic model (GSMM) of Y. lipolytica (iYLI647) by substantially expanding the previous models. Subsequently, the model was validated using three sets of published culture experiment data. It was finally exploited to identify genetic engineering targets for overexpression, knockout, and cofactor modification by applying several in silico strain design methods, which potentially give rise to high yield production of the industrially relevant long-chain DCAs, e.g., dodecanedioic acid (DDDA). The resultant targets include (1) malate dehydrogenase and malic enzyme genes and (2) glutamate dehydrogenase gene, in silico overexpression of which generated additional NADPH required for fatty acid synthesis, leading to the increased DDDA fluxes by 48% and 22% higher, respectively, compared to wild-type. We further investigated the effect of supplying branched-chain amino acids on the acetyl-CoA turn-over rate which is key metabolite for fatty acid synthesis, suggesting their significance for production of DDDA in Y. lipolytica. In silico model-based strain design strategies allowed us to identify several metabolic engineering targets for overproducing DCAs in lipid accumulating yeast, Y. lipolytica. Thus, the current study can provide a methodological framework that is applicable to other oleaginous yeasts for value-added biochemical production.

The impact of a universal intervention targeting perfectionism in children: An exploratory controlled trial.

PubMed

Vekas, Eva J; Wade, Tracey D

2017-11-01

Perfectionism is considered to be an underlying mechanism of relevance to a broad array of indicators of psychological distress. The current research examined the impact of a three-session intervention targeting perfectionism in children on perfectionism, self-criticism, and well-being. The design of the current study can be considered quasi-experimental as the intervention and control classes were not randomly allocated but decided by convenience factors at the school level. Students (aged 10.08-12.79 years) were allocated to the intervention (N = 107, 41 boys) or control condition (N = 105, 33 boys), completing self-report assessments on perfectionism, self-criticism, and well-being at baseline, post-intervention, and 3-month follow-up. At post-intervention, children in the intervention group had significantly lower perfectionism than the control group (d = 0.35, 95% confidence intervals [CI]: 0.07-0.62) and at 3-month follow-up had significantly higher levels of well-being (d = 0.33, 95% CI: 0.06-0.60). As predicted by theory, decreases in perfectionism mediated the relationship between condition and improved well-being. This exploratory study provides evidence for the usefulness of a brief universal prevention programme targeting perfectionism. Future research should use more robust designs, explore longer-term effects, and the impact on a wider range of variables, including scholastic achievement. Clinical implications Perfectionism linked with negative outcomes in children can be decreased in a classroom setting. Decreasing perfectionism leads to improved well-being in children. Limitations More rigorous designs along with better assessment of perfectionism are required in further evaluations. The impact of perfectionism on scholastic achievement in children requires further investigation. © 2017 The British Psychological Society.

SECOND TARGET STATION MODERATOR PERFORMANCE WITH A ROTATING TARGET

DOE Office of Scientific and Technical Information (OSTI.GOV)

Remec, Igor; Gallmeier, Franz X; Rennich, Mark J

2016-01-01

Oak Ridge National Laboratory manages and operates the Spallation Neutron Source and the High Flux Isotope Reactor, two of the world's most advanced neutron scattering facilities. Both facilities are funded by the U.S. Department of Energy, Office of Science, Office of Basic Energy Science, and are available to researchers from all over the world. Delivering cutting edge science requires continuous improvements and development of the facilities and instruments. The SNS was designed from the outset to accommodate an additional target station, or Second Target Station (STS), and an upgraded accelerator feeding proton beams to STS and the existing First Targetmore » Station (FTS). Upgrade of the accelerator and the design and construction of STS are being proposed. The presently considered STS configuration is driven with short (<1 s) proton pulses at 10 Hz repetition rate and 467 kW proton beam power, and is optimized for high intensity and high resolution long wavelength neutron applications. STS will allow installation of 22 beamlines and will expand and complement the current national neutron scattering capabilities. In 2015 the STS studies were performed for a compact tungsten target; first a stationary tungsten plate target was analyzed to considerable details and then dropped in favor of a rotating target. For both target options the proton beam footprint as small as acceptable from mechanical and heat removal aspects is required to arrive at a compact-volume neutron production zone in the target, which is essential for tight coupling of target and moderators and for achieving high-intensity peak neutron fluxes. This paper will present recent STS work with the emphasis on neutronics and moderator performance.« less

Electromagnetic Pumps for Conductive-Propellant Feed Systems

NASA Technical Reports Server (NTRS)

Markusic, Thomas E.; Polzin, Kurt A.; Dehoyos, Amado

2005-01-01

Prototype electromagnetic pumps for use with lithium and bismuth propellants were constructed and tested. Such pumps may be used to pressurize future electric propulsion liquid metal feed systems, with the primary advantages being the compactness and simplicity versus alternative pressurization technologies. Design details for two different pumps are described: the first was designed to withstand (highly corrosive) lithium propellant, and t he second was designed to tolerate the high temperature required to pump liquid bismuth. Both qualitative and quantitative test results are presented. Open-loop tests demonstrated the capability of each device to electromagnetically pump its design propellant (lithium or bismuth). A second set of tests accurately quantified the pump pressure developed as a function of current. These experiments, which utilized a more easily handled material (gallium), demonstrated continuously-adjustable pump pressure levels ranging from 0-100 Torr for corresponding input current levels of 0-75 A. While the analysis and testing in this study specifically targeted lithium and bismuth propellants, the underlying design principles should be useful in implementing liquid metal pumps in any conductive-propellant feed system.

Collaborative real-time motion video analysis by human observer and image exploitation algorithms

NASA Astrophysics Data System (ADS)

Hild, Jutta; Krüger, Wolfgang; Brüstle, Stefan; Trantelle, Patrick; Unmüßig, Gabriel; Heinze, Norbert; Peinsipp-Byma, Elisabeth; Beyerer, Jürgen

2015-05-01

Motion video analysis is a challenging task, especially in real-time applications. In most safety and security critical applications, a human observer is an obligatory part of the overall analysis system. Over the last years, substantial progress has been made in the development of automated image exploitation algorithms. Hence, we investigate how the benefits of automated video analysis can be integrated suitably into the current video exploitation systems. In this paper, a system design is introduced which strives to combine both the qualities of the human observer's perception and the automated algorithms, thus aiming to improve the overall performance of a real-time video analysis system. The system design builds on prior work where we showed the benefits for the human observer by means of a user interface which utilizes the human visual focus of attention revealed by the eye gaze direction for interaction with the image exploitation system; eye tracker-based interaction allows much faster, more convenient, and equally precise moving target acquisition in video images than traditional computer mouse selection. The system design also builds on prior work we did on automated target detection, segmentation, and tracking algorithms. Beside the system design, a first pilot study is presented, where we investigated how the participants (all non-experts in video analysis) performed in initializing an object tracking subsystem by selecting a target for tracking. Preliminary results show that the gaze + key press technique is an effective, efficient, and easy to use interaction technique when performing selection operations on moving targets in videos in order to initialize an object tracking function.

Evolution and Development of Effective Feedstock Specifications

DOE Office of Scientific and Technical Information (OSTI.GOV)

Garold Gresham; Rachel Emerson; Amber Hoover

The U.S. Department of Energy promotes the production of a range of liquid fuels and fuel blend stocks from lignocellulosic biomass feedstocks by funding fundamental and applied research that advances the state of technology in biomass collection, conversion, and sustainability. As part of its involvement in this program, the Idaho National Laboratory (INL) investigates the feedstock logistics economics and sustainability of these fuels. The 2012 feedstock logistics milestone demonstrated that for high-yield areas that minimize the transportation distances of a low-density, unstable biomass, we could achieve a delivered cost of $35/ton. Based on current conventional equipment and processes, the 2012more » logistics design is able to deliver the volume of biomass needed to fulfill the 2012 Renewable Fuel Standard’s targets for ethanol. However, the Renewable Fuel Standard’s volume targets are continuing to increase and are expected to peak in 2022 at 36 billion gallons. Meeting these volume targets and achieving a national-scale biofuels industry will require expansion of production capacity beyond the 2012 Conventional Feedstock Supply Design Case to access diverse available feedstocks, regardless of their inherent ability to meet preliminary biorefinery quality feedstock specifications. Implementation of quality specifications (specs), as outlined in the 2017 Design Case – “Feedstock Supply System Design and Economics for Conversion of Lignocellulosic Biomass to Hydrocarbon Fuels” (in progress), requires insertion of deliberate, active quality controls into the feedstock supply chain, whereas the 2012 Conventional Design only utilizes passive quality controls.« less

Analysis of the Reactor Physics of Low-Enrichment Fuel for the INL Advanced Test Reactor in support of RERTR

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mark DeHart; William Skerjanc; Sean Morrell

2012-06-01

Analysis of the performance of the ATR with a LEU fuel design shows promise in terms of a core design that will yield the same neutron sources in target locations. A proposed integral cladding burnable absorber design appears to meet power profile requirements that will satisfy power distributions for safety limits. Performance of this fuel design is ongoing; the current work is the initial evaluation of the core performance of this fuel design with increasing burnup. Results show that LEU fuel may have a longer lifetime that HEU fuel however, such limits may be set by mechanical performance of themore » fuel rather that available reactivity. Changes seen in the radial fuel power distribution with burnup in LEU fuel will require further study to ascertain the impact on neutron fluxes in target locations. Source terms for discharged fuel have also been studied. By its very nature, LEU fuel produces much more plutonium than is present in HEU fuel at discharge. However, the effect of the plutonium inventory appears to have little affect on radiotoxicity or decay heat in the fuel.« less

A new paradigm on battery powered embedded system design based on User-Experience-Oriented method

NASA Astrophysics Data System (ADS)

Wang, Zhuoran; Wu, Yue

2014-03-01

The battery sustainable time has been an active research topic recently for the development of battery powered embedded products such as tablets and smart phones, which are determined by the battery capacity and power consumption. Despite numerous efforts on the improvement of battery capacity in the field of material engineering, the power consumption also plays an important role and easier to ameliorate in delivering a desirable user-experience, especially considering the moderate advancement on batteries for decades. In this study, a new Top-Down modelling method, User-Experience-Oriented Battery Powered Embedded System Design Paradigm, is proposed to estimate the target average power consumption, to guide the hardware and software design, and eventually to approach the theoretical lowest power consumption that the application is still able to provide the full functionality. Starting from the 10-hour sustainable time standard, average working current is defined with battery design capacity and set as a target. Then an implementation is illustrated from both hardware perspective, which is summarized as Auto-Gating power management, and from software perspective, which introduces a new algorithm, SleepVote, to guide the system task design and scheduling.

Development of Eddy Current Techniques for Detection of Deep Fatigue Cracks in Multi-Layer Airframe Components

NASA Technical Reports Server (NTRS)

Wincheski, Russell A.

2008-01-01

Thick, multi-layer aluminum structure has been widely used in aircraft design in critical wing splice areas. The multi-layer structure generally consists of three or four aluminum layers with different geometry and varying thickness, which are held together with fasteners. The detection of cracks under fasteners with ultrasonic techniques in subsurface layers away from the skin is impeded primarily by interlayer bonds and faying sealant condition. Further, assessment of such sealant condition is extremely challenging in terms of complexity of structure, limited access, and inspection cost. Although Eddy current techniques can be applied on in-service aircraft from the exterior of the skin without knowing sealant condition, the current eddy current techniques are not able to detect defects with wanted sensitivity. In this work a series of low frequency eddy current probes have been designed, fabricated and tested for this application. A probe design incorporating a shielded magnetic field sensor concentrically located in the interior of a drive coil has been employed to enable a localized deep diffusion of the electromagnetic field into the part under test. Due to the required low frequency inspections, probes have been testing using a variety of magnetic field sensors (pickup coil, giant magneto-resistive, anisotropic magneto-resistive, and spin-dependent tunneling). The probe designs as well as capabilities based upon a target inspection for sub-layer cracking in an airframe wing spar joint is presented.

Experimental design and quantitative analysis of microbial community multiomics.

PubMed

Mallick, Himel; Ma, Siyuan; Franzosa, Eric A; Vatanen, Tommi; Morgan, Xochitl C; Huttenhower, Curtis

2017-11-30

Studies of the microbiome have become increasingly sophisticated, and multiple sequence-based, molecular methods as well as culture-based methods exist for population-scale microbiome profiles. To link the resulting host and microbial data types to human health, several experimental design considerations, data analysis challenges, and statistical epidemiological approaches must be addressed. Here, we survey current best practices for experimental design in microbiome molecular epidemiology, including technologies for generating, analyzing, and integrating microbiome multiomics data. We highlight studies that have identified molecular bioactives that influence human health, and we suggest steps for scaling translational microbiome research to high-throughput target discovery across large populations.

Design and Status of the Balloon Experimental Twin Telescope for Infrared Interferometry (BETTII): An Interferometer at the Edge of Space

NASA Technical Reports Server (NTRS)

Rinehart, Stephen A.; Barclay, Richard B.; Barry, R. K.; Benford, D. J.; Calhoun, P. C.; Fixsen, D. J.; Gorman, E. T.; Jackson, M. L.; Jhabvala, C. A.; Leisawitz, D. T.;

The NDCX-II engineering design

NASA Astrophysics Data System (ADS)

Waldron, W. L.; Abraham, W. J.; Arbelaez, D.; Friedman, A.; Galvin, J. E.; Gilson, E. P.; Greenway, W. G.; Grote, D. P.; Jung, J.-Y.; Kwan, J. W.; Leitner, M.; Lidia, S. M.; Lipton, T. M.; Reginato, L. L.; Regis, M. J.; Roy, P. K.; Sharp, W. M.; Stettler, M. W.; Takakuwa, J. H.; Volmering, J.; Vytla, V. K.

2014-01-01

The Neutralized Drift Compression Experiment (NDCX-II) is a user facility located at Lawrence Berkeley National Laboratory which is uniquely designed for ion-beam-driven high energy density laboratory physics and heavy ion fusion research. Construction was completed in March 2012 and the facility is now in the commissioning phase. A significant amount of engineering was carried out in order to meet the performance parameters required for a wide range of target heating experiments while making the most cost-effective use of high-value hardware available from a decommissioned high current electron induction accelerator. The technical challenges and design of this new ion induction accelerator facility are described.

Development and evaluation of task-specific NLP framework in China.

PubMed

Ge, Caixia; Zhang, Yinsheng; Huang, Zhenzhen; Jia, Zheng; Ju, Meizhi; Duan, Huilong; Li, Haomin

2015-01-01

Natural language processing (NLP) has been designed to convert narrative text into structured data. Although some general NLP architectures have been developed, a task-specific NLP framework to facilitate the effective use of data is still a challenge in lexical resource limited regions, such as China. The purpose of this study is to design and develop a task-specific NLP framework to extract targeted information from particular documents by adopting dedicated algorithms on current limited lexical resources. In this framework, a shared and evolving ontology mechanism was designed. The result has shown that such a free text driven platform will accelerate the NLP technology acceptance in China.

A weighted sampling algorithm for the design of RNA sequences with targeted secondary structure and nucleotide distribution.

PubMed

Reinharz, Vladimir; Ponty, Yann; Waldispühl, Jérôme

2013-07-01

The design of RNA sequences folding into predefined secondary structures is a milestone for many synthetic biology and gene therapy studies. Most of the current software uses similar local search strategies (i.e. a random seed is progressively adapted to acquire the desired folding properties) and more importantly do not allow the user to control explicitly the nucleotide distribution such as the GC-content in their sequences. However, the latter is an important criterion for large-scale applications as it could presumably be used to design sequences with better transcription rates and/or structural plasticity. In this article, we introduce IncaRNAtion, a novel algorithm to design RNA sequences folding into target secondary structures with a predefined nucleotide distribution. IncaRNAtion uses a global sampling approach and weighted sampling techniques. We show that our approach is fast (i.e. running time comparable or better than local search methods), seedless (we remove the bias of the seed in local search heuristics) and successfully generates high-quality sequences (i.e. thermodynamically stable) for any GC-content. To complete this study, we develop a hybrid method combining our global sampling approach with local search strategies. Remarkably, our glocal methodology overcomes both local and global approaches for sampling sequences with a specific GC-content and target structure. IncaRNAtion is available at csb.cs.mcgill.ca/incarnation/. Supplementary data are available at Bioinformatics online.

Evaluation and rational design of guide RNAs for efficient CRISPR/Cas9-mediated mutagenesis in Ciona

PubMed Central

Gandhi, Shashank; Haeussler, Maximilian; Razy-Krajka, Florian; Christiaen, Lionel; Stolfi, Alberto

2017-01-01

The CRISPR/Cas9 system has emerged as an important tool for various genome engineering applications. A current obstacle to high throughput applications of CRISPR/Cas9 is the imprecise prediction of highly active single guide RNAs (sgRNAs). We previously implemented the CRISPR/Cas9 system to induce tissue-specific mutations in the tunicate Ciona. In the present study, we designed and tested 83 single guide RNA (sgRNA) vectors targeting 23 genes expressed in the cardiopharyngeal progenitors and surrounding tissues of Ciona embryo. Using high-throughput sequencing of mutagenized alleles, we identified guide sequences that correlate with sgRNA mutagenesis activity and used this information for the rational design of all possible sgRNAs targeting the Ciona transcriptome. We also describe a one-step cloning-free protocol for the assembly of sgRNA expression cassettes. These cassettes can be directly electroporated as unpurified PCR products into Ciona embryos for sgRNA expression in vivo, resulting in high frequency of CRISPR/Cas9-mediated mutagenesis in somatic cells of electroporated embryos. We found a strong correlation between the frequency of an Ebf loss-of-function phenotype and the mutagenesis efficacies of individual Ebf-targeting sgRNAs tested using this method. We anticipate that our approach can be scaled up to systematically design and deliver highly efficient sgRNAs for the tissue-specific investigation of gene functions in Ciona. PMID:28341547

Uncertainty Requirement Analysis for the Orbit, Attitude, and Burn Performance of the 1st Lunar Orbit Insertion Maneuver

NASA Astrophysics Data System (ADS)

Song, Young-Joo; Bae, Jonghee; Kim, Young-Rok; Kim, Bang-Yeop

2016-12-01

In this study, the uncertainty requirements for orbit, attitude, and burn performance were estimated and analyzed for the execution of the 1st lunar orbit insertion (LOI) maneuver of the Korea Pathfinder Lunar Orbiter (KPLO) mission. During the early design phase of the system, associate analysis is an essential design factor as the 1st LOI maneuver is the largest burn that utilizes the onboard propulsion system; the success of the lunar capture is directly affected by the performance achieved. For the analysis, the spacecraft is assumed to have already approached the periselene with a hyperbolic arrival trajectory around the moon. In addition, diverse arrival conditions and mission constraints were considered, such as varying periselene approach velocity, altitude, and orbital period of the capture orbit after execution of the 1st LOI maneuver. The current analysis assumed an impulsive LOI maneuver, and two-body equations of motion were adapted to simplify the problem for a preliminary analysis. Monte Carlo simulations were performed for the statistical analysis to analyze diverse uncertainties that might arise at the moment when the maneuver is executed. As a result, three major requirements were analyzed and estimated for the early design phase. First, the minimum requirements were estimated for the burn performance to be captured around the moon. Second, the requirements for orbit, attitude, and maneuver burn performances were simultaneously estimated and analyzed to maintain the 1st elliptical orbit achieved around the moon within the specified orbital period. Finally, the dispersion requirements on the B-plane aiming at target points to meet the target insertion goal were analyzed and can be utilized as reference target guidelines for a mid-course correction (MCC) maneuver during the transfer. More detailed system requirements for the KPLO mission, particularly for the spacecraft bus itself and for the flight dynamics subsystem at the ground control center, are expected to be prepared and established based on the current results, including a contingency trajectory design plan.

SU-F-J-45: Sparing Normal Tissue with Ultra-High Dose Rate in Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Feng, Y

Purpose: To spare normal tissue by reducing the location uncertainty of a moving target, we proposed an ultra-high dose rate system and evaluated. Methods: High energy electrons generated with a linear accelerator were injected into a storage ring to be accumulated. The number of the electrons in the ring was determined based on the prescribed radiation dose. The dose was delivered within a millisecond, when an online imaging system found that the target was in the position that was consistent with that in a treatment plan. In such a short time period, the displacement of the target was negligible. Themore » margin added to the clinical target volume (CTV) could be reduced that was evaluated by comparing of volumes between CTV and ITV in 14 cases of lung stereotactic body radiation therapy (SBRT) treatments. A design of the ultra-high dose rate system was evaluated based clinical needs and the recent developments of low energy (a few MeV) electron storage ring. Results: This design of ultra-high dose rate system was feasible based on the techniques currently available. The reduction of a target volume was significant by reducing the margin that accounted the motion of the target. ∼50% volume reduction of the internal target volume (ITV) could be achieved in lung SBRT treatments. Conclusion: With this innovation of ultra-high dose rate system, the margin of target is able to be significantly reduced. It will reduce treatment time of gating and allow precisely specified gating window to improve the accuracy of dose delivering.« less

Cockpit resource management at USAir

NASA Technical Reports Server (NTRS)

Sellards, Robert

1987-01-01

The current USAir CRM program is presented. The lessons learned and the program issues are combined. The training material was developed after an extensive literature search and pilot interview survey to determine the problem. The investigation led to the design, implementation, and evaluation of a behavioral science awareness training program. The need was found, and the target population was identified as the pilot group.

Targeting Body Image Schema for Smoking Cessation among College Females: Rationale, Program Description, and Pilot Study Results

ERIC Educational Resources Information Center

Napolitano, Melissa A.; Lloyd-Richardson, Elizabeth E.; Fava, Joseph L.; Marcus, Bess H.

2011-01-01

Smoking among young adults is a significant public health problem. Despite the negative health effects, many young women smoke for weight and body image reasons. Understanding the factors that prompt young women to initiate and continue smoking is important for designing smoking cessation interventions. The aim of the current article is to outline…

Development of a Novel Screening Method for the Isolation of “Cronobacter” spp. (Enterobacter sakazakii)▿

PubMed Central

Iversen, Carol; Druggan, Patrick; Schumacher, Sandra; Lehner, Angelika; Feer, Claudia; Gschwend, Karl; Joosten, Han; Stephan, Roger

2008-01-01

A differential medium, “Cronobacter” screening broth, has been designed to complement agars based on hydrolysis of chromogenic α-glucopyranoside substrates. The broth was evaluated using 329 Enterobacteriaceae strains (229 target isolates), spiked/naturally contaminated samples, and a parallel comparison with current methods for raw materials, line/end products, and factory environment samples. PMID:18310415

XDesign: an open-source software package for designing X-ray imaging phantoms and experiments.

PubMed

Ching, Daniel J; Gürsoy, Dogˇa

2017-03-01

The development of new methods or utilization of current X-ray computed tomography methods is impeded by the substantial amount of expertise required to design an X-ray computed tomography experiment from beginning to end. In an attempt to make material models, data acquisition schemes and reconstruction algorithms more accessible to researchers lacking expertise in some of these areas, a software package is described here which can generate complex simulated phantoms and quantitatively evaluate new or existing data acquisition schemes and image reconstruction algorithms for targeted applications.

XDesign: An open-source software package for designing X-ray imaging phantoms and experiments

DOE PAGES

Ching, Daniel J.; Gursoy, Dogˇa

2017-02-21

Here, the development of new methods or utilization of current X-ray computed tomography methods is impeded by the substantial amount of expertise required to design an X-ray computed tomography experiment from beginning to end. In an attempt to make material models, data acquisition schemes and reconstruction algorithms more accessible to researchers lacking expertise in some of these areas, a software package is described here which can generate complex simulated phantoms and quantitatively evaluate new or existing data acquisition schemes and image reconstruction algorithms for targeted applications.

The Stealth Biplane: a Proposal in Response to a Low Reynolds Number Station Keeping Mission

NASA Technical Reports Server (NTRS)

Walsh, Timothy E.; Flynn, Kevin T.; Donovan, Steven; Paul, Chris; Pangilinan, Harold; Padgett, John; Twomey, Daniel

1990-01-01

The Stealth Biplane is conceived and constructed to serve as a remotely piloted vehicle designed to navigate a low-level figure-eight course at a target Reynolds number of 100,000. This flight vehicle will combine the latest in lightweight radio controlled hardware in conjunction with current low Reynolds number aerodynamic research to demonstrate feasible operation in a variety of applications. These potential low Reynolds number applications include high altitude atmospheric sampling, search and rescue, and even law enforcement. Design specs and fabrication technique are discussed.

Shaping the Future of Nanomedicine: Anisotropy in Polymeric Nanoparticle Design

PubMed Central

Meyer, Randall A.; Green, Jordan J.

2015-01-01

Nanofabrication and biomedical applications of polymeric nanoparticles have become important areas of research. Biocompatible polymeric nanoparticles have been investigated for their use as delivery vehicles for therapeutic and diagnostic agents. Although polymeric nanoconstructs have traditionally been fabricated as isotropic spheres, anisotropic, non-spherical nanoparticles have gained interest in the biomaterials community due to their unique interactions with biological systems. Polymeric nanoparticles with different forms of anisotropy have been manufactured utilizing a variety of novel methods in recent years. In addition, they have enhanced physical, chemical, and biological properties compared to spherical nanoparticles, including increased targeting avidity and decreased non-specific in vivo clearance. With these desirable properties, anisotropic nanoparticles have been successfully utilized in many biomedical settings and have performed superiorly to analogous spherical nanoparticles. We summarize the current state-of-the-art fabrication methods for anisotropic polymeric nanoparticles including top-down, bottom-up, and microfluidic design approaches. We also summarize the current and potential future applications of these nanoparticles, including drug delivery, biological targeting, immunoengineering, and tissue engineering. Ongoing research into the properties and utility of anisotropic polymeric nanoparticles will prove critical to realizing their potential in nanomedicine. PMID:25981390

The current crisis in emergency care and the impact on disaster preparedness.

PubMed

Cherry, Robert A; Trainer, Marcia

2008-05-01

The Homeland Security Act (HSA) of 2002 provided for the designation of a critical infrastructure protection program. This ultimately led to the designation of emergency services as a targeted critical infrastructure. In the context of an evolving crisis in hospital-based emergency care, the extent to which federal funding has addressed disaster preparedness will be examined. After 9/11, federal plans, procedures and benchmarks were mandated to assure a unified, comprehensive disaster response, ranging from local to federal activation of resources. Nevertheless, insufficient federal funding has contributed to a long-standing counter-trend which has eroded emergency medical care. The causes are complex and multifactorial, but they have converged to present a severely overburdened system that regularly exceeds emergency capacity and capabilities. This constant acute overcrowding, felt in communities all across the country, indicates a nation at risk. Federal funding has not sufficiently prioritized the improvements necessary for an emergency care infrastructure that is critical for an all hazards response to disaster and terrorist emergencies. Currently, the nation is unable to meet presidential preparedness mandates for emergency and disaster care. Federal funding strategies must therefore be re-prioritized and targeted in a way that reasonably and consistently follows need.

Closing the door on flaviviruses: entry as a target for antiviral drug design.

PubMed

Perera, Rushika; Khaliq, Mansoora; Kuhn, Richard J

2008-10-01

With the emergence and rapid spread of West Nile virus in the United States since 1999, and the 50-100 million infections per year caused by dengue virus globally, the threat of flaviviruses as re-emerging human pathogens has become a reality. To support the efforts that are currently being pursued to develop effective vaccines against these viruses, researchers are also actively pursuing the development of small molecule compounds that target various aspects of the virus life cycle. Recent advances in the structural characterization of the flaviviruses have provided a strong foundation towards these efforts. These studies have provided the pseudo-atomic structures of virions from several members of the genus as well as atomic resolution structures of several viral proteins. Most importantly, these studies have highlighted specific structural rearrangements that occur within the virion that are necessary for the virus to complete its life cycle. These rearrangements occur when the virus must transition from immature, to mature, to fusion-active states and rely heavily on the conformational flexibility of the envelope (E) protein that forms the outer glycoprotein shell of the virus. Analysis of these conformational changes can suggest promising targets for structure-based antiviral design. For instance, by targeting the flexibility of the E protein, it might be possible to inhibit required rearrangements of this protein and trap the virus in a specific state. This would interfere with a productive flaviviral infection. This review presents a structural perspective of the flavivirus life cycle and focuses on the role of the E protein as an opportune target for structure-based antiviral drug design.

A review of NIR dyes in cancer targeting and imaging.

PubMed

Luo, Shenglin; Zhang, Erlong; Su, Yongping; Cheng, Tianmin; Shi, Chunmeng

2011-10-01

The development of multifunctional agents for simultaneous tumor targeting and near infrared (NIR) fluorescence imaging is expected to have significant impact on future personalized oncology owing to the very low tissue autofluorescence and high tissue penetration depth in the NIR spectrum window. Cancer NIR molecular imaging relies greatly on the development of stable, highly specific and sensitive molecular probes. Organic dyes have shown promising clinical implications as non-targeting agents for optical imaging in which indocyanine green has long been implemented in clinical use. Recently, significant progress has been made on the development of unique NIR dyes with tumor targeting properties. Current ongoing design strategies have overcome some of the limitations of conventional NIR organic dyes, such as poor hydrophilicity and photostability, low quantum yield, insufficient stability in biological system, low detection sensitivity, etc. This potential is further realized with the use of these NIR dyes or NIR dye-encapsulated nanoparticles by conjugation with tumor specific ligands (such as small molecules, peptides, proteins and antibodies) for tumor targeted imaging. Very recently, natively multifunctional NIR dyes that can preferentially accumulate in tumor cells without the need of chemical conjugation to tumor targeting ligands have been developed and these dyes have shown unique optical and pharmaceutical properties for biomedical imaging with superior signal-to-background contrast index. The main focus of this article is to provide a concise overview of newly developed NIR dyes and their potential applications in cancer targeting and imaging. The development of future multifunctional agents by combining targeting, imaging and even therapeutic routes will also be discussed. We believe these newly developed multifunctional NIR dyes will broaden current concept of tumor targeted imaging and hold promise to make an important contribution to the diagnosis and therapeutics for the treatment of cancer. Copyright © 2011 Elsevier Ltd. All rights reserved.

Spatial and polarity precision of concentric high-definition transcranial direct current stimulation (HD-tDCS)

NASA Astrophysics Data System (ADS)

Alam, Mahtab; Truong, Dennis Q.; Khadka, Niranjan; Bikson, Marom

2016-06-01

Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique that applies low amplitude current via electrodes placed on the scalp. Rather than directly eliciting a neuronal response, tDCS is believed to modulate excitability—enhancing or suppressing neuronal activity in regions of the brain depending on the polarity of stimulation. The specificity of tDCS to any therapeutic application derives in part from how electrode configuration determines the brain regions that are stimulated. Conventional tDCS uses two relatively large pads (>25 cm2) whereas high-definition tDCS (HD-tDCS) uses arrays of smaller electrodes to enhance brain targeting. The 4  ×  1 concentric ring HD-tDCS (one center electrode surrounded by four returns) has been explored in application where focal targeting of cortex is desired. Here, we considered optimization of concentric ring HD-tDCS for targeting: the role of electrodes in the ring and the ring’s diameter. Finite element models predicted cortical electric field generated during tDCS. High resolution MRIs were segmented into seven tissue/material masks of varying conductivities. Computer aided design (CAD) model of electrodes, gel, and sponge pads were incorporated into the segmentation. Volume meshes were generated and the Laplace equation (\

Radiometals (non-Tc, non-Re) and Bifunctional Labeling Chemistry

NASA Astrophysics Data System (ADS)

Fani, M.; Good, S.; Maecke, H. R.

Radiometals are of increased current interest because of the growing use of targeted radiotherapy for tumors and the development of generators that produce positron-emitting radiometals. In addition, biomedical cyclotrons allow the cheap production of some relevant radiometals. The design of the corresponding radiopharmaceuticals includes the synthesis of bifunctional chelators, which carry a functional unit for the immobilization of the radiometal and a functional group for the covalent attachment to a vector molecule. Radiometals of interest for therapeutic applications are some lanthanides, 67Cu, and 90Y. For diagnostic applications 61Cu, 62Cu, 64Cu, 89Zr, and 68Ga are currently used and corresponding radiopharmaceuticals are being designed. In this chapter, some properties and the synthesis of bifunctional chelators including metal ion selectivity and special aspects of coupling chemistry are being described.

Achondroplasia: pathogenesis and implications for future treatment.

PubMed

Laederich, Melanie B; Horton, William A

2010-08-01

Although the genetic defect underlying achondroplasia has been known for over a decade, no effective therapies to stimulate bone growth have emerged. Here we review the recent literature and summarize the molecular mechanisms underlying disease pathology and examine their potential as therapeutic targets. Currently used preclinical models are discussed in the context of recent advances with a special focus on C-type natriuretic peptide. Research on the mutation in Fibroblast Growth Factor Receptor 3 (FGFR3) that causes achondroplasia suggests that disease results from increased signal transduction from the mutant receptor. Thus, current therapeutic strategies have focused on reducing signals emanating from FGFR3. First-generation therapies directly targeting FGFR3, such as kinase inhibitors and neutralizing antibodies, designed for targeting FGFR3 in cancer, are still in the preclinical phase and have yet to translate into the management of achondroplasia. Counteracting signal transduction pathways downstream of FGFR3 holds promise with the discovery that administration of C-type natriuretic peptide to achondroplastic mice ameliorates their clinical phenotype. However, more research into long-term effectiveness and safety of this strategy is needed. Direct targeting of therapeutic agents to growth plate cartilage may enhance efficacy and minimize side effects of these and future therapies. Current research into the pathogenesis of achondroplasia has expanded our understanding of the mechanisms of FGFR3-induced disease and has increased the number of approaches that we may use to potentially correct it. Further research is needed to validate these approaches in preclinical models of achondroplasia.

Efficient Blood-Brain Barrier Opening in Primates with Neuronavigation-Guided Ultrasound and Real-Time Acoustic Mapping.

PubMed

Wu, Shih-Ying; Aurup, Christian; Sanchez, Carlos Sierra; Grondin, Julien; Zheng, Wenlan; Kamimura, Hermes; Ferrera, Vincent P; Konofagou, Elisa E

2018-05-22

Brain diseases including neurological disorders and tumors remain under treated due to the challenge to access the brain, and blood-brain barrier (BBB) restricting drug delivery which, also profoundly limits the development of pharmacological treatment. Focused ultrasound (FUS) with microbubbles is the sole method to open the BBB noninvasively, locally, and transiently and facilitate drug delivery, while translation to the clinic is challenging due to long procedure, targeting limitations, or invasiveness of current systems. In order to provide rapid, flexible yet precise applications, we have designed a noninvasive FUS and monitoring system with the protocol tested in monkeys (from in silico preplanning and simulation, real-time targeting and acoustic mapping, to post-treatment assessment). With a short procedure (30 min) similar to current clinical imaging duration or radiation therapy, the achieved targeting (both cerebral cortex and subcortical structures) and monitoring accuracy was close to the predicted 2-mm lower limit. This system would enable rapid clinical transcranial FUS applications outside of the MRI system without a stereotactic frame, thereby benefiting patients especially in the elderly population.

Hepatitis C Virus NS3/4A Protease Inhibitors: A Light at the End of the Tunnel

PubMed Central

Chatel-Chaix, Laurent; Baril, Martin; Lamarre, Daniel

2010-01-01

Hepatitis C virus (HCV) infection is a serious and growing threat to human health. The current treatment provides limited efficacy and is poorly tolerated, highlighting the urgent medical need for novel therapeutics. The membrane-targeted NS3 protein in complex with the NS4A comprises a serine protease domain (NS3/4A protease) that is essential for viral polyprotein maturation and contributes to the evasion of the host innate antiviral immunity by HCV. Therefore, the NS3/4A protease represents an attractive target for drug discovery, which is tied in with the challenge to develop selective small-molecule inhibitors. A rational drug design approach, based on the discovery of N-terminus product inhibition, led to the identification of potent and orally bioavailable NS3 inhibitors that target the highly conserved protease active site. This review summarizes the NS3 protease inhibitors currently challenged in clinical trials as one of the most promising antiviral drug class, and possibly among the first anti-HCV agents to be approved for the treatment of HCV infection. PMID:21994705

Sustainable-yield estimation for the Sparta Aquifer in Union County, Arkansas

USGS Publications Warehouse

Hays, Phillip D.

2000-01-01

Options for utilizing alternative sources of water to alleviate overdraft from the Sparta aquifer and ensure that the aquifer can continue to provide abundant water of excellent quality for the future are being evaluated by water managers in Union County. Sustainable yield is a critical element in identifying and designing viable water supply alternatives. With sustainable yield defined and a knowledge of total water demand in an area, any unmet demand can be calculated. The ground-water flow model of the Sparta aquifer was used to estimate sustainable yield using an iterative approach. The Sparta aquifer is a confined aquifer of regional importance that comprises a sequence of unconsolidated sand units that are contained within the Sparta Sand. Currently, the rate of withdrawal in some areas greatly exceeds the rate of recharge to the aquifer and considerable water-level declines have occurred. Ground-water flow model results indicate that the aquifer cannot continue to meet growing water-use demands indefinitely and that water levels will drop below the top of the primary producing sand unit in Union County (locally termed the El Dorado sand) by 2008 if current water-use trends continue. Declines of that magnitude will initiate dewatering of the El Dorado sand. The sustainable yield of the aquifer was calculated by targeting a specified minimum acceptable water level within Union County and varying Union County pumpage within the model to achieve the target water level. Selection of the minimum target water level for sustainable-yield estimation was an important criterion for the modeling effort. In keeping with the State Critical Ground-Water Area designation criteria and the desire of water managers in Union County to improve aquifer conditions and bring the area out of the Critical Ground-Water Area designation, the approximate altitude of the top of the Sparta Sand in central Union County was used as the minimum water level target for estimation of sustainable yield in the county. A specific category of sustainable yield? stabilization yield, reflecting the amount of water that the aquifer can provide while maintaining current water levels? also was determined and provides information for short-term management. The top of the primary producing sand unit (the El Dorado sand) was used as the minimum water-level target for estimating stabilization yield in the county because current minimum water levels in central Union County are near the top of the El Dorado sand. Model results show that withdrawals from the Sparta aquifer in Union County must be reduced to 28 percent of 1997 values to achieve sustainable yield and maintain water levels at the top of the Sparta Sand if future pumpage outside of Union County is assumed to increase at the rate observed from 1985-1997. Results of the simulation define a very large current unmet demand and represent a substantial reduction in the county?s current dependence upon the aquifer. If future pumpage outside of Union County is assumed to increase at double the rate observed from 1985-1997, withdrawals from the Sparta aquifer in Union County must be reduced to 25 percent of 1997 values to achieve sustainable yield. Withdrawals from the Sparta aquifer in Union County must be reduced to about 88 to 91 percent (depending on pumpage growth outside of the county) of 1997 values to stabilize water levels at the top of the El Dorado sand. This result shows that 1997 rate of withdrawal in the county is considerably greater than the rate needed to halt the rapid decline in water levels.

Content analysis of targeted food and beverage advertisements in a Chinese-American neighbourhood

PubMed Central

Bragg, Marie A; Pageot, Yrvane K; Hernández-Villarreal, Olivia; Kaplan, Sue A; Kwon, Simona C

2017-01-01

Objectives The current descriptive study aimed to: (i) quantify the number and type of advertisements (ads) located in a Chinese-American neighbourhood in a large, urban city; and (ii) catalogue the targeted marketing themes used in the food/beverage ads. Design Ten pairs of trained research assistants photographed all outdoor ads in a 0.6 mile2 (1.6 km2) area where more than 60.0 % of residents identify as Chinese American. We used content analysis to assess the marketing themes of ads, including references to: Asian cultures; health; various languages; children; food or beverage type (e.g. sugar-sweetened soda). Setting Lower East Side, a neighbourhood located in the borough of Manhattan in New York City, USA. Subjects Ads (n 1366) in the designated neighbourhood. Results Food/beverage ads were the largest ad category (29.7 %, n 407), followed by services (e.g. mobile phone services; 21.0 %, n 288). Sixty-seven per cent (66.9 %) of beverages featured were sugar-sweetened, and 50.8 % of food ads promoted fast food. Fifty-five per cent (54.9 %) of food/beverage ads targeted Asian Americans through language, ethnicity of person(s) in the ad or inclusion of culturally relevant images. Fifty per cent (50.2 %) of ads were associated with local/small brands. Conclusions Food/beverage marketing practices are known to promote unhealthy food and beverage products. Research shows that increased exposure leads to excessive short-term consumption among consumers and influences children’s food preferences and purchase requests. Given the frequency of racially targeted ads for unhealthy products in the current study and increasing rates of obesity-related diseases among Asian Americans, research and policies should address the implications of food and beverage ads on health. PMID:28587693

Computational Modeling and Neuroimaging Techniques for Targeting during Deep Brain Stimulation

PubMed Central

Sweet, Jennifer A.; Pace, Jonathan; Girgis, Fady; Miller, Jonathan P.

2016-01-01

Accurate surgical localization of the varied targets for deep brain stimulation (DBS) is a process undergoing constant evolution, with increasingly sophisticated techniques to allow for highly precise targeting. However, despite the fastidious placement of electrodes into specific structures within the brain, there is increasing evidence to suggest that the clinical effects of DBS are likely due to the activation of widespread neuronal networks directly and indirectly influenced by the stimulation of a given target. Selective activation of these complex and inter-connected pathways may further improve the outcomes of currently treated diseases by targeting specific fiber tracts responsible for a particular symptom in a patient-specific manner. Moreover, the delivery of such focused stimulation may aid in the discovery of new targets for electrical stimulation to treat additional neurological, psychiatric, and even cognitive disorders. As such, advancements in surgical targeting, computational modeling, engineering designs, and neuroimaging techniques play a critical role in this process. This article reviews the progress of these applications, discussing the importance of target localization for DBS, and the role of computational modeling and novel neuroimaging in improving our understanding of the pathophysiology of diseases, and thus paving the way for improved selective target localization using DBS. PMID:27445709

Effect of non-Newtonian characteristics of blood on magnetic particle capture in occluded blood vessel

NASA Astrophysics Data System (ADS)

Bose, Sayan; Banerjee, Moloy

2015-01-01

Magnetic nanoparticles drug carriers continue to attract considerable interest for drug targeting in the treatment of cancer and other pathological conditions. Magnetic carrier particles with surface-bound drug molecules are injected into the vascular system upstream from the desired target site, and are captured at the target site via a local applied magnetic field. Herein, a numerical investigation of steady magnetic drug targeting (MDT) using functionalized magnetic micro-spheres in partly occluded blood vessel having a 90° bent is presented considering the effects of non-Newtonian characteristics of blood. An Eulerian-Lagrangian technique is adopted to resolve the hemodynamic flow and the motion of the magnetic particles in the flow using ANSYS FLUENT. An implantable infinitely long cylindrical current carrying conductor is used to create the requisite magnetic field. Targeted transport of the magnetic particles in a partly occluded vessel differs distinctly from the same in a regular unblocked vessel. Parametric investigation is conducted and the influence of the insert configuration and its position from the central plane of the artery (zoffset), particle size (dp) and its magnetic property (χ) and the magnitude of current (I) on the "capture efficiency" (CE) is reported. Analysis shows that there exists an optimum regime of operating parameters for which deposition of the drug carrying magnetic particles in a target zone on the partly occluded vessel wall can be maximized. The results provide useful design bases for in vitro set up for the investigation of MDT in stenosed blood vessels.

The target invites a foe: antibody-drug conjugates in gynecologic oncology.

PubMed

Campos, Maira P; Konecny, Gottfried E

2018-02-01

Antibody-drug conjugates (ADCs) represent a promising new class of cancer therapeutics. Currently more than 60 ADCs are in clinical development, however, only very few trials focus on gynecologic malignancies. In this review, we summarize the most recent advances in ADC drug development with an emphasis on how this progress relates to patients diagnosed with gynecologic malignancies and breast cancer. The cytotoxic payloads of the majority of the ADCs that are currently in clinical trials for gynecologic malignancies or breast cancer are auristatins (MMAE, MMAF), maytansinoids (DM1, DM4), calicheamicin, pyrrolobenzodiazepines and SN-38. Both cleavable and noncleavable linkers are currently being investigated in clinical trials. A number of novel target antigens are currently being validated in ongoing clinical trials including folate receptor alpha, mesothelin, CA-125, NaPi2b, NOTCH3, protein tyrosine kinase-like 7, ephrin-A4, TROP2, CEACAM5, and LAMP1. For most ADCs currently in clinical development, dose-limiting toxicities appear to be unrelated to the targeted antigen but more tightly associated with the payload. Rational drug design involving optimization of the antibody, the linker and the conjugation chemistry is aimed at improving the therapeutic index of new ADCs. Antibody-drug conjugates can increase the efficacy and decrease the toxicity of their payloads in comparison with traditional cyctotoxic agents. A better and quicker translation of recent scientific advances in the field of ADCs into rational clinical trials for patients diagnosed with ovarian, endometrial or cervical cancer could create real improvements in tumor response, survival and quality of life for our patients.

An Aperture Photometry Pipeline for K2 Data

NASA Astrophysics Data System (ADS)

Buzasi, Derek L.; Carboneau, Lindsey; Lezcano, Andy; Vydra, Ekaterina

2016-01-01

As part of an ongoing research program with undergraduate students at Florida Gulf Coast University, we have constructed an aperture photometry pipeline for K2 data. The pipeline performs dynamic automated aperture mask definition for all targets in the K2 fields, followed by aperture photometry and detrending. Our pipeline is currently used to support a number of projects, including studies of stellar rotation and activity, red giant asteroseismology, gyrochronology, and exoplanet searches. In addition, output is used to support an undergraduate class on exoplanets aimed at a student audience of both majors and non-majors. The pipeline is designed for both batch and single-target use, and is easily extensible to data from other missions, and pipeline output is available to the community. This paper will describe our pipeline and its capabilities and illustrate the quality of the results, drawing on all of the applications for which it is currently used.

Reports of coal’s terminal decline may be exaggerated

NASA Astrophysics Data System (ADS)

Edenhofer, Ottmar; Steckel, Jan Christoph; Jakob, Michael; Bertram, Christoph

2018-02-01

We estimate the cumulative future emissions expected to be released by coal power plants that are currently under construction, announced, or planned. Even though coal consumption has recently declined and plans to build new coal-fired capacities have been shelved, constructing all these planned coal-fired power plants would endanger national and international climate targets. Plans to build new coal-fired power capacity would likely undermine the credibility of some countries’ (Intended) Nationally Determined Contributions submitted to the UNFCCC. If all the coal-fired power plants that are currently planned were built, the carbon budget for reaching the 2 °C temperature target would nearly be depleted. Propositions about ‘coal’s terminal decline’ may thereby be premature. The phase-out of coal requires dedicated and well-designed policies. We discuss the political economy of policy options that could avoid a continued build-up of coal-fired power plants.

The sweet tooth of biopharmaceuticals: importance of recombinant protein glycosylation analysis.

PubMed

Lingg, Nico; Zhang, Peiqing; Song, Zhiwei; Bardor, Muriel

2012-12-01

Biopharmaceuticals currently represent the fastest growing sector of the pharmaceutical industry, mainly driven by a rapid expansion in the manufacture of recombinant protein-based drugs. Glycosylation is the most prominent post-translational modification occurring on these protein drugs. It constitutes one of the critical quality attributes that requires thorough analysis for optimal efficacy and safety. This review examines the functional importance of glycosylation of recombinant protein drugs, illustrated using three examples of protein biopharmaceuticals: IgG antibodies, erythropoietin and glucocerebrosidase. Current analytical methods are reviewed as solutions for qualitative and quantitative measurements of glycosylation to monitor quality target product profiles of recombinant glycoprotein drugs. Finally, we propose a framework for designing the quality target product profile of recombinant glycoproteins and planning workflow for glycosylation analysis with the selection of available analytical methods and tools. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

EBCO Technologies TR Cyclotrons, Dynamics, Equipment, and Applications

DOE Office of Scientific and Technical Information (OSTI.GOV)

Johnson, R.R.; Univ British Columbia; Erdman, K. L.

2003-08-26

The Ebco Technologies TR cyclotrons have a common parent in the 500 MeV negative ion cyclotron at TRIUMF in Vancouver. As such, the TR cyclotrons have features that can be adapted for specific application. The cyclotron design is modularized into ion source and injection system, central region and then extraction. The cyclotron ion source is configured for cyclotron beam currents ranging from 50 microAmps to 2 milliAmps. The injection line can be operated in either continuous (CW) or in pulsed mode. The center region of the cyclotron is configured to match the ion source configuration. The extracted beams are directedmore » either to a local target station or to beam lines and thence to target stations. There has been development both in solid, liquid and gas targets. There has been development in radioisotope handling techniques, target material recovery and radiochemical synthesis.« less

Effects of Type and Strength of Force Feedback on Movement Time in a Target Selection Task

NASA Technical Reports Server (NTRS)

Rorie, Robert Conrad; Vu, Kim-Phuong L.; Marayong, Panadda; Robles, Jose; Strybel, Thomas Z.; Battiste, Vernol

2013-01-01

Future cockpits will likely include new onboard technologies, such as cockpit displays of traffic information, to help support future flight deck roles and responsibilities. These new technologies may benefit from multimodal feedback to aid pilot information processing. The current study investigated the effects of multiple levels of force feedback on operator performance in an aviation task. Participants were presented with two different types of force feedback (gravitational and spring force feedback) for a discrete targeting task, with multiple levels of gain examined for each force feedback type. Approach time and time in target were recorded. Results suggested that the two highest levels of gravitational force significantly reduced approach times relative to the lowest level of gravitational force. Spring force level only affected time in target. Implications of these findings for the design of future cockpit displays will be discussed.

Sequence-specific antimicrobials using efficiently delivered RNA-guided nucleases.

PubMed

Citorik, Robert J; Mimee, Mark; Lu, Timothy K

2014-11-01

Current antibiotics tend to be broad spectrum, leading to indiscriminate killing of commensal bacteria and accelerated evolution of drug resistance. Here, we use CRISPR-Cas technology to create antimicrobials whose spectrum of activity is chosen by design. RNA-guided nucleases (RGNs) targeting specific DNA sequences are delivered efficiently to microbial populations using bacteriophage or bacteria carrying plasmids transmissible by conjugation. The DNA targets of RGNs can be undesirable genes or polymorphisms, including antibiotic resistance and virulence determinants in carbapenem-resistant Enterobacteriaceae and enterohemorrhagic Escherichia coli. Delivery of RGNs significantly improves survival in a Galleria mellonella infection model. We also show that RGNs enable modulation of complex bacterial populations by selective knockdown of targeted strains based on genetic signatures. RGNs constitute a class of highly discriminatory, customizable antimicrobials that enact selective pressure at the DNA level to reduce the prevalence of undesired genes, minimize off-target effects and enable programmable remodeling of microbiota.

Sulfonylureas and Glinides as New PPARγ Agonists:. Virtual Screening and Biological Assays

NASA Astrophysics Data System (ADS)

Scarsi, Marco; Podvinec, Michael; Roth, Adrian; Hug, Hubert; Kersten, Sander; Albrecht, Hugo; Schwede, Torsten; Meyer, Urs A.; Rücker, Christoph

2007-12-01

This work combines the predictive power of computational drug discovery with experimental validation by means of biological assays. In this way, a new mode of action for type 2 diabetes drugs has been unvealed. Most drugs currently employed in the treatment of type 2 diabetes either target the sulfonylurea receptor stimulating insulin release (sulfonylureas, glinides), or target PPARγ improving insulin resistance (thiazolidinediones). Our work shows that sulfonylureas and glinides bind to PPARγ and exhibit PPARγ agonistic activity. This result was predicted in silico by virtual screening and confirmed in vitro by three biological assays. This dual mode of action of sulfonylureas and glinides may open new perspectives for the molecular pharmacology of antidiabetic drugs, since it provides evidence that drugs can be designed which target both the sulfonylurea receptor and PPARγ. Targeting both receptors could in principle allow to increase pancreatic insulin secretion, as well as to improve insulin resistance.

Outlier and target detection in aerial hyperspectral imagery: a comparison of traditional and percentage occupancy hit or miss transform techniques

NASA Astrophysics Data System (ADS)

Young, Andrew; Marshall, Stephen; Gray, Alison

2016-05-01

The use of aerial hyperspectral imagery for the purpose of remote sensing is a rapidly growing research area. Currently, targets are generally detected by looking for distinct spectral features of the objects under surveillance. For example, a camouflaged vehicle, deliberately designed to blend into background trees and grass in the visible spectrum, can be revealed using spectral features in the near-infrared spectrum. This work aims to develop improved target detection methods, using a two-stage approach, firstly by development of a physics-based atmospheric correction algorithm to convert radiance into re ectance hyperspectral image data and secondly by use of improved outlier detection techniques. In this paper the use of the Percentage Occupancy Hit or Miss Transform is explored to provide an automated method for target detection in aerial hyperspectral imagery.

Development of Cell‐Permeable, Non‐Helical Constrained Peptides to Target a Key Protein–Protein Interaction in Ovarian Cancer

PubMed Central

Wiedmann, Mareike M.; Tan, Yaw Sing; Wu, Yuteng; Aibara, Shintaro; Xu, Wenshu; Sore, Hannah F.; Verma, Chandra S.; Itzhaki, Laura; Stewart, Murray; Brenton, James D.

2016-01-01

Abstract There is a lack of current treatment options for ovarian clear cell carcinoma (CCC) and the cancer is often resistant to platinum‐based chemotherapy. Hence there is an urgent need for novel therapeutics. The transcription factor hepatocyte nuclear factor 1β (HNF1β) is ubiquitously overexpressed in CCC and is seen as an attractive therapeutic target. This was validated through shRNA‐mediated knockdown of the target protein, HNF1β, in five high‐ and low‐HNF1β‐expressing CCC lines. To inhibit the protein function, cell‐permeable, non‐helical constrained proteomimetics to target the HNF1β–importin α protein–protein interaction were designed, guided by X‐ray crystallographic data and molecular dynamics simulations. In this way, we developed the first reported series of constrained peptide nuclear import inhibitors. Importantly, this general approach may be extended to other transcription factors. PMID:27918136

Raytracing and Direct-Drive Targets

NASA Astrophysics Data System (ADS)

Schmitt, Andrew J.; Bates, Jason; Fyfe, David; Eimerl, David

2013-10-01

Accurate simulation of the effects of laser imprinting and drive asymmetries in directly driven targets requires the ability to distinguish between raytrace noise and the intensity structure produced by the spatial and temporal incoherence of optical smoothing. We have developed and implemented a smoother raytrace algorithm for our mpi-parallel radiation hydrodynamics code, FAST3D. The underlying approach is to connect the rays into either sheets (in 2D) or volume-enclosing chunks (in 3D) so that the absorbed energy distribution continuously covers the propagation area illuminated by the laser. We will describe the status and show the different scalings encountered in 2D and 3D problems as the computational size, parallelization strategy, and number of rays is varied. Finally, we show results using the method in current NIKE experimental target simulations and in proposed symmetric and polar direct-drive target designs. Supported by US DoE/NNSA.

Species-specific identification of Dekkera/Brettanomyces yeasts by fluorescently labeled DNA probes targeting the 26S rRNA.

PubMed

Röder, Christoph; König, Helmut; Fröhlich, Jürgen

2007-09-01

Sequencing of the complete 26S rRNA genes of all Dekkera/Brettanomyces species colonizing different beverages revealed the potential for a specific primer and probe design to support diagnostic PCR approaches and FISH. By analysis of the complete 26S rRNA genes of all five currently known Dekkera/Brettanomyces species (Dekkera bruxellensis, D. anomala, Brettanomyces custersianus, B. nanus and B. naardenensis), several regions with high nucleotide sequence variability yet distinct from the D1/D2 domains were identified. FISH species-specific probes targeting the 26S rRNA gene's most variable regions were designed. Accessibility of probe targets for hybridization was facilitated by the construction of partially complementary 'side'-labeled probes, based on secondary structure models of the rRNA sequences. The specificity and routine applicability of the FISH-based method for yeast identification were tested by analyzing different wine isolates. Investigation of the prevalence of Dekkera/Brettanomyces yeasts in the German viticultural regions Wonnegau, Nierstein and Bingen (Rhinehesse, Rhineland-Palatinate) resulted in the isolation of 37 D. bruxellensis strains from 291 wine samples.

Recommendations for Improving Identification and Quantification in Non-Targeted, GC-MS-Based Metabolomic Profiling of Human Plasma

PubMed Central

Wang, Hanghang; Muehlbauer, Michael J.; O’Neal, Sara K.; Newgard, Christopher B.; Hauser, Elizabeth R.; Shah, Svati H.

2017-01-01

The field of metabolomics as applied to human disease and health is rapidly expanding. In recent efforts of metabolomics research, greater emphasis has been placed on quality control and method validation. In this study, we report an experience with quality control and a practical application of method validation. Specifically, we sought to identify and modify steps in gas chromatography-mass spectrometry (GC-MS)-based, non-targeted metabolomic profiling of human plasma that could influence metabolite identification and quantification. Our experimental design included two studies: (1) a limiting-dilution study, which investigated the effects of dilution on analyte identification and quantification; and (2) a concentration-specific study, which compared the optimal plasma extract volume established in the first study with the volume used in the current institutional protocol. We confirmed that contaminants, concentration, repeatability and intermediate precision are major factors influencing metabolite identification and quantification. In addition, we established methods for improved metabolite identification and quantification, which were summarized to provide recommendations for experimental design of GC-MS-based non-targeted profiling of human plasma. PMID:28841195

Structure of the Trypanosoma cruzi protein tyrosine phosphatase TcPTP1, a potential therapeutic target for Chagas' disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lountos, George T.; Tropea, Joseph E.; Waugh, David S.

2013-06-05

Chagas’ disease, a neglected tropical affliction transmitted by the flagellated protozoan Trypanosoma cruzi, is prevalent in Latin America and affects nearly 18 million people worldwide, yet few approved drugs are available to treat the disease. Moreover, the currently available drugs exhibit severe toxicity or are poorly effective in the chronic phase of the disease. This limitation, along with the large population at risk, underscores the urgent need to discover new molecular targets and novel therapeutic agents. Recently, the T. cruzi protein tyrosine phosphatase TcPTP1 has been implicated in the cellular differentiation and infectivity of the parasite and is therefore amore » promising target for the design of novel anti-parasitic drugs. Here, we report the X-ray crystal structure of TcPTP1 refined to a resolution of 2.18 Å, which provides structural insights into the active site environment that can be used to initiate structure-based drug design efforts to develop specific TcPTP1 inhibitors. Potential strategies to develop such inhibitors are also discussed.« less

Nuclease-mediated genome editing: At the front-line of functional genomics technology.

PubMed

Sakuma, Tetsushi; Woltjen, Knut

2014-01-01

Genome editing with engineered endonucleases is rapidly becoming a staple method in developmental biology studies. Engineered nucleases permit random or designed genomic modification at precise loci through the stimulation of endogenous double-strand break repair. Homology-directed repair following targeted DNA damage is mediated by co-introduction of a custom repair template, allowing the derivation of knock-out and knock-in alleles in animal models previously refractory to classic gene targeting procedures. Currently there are three main types of customizable site-specific nucleases delineated by the source mechanism of DNA binding that guides nuclease activity to a genomic target: zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and clustered regularly interspaced short palindromic repeats (CRISPR). Among these genome engineering tools, characteristics such as the ease of design and construction, mechanism of inducing DNA damage, and DNA sequence specificity all differ, making their application complementary. By understanding the advantages and disadvantages of each method, one may make the best choice for their particular purpose. © 2014 The Authors Development, Growth & Differentiation © 2014 Japanese Society of Developmental Biologists.

SETI prototype system for NASA's Sky Survey microwave observing project - A progress report

NASA Technical Reports Server (NTRS)

Klein, M. J.; Gulkis, S.; Wilck, H. C.

1990-01-01

Two complementary search strategies, a Targeted Search and a Sky Survey, are part of NASA's SETI microwave observing project scheduled to begin in October of 1992. The current progress in the development of hardware and software elements of the JPL Sky Survey data processing system are presented. While the Targeted Search stresses sensitivity allowing the detection of either continuous or pulsed signals over the 1-3 GHz frequency range, the Sky Survey gives up sensitivity to survey the 99 percent of the sky that is not covered by the Targeted Search. The Sky Survey spans a larger frequency range from 1-10 GHz. The two searches will deploy special-purpose digital signal processing equipment designed and built to automate the observing and data processing activities. A two-million channel digital wideband spectrum analyzer and a signal processor system will serve as a prototype for the SETI Sky Survey processor. The design will permit future expansion to meet the SETI requirement that the processor concurrently search for left and right circularly polarized signals.

Progress Toward Fabrication of Machined Metal Shells for the First Double-Shell Implosions at the National Ignition Facility

DOE PAGES

Cardenas, Tana; Schmidt, Derek W.; Loomis, Eric N.; ...

2018-01-25

The double-shell platform fielded at the National Ignition Facility requires developments in new machining techniques and robotic assembly stations to meet the experimental specifications. Current double-shell target designs use a dense high-Z inner shell, a foam cushion, and a low-Z outer shell. The design requires that the inner shell be gas filled using a fill tube. This tube impacts the entire machining and assembly design. Other intermediate physics designs have to be fielded to answer physics questions and advance the technology to be able to fabricate the full point design in the near future. One of these intermediate designs ismore » a mid-Z imaging design. The methods of designing, fabricating, and characterizing each of the major components of an imaging double shell are discussed with an emphasis on the fabrication of the machined outer metal shell.« less

Progress Toward Fabrication of Machined Metal Shells for the First Double-Shell Implosions at the National Ignition Facility

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cardenas, Tana; Schmidt, Derek W.; Loomis, Eric N.

The double-shell platform fielded at the National Ignition Facility requires developments in new machining techniques and robotic assembly stations to meet the experimental specifications. Current double-shell target designs use a dense high-Z inner shell, a foam cushion, and a low-Z outer shell. The design requires that the inner shell be gas filled using a fill tube. This tube impacts the entire machining and assembly design. Other intermediate physics designs have to be fielded to answer physics questions and advance the technology to be able to fabricate the full point design in the near future. One of these intermediate designs ismore » a mid-Z imaging design. The methods of designing, fabricating, and characterizing each of the major components of an imaging double shell are discussed with an emphasis on the fabrication of the machined outer metal shell.« less

Clinical Trials of Precision Medicine through Molecular Profiling: Focus on Breast Cancer.

PubMed

Zardavas, Dimitrios; Piccart-Gebhart, Martine

2015-01-01

High-throughput technologies of molecular profiling in cancer, such as gene-expression profiling and next-generation sequencing, are expanding our knowledge of the molecular landscapes of several cancer types. This increasing knowledge coupled with the development of several molecularly targeted agents hold the promise for personalized cancer medicine to be fully realized. Moreover, an expanding armamentarium of targeted agents has been approved for the treatment of specific molecular cancer subgroups in different diagnoses. According to this paradigm, treatment selection should be dictated by the specific molecular aberrations found in each patient's tumor. The classical clinical trials paradigm of patients' eligibility being based on clinicopathologic parameters is being abandoned, with current clinical trials enrolling patients on the basis of specific molecular aberrations. New, innovative trial designs have been generated to better tackle the multiple challenges induced by the increasing molecular fragmentation of cancer, namely: (1) longitudinal cohort studies with or without downstream trials, (2) studies assessing the clinical utility of molecular profiling, (3) master or umbrella trials, (4) basket trials, (5) N-of-1 trials, and (6) adaptive design trials. This article provides an overview of the challenges for clinical trials in the era of molecular profiling of cancer. Subsequently, innovative trial designs with respective examples and their potential to expedite efficient clinical development of targeted anticancer agents is discussed.

Design of an EBIS charge breeder system for rare-isotope beams

NASA Astrophysics Data System (ADS)

Park, Young-Ho; Son, Hyock-Jun; Kim, Jongwon

2016-09-01

Rare-isotope beams will be produced by using the isotope separation on-line (ISOL) system at the Rare Isotope Science Project (RISP). A proton cyclotron is the driver accelerator for ISOL targets, and uranium carbide (UCx) will be a major target material. An isotope beam of interest extracted from the target will be ionized and selected by using a mass separator. The beam emittance will then be reduced by using a radio-frequency quadrupole (RFQ) cooler before the beam is injected into the electron-beam ion-source (EBIS) charge breeder (CB). The maximum electron beam current of the EBIS is 3 A from a cathode made of IrCe in an applied magnetic field of 0.2 T. The size of the electron beam is compressed by magnetic fields of up to 6 T caused in the charge-breeding region by a superconducting solenoid. The design of EBIS-CB was performed by using mechanics as well as beam optics. A test stand for the electron gun and its collector, which can take an electron-beam power of 20 kW, are under construction. The gun assembly was first tested by using a high-voltage pulse so as to measure its perveance. The design of the EBIS, along with its test stand, is described.

Optical design of common aperture, common focal plane, multispectral optics for military applications

NASA Astrophysics Data System (ADS)

Thompson, Nicholas Allan

2013-06-01

With recent developments in multispectral detector technology, the interest in common aperture, common focal plane multispectral imaging systems is increasing. Such systems are particularly desirable for military applications, where increased levels of target discrimination and identification are required in cost-effective, rugged, lightweight systems. During the optical design of dual waveband or multispectral systems, the options for material selection are limited. This selection becomes even more restrictive for military applications, where material resilience, thermal properties, and color correction must be considered. We discuss the design challenges that lightweight multispectral common aperture systems present, along with some potential design solutions. Consideration is given to material selection for optimum color correction, as well as material resilience and thermal correction. This discussion is supported using design examples currently in development at Qioptiq.

The design improvement of horizontal stripline kicker in TPS storage ring

NASA Astrophysics Data System (ADS)

Chou, P. J.; Chan, C. K.; Chang, C. C.; Hsu, K. T.; Hu, K. H.; Kuan, C. K.; Sheng, I. C.

2017-07-01

We plan to replace the existing horizontal stripline kicker of the transverse feedback system with an improved design. Large reflected power was observed at the downstream port of stripline kicker driven by the feedback amplifier. A rapid surge of vacuum pressure was observed when we tested the high current operation in TPS storage ring in April 2016. A burned feedthrough of the horizontal stripline kicker was discovered during a maintenance shutdown. The improved design is targeted to reduce the reflection of driving power from feedback system and to reduce beam induced RF heating. This major modification of the design is described. The results of RF simulation performed with the electromagnetic code GdfidL are reported as well.

Design study of an ultra-compact superconducting cyclotron for isotope production

NASA Astrophysics Data System (ADS)

Smirnov, V.; Vorozhtsov, S.; Vincent, J.

2014-11-01

A 12.5 MeV, 25 μA, proton compact superconducting cyclotron for medical isotope production has been designed and is currently in fabrication. The machine is initially aimed at producing 13N ammonia for Positron Emission Tomography (PET) cardiology applications. With an ultra-compact size and cost-effective price point, this system will offer clinicians unprecedented access to the preferred radiopharmaceutical isotope for cardiac PET imaging. A systems approach that carefully balanced the subsystem requirements coupled to precise beam dynamics calculations was followed. The system is designed to irradiate a liquid target internal to the cyclotron and to minimize the need for radiation shielding. The main parameters of the cyclotron, its design, and principal steps of the development work are presented here.

NASA's Advanced Exploration Systems Mars Transit Habitat Refinement Point of Departure Design

NASA Technical Reports Server (NTRS)

Simon, Matthew; Latorella, Kara; Martin, John; Cerro, Jeff; Lepsch, Roger; Jefferies, Sharon; Goodliff, Kandyce; McCleskey, Carey; Smitherman, David; Stromgren, Chel

2017-01-01

This paper describes the recently developed point of departure design for a long duration, reusable Mars Transit Habitat, which was established during a 2016 NASA habitat design refinement activity supporting the definition of NASA's Evolvable Mars Campaign. As part of its development of sustainable human Mars mission concepts achievable in the 2030s, the Evolvable Mars Campaign has identified desired durations and mass/dimensional limits for long duration Mars habitat designs to enable the currently assumed solar electric and chemical transportation architectures. The Advanced Exploration Systems Mars Transit Habitat Refinement Activity brought together habitat subsystem design expertise from across NASA to develop an increased fidelity, consensus design for a transit habitat within these constraints. The resulting design and data (including a mass equipment list) contained in this paper are intended to help teams across the agency and potential commercial, academic, or international partners understand: 1) the current architecture/habitat guidelines and assumptions, 2) performance targets of such a habitat (particularly in mass, volume, and power), 3) the driving technology/capability developments and architectural solutions which are necessary for achieving these targets, and 4) mass reduction opportunities and research/design needs to inform the development of future research and proposals. Data presented includes: an overview of the habitat refinement activity including motivation and process when informative; full documentation of the baseline design guidelines and assumptions; detailed mass and volume breakdowns; a moderately detailed concept of operations; a preliminary interior layout design with rationale; a list of the required capabilities necessary to enable the desired mass; and identification of any worthwhile trades/analyses which could inform future habitat design efforts. As a whole, the data in the paper show that a transit habitat meeting the 43 metric tons launch mass/trans-Mars injection burn limits specified by the Evolvable Mars Campaign is achievable near the desired timeframe with moderate strategic investments including maintainable life support systems, repurposable structures and packaging, and lightweight exercise modalities. It also identifies operational and technological options to reduce this mass to less than 41 metric tons including staging of launch structure/packaging and alternate structural materials.

Individualized model predicts brain current flow during transcranial direct-current stimulation treatment in responsive stroke patient.

PubMed

Datta, Abhishek; Baker, Julie M; Bikson, Marom; Fridriksson, Julius

2011-07-01

Although numerous published reports have demonstrated the beneficial effects of transcranial direct-current stimulation (tDCS) on task performance, fundamental questions remain regarding the optimal electrode configuration on the scalp. Moreover, it is expected that lesioned brain tissue will influence current flow and should therefore be considered (and perhaps leveraged) in the design of individualized tDCS therapies for stroke. The current report demonstrates how different electrode configurations influence the flow of electrical current through brain tissue in a patient who responded positively to a tDCS treatment targeting aphasia. The patient, a 60-year-old man, sustained a left hemisphere ischemic stroke (lesion size = 87.42 mL) 64 months before his participation. In this study, we present results from the first high-resolution (1 mm(3)) model of tDCS in a brain with considerable stroke-related damage; the model was individualized for the patient who received anodal tDCS to his left frontal cortex with the reference cathode electrode placed on his right shoulder. We modeled the resulting brain current flow and also considered three additional reference electrode positions: right mastoid, right orbitofrontal cortex, and a "mirror" configuration with the anode over the undamaged right cortex. Our results demonstrate the profound effect of lesioned tissue on resulting current flow and the ability to modulate current pattern through the brain, including perilesional regions, through electrode montage design. The complexity of brain current flow modulation by detailed normal and pathologic anatomy suggest: (1) That computational models are critical for the rational interpretation and design of individualized tDCS stroke-therapy; and (2) These models must accurately reproduce head anatomy as shown here. Copyright © 2011 Elsevier Inc. All rights reserved.

Triggering receptor expressed on myeloid cells 2 (TREM2): a potential therapeutic target for Alzheimer disease?

PubMed

Deming, Yuetiva; Li, Zeran; Benitez, Bruno A; Cruchaga, Carlos

2018-06-20

There are currently no effective therapeutics for Alzheimer disease (AD). Clinical trials targeting amyloid beta thus far have shown very little benefit and only in the earliest stages of disease. These limitations have driven research to identify alternative therapeutic targets, one of the most promising is the triggering receptor expressed on myeloid cells 2 (TREM2). Areas covered: Here, we review the literature to-date and discuss the potentials and pitfalls for targeting TREM2 as a potential therapeutic for AD. We focus on research in animal and cell models for AD and central nervous system injury models which may help in understanding the role of TREM2 in disease. Expert opinion: Studies suggest TREM2 plays a key role in AD pathology; however, results have been conflicting about whether TREM2 is beneficial or harmful. More research is necessary before designing TREM2-targeting therapies. Successful therapeutics will most likely be administered early in disease.

RchyOptimyx: Cellular Hierarchy Optimization for Flow Cytometry

PubMed Central

Aghaeepour, Nima; Jalali, Adrin; O’Neill, Kieran; Chattopadhyay, Pratip K.; Roederer, Mario; Hoos, Holger H.; Brinkman, Ryan R.

2013-01-01

Analysis of high-dimensional flow cytometry datasets can reveal novel cell populations with poorly understood biology. Following discovery, characterization of these populations in terms of the critical markers involved is an important step, as this can help to both better understand the biology of these populations and aid in designing simpler marker panels to identify them on simpler instruments and with fewer reagents (i.e., in resource poor or highly regulated clinical settings). However, current tools to design panels based on the biological characteristics of the target cell populations work exclusively based on technical parameters (e.g., instrument configurations, spectral overlap, and reagent availability). To address this shortcoming, we developed RchyOptimyx (cellular hieraRCHY OPTIMization), a computational tool that constructs cellular hierarchies by combining automated gating with dynamic programming and graph theory to provide the best gating strategies to identify a target population to a desired level of purity or correlation with a clinical outcome, using the simplest possible marker panels. RchyOptimyx can assess and graphically present the trade-offs between marker choice and population specificity in high-dimensional flow or mass cytometry datasets. We present three proof-of-concept use cases for RchyOptimyx that involve 1) designing a panel of surface markers for identification of rare populations that are primarily characterized using their intracellular signature; 2) simplifying the gating strategy for identification of a target cell population; 3) identification of a non-redundant marker set to identify a target cell population. PMID:23044634

MRP4/ABCC4 as a new therapeutic target: meta-analysis to determine cAMP binding sites as a tool for drug design.

PubMed

Yaneff, Agustín; Sahores, Ana; Gomez, Natalia; Carozzo, Alejandro; Shayo, Carina; Davio, Carlos

2017-12-29

MRP4 transports multiple endogenous and exogenous substances and is critical not only for detoxification but also in the homeostasis of several signaling molecules. Its dysregulation has been reported in numerous pathological disorders, thus MRP4 appears as an attractive therapeutic target. However, the efficacy of MRP4 inhibitors is still controversial. The design of specific pharmacological agents with the ability to selectively modulate the activity of this transporter or modify its affinity to certain substrates represents a challenge in current medicine and chemical biology. The first step in the long process of drug rational design is to identify the therapeutic target and characterize the mechanism by which it affects the given pathology. In order to develop a pharmacological agent with high specific activity, the second step is to systematically study the structure of the target and identify all the possible binding sites. Using available homology models and mutagenesis assays, in this review we recapitulate the up-to-date knowledge about MRP structure and aligned amino acid sequences to identify the candidate MRP4 residues where cyclic nucleotides bind. We have also listed the most relevant MRP inhibitors studied to date, considering drug safety and specificity for MRP4 in particular. This metaanalysis platform may serve as a basis for the future development of inhibitors of MRP4 cAMP specific transport. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

A randomized controlled trial of a smoking cessation self-help intervention for dual users of tobacco cigarettes and E-cigarettes: Intervention development and research design.

PubMed

Meltzer, Lauren R; Simmons, Vani N; Sutton, Steven K; Drobes, David J; Quinn, Gwendolyn P; Meade, Cathy D; Unrod, Marina; Brandon, Karen O; Harrell, Paul T; Eissenberg, Thomas; Bullen, Christopher R; Brandon, Thomas H

2017-09-01

Electronic Nicotine Delivery Systems, also called electronic cigarettes or e-cigarettes, have been available for over a decade and use has been increasing dramatically. The primary reported reasons for use are to aid smoking cessation or reduction, yet a significant proportion appear to be long-term users of both products ("dual users"). Dual users may be motivated to quit smoking and might benefit from a behavioral intervention for smoking cessation. This paper describes the intervention development, as well as the design, methods, and data analysis plans for an ongoing randomized controlled trial (RCT). Formative research and learner verification were conducted to create a usable, understandable, and acceptable self-help intervention targeting dual users. The efficacy is being tested in an RCT with current dual users (N=2900) recruited nationally and randomized to one of three conditions. The Assessment Only (ASSESS) group only completes assessments. The Generic Self-Help (GENERIC) group receives non-targeted smoking cessation booklets and supplemental materials sent monthly over 18months. The e-cigarette Targeted Self-Help (eTARGET) group receives the newly developed intervention (targeted booklets and supplemental materials) sent over the same period. All participants complete self-report surveys every 3months over 2years. The primary study outcome is self-reported 7-day point prevalence abstinence. Cost-effectiveness metrics for the GENERIC and eTARGET interventions will also be calculated. Copyright © 2017 Elsevier Inc. All rights reserved.

OmniSearch: a semantic search system based on the Ontology for MIcroRNA Target (OMIT) for microRNA-target gene interaction data.

PubMed

Huang, Jingshan; Gutierrez, Fernando; Strachan, Harrison J; Dou, Dejing; Huang, Weili; Smith, Barry; Blake, Judith A; Eilbeck, Karen; Natale, Darren A; Lin, Yu; Wu, Bin; Silva, Nisansa de; Wang, Xiaowei; Liu, Zixing; Borchert, Glen M; Tan, Ming; Ruttenberg, Alan

2016-01-01

As a special class of non-coding RNAs (ncRNAs), microRNAs (miRNAs) perform important roles in numerous biological and pathological processes. The realization of miRNA functions depends largely on how miRNAs regulate specific target genes. It is therefore critical to identify, analyze, and cross-reference miRNA-target interactions to better explore and delineate miRNA functions. Semantic technologies can help in this regard. We previously developed a miRNA domain-specific application ontology, Ontology for MIcroRNA Target (OMIT), whose goal was to serve as a foundation for semantic annotation, data integration, and semantic search in the miRNA field. In this paper we describe our continuing effort to develop the OMIT, and demonstrate its use within a semantic search system, OmniSearch, designed to facilitate knowledge capture of miRNA-target interaction data. Important changes in the current version OMIT are summarized as: (1) following a modularized ontology design (with 2559 terms imported from the NCRO ontology); (2) encoding all 1884 human miRNAs (vs. 300 in previous versions); and (3) setting up a GitHub project site along with an issue tracker for more effective community collaboration on the ontology development. The OMIT ontology is free and open to all users, accessible at: http://purl.obolibrary.org/obo/omit.owl. The OmniSearch system is also free and open to all users, accessible at: http://omnisearch.soc.southalabama.edu/index.php/Software.

Newly Enacted Intent Changes to ADS-B MASPS: Emphasis on Operations, Compatibility, and Integrity

NASA Technical Reports Server (NTRS)

Barhydt, Richard; Warren, Anthony W.

2002-01-01

Significant changes to the intent reporting structure in the Minimum Aviation System Performance Standards (MASPS) for Automatic Dependent Surveillance Broadcast (ADS-B) have recently been approved by RTCA Special Committee 186. The re-structured intent formats incorporate two major changes to the current MASPS (DO-242): addition of a Target State (TS) report that provides information on the horizontal and vertical targets for the current flight segment and replacement of the current Trajectory Change Point (TCP) and TCP+1 reports with Trajectory Change (TC) reports. TC reports include expanded information about TCPs and their connecting flight segments, in addition to making provisions for trajectory conformance elements. New intent elements are designed to accommodate a greater range of intent information, better reflect operational use and capabilities of existing and future aircraft avionics, and aid trajectory synthesis and conformance monitoring systems. These elements are expected to benefit near-term and future Air Traffic Management (ATM) applications, including separation assurance, local traffic flow management, and conformance monitoring. The current MASPS revision (DO-242A) implements those intent elements that are supported by current avionics standards and data buses. Additional elements are provisioned for inclusion in future MASPS revisions (beyond DO-242A) as avionics systems are evolved.

Neuronal and Cardiovascular Potassium Channels as Therapeutic Drug Targets

PubMed Central

Humphries, Edward S. A.

2015-01-01

Potassium (K+) channels, with their diversity, often tissue-defined distribution, and critical role in controlling cellular excitability, have long held promise of being important drug targets for the treatment of dysrhythmias in the heart and abnormal neuronal activity within the brain. With the exception of drugs that target one particular class, ATP-sensitive K+ (KATP) channels, very few selective K+ channel activators or inhibitors are currently licensed for clinical use in cardiovascular and neurological disease. Here we review what a range of human genetic disorders have told us about the role of specific K+ channel subunits, explore the potential of activators and inhibitors of specific channel populations as a therapeutic strategy, and discuss possible reasons for the difficulty in designing clinically relevant K+ channel modulators. PMID:26303307

Formal methods for test case generation

NASA Technical Reports Server (NTRS)

Rushby, John (Inventor); De Moura, Leonardo Mendonga (Inventor); Hamon, Gregoire (Inventor)

2011-01-01

The invention relates to the use of model checkers to generate efficient test sets for hardware and software systems. The method provides for extending existing tests to reach new coverage targets; searching *to* some or all of the uncovered targets in parallel; searching in parallel *from* some or all of the states reached in previous tests; and slicing the model relative to the current set of coverage targets. The invention provides efficient test case generation and test set formation. Deep regions of the state space can be reached within allotted time and memory. The approach has been applied to use of the model checkers of SRI's SAL system and to model-based designs developed in Stateflow. Stateflow models achieving complete state and transition coverage in a single test case are reported.

Novel biotechnology approaches in colorectal cancer diagnosis and therapy.

PubMed

Kavousipour, Soudabeh; Khademi, Fathemeh; Zamani, Mozhdeh; Vakili, Bahareh; Mokarram, Pooneh

2017-06-01

With ever-increasing molecular information about colorectal cancer (CRC), there is an expectation to detect more sensitive and specific molecular markers for new advanced diagnostic methods that can surpass the limitations of current screening tests. Moreover, enhanced molecular pathology knowledge about cancer has led to the development of targeted therapies, designed to interfere with specific aberrant biological pathways in cancer. Furthermore, biotechnology has opened a new window in CRC diagnosis and treatment by introducing different application of antibodies, antibody fragments, non-Ig scaffold proteins, and aptamers in targeted therapy and drug delivery. This review summarizes the molecular diagnostic and therapeutic approaches in CRC with a focus on genetic and epigenetic alterations, protein and metabolite markers as well as targeted therapy and drug delivery by Ig-scaffold proteins, non-Ig scaffold proteins, nanobodies, and aptamers.

Open-target sparse sensing of biological agents using DNA microarray

PubMed Central

2011-01-01

Background Current biosensors are designed to target and react to specific nucleic acid sequences or structural epitopes. These 'target-specific' platforms require creation of new physical capture reagents when new organisms are targeted. An 'open-target' approach to DNA microarray biosensing is proposed and substantiated using laboratory generated data. The microarray consisted of 12,900 25 bp oligonucleotide capture probes derived from a statistical model trained on randomly selected genomic segments of pathogenic prokaryotic organisms. Open-target detection of organisms was accomplished using a reference library of hybridization patterns for three test organisms whose DNA sequences were not included in the design of the microarray probes. Results A multivariate mathematical model based on the partial least squares regression (PLSR) was developed to detect the presence of three test organisms in mixed samples. When all 12,900 probes were used, the model correctly detected the signature of three test organisms in all mixed samples (mean(R2)) = 0.76, CI = 0.95), with a 6% false positive rate. A sampling algorithm was then developed to sparsely sample the probe space for a minimal number of probes required to capture the hybridization imprints of the test organisms. The PLSR detection model was capable of correctly identifying the presence of the three test organisms in all mixed samples using only 47 probes (mean(R2)) = 0.77, CI = 0.95) with nearly 100% specificity. Conclusions We conceived an 'open-target' approach to biosensing, and hypothesized that a relatively small, non-specifically designed, DNA microarray is capable of identifying the presence of multiple organisms in mixed samples. Coupled with a mathematical model applied to laboratory generated data, and sparse sampling of capture probes, the prototype microarray platform was able to capture the signature of each organism in all mixed samples with high sensitivity and specificity. It was demonstrated that this new approach to biosensing closely follows the principles of sparse sensing. PMID:21801424

CHAMP - Camera, Handlens, and Microscope Probe

NASA Technical Reports Server (NTRS)

Mungas, G. S.; Beegle, L. W.; Boynton, J.; Sepulveda, C. A.; Balzer, M. A.; Sobel, H. R.; Fisher, T. A.; Deans, M.; Lee, P.

2005-01-01

CHAMP (Camera, Handlens And Microscope Probe) is a novel field microscope capable of color imaging with continuously variable spatial resolution from infinity imaging down to diffraction-limited microscopy (3 micron/pixel). As an arm-mounted imager, CHAMP supports stereo-imaging with variable baselines, can continuously image targets at an increasing magnification during an arm approach, can provide precision range-finding estimates to targets, and can accommodate microscopic imaging of rough surfaces through a image filtering process called z-stacking. Currently designed with a filter wheel with 4 different filters, so that color and black and white images can be obtained over the entire Field-of-View, future designs will increase the number of filter positions to include 8 different filters. Finally, CHAMP incorporates controlled white and UV illumination so that images can be obtained regardless of sun position, and any potential fluorescent species can be identified so the most astrobiologically interesting samples can be identified.

Target selection for a hypervelocity asteroid intercept vehicle flight validation mission

NASA Astrophysics Data System (ADS)

Wagner, Sam; Wie, Bong; Barbee, Brent W.

2015-02-01

Asteroids and comets have collided with the Earth in the past and will do so again in the future. Throughout Earth's history these collisions have played a significant role in shaping Earth's biological and geological histories. The planetary defense community has been examining a variety of options for mitigating the impact threat of asteroids and comets that approach or cross Earth's orbit, known as near-Earth objects (NEOs). This paper discusses the preliminary study results of selecting small (100-m class) NEO targets and mission analysis and design trade-offs for validating the effectiveness of a Hypervelocity Asteroid Intercept Vehicle (HAIV) concept, currently being investigated for a NIAC (NASA Advanced Innovative Concepts) Phase 2 study. In particular this paper will focus on the mission analysis and design for single spacecraft direct impact trajectories, as well as several mission types that enable a secondary rendezvous spacecraft to observe the HAIV impact and evaluate it's effectiveness.

Design of patient-specific focused ultrasound arrays for non-invasive brain therapy with increased trans-skull transmission and steering range

NASA Astrophysics Data System (ADS)

Hughes, Alec; Hynynen, Kullervo

2017-09-01

The use of a phased array of ultrasound transducer elements to sonicate through the skull has opened the way for new treatments and the delivery of therapeutics beyond the blood-brain barrier. The limited steering range of current clinical devices, particularly at higher frequencies, limits the regions of the brain that are considered treatable by ultrasound. A new array design is introduced that allows for high levels of beam steering and increased transmission throughout the brain. These improvements are achieved using concave transducers normal to the outer-skull surface in a patient-specific configuration to target within the skull, so that the far-field of each beam is within the brain. It is shown that by using pulsed ultrasound waves timed to arrive in-phase at the desired target, sufficient levels of acoustic energy are delivered for blood-brain barrier opening throughout the brain.

Design of patient-specific focused ultrasound arrays for non-invasive brain therapy with increased trans-skull transmission and steering range.

PubMed

Hughes, Alec; Hynynen, Kullervo

2017-08-03

The use of a phased array of ultrasound transducer elements to sonicate through the skull has opened the way for new treatments and the delivery of therapeutics beyond the blood-brain barrier. The limited steering range of current clinical devices, particularly at higher frequencies, limits the regions of the brain that are considered treatable by ultrasound. A new array design is introduced that allows for high levels of beam steering and increased transmission throughout the brain. These improvements are achieved using concave transducers normal to the outer-skull surface in a patient-specific configuration to target within the skull, so that the far-field of each beam is within the brain. It is shown that by using pulsed ultrasound waves timed to arrive in-phase at the desired target, sufficient levels of acoustic energy are delivered for blood-brain barrier opening throughout the brain.

A 200-Channel Area-Power-Efficient Chemical and Electrical Dual-Mode Acquisition IC for the Study of Neurodegenerative Diseases.

PubMed

Guo, Jing; Ng, Waichiu; Yuan, Jie; Li, Suwen; Chan, Mansun

2016-06-01

Microelectrode array (MEA) can be used in the study of neurodegenerative diseases by monitoring the chemical neurotransmitter release and the electrical potential simultaneously at the cellular level. Currently, the MEA technology is migrating to more electrodes and higher electrode density, which raises power and area constraints on the design of acquisition IC. In this paper, we report the design of a 200-channel dual-mode acquisition IC with highly efficient usage of power and area. Under the constraints of target noise and fast settling, the current channel design saves power by including a novel current buffer biased in discrete time (DT) before the TIA (transimpedance amplifier). The 200 channels are sampled at 20 kS/s and quantized by column-wise SAR ADCs. The prototype IC was fabricated in a 0.18 μm CMOS process. Silicon measurements show the current channel has 21.6 pArms noise with cyclic voltammetry (CV) and 0.48 pArms noise with constant amperometry (CA) while consuming 12.1 μW . The voltage channel has 4.07 μVrms noise in the bandwidth of 100 kHz and 0.2% nonlinearity while consuming 9.1 μW. Each channel occupies 0.03 mm(2) area, which is among the smallest.

Profile of epratuzumab and its potential in the treatment of systemic lupus erythematosus

PubMed Central

Al Rayes, Hanan; Touma, Zahi

2014-01-01

Management of systemic lupus erythematosus (SLE) represents a fascinating, emerging field. Research has recently provided us with a better understanding of the immunologic alterations of SLE, leading to the creation of immunomodulatory agents designed to disrupt specific cell targets and pro-inflammatory pathways. Despite the improvement in the prognosis of SLE in the last 50 years with the use of immunosuppressive therapy such as cyclophosphamide and mycophenolate mofetil, cytotoxicity remains a major complication of these medications and the need for more specific targeted immunotherapy is increasing. Early recognition and treatment of SLE with targeted immunotherapy has the potential to improve quality of life and reduce the risk of disease flare-ups and complications. In this review, we will explore the role of B-cells in the pathogenesis of SLE highlighting current insights into SLE development and management. In addition, we will discuss epratuzumab’s role in the treatment of SLE. Epratuzumab is a humanized anti-CD22 monoclonal antibody that targets CD22 on B-cell and its role in B-cell modulation, migration, function, and inhibition of B-cell receptor signaling. Epratuzumab is currently in a Phase III study evaluating its efficacy in the management of moderate to severe SLE. All published trials on epratuzumab have shown great promise with safe profiles. PMID:25429203

The Impact of a Summer Institute on Inservice Early Childhood Teachers' Knowledge of Earth and Space Science Concepts

ERIC Educational Resources Information Center

Sackes, Mesut; Trundle, Kathy Cabe; Krissek, Lawrence A.

2011-01-01

This study investigated inservice PreK to Grade two teachers' knowledge of some earth and space science concepts before and after a short-term teacher institute. A one-group pre-test-post-test design was used in the current study. Earth science concepts targeted during the professional development included properties of rocks and soils, and the…

Effects of Form-Focused Instruction and Corrective Feedback on L2 Pronunciation Development of /[alveolar approximant]/ by Japanese Learners of English

ERIC Educational Resources Information Center

Saito, Kazuya; Lyster, Roy

2012-01-01

Sixty-five Japanese learners of English participated in the current study, which investigated the acquisitional value of form-focused instruction (FFI) with and without corrective feedback (CF) on learners' pronunciation development. All students received a 4-hr FFI treatment designed to encourage them to notice and practice the target feature of…

Evaluating the Effects of Traffic on Driver Stopping and Turn Signal Use at a Stop Sign: A Systematic Replication

ERIC Educational Resources Information Center

Lebbon, Angela R.; Austin, John; Van Houten, Ron; Malenfant, Louis E.

2007-01-01

The current analyses of observational data found that oncoming traffic substantially affected driver stopping patterns and turn signal use at the target stop sign. The percentage of legal stops and turn signal use by drivers in the presence and absence of traffic was analyzed using a multi-element design. The results showed that legal stops were…

The Effect of Contingent Reinforcement on Target Variables in Outpatient Psychotherapy for Depression: A Successful and Unsuccessful Case Using Functional Analytic Psychotherapy

ERIC Educational Resources Information Center

Kanter, Jonathan W.; Landes, Sara J.; Busch, Andrew M.; Rusch, Laura C.; Brown, Keri R.; Baruch, David E.; Holman, Gareth I.

2006-01-01

The current study investigated a behavior-analytic treatment, functional analytic psychotherapy (FAP), for outpatient depression utilizing two single-subject A/A+B designs. The baseline condition was cognitive behavioral therapy. Results demonstrated treatment success in 1 client after the addition of FAP and treatment failure in the 2nd. This…

The Employment Retention and Advancement Project: How Effective Are Different Approaches Aiming to Increase Employment Retention and Advancement? Final Impacts for Twelve Models. Executive Summary

ERIC Educational Resources Information Center

Hendra, Richard; Dillman, Keri-Nicole; Hamilton, Gayle; Lundquist, Erika; Martinson, Karin; Wavelet, Melissa

2010-01-01

This report summarizes the final impact results for the national Employment Retention and Advancement (ERA) project. This project tested, using a random assignment design, the effectiveness of numerous programs intended to promote steady work and career advancement. All the programs targeted current and former welfare recipients and other low-wage…

Engaging Teens with Asthma in Designing a Patient-Centered Mobile App to Aid Disease Self-Management.

PubMed

Schneider, Tali; Panzera, Anthony D; Couluris, Marisa; Lindenberger, James; McDermott, Robert; Bryant, Carol A

2015-08-10

Despite the growing market of e-health disease self-management tools, few studies have reported the presence of teen patients in all phases of product design. While rates of American teens using mobile Internet grow, an opportunity to deliver disease self-management targeted for teen patients exists. Building on findings from previous investigations with teens with asthma, we explored teens' insights on the development of a patient-centered asthma management application (app). Two existing asthma apps were used by 16 teen asthmatics for 7-10 days. At the end of the trial period, in-depth interviews were conducted with each participant to gather insights about the user experience. Participants requested more asthma-related content that educates them about their condition. Suggested improvements to currently available apps included a longer list of selectable symptoms to track, medication tracking, and more compelling interface features. Participants showed interest in using apps for managing their asthma, yet recommended improvements on current design. Whereas national figures point to a more ubiquitous mobile device environment, implementation efforts must respond to participants' recommendations while minding lingering digital divides. Currently available apps lack appealing components that teens seek or desire. Subsequent development should include teens' participation in component design insights.

Learning lessons from drugs that have recently entered the market.

PubMed

Teague, Simon J

2011-05-01

Which projects in the drug discovery field are most likely to be successful? In this article, I provide guidelines for answering this question by examining recent drug market entrants in detail, in particular their route of administration, trial design, novelty, therapeutic target and toxicities. I identify targets, trials and organizations as the key issues that are currently leading to the poor productivity in the pharmaceutical industry. Here, I outline some solutions and reasons for optimism, and suggest that the key determinants for success in drug discovery can be defined by studying recently launched drugs. Copyright © 2011 Elsevier Ltd. All rights reserved.

A simulation system to hide dynamic objects selectively at visible wavelengths

NASA Astrophysics Data System (ADS)

Cheng, Qiluan; Zhang, Shu; Ding, Chizhu; Tan, Zuojun; Wang, Guo Ping

2018-04-01

Currently, invisibility devices are increasingly approaching practical application requirements, such as using easily obtained materials for construction and hiding dynamic objects. Here, using phase retrieval and computer-generated holography techniques, we design an invisibility system in simulation to produce a phase-conjugation signal that changes with the dynamic object to hide it. This system is highly selective for the hidden objects, i.e., it only hides the target object and has no effect on the others. Such function may provide our invisibility system with great potential in special fields, such as biology and military applications for living and dynamic target recognition, selective camouflaging, and others.

Measurement of positron annihilation lifetimes for positron burst by multi-detector array

NASA Astrophysics Data System (ADS)

Wang, B. Y.; Kuang, P.; Liu, F. Y.; Han, Z. J.; Cao, X. Z.; Zhang, P.

2018-03-01

It is currently impossible to exploit the timing information in a gamma-ray pulse generated within nanoseconds when a high-intensity positron burst annihilation event occurs in a target using conventional single-detector methods. A state-of-the-art solution to the problem is proposed in this paper. In this approach, a multi-detector array composed of many independent detection cells mounted spherically around the target is designed to detect the time distribution of the annihilated gamma rays generated following, in particular, a positron burst emitting huge amounts of positrons in a short pulse duration, even less than a few nano- or picoseconds.

Transferrin-Conjugated Nanocarriers as Active-Targeted Drug Delivery Platforms for Cancer Therapy.

PubMed

Nogueira-Librelotto, Daniele R; Codevilla, Cristiane F; Farooqi, Ammad; Rolim, Clarice M B

2017-01-01

A lot of effort has been devoted to achieving active targeting for cancer therapy in order to reach the right cells. Hence, increasingly it is being realized that active-targeted nanocarriers notably reduce off-target effects, mainly because of targeted localization in tumors and active cellular uptake. In this context, by taking advantage of the overexpression of transferrin receptors on the surface of tumor cells, transferrin-conjugated nanodevices have been designed, in hope that the biomarker grafting would help to maximize the therapeutic benefit and to minimize the side effects. Notably, active targeting nanoparticles have shown improved therapeutic performances in different tumor models as compared to their passive targeting counterparts. In this review, current development of nano-based devices conjugated with transferrin for active tumor-targeting drug delivery are highlighted and discussed. The main objective of this review is to provide a summary of the vast types of nanomaterials that have been used to deliver different chemotherapeutics into tumor cells, and to ultimately evaluate the progression on the strategies for cancer therapy in view of the future research. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

The Effects of Mirror Feedback during Target Directed Movements on Ipsilateral Corticospinal Excitability

PubMed Central

Yarossi, Mathew; Manuweera, Thushini; Adamovich, Sergei V.; Tunik, Eugene

2017-01-01

Mirror visual feedback (MVF) training is a promising technique to promote activation in the lesioned hemisphere following stroke, and aid recovery. However, current outcomes of MVF training are mixed, in part, due to variability in the task undertaken during MVF. The present study investigated the hypothesis that movements directed toward visual targets may enhance MVF modulation of motor cortex (M1) excitability ipsilateral to the trained hand compared to movements without visual targets. Ten healthy subjects participated in a 2 × 2 factorial design in which feedback (veridical, mirror) and presence of a visual target (target present, target absent) for a right index-finger flexion task were systematically manipulated in a virtual environment. To measure M1 excitability, transcranial magnetic stimulation (TMS) was applied to the hemisphere ipsilateral to the trained hand to elicit motor evoked potentials (MEPs) in the untrained first dorsal interosseous (FDI) and abductor digiti minimi (ADM) muscles at rest prior to and following each of four 2-min blocks of 30 movements (B1–B4). Targeted movement kinematics without visual feedback was measured before and after training to assess learning and transfer. FDI MEPs were decreased in B1 and B2 when movements were made with veridical feedback and visual targets were absent. FDI MEPs were decreased in B2 and B3 when movements were made with mirror feedback and visual targets were absent. FDI MEPs were increased in B3 when movements were made with mirror feedback and visual targets were present. Significant MEP changes were not present for the uninvolved ADM, suggesting a task-specific effect. Analysis of kinematics revealed learning occurred in visual target-directed conditions, but transfer was not sensitive to mirror feedback. Results are discussed with respect to current theoretical mechanisms underlying MVF-induced changes in ipsilateral excitability. PMID:28553218

First-Principles-Driven Model-Based Optimal Control of the Current Profile in NSTX-U

NASA Astrophysics Data System (ADS)

Ilhan, Zeki; Barton, Justin; Wehner, William; Schuster, Eugenio; Gates, David; Gerhardt, Stefan; Kolemen, Egemen; Menard, Jonathan

2014-10-01

Regulation in time of the toroidal current profile is one of the main challenges toward the realization of the next-step operational goals for NSTX-U. A nonlinear, control-oriented, physics-based model describing the temporal evolution of the current profile is obtained by combining the magnetic diffusion equation with empirical correlations obtained at NSTX-U for the electron density, electron temperature, and non-inductive current drives. In this work, the proposed model is embedded into the control design process to synthesize a time-variant, linear-quadratic-integral, optimal controller capable of regulating the safety factor profile around a desired target profile while rejecting disturbances. Neutral beam injectors and the total plasma current are used as actuators to shape the current profile. The effectiveness of the proposed controller in regulating the safety factor profile in NSTX-U is demonstrated via closed-loop predictive simulations carried out in PTRANSP. Supported by PPPL.

Development of aluminum-stabilized superconducting cables for the Mu2e detector solenoid

DOE PAGES

Lombardo, Vito; Buehler, M.; Lamm, M.; ...

2016-06-01

Here, the Mu2e experiment at Fermilab is designed to measure the rare process of direct muon-to-electron conversion in the field of a nucleus. The experiment comprises a system of three superconducting solenoids, which focus secondary muons from the production target and transport them to an aluminum stopping target, while minimizing the associated background. The Detector Solenoid (DS) is the last magnet in the transport line and its main functions are to provide a graded field in the region of the stopping target as well as a precision magnetic field in a volume large enough to house the tracker downstream ofmore » the stopping target. The Detector Solenoid coils are designed to be wound using NbTi Rutherford cables conformed in high purity aluminum for stabilization and then cold-worked for strength. Two types of Al-stabilized conductor are required to build the DS coils, one for the gradient section and one for the spectrometer section of the solenoid. The dimensions are optimized to generate the required field profile when the same current is transported in both conductors. The conductors contain NbTi Rutherford cables with 12 (DS1) and 8 (DS2) strands respectively and are manufactured by two different vendors. This paper describes the results of the manufacturing of production lengths of the Al-stabilized cables needed to build the Mu2e Detector Solenoid as well as the testing campaigns and main results. The main cable properties and results of electrical and mechanical tests are summarized and discussed for each stage of the cable development process. Results are compared to design values to show how the production cables satisfy all the design criteria starting from the NbTi wires to the Al-stabilized cables.« less

Balancing novelty with confined chemical space in modern drug discovery.

PubMed

Medina-Franco, José L; Martinez-Mayorga, Karina; Meurice, Nathalie

2014-02-01

The concept of chemical space has broad applications in drug discovery. In response to the needs of drug discovery campaigns, different approaches are followed to efficiently populate, mine and select relevant chemical spaces that overlap with biologically relevant chemical spaces. This paper reviews major trends in current drug discovery and their impact on the mining and population of chemical space. We also survey different approaches to develop screening libraries with confined chemical spaces balancing physicochemical properties. In this context, the confinement is guided by criteria that can be divided in two broad categories: i) library design focused on a relevant therapeutic target or disease and ii) library design focused on the chemistry or a desired molecular function. The design and development of chemical libraries should be associated with the specific purpose of the library and the project goals. The high complexity of drug discovery and the inherent imperfection of individual experimental and computational technologies prompt the integration of complementary library design and screening approaches to expedite the identification of new and better drugs. Library design approaches including diversity-oriented synthesis, biological-oriented synthesis or combinatorial library design, to name a few, and the design of focused libraries driven by target/disease, chemical structure or molecular function are more efficient if they are guided by multi-parameter optimization. In this context, consideration of pharmaceutically relevant properties is essential for balancing novelty with chemical space in drug discovery.

Help Me Please!: Designing and Developing Application for Emergencies

NASA Astrophysics Data System (ADS)

Hong, Ng Ken; Hafit, Hanayanti; Wahid, Norfaradilla; Kasim, Shahreen; Yusof, Munirah Mohd

2017-08-01

Help Me Please! Application is an android platform emergency button application that is designed to transmit emergency messages to target receivers with real time information. The purpose of developing this application is to help people to notify any emergency circumstances via Short Message Service (SMS) in android platform. The application will receive the current location from Global Positioning System (GPS), will obtain the current time from the mobile device and send this information to the receivers when user presses the emergency button. Simultaneously, the application will keep sending the emergency alerts to receivers and will update to database based on the time interval set by user until user stop the function. Object-oriented Software Development model is employed to guide the development of this application with the knowledge of Java language and Android Studio. In conclusion, this application plays an important role in rescuing process when emergency circumstances happen. The rescue process will become more effective by notifying the emergency circumstances and send the current location of user to others in the early hours.

Imaging transcranial direct current stimulation (tDCS) of the prefrontal cortex-correlation or causality in stimulation-mediated effects?

PubMed

Wörsching, Jana; Padberg, Frank; Ertl-Wagner, Birgit; Kumpf, Ulrike; Kirsch, Beatrice; Keeser, Daniel

2016-10-01

Transcranial current stimulation approaches include neurophysiologically distinct non-invasive brain stimulation techniques widely applied in basic, translational and clinical research: transcranial direct current stimulation (tDCS), oscillating transcranial direct current stimulation (otDCS), transcranial alternating current stimulation (tACS) and transcranial random noise stimulation (tRNS). Prefrontal tDCS seems to be an especially promising tool for clinical practice. In order to effectively modulate relevant neural circuits, systematic research on prefrontal tDCS is needed that uses neuroimaging and neurophysiology measures to specifically target and adjust this method to physiological requirements. This review therefore analyses the various neuroimaging methods used in combination with prefrontal tDCS in healthy and psychiatric populations. First, we provide a systematic overview on applications, computational models and studies combining neuroimaging or neurophysiological measures with tDCS. Second, we categorise these studies in terms of their experimental designs and show that many studies do not vary the experimental conditions to the extent required to demonstrate specific relations between tDCS and its behavioural or neurophysiological effects. Finally, to support best-practice tDCS research we provide a methodological framework for orientation among experimental designs. Copyright © 2016 Elsevier Ltd. All rights reserved.

Present status and future prospects of heavy ion beams as drivers for ICF

NASA Astrophysics Data System (ADS)

Godlove, Terry F.

1986-01-01

A candidate driver for a practical inertial fusion reactor system must, among other characteristics, be cost effective and reliable for the parameters required by the fusion target and the remainder of the system. Although the history of large particle accelerators provides abundant evidence of their reliability at high repetition rates, their capital cost for the fusion application has been open to question. Attempts to design cost effective systems began with accelerators based on currently available technology such as RF linacs and storage rings. The West German HIBALL and the Japanese HIBLIC are examples of this initial effort. These designs are sufficiently credible that a strong argument can be made for the heavy ion method in general, but to reduce the cost per unit power it was found necessary to design for large scale, hence high capital cost. Emphasis in the U.S. shifted to newer technologies which offer hope of significant improvement in cost. In this paper the status of various heavy ion driver designs are compared with currently perceived requirements in order to illustrate their potential and assess their development needs.

Mars Reconnaissance Orbiter Mission: Systems Engineering Challenges on the Mars Reconnaissance Orbiter Mission

NASA Technical Reports Server (NTRS)

Havens, Glen G.

2007-01-01

MRO project is a system of systems requiring system engineering team to architect, design, integrate, test, and operate these systems at each level of the project. The challenge of system engineering mission objectives into a single mission architecture that can be integrated tested, launched, and operated. Systems engineering must translate high-level requirements into integrated mission design. Systems engineering challenges were overcome utilizing a combination by creative designs built into MRO's flight and ground systems: a) Design of sophisticated spacecraft targeting and data management capabilities b) Establishment of a strong operations team organization; c) Implementation of robust operational processes; and d) Development of strategic ground tools. The MRO system has met the challenge of its driving requirements: a) MRO began its two-year primary science phase on November 7, 2006, and by July 2007, met it minimum requirement to collect 15 Tbits of data after only eight months of operations. Currently we have collected 22 Tbits. b) Based on current performance, mission data return could return 70 Tbits of data by the end of the primary science phase in 2008.

Hohlraum design for the LMJ ignition target

NASA Astrophysics Data System (ADS)

Malinie, G.; Cherfils, C.; Gauthier, P.; Lambert, F.; Monteil, M. C.

2011-10-01

First experiments with the Laser MegaJoule (LMJ) are scheduled to be performed in 2014. The current nominal point design for ignition with 160 beams on the LMJ has been described in. It consists of an indirectly driven A943 capsule, with a plastic ablator doped with Germanium. This capsule is mounted in the center of a Rugby-shaped hohlraum, which is filled with a low density H/He gas, and has a gold-uranium cocktail wall lined with pure gold. We investigate the influence of two key parameters of the hohlraum design: the radius of the laser entrance holes (LEHs), and the thickness of the cocktail layer. Since the Rugby shape of the nominal point design is that of a half-ellipse going from the hohlraum waist to the LEH, any change in the LEH radius has a global effect on the hohlraum shape. Taking into account the current laser spot profiles of the LMJ and using 2D integrated calculations with our FCI2 radiation hydrodynamics code, we assess the flexiblility we have to reduce the LEH radius and/or the cocktail layer thickness.

UCx target preparations and characterizations

NASA Astrophysics Data System (ADS)

Andrighetto, Alberto; Corradetti, Stefano; Manzolaro, Mattia; Scarpa, Daniele; Monetti, Alberto; Rossignoli, Massimo; Borgna, Francesca; Ballan, Michele; Agostini, Mattia; D'Agostini, Fabio; Ferrari, Matteo; Zenoni, Aldo

2018-05-01

The Target-Ion Source unit is the core of an ISOL-RIB facility. Many international ISOL facilities have chosen different layouts of this unit. Many research groups are involved in research and development of targets capable of dissipating high power and, at the same time, be able to have a fast isotope release. This is mandatory in order to produce beams of short half-life isotopes. The research of new materials with advanced microstructural features is crucial in this field. The design of a proper target is indeed strictly related to the obtainment of porous refractory materials, which are capable to work under extreme conditions (temperatures up to 2000 °C in high vacuum) with a high release efficiency. For SPES, the second generation Italian ISOL-RIB Facility, the target will be made of uranium carbide (UCx) in which, by fission induced by a proton beam of 40 MeV of energy (8 kW of power), isotopes in the 60-160 amu mass region are produced. The current technological developments are also crucial in the study of third generation ISOL facilities.

Bifunctional Coupling Agents for Radiolabeling of Biomolecules and Target-Specific Delivery of Metallic Radionuclides

PubMed Central

Liu, Shuang

2008-01-01

Receptor-based radiopharmaceuticals are of great current interest in early molecular imaging and radiotherapy of cancers, and provide a unique tool for target-specific delivery of radionuclides to the diseased tissues. In general, a target-specific radiopharmaceutical can be divided into four parts: targeting biomolecule (BM), pharmacokinetic modifying (PKM) linker, bifunctional coupling or chelating agent (BFC), and radionuclide. The targeting biomolecule serves as a “carrier” for specific delivery of the radionuclide. PKM linkers are used to modify radiotracer excretion kinetics. BFC is needed for radiolabeling of biomolecules with a metallic radionuclide. Different radiometals have significant difference in their coordination chemistry, and require BFCs with different donor atoms and chelator frameworks. Since the radiometal chelate can have a significant impact on physical and biological properties of the target-specific radiopharmaceutical, its excretion kinetics can be altered by modifying the coordination environment with various chelators or coligand, if needed. This review will focus on the design of BFCs and their coordination chemistry with technetium, copper, gallium, indium, yttrium and lanthanide radiometals. PMID:18538888

Selection and response bias as determinants of priming of pop-out search: Revelations from diffusion modeling.

PubMed

Burnham, Bryan R

2018-05-03

During visual search, both top-down factors and bottom-up properties contribute to the guidance of visual attention, but selection history can influence attention independent of bottom-up and top-down factors. For example, priming of pop-out (PoP) is the finding that search for a singleton target is faster when the target and distractor features repeat than when those features trade roles between trials. Studies have suggested that such priming (selection history) effects on pop-out search manifest either early, by biasing the selection of the preceding target feature, or later in processing, by facilitating response and target retrieval processes. The present study was designed to examine the influence of selection history on pop-out search by introducing a speed-accuracy trade-off manipulation in a pop-out search task. Ratcliff diffusion modeling (RDM) was used to examine how selection history influenced both attentional bias and response execution processes. The results support the hypothesis that selection history biases attention toward the preceding target's features on the current trial and also influences selection of the response to the target.

A Multi-targeted Approach to Suppress Tumor-Promoting Inflammation

PubMed Central

Samadi, Abbas K.; Georgakilas, Alexandros G.; Amedei, Amedeo; Amin, Amr; Bishayee, Anupam; Lokeshwar, Bal L.; Grue, Brendan; Panis, Carolina; Boosani, Chandra S.; Poudyal, Deepak; Stafforini, Diana M.; Bhakta, Dipita; Niccolai, Elena; Guha, Gunjan; Rupasinghe, H.P. Vasantha; Fujii, Hiromasa; Honoki, Kanya; Mehta, Kapil; Aquilano, Katia; Lowe, Leroy; Hofseth, Lorne J.; Ricciardiello, Luigi; Ciriolo, Maria Rosa; Singh, Neetu; Whelan, Richard L.; Chaturvedi, Rupesh; Ashraf, S. Salman; Kumara, HMC Shantha; Nowsheen, Somaira; Mohammed, Sulma I.; Helferich, William G.; Yang, Xujuan

2015-01-01

Cancers harbor significant genetic heterogeneity and patterns of relapse following many therapies are due to evolved resistance to treatment. While efforts have been made to combine targeted therapies, significant levels of toxicity have stymied efforts to effectively treat cancer with multi-drug combinations using currently approved therapeutics. We discuss the relationship between tumor-promoting inflammation and cancer as part of a larger effort to develop a broad-spectrum therapeutic approach aimed at a wide range of targets to address this heterogeneity. Specifically, macrophage migration inhibitory factor, cyclooxygenase-2, transcription factor nuclear factor-kappaB, tumor necrosis factor alpha, inducible nitric oxide synthase, protein kinase B, and CXC chemokines are reviewed as important antiinflammatory targets while curcumin, resveratrol, epigallocatechin gallate, genistein, lycopene, and anthocyanins are reviewed as low-cost, low toxicity means by which these targets might all be reached simultaneously. Future translational work will need to assess the resulting synergies of rationally designed antiinflammatory mixtures (employing low-toxicity constituents), and then combine this with similar approaches targeting the most important pathways across the range of cancer hallmark phenotypes. PMID:25951989

Development of a Muon Rotating Target for J-PARC/MUSE

NASA Astrophysics Data System (ADS)

Makimura, Shunsuke; Kobayashi, Yasuo; Miyake, Yasuhiro; Kawamura, Naritoshi; Strasser, Patrick; Koda, Akihiro; Shimomura, Koichiro; Fujimori, Hiroshi; Nishiyama, Kusuo; Kato, Mineo; Kojima, Kenji; Higemoto, Wataru; Ito, Takashi; Shimizu, Ryou; Kadono, Ryosuke

At the J-PARC muon science facility (J-PARC/MUSE), a graphite target with a thickness of 20 mm has been used in vacuum to obtain an intense pulsed muon beam from the RCS 3-GeV proton beam [1], [2]. In the current design, the target frame is constructed using copper with a stainless steel tube embedded for water cooling. The energy deposited by the proton beam at 1 MW is evaluated to be 3.3 kW on the graphite target and 600 W on the copper frame by a Monte-Carlo simulation code, PHITS [3]. Graphite materials are known to lose their crystal structure and can be shrunk under intense proton beam irradiation. Consequently, the lifetime of the muon target is essentially determined by the radiation damage in graphite, and is evaluated to be half a year [4]. Hence, we are planning to distribute the radiation damage by rotating a graphite wheel. Although the lifetime of graphite in this case will be more than 10 years, the design of the bearing must be carefully considered. Because the bearing in JPARC/MUSE is utilized in vacuum, under high radiation, and at high temperature, an inorganic and solid lubricant must be applied to the bearing. Simultaneously, the temperature of the bearing must also be decreased to extend the lifetime. In 2009, a mock-up of the Muon Rotating Target, which could heat up and rotate a graphite wheel, was fabricated. Then several tests were started to select the lubricant and to determine the structure of the Muon Rotating Target, the control system and so on. In this report, the present status of the Muon Rotating Target for J-PARC/MUSE, especially the development of a rotation system in vacuum, is described.

Neutral Kaon Spectrometer 2

NASA Astrophysics Data System (ADS)

Kaneta, M.; Beckford, B.; Fujii, T.; Fujii, Y.; Futatsukawa, K.; Han, Y. C.; Hashimoto, O.; Hirose, K.; Ishikawa, T.; Kanda, H.; Kimura, C.; Maeda, K.; Nakamura, S. N.; Suzuki, K.; Tsukada, K.; Yamamoto, F.; Yamazaki, H.

2018-04-01

A large-acceptance spectrometer, Neutral Kaon Spectrometer 2 (NKS2), was newly constructed to explore various photoproduction reactions in the gigaelectronvolt region at the Laboratory of Nuclear Science (LNS, currently ELPH), Tohoku University. The spectrometer consisted of a dipole magnet, drift chambers, and plastic scintillation counters. NKS2 was designed to separate pions and protons in a momentum range of less than 1 GeV/ c, and was placed in a tagged photon beamline. A cryogenic H2/D2 target fitted to the spectrometer were designed. The design and performance of the detectors are described. The results of the NKS2 experiment on analyzing strangeness photoproduction data using a 0.8-1.1 GeV tagged photon beam are also presented.

Designing highly active siRNAs for therapeutic applications.

PubMed

Walton, S Patrick; Wu, Ming; Gredell, Joseph A; Chan, Christina

2010-12-01

The discovery of RNA interference (RNAi) generated considerable interest in developing short interfering RNAs (siRNAs) for understanding basic biology and as the active agents in a new variety of therapeutics. Early studies showed that selecting an active siRNA was not as straightforward as simply picking a sequence on the target mRNA and synthesizing the siRNA complementary to that sequence. As interest in applying RNAi has increased, the methods for identifying active siRNA sequences have evolved from focusing on the simplicity of synthesis and purification, to identifying preferred target sequences and secondary structures, to predicting the thermodynamic stability of the siRNA. As more specific details of the RNAi mechanism have been defined, these have been incorporated into more complex siRNA selection algorithms, increasing the reliability of selecting active siRNAs against a single target. Ultimately, design of the best siRNA therapeutics will require design of the siRNA itself, in addition to design of the vehicle and other components necessary for it to function in vivo. In this minireview, we summarize the evolution of siRNA selection techniques with a particular focus on one issue of current importance to the field, how best to identify those siRNA sequences likely to have high activity. Approaches to designing active siRNAs through chemical and structural modifications will also be highlighted. As the understanding of how to control the activity and specificity of siRNAs improves, the potential utility of siRNAs as human therapeutics will concomitantly grow. © 2010 The Authors Journal compilation © 2010 FEBS.

A nested array of rRNA targeted probes for the detection and identification of enterococci by reverse hybridization.

PubMed

Behr, T; Koob, C; Schedl, M; Mehlen, A; Meier, H; Knopp, D; Frahm, E; Obst, U; Schleifer, K; Niessner, R; Ludwig, W

2000-12-01

Complete 23S and almost complete 16S rRNA gene sequences were determined for the type strains of the validly described Enterococcus species, Melissococcus pluton and Tetragenococcus halophilus. A comprehensive set of rRNA targeted specific oligonucleotide hybridization probes was designed according to the multiple probe concept. In silico probe design and evaluation was performed using the respective tools of the ARB program package in combination with the ARB databases comprising the currently available 16S as well as 23S rRNA primary structures. The probes were optimized with respect to their application for reverse hybridization in microplate format. The target comprising 16S and 23S rDNA was amplified and labeled by PCR (polymerase chain reaction) using general primers targeting a wide spectrum of bacteria. Alternatively, amplification of two adjacent rDNA fragments of enterococci was performed by using specific primers. In vitro evaluation of the probe set was done including all Enterococcus type strains, and a selection of other representatives of the gram-positive bacteria with a low genomic DNA G+C content. The optimized probe set was used to analyze enriched drinking water samples as well as original samples from waste water treatment plants.

Construction and evaluation of an ultrahigh-vacuum-compatible sputter deposition source

NASA Astrophysics Data System (ADS)

Lackner, Peter; Choi, Joong Il Jake; Diebold, Ulrike; Schmid, Michael

2017-10-01

A sputter deposition source for the use in ultrahigh vacuum (UHV) is described, and some properties of the source are analyzed. The operating principle is based on the design developed by Mayr et al. [Rev. Sci. Instrum. 84, 094103 (2013)], where electrons emitted from a filament ionize argon gas and the Ar+ ions are accelerated to the target. In contrast to the original design, two grids are used to direct a large fraction of the Ar+ ions to the target, and the source has a housing cooled by liquid nitrogen to reduce contaminations. The source has been used for the deposition of zirconium, a material that is difficult to evaporate in standard UHV evaporators. At an Ar pressure of 9 ×1 0-6 mbar in the UHV chamber and moderate emission current, a highly reproducible deposition rate of ≈1 ML in 250 s was achieved at the substrate (at a distance of ≈50 mm from the target). Higher deposition rates are easily possible. X-ray photoelectron spectroscopy shows a high purity of the deposited films. Depending on the grid voltages, the substrate gets mildly sputtered by Ar+ ions; in addition, the substrate is also reached by electrons from the negatively biased sputter target.

Ebola virus: A gap in drug design and discovery - experimental and computational perspective.

PubMed

Balmith, Marissa; Faya, Mbuso; Soliman, Mahmoud E S

2017-03-01

The Ebola virus, formally known as the Ebola hemorrhagic fever, is an acute viral syndrome causing sporadic outbreaks that have ravaged West Africa. Due to its extreme virulence and highly transmissible nature, Ebola has been classified as a category A bioweapon organism. Only recently have vaccine or drug regimens for the Ebola virus been developed, including Zmapp and peptides. In addition, existing drugs which have been repurposed toward anti-Ebola virus activity have been re-examined and are seen to be promising candidates toward combating Ebola. Drug development involving computational tools has been widely employed toward target-based drug design. Screening large libraries have greatly stimulated research toward effective anti-Ebola virus drug regimens. Current emphasis has been placed on the investigation of host proteins and druggable viral targets. There is a huge gap in the literature regarding guidelines in the discovery of Ebola virus inhibitors, which may be due to the lack of information on the Ebola drug targets, binding sites, and mechanism of action of the virus. This review focuses on Ebola virus inhibitors, drugs which could be repurposed to combat the Ebola virus, computational methods which study drug-target interactions as well as providing further insight into the mode of action of the Ebola virus. © 2016 John Wiley & Sons A/S.

Exploration-Related Research on the International Space Station: Connecting Science Results to the Design of Future Missions

NASA Technical Reports Server (NTRS)

Rhatigan, Jennifer L.; Robinson, Julie A.; Sawin, Charles F.; Ahlf, Peter R.

2005-01-01

In January, 2004, the US President announced a vision for space exploration, and charged NASA with utilizing the International Space Station (ISS) for research and technology targeted at supporting the US space exploration goals. This paper describes: 1) what we have learned from the first four years of research on ISS relative to the exploration mission, 2) the on-going research being conducted in this regard, 3) our current understanding of the major exploration mission risks that the ISS can be used to address, and 4) current progress in realigning NASA s research portfolio for ISS to support exploration missions. Specifically, we discuss the focus of research on solving the perplexing problems of maintaining human health on long-duration missions, and the development of countermeasures to protect humans from the space environment, enabling long duration exploration missions. The interchange between mission design and research needs is dynamic, where design decisions influence the type of research needed, and results of research influence design decisions. The fundamental challenge to science on ISS is completing experiments that answer key questions in time to shape design decisions for future exploration. In this context, exploration-relevant research must do more than be conceptually connected to design decisions-it must become a part of the mission design process.

Key metrics for HFIR HEU and LEU models

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ilas, Germina; Betzler, Benjamin R.; Chandler, David

This report compares key metrics for two fuel design models of the High Flux Isotope Reactor (HFIR). The first model represents the highly enriched uranium (HEU) fuel currently in use at HFIR, and the second model considers a low-enriched uranium (LEU) interim design fuel. Except for the fuel region, the two models are consistent, and both include an experiment loading that is representative of HFIR's current operation. The considered key metrics are the neutron flux at the cold source moderator vessel, the mass of 252Cf produced in the flux trap target region as function of cycle time, the fast neutronmore » flux at locations of interest for material irradiation experiments, and the reactor cycle length. These key metrics are a small subset of the overall HFIR performance and safety metrics. They were defined as a means of capturing data essential for HFIR's primary missions, for use in optimization studies assessing the impact of HFIR's conversion from HEU fuel to different types of LEU fuel designs.« less

Design Tools for Cost-Effective Implementation of Planetary Protection Requirements

NASA Technical Reports Server (NTRS)

Hamlin, Louise; Belz, Andrea; Evans, Michael; Kastner, Jason; Satter, Celeste; Spry, Andy

2006-01-01

Since the Viking missions to Mars in the 1970s, accounting for the costs associated with planetary protection implementation has not been done systematically during early project formulation phases, leading to unanticipated costs during subsequent implementation phases of flight projects. The simultaneous development of more stringent planetary protection requirements, resulting from new knowledge about the limits of life on Earth, together with current plans to conduct life-detection experiments on a number of different solar system target bodies motivates a systematic approach to integrating planetary protection requirements and mission design. A current development effort at NASA's Jet Propulsion Laboratory is aimed at integrating planetary protection requirements more fully into the early phases of mission architecture formulation and at developing tools to more rigorously predict associated cost and schedule impacts of architecture options chosen to meet planetary protection requirements.

Current trends in α-helical membrane protein crystallization: An update

PubMed Central

Parker, Joanne L; Newstead, Simon

2012-01-01

α-Helical membrane proteins (MPs) are the targets for many pharmaceutical drugs and play important roles in human physiology. In recent years, significant progress has been made in determining their atomic structure using X-ray crystallography. However, a major bottleneck in MP crystallography still remains, namely, the identification of conditions that give crystals that are suitable for structural determination. In 2008, we undertook an analysis of the crystallization conditions for 121 α-helical MPs to design a rationalized sparse matrix crystallization screen, MemGold. We now report an updated analysis that includes a further 133 conditions. The results reveal the current trends in α-helical MP crystallization with notable differences since 2008. The updated information has been used to design new crystallization and additive screens that should prove useful for both initial crystallization scouting and subsequent crystal optimization. PMID:22811290

Rational and Modular Design of Potent Ligands Targeting the RNA that Causes Myotonic Dystrophy 2

PubMed Central

Lee, Melissa M.; Pushechnikov, Alexei; Disney, Matthew D.

2009-01-01

Most ligands targeting RNA are identified through screening a therapeutic target for binding members of a ligand library. A potential alternative way to construct RNA binders is through rational design using information about the RNA motifs ligands prefer to bind. Herein, we describe such an approach to design modularly assembled ligands targeting the RNA that causes myotonic dystrophy type 2 (DM2), a currently untreatable disease. A previous study identified that 6′-N-5-hexynoate kanamycin A (1) prefers to bind 2×2 nucleotide, pyrimidine-rich RNA internal loops. Multiple copies of such loops were found in the RNA hairpin that causes DM2. The 1 ligand was then modularly displayed on a peptoid scaffold with varied number and spacing to target several internal loops simultaneously. Modularly assembled ligands were tested for binding to a series of RNAs and for inhibiting the formation of the toxic DM2 RNA-muscleblind protein (MBNL-1) interaction. The most potent ligand displays three 1 modules, each separated by four spacing submonomers, and inhibits the formation of the RNA-protein complex with an IC50 of 25 nM. This ligand is higher affinity and more specific for binding DM2 RNA than MBNL-1. It binds the DM2 RNA at least 20-times more tightly than related RNAs and 15-fold more tightly than MBNL-1. A related control peptoid displaying 6′-N-5-hexynoate neamine (2) is >100-fold less potent at inhibiting the RNA-protein interaction and binds to DM2 RNA >125-fold more weakly. Uptake studies into a mouse myoblast cell line also show that the most potent ligand is cell permeable. PMID:19348464

Targeted social protection in a pastoralist economy: case study from Kenya.

PubMed

Janzen, S A; Jensen, N D; Mude, A G

2016-11-01

Social protection programmes are designed to help vulnerable populations - including pastoralists - maintain a basic level of well-being, manage risk, and cope with negative shocks. Theory suggests that differential targeting according to poverty status can increase the reach and effectiveness of budgeted social protection programmes. Chronically poor households benefit most from social protection designed to help them meet their basic needs and make vital investments necessary to graduate from poverty. Vulnerable non-destitute households benefit from protection against costly temporary shocks, but do not necessarily need regular assistance. Welfare gains occur when a comprehensive social protection programme considers the needs of both types of households. The authors use evidence-based understanding of poverty dynamics in the pastoralist-based economy of northern Kenya's arid and semi-arid lands as a case study to discuss and compare the observed impacts of two different social protection schemes on heterogeneous pastoralist households: a targeted, unconditional, cash-transfer programme designed to support the poorest, and an index-based livestock insurance programme, which acts as a productive 'safety net' to help stem a descent into poverty and increase resilience. Both types of social protection scheme have been shown to decrease poverty, improve food security and protect child health. However, the behavioural response for asset accumulation varies with the type of protection and the household's unique situation. Poor households that receive cash transfers retain and accumulate assets quickly. Insured households, who are typically vulnerable yet not destitute, protect existing herds and invest more in the livestock they already own. The authors argue that differential targeting increases programme efficiency, and discuss Kenya's current approach to implementing differentially targeted social protection.

Advantages of Structure-Based Drug Design Approaches in Neurological Disorders

PubMed Central

Aarthy, Murali; Panwar, Umesh; Selvaraj, Chandrabose; Singh, Sanjeev Kumar

2017-01-01

Objective: The purpose of the review is to portray the theoretical concept on neurological disorders from research data. Background: The freak changes in chemical response of nerve impulse causes neurological disorders. The research evidence of the effort done in the older history suggests that the biological drug targets and their effective feature with responsive drugs could be valuable in promoting the future development of health statistics structure for improved treatment for curing the nervous disorders. Methods: In this review, we summarized the most iterative theoretical concept of structure based drug design approaches in various neurological disorders to unfathomable understanding of reported information for future drug design and development. Results: On the premise of reported information we analyzed the model of theoretical drug designing process for understanding the mechanism and pathology of the neurological diseases which covers the development of potentially effective inhibitors against the biological drug targets. Finally, it also suggests the management and implementation of the current treatment in improving the human health system behaviors. Conclusion: With the survey of reported information we concluded the development strategies of diagnosis and treatment against neurological diseases which leads to supportive progress in the drug discovery. PMID:28042767

Nanoparticle drug-delivery systems for peritoneal cancers: a case study of the design, characterization and development of the expansile nanoparticle.

PubMed

Colby, Aaron H; Oberlies, Nicholas H; Pearce, Cedric J; Herrera, Victoria L M; Colson, Yolonda L; Grinstaff, Mark W

2017-05-01

Nanoparticle (NP)-based drug-delivery systems are frequently employed to improve the intravenous administration of chemotherapy; however, few reports explore their application as an intraperitoneal therapy. We developed a pH-responsive expansile nanoparticle (eNP) specifically designed to leverage the intraperitoneal route of administration to treat intraperitoneal malignancies, such as mesothelioma, ovarian, and pancreatic carcinomatoses. This review describes the design, evaluation, and evolution of the eNP technology and, specifically, a Materials-Based Targeting paradigm that is unique among the many active- and passive-targeting strategies currently employed by NP-delivery systems. pH-responsive eNP swelling is responsible for the extended residence at the target tumor site as well as the subsequent improvement in tumoral drug delivery and efficacy observed with paclitaxel-loaded eNPs (PTX-eNPs) compared to the standard clinical formulation of paclitaxel, Taxol®. Superior PTX-eNP efficacy is demonstrated in two different orthotopic models of peritoneal cancer-mesothelioma and ovarian cancer; in a third model-of pancreatic cancer-PTX-eNPs demonstrated comparable efficacy to Taxol with reduced toxicity. Furthermore, the unique structural and responsive characteristics of eNPs enable them to be used in three additional treatment paradigms, including: treatment of lymphatic metastases in breast cancer; use as a highly fluorescent probe to visually guide the resection of peritoneal implants; and, in a two-step delivery paradigm for concentrating separately administered NP and drug at a target site. This case study serves as an important example of using the targeted disease-state's pathophysiology to inform the NP design as well as the method of use of the delivery system. WIREs Nanomed Nanobiotechnol 2017, 9:e1451. doi: 10.1002/wnan.1451 For further resources related to this article, please visit the WIREs website. © 2017 Wiley Periodicals, Inc.

Genomic Target Database (GTD): A database of potential targets in human pathogenic bacteria

PubMed Central

Barh, Debmalya; Kumar, Anil; Misra, Amarendra Narayana

2009-01-01

A Genomic Target Database (GTD) has been developed having putative genomic drug targets for human bacterial pathogens. The selected pathogens are either drug resistant or vaccines are yet to be developed against them. The drug targets have been identified using subtractive genomics approaches and these are subsequently classified into Drug targets in pathogen specific unique metabolic pathways,Drug targets in host-pathogen common metabolic pathways, andMembrane localized drug targets. HTML code is used to link each target to its various properties and other available public resources. Essential resources and tools for subtractive genomic analysis, sub-cellular localization, vaccine and drug designing are also mentioned. To the best of authors knowledge, no such database (DB) is presently available that has listed metabolic pathways and membrane specific genomic drug targets based on subtractive genomics. Listed targets in GTD are readily available resource in developing drug and vaccine against the respective pathogen, its subtypes, and other family members. Currently GTD contains 58 drug targets for four pathogens. Shortly, drug targets for six more pathogens will be listed. Availability GTD is available at IIOAB website http://www.iioab.webs.com/GTD.htm. It can also be accessed at http://www.iioabdgd.webs.com.GTD is free for academic research and non-commercial use only. Commercial use is strictly prohibited without prior permission from IIOAB. PMID:20011153

Magnetic shielding investigation for a 6 MV in-line linac within the parallel configuration of a linac-MR system.

PubMed

Santos, D M; St Aubin, J; Fallone, B G; Steciw, S

2012-02-01

In our current linac-magnetic resonance (MR) design, a 6 MV in-line linac is placed along the central axis of the MR's magnet where the MR's fringe magnetic fields are parallel to the overall electron trajectories in the linac waveguide. Our previous study of this configuration comprising a linac-MR SAD of 100 cm and a 0.5 T superconducting (open, split) MR imager. It showed the presence of longitudinal magnetic fields of 0.011 T at the electron gun, which caused a reduction in target current to 84% of nominal. In this study, passive and active magnetic shielding was investigated to recover the linac output losses caused by magnetic deflections of electron trajectories in the linac within a parallel linac-MR configuration. Magnetic materials and complex shield structures were used in a 3D finite element method (FEM) magnetic field model, which emulated the fringe magnetic fields of the MR imagers. The effects of passive magnetic shielding was studied by surrounding the electron gun and its casing with a series of capped steel cylinders of various inner lengths (26.5-306.5 mm) and thicknesses (0.75-15 mm) in the presence of the fringe magnetic fields from a commercial MR imager. In addition, the effects of a shield of fixed length (146.5 mm) with varying thicknesses were studied against a series of larger homogeneous magnetic fields (0-0.2 T). The effects of active magnetic shielding were studied by adding current loops around the electron gun and its casing. The loop currents, separation, and location were optimized to minimize the 0.011 T longitudinal magnetic fields in the electron gun. The magnetic field solutions from the FEM model were added to a validated linac simulation, consisting of a 3D electron gun (using OPERA-3d/scala) and 3D waveguide (using comsol Multiphysics and PARMELA) simulations. PARMELA's target current and output phase-space were analyzed to study the linac's output performance within the magnetic shields. The FEM model above agreed within 1.5% with the manufacturer supplied fringe magnetic field isoline data. When passive magnetic shields are used, the target current is recoverable to greater than 99% of nominal for shield thicknesses greater than 0.75 mm. The optimized active shield which resulted in 100% target current recovery consists of two thin current rings 110 mm in diameter with 625 and 430 A-turns in each ring. With the length of the passive shield kept constant, the thickness of the shield had to be increased to achieve the same target current within the increased longitudinal magnetic fields. A ≥99% original target current is recovered with passive shield thicknesses >0.75 mm. An active shield consisting of two current rings of diameter of 110 mm with 625 and 430 A-turns fully recovers the loss that would have been caused by the magnetic fields. The minimal passive or active shielding requirements to essentially fully recover the current output of the linac in our parallel-configured linac-MR system have been determined and are easily achieved for practical implementation of the system.

Beam-induced back-streaming electron suppression analysis for an accelerator type neutron generator designed for 40Ar/39Ar geochronology.

PubMed

Waltz, Cory; Ayllon, Mauricio; Becker, Tim; Bernstein, Lee; Leung, Ka-Ngo; Kirsch, Leo; Renne, Paul; Bibber, Karl Van

2017-07-01

A facility based on a next-generation, high-flux D-D neutron generator has been commissioned and it is now operational at the University of California, Berkeley. The current generator designed for 40 Ar/ 39 Ar dating of geological materials produces nearly monoenergetic 2.45MeV neutrons at outputs of 10 8 n/s. The narrow energy range is advantageous relative to the 235 U fission spectrum neutrons due to (i) reduced 39 Ar recoil energy, (ii) minimized production of interfering argon isotopes from K, Ca, and Cl, and (iii) reduced total activity for radiological safety and waste generation. Calculations provided show that future conditioning at higher currents and voltages will allow for a neutron output of over 10 10 n/s, which is a necessary requirement for production of measurable quantities of 39 Ar through the reaction 39 K(n,p) 39 Ar. A significant problem encountered with increasing deuteron current was beam-induced electron backstreaming. Two methods of suppressing secondary electrons resulting from the deuterium beam striking the target were tested: the application of static electric and magnetic fields. Computational simulations of both techniques were done using a finite element analysis in COMSOL Multiphysics ® . Experimental tests verified these simulations. The most reliable suppression was achieved via the implementation of an electrostatic shroud with a voltage offset of -800V relative to the target. Copyright © 2017. Published by Elsevier Ltd.

Definition of a 5MW/61.5m wind turbine blade reference model.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Resor, Brian Ray

2013-04-01

A basic structural concept of the blade design that is associated with the frequently utilized %E2%80%9CNREL offshore 5-MW baseline wind turbine%E2%80%9D is needed for studies involving blade structural design and blade structural design tools. The blade structural design documented in this report represents a concept that meets basic design criteria set forth by IEC standards for the onshore turbine. The design documented in this report is not a fully vetted blade design which is ready for manufacture. The intent of the structural concept described by this report is to provide a good starting point for more detailed and targeted investigationsmore » such as blade design optimization, blade design tool verification, blade materials and structures investigations, and blade design standards evaluation. This report documents the information used to create the current model as well as the analyses used to verify that the blade structural performance meets reasonable blade design criteria.« less

Application of computer assisted combinatorial chemistry in antivirial, antimalarial and anticancer agents design

NASA Astrophysics Data System (ADS)

Burello, E.; Bologa, C.; Frecer, V.; Miertus, S.

Combinatorial chemistry and technologies have been developed to a stage where synthetic schemes are available for generation of a large variety of organic molecules. The innovative concept of combinatorial design assumes that screening of a large and diverse library of compounds will increase the probability of finding an active analogue among the compounds tested. Since the rate at which libraries are screened for activity currently constitutes a limitation to the use of combinatorial technologies, it is important to be selective about the number of compounds to be synthesized. Early experience with combinatorial chemistry indicated that chemical diversity alone did not result in a significant increase in the number of generated lead compounds. Emphasis has therefore been increasingly put on the use of computer assisted combinatorial chemical techniques. Computational methods are valuable in the design of virtual libraries of molecular models. Selection strategies based on computed physicochemical properties of the models or of a target compound are introduced to reduce the time and costs of library synthesis and screening. In addition, computational structure-based library focusing methods can be used to perform in silico screening of the activity of compounds against a target receptor by docking the ligands into the receptor model. Three case studies are discussed dealing with the design of targeted combinatorial libraries of inhibitors of HIV-1 protease, P. falciparum plasmepsin and human urokinase as potential antivirial, antimalarial and anticancer drugs. These illustrate library focusing strategies.

Evaluation and rational design of guide RNAs for efficient CRISPR/Cas9-mediated mutagenesis in Ciona.

PubMed

Gandhi, Shashank; Haeussler, Maximilian; Razy-Krajka, Florian; Christiaen, Lionel; Stolfi, Alberto

2017-05-01

The CRISPR/Cas9 system has emerged as an important tool for various genome engineering applications. A current obstacle to high throughput applications of CRISPR/Cas9 is the imprecise prediction of highly active single guide RNAs (sgRNAs). We previously implemented the CRISPR/Cas9 system to induce tissue-specific mutations in the tunicate Ciona. In the present study, we designed and tested 83 single guide RNA (sgRNA) vectors targeting 23 genes expressed in the cardiopharyngeal progenitors and surrounding tissues of Ciona embryo. Using high-throughput sequencing of mutagenized alleles, we identified guide sequences that correlate with sgRNA mutagenesis activity and used this information for the rational design of all possible sgRNAs targeting the Ciona transcriptome. We also describe a one-step cloning-free protocol for the assembly of sgRNA expression cassettes. These cassettes can be directly electroporated as unpurified PCR products into Ciona embryos for sgRNA expression in vivo, resulting in high frequency of CRISPR/Cas9-mediated mutagenesis in somatic cells of electroporated embryos. We found a strong correlation between the frequency of an Ebf loss-of-function phenotype and the mutagenesis efficacies of individual Ebf-targeting sgRNAs tested using this method. We anticipate that our approach can be scaled up to systematically design and deliver highly efficient sgRNAs for the tissue-specific investigation of gene functions in Ciona. Copyright © 2017 Elsevier Inc. All rights reserved.

MMP Inhibitors: Past, present and future.

PubMed

Cathcart, Jillian M; Cao, Jian

2015-06-01

  Development of inhibitors of matrix metalloproteinases (MMPs) has been fraught with challenges. Early compounds largely failed due to poor selectivity and bioavailability. Dose-limiting side effects, off-target interactions, and improperly designed clinical trials significantly impeded clinical success. As information becomes available and technology evolves, tools to combat these obstacles have been developed. Improved methods for high throughput screening and drug design have led to identification of compounds exhibiting high potency, binding affinity, and favorable pharmacokinetic profiles. Current research into MMP inhibitors employs innovative approaches for drug delivery methods and allosteric inhibitors. Such innovation is key for development of clinically successful compounds.

AC Loss Analysis of MgB2-Based Fully Superconducting Machines

NASA Astrophysics Data System (ADS)

Feddersen, M.; Haran, K. S.; Berg, F.

2017-12-01

Superconducting electric machines have shown potential for significant increase in power density, making them attractive for size and weight sensitive applications such as offshore wind generation, marine propulsion, and hybrid-electric aircraft propulsion. Superconductors exhibit no loss under dc conditions, though ac current and field produce considerable losses due to hysteresis, eddy currents, and coupling mechanisms. For this reason, many present machines are designed to be partially superconducting, meaning that the dc field components are superconducting while the ac armature coils are conventional conductors. Fully superconducting designs can provide increases in power density with significantly higher armature current; however, a good estimate of ac losses is required to determine the feasibility under the machines intended operating conditions. This paper aims to characterize the expected losses in a fully superconducting machine targeted towards aircraft, based on an actively-shielded, partially superconducting machine from prior work. Various factors are examined such as magnet strength, operating frequency, and machine load to produce a model for the loss in the superconducting components of the machine. This model is then used to optimize the design of the machine for minimal ac loss while maximizing power density. Important observations from the study are discussed.

Redesigning the specificity of protein-DNA interactions with Rosetta.

PubMed

Thyme, Summer; Baker, David

2014-01-01

Building protein tools that can selectively bind or cleave specific DNA sequences requires efficient technologies for modifying protein-DNA interactions. Computational design is one method for accomplishing this goal. In this chapter, we present the current state of protein-DNA interface design with the Rosetta macromolecular modeling program. The LAGLIDADG endonuclease family of DNA-cleaving enzymes, under study as potential gene therapy reagents, has been the main testing ground for these in silico protocols. At this time, the computational methods are most useful for designing endonuclease variants that can accommodate small numbers of target site substitutions. Attempts to engineer for more extensive interface changes will likely benefit from an approach that uses the computational design results in conjunction with a high-throughput directed evolution or screening procedure. The family of enzymes presents an engineering challenge because their interfaces are highly integrated and there is significant coordination between the binding and catalysis events. Future developments in the computational algorithms depend on experimental feedback to improve understanding and modeling of these complex enzymatic features. This chapter presents both the basic method of design that has been successfully used to modulate specificity and more advanced procedures that incorporate DNA flexibility and other properties that are likely necessary for reliable modeling of more extensive target site changes.

Selection is more intelligent than design: improving the affinity of a bivalent ligand through directed evolution.

PubMed

Ahmad, Kareem M; Xiao, Yi; Soh, H Tom

2012-12-01

Multivalent molecular interactions can be exploited to dramatically enhance the performance of an affinity reagent. The enhancement in affinity and specificity achieved with a multivalent construct depends critically on the effectiveness of the scaffold that joins the ligands, as this determines their positions and orientations with respect to the target molecule. Currently, no generalizable design rules exist for construction of an optimal multivalent ligand for targets with known structures, and the design challenge remains an insurmountable obstacle for the large number of proteins whose structures are not known. As an alternative to such design-based strategies, we report here a directed evolution-based method for generating optimal bivalent aptamers. To demonstrate this approach, we fused two thrombin aptamers with a randomized DNA sequence and used a microfluidic in vitro selection strategy to isolate scaffolds with exceptionally high affinities. Within five rounds of selection, we generated a bivalent aptamer that binds thrombin with an apparent dissociation constant (K(d)) <10 pM, representing a ∼200-fold improvement in binding affinity over the monomeric aptamers and a ∼15-fold improvement over the best designed bivalent construct. The process described here can be used to produce high-affinity multivalent aptamers and could potentially be adapted to other classes of biomolecules.

The Foundations Framework for Developing and Reporting New Models of Care for Multimorbidity

PubMed Central

Stokes, Jonathan; Man, Mei-See; Guthrie, Bruce; Mercer, Stewart W.; Salisbury, Chris; Bower, Peter

2017-01-01

PURPOSE Multimorbidity challenges health systems globally. New models of care are urgently needed to better manage patients with multimorbidity; however, there is no agreed framework for designing and reporting models of care for multimorbidity and their evaluation. METHODS Based on findings from a literature search to identify models of care for multimorbidity, we developed a framework to describe these models. We illustrate the application of the framework by identifying the focus and gaps in current models of care, and by describing the evolution of models over time. RESULTS Our framework describes each model in terms of its theoretical basis and target population (the foundations of the model) and of the elements of care implemented to deliver the model. We categorized elements of care into 3 types: (1) clinical focus, (2) organization of care, (3) support for model delivery. Application of the framework identified a limited use of theory in model design and a strong focus on some patient groups (elderly, high users) more than others (younger patients, deprived populations). We found changes in elements with time, with a decrease in models implementing home care and an increase in models offering extended appointments. CONCLUSIONS By encouragin greater clarity about the underpinning theory and target population, and by categorizing the wide range of potentially important elements of an intervention to improve care for patients with multimorbidity, the framework may be useful in designing and reporting models of care and help advance the currently limited evidence base. PMID:29133498

Accelerator driven neutron source design via beryllium target and 208Pb moderator for boron neutron capture therapy in alternative treatment strategy by Monte Carlo method.

PubMed

Khorshidi, Abdollah

2017-01-01

The reactor has increased its area of application into medicine especially boron neutron capture therapy (BNCT); however, accelerator-driven neutron sources can be used for therapy purposes. The present study aimed to discuss an alternative method in BNCT functions by a small cyclotron with low current protons based on Karaj cyclotron in Iran. An epithermal neutron spectrum generator was simulated with 30 MeV proton energy for BNCT purposes. A low current of 300 μA of the proton beam in spallation target concept via 9Be target was accomplished to model neutron spectrum using 208Pb moderator around the target. The graphite reflector and dual layer collimator were planned to prevent and collimate the neutrons produced from proton interactions. Neutron yield per proton, energy distribution, flux, and dose components in the simulated head phantom were estimated by MCNPX code. The neutron beam quality was investigated by diverse filters thicknesses. The maximum epithermal flux transpired using Fluental, Fe, Li, and Bi filters with thicknesses of 7.4, 3, 0.5, and 4 cm, respectively; as well as the epithermal to thermal neutron flux ratio was 161. Results demonstrated that the induced neutrons from a low energy and low current proton may be effective in tumor therapy using 208Pb moderator with average lethargy and also graphite reflector with low absorption cross section to keep the generated neutrons. Combination of spallation-based BNCT and proton therapy can be especially effective, if a high beam intensity cyclotron becomes available.

New advances in models and strategies for developing anti-obesity drugs

PubMed Central

Kim, Gilbert W.; Lin, Jieru E.; Blomain, Erik S.; Waldman, Scott A.

2014-01-01

Introduction Obesity is a worldwide pandemic. Obesity-related health and economic costs are staggering. Existing strategies to combat obesity through lifestyle improvements and medical intervention have had limited success. Pharmacotherapy, in combination with lifestyle modification, may play a vital role in reversing the disease burden. However, past and current weight-loss medications have had serious safety risks, notably cardiovascular and psychiatric events. Areas covered We review the strategies for designing new anti-obesity drugs by describing those currently in development. We describe their target, mechanism of action, and developmental or regulatory status. We also discuss the problem of weight regain following weight loss, and its relevance to the long-term success of anti-obesity pharmacotherapy. Expert opinion For weight management drugs to achieve the safety and efficacy required to be impactful, current studies are uncovering and characterizing new targets, including new signaling circuits and hormones regulating appetite and metabolism, and re-evaluating the role of pharmacotherapy in weight management. To avoid the safety failures of many past weight-loss drugs, the models and strategies covered in this article incorporate recent advances in knowledge and technology. We discuss the emergence of cGMP signaling as a potentially transformative target in weight management. Modulating cGMP signaling may represent an ideal goal for an anti-obesity pharmacotherapy, reflecting some of the major themes described in the present review: targeting pathways that are newly realized as relevant for weight management; promoting safety by re-purposing drugs that are safe, proven, and approved for clinical use; and having a synergistic effect on multiple, reinforcing pathways. PMID:23621300

Breaking-Cas—interactive design of guide RNAs for CRISPR-Cas experiments for ENSEMBL genomes

PubMed Central

Oliveros, Juan C.; Franch, Mònica; Tabas-Madrid, Daniel; San-León, David; Montoliu, Lluis; Cubas, Pilar; Pazos, Florencio

2016-01-01

The CRISPR/Cas technology is enabling targeted genome editing in multiple organisms with unprecedented accuracy and specificity by using RNA-guided nucleases. A critical point when planning a CRISPR/Cas experiment is the design of the guide RNA (gRNA), which directs the nuclease and associated machinery to the desired genomic location. This gRNA has to fulfil the requirements of the nuclease and lack homology with other genome sites that could lead to off-target effects. Here we introduce the Breaking-Cas system for the design of gRNAs for CRISPR/Cas experiments, including those based in the Cas9 nuclease as well as others recently introduced. The server has unique features not available in other tools, including the possibility of using all eukaryotic genomes available in ENSEMBL (currently around 700), placing variable PAM sequences at 5′ or 3′ and setting the guide RNA length and the scores per nucleotides. It can be freely accessed at: http://bioinfogp.cnb.csic.es/tools/breakingcas, and the code is available upon request. PMID:27166368

Allosteric Modulation of protein oligomerization: an emerging approach to drug design

NASA Astrophysics Data System (ADS)

Gabizon, Ronen; Friedler, Assaf

2014-03-01

Many disease-related proteins are in equilibrium between different oligomeric forms. The regulation of this equilibrium plays a central role in maintaining the activity of these proteins in vitro and in vivo. Modulation of the oligomerization equilibrium of proteins by molecules that bind preferentially to a specific oligomeric state is emerging as a potential therapeutic strategy that can be applied to many biological systems such as cancer and viral infections. The target proteins for such compounds are diverse in structure and sequence, and may require different approaches for shifting their oligomerization equilibrium. The discovery of such oligomerization-modulating compounds is thus achieved based on existing structural knowledge about the specific target proteins, as well as on their interactions with partner proteins or with ligands. In silico design and combinatorial tools such as peptide arrays and phage display are also used for discovering compounds that modulate protein oligomerization. The current review highlights some of the recent developments in the design of compounds aimed at modulating the oligomerization equilibrium of proteins, including the "shiftides" approach developed in our lab.

Magnetic configuration flexibility of snowflake divertor for HL-2M [Analysis of snowflake divertor configurations for HL-2M

DOE PAGES

Zheng, G. Y.; Xu, X. Q.; Ryutov, D. D.; ...

2014-07-09

HL-2M (Li, 2013 [1]) is a tokamak device that is under construction. Based on the magnetic coils design of HL-2M, four kinds of divertor configurations are calculated by CORSICA code (Pearlstein et al., 2001 [2]) with the same main plasma parameters, which are standard divertor, exact snowflake divertor, snowflake-plus divertor and snowflake-minus divertor configurations. The potential properties of these divertors are analyzed and presented in this paper: low poloidal field area around X-point, connection length from outside mid-plane to the primary X-point, target plate design and magnetic field shear. The results show that the snowflake configurations not only can reducemore » the heat load at divertor target plates, but also may improve the magneto-hydrodynamic stability by stronger magnetic shear at the edge. Furthermore, a new divertor configuration, named “tripod divertor”, is designed by adjusting the positions of the two X-points according to plasma parameters and magnetic coils current of HL-2M.« less

Current beliefs and practice patterns among urologists regarding prostate magnetic resonance imaging and magnetic resonance-targeted biopsy.

PubMed

Muthigi, Akhil; Sidana, Abhinav; George, Arvin K; Kongnyuy, Michael; Maruf, Mahir; Valayil, Subin; Wood, Bradford J; Pinto, Peter A

2017-01-01

Multiparametric magnetic resonance imaging (MRI) and magnetic resonance (MR) -targeted biopsy have a growing role in the screening and evaluation of prostate cancer. We aim to evaluate the current knowledge, attitude, and practice patterns of urologists regarding this new technique. An anonymous online questionnaire was designed to collect information on urologists' beliefs and use of prostate multiparametric MRI and MR-targeted biopsy. The survey was sent to members of the Society of Urologic Oncology, the Endourological Society, and European Association of Urology. Multivariate logistic regression analysis was performed to determine predictors for use of prostate MRI and MR-targeted biopsy. A total of 302 responses were received (Endourological Society: 175, European Association of Urology: 23, and Society of Urologic Oncology: 104). Most respondents (83.6%) believe MR-targeted biopsy to be moderately to extremely beneficial in the evaluation of prostate cancer. Overall, 85.7% of responders use prostate MRI in their practice, and 63.0% use MR-targeted biopsy. The 2 most common settings for use of MR-targeted biopsy include patients with history of prior negative biopsy result (96.3%) and monitoring patients on active surveillance (72.5%). In those who do not use MR-targeted biopsy, the principal reasons were lack of necessary infrastructure (64.1%) and prohibitive costs (48.1%). On multivariate logistic regression analysis, practice in an academic setting (1.86 [1.02-3.40], P = 0.043) and performing greater than 25 radical prostatectomies per year (2.32 [1.18-4.56], P = 0.015) remained independent predictors for using MR-targeted biopsy. Most respondents of our survey look favorably on use of prostate MRI and MR-targeted biopsy in clinical practice. Over time, reduction in fixed costs and easier access to equipment may lead to further dissemination of this novel and potentially transformative technology. Published by Elsevier Inc.

Gene editing for skin diseases: designer nucleases as tools for gene therapy of skin fragility disorders.

PubMed

March, Oliver P; Reichelt, Julia; Koller, Ulrich

2018-04-01

What is the topic of this review? This review concerns current gene editing strategies for blistering skin diseases with respect to individual genetic constellations and distinct conditions. What advances does it highlight? Specificity and safety dominate the discussion of gene editing applications for gene therapy, where a number of tools are implemented. Recent developments in this rapidly progressing field pose further questions regarding which tool is best suited for each particular use. The current treatment of inherited blistering skin diseases, such as epidermolysis bullosa (EB), is largely restricted to wound care and pain management. More effective therapeutic strategies are urgently required, and targeting the genetic basis of these severe diseases is now within reach. Here, we describe current gene editing tools and their potential to correct gene function in monogenetic blistering skin diseases. We present the features of the most frequently used gene editing techniques, transcription activator-like effector nuclease (TALEN) and clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9), determining their preferential application for specific genetic conditions, including the type of mutational inheritance, the targeting site within the gene or the possibility to target the mutation specifically. Both tools have traits beneficial in specific situations. Promising developments in the field engender gene editing as a potentially powerful therapeutic option for future clinical applications. © 2017 The Authors. Experimental Physiology © 2017 The Physiological Society.

Multitarget transcranial direct current stimulation for freezing of gait in Parkinson's disease.

PubMed

Dagan, Moria; Herman, Talia; Harrison, Rachel; Zhou, Junhong; Giladi, Nir; Ruffini, Giulio; Manor, Brad; Hausdorff, Jeffrey M

2018-04-01

Recent findings suggest that transcranial direct current stimulation of the primary motor cortex may ameliorate freezing of gait. However, the effects of multitarget simultaneous stimulation of motor and cognitive networks are mostly unknown. The objective of this study was to evaluate the effects of multitarget transcranial direct current stimulation of the primary motor cortex and left dorsolateral prefrontal cortex on freezing of gait and related outcomes. Twenty patients with Parkinson's disease and freezing of gait received 20 minutes of transcranial direct current stimulation on 3 separate visits. Transcranial direct current stimulation targeted the primary motor cortex and left dorsolateral prefrontal cortex simultaneously, primary motor cortex only, or sham stimulation (order randomized and double-blinded assessments). Participants completed a freezing of gait-provoking test, the Timed Up and Go, and the Stroop test before and after each transcranial direct current stimulation session. Performance on the freezing of gait-provoking test (P = 0.010), Timed Up and Go (P = 0.006), and the Stroop test (P = 0.016) improved after simultaneous stimulation of the primary motor cortex and left dorsolateral prefrontal cortex, but not after primary motor cortex only or sham stimulation. Transcranial direct current stimulation designed to simultaneously target motor and cognitive regions apparently induces immediate aftereffects in the brain that translate into reduced freezing of gait and improvements in executive function and mobility. © 2018 International Parkinson and Movement Disorder Society. © 2018 International Parkinson and Movement Disorder Society.

Development of Design Rules for Reliable Antisense RNA Behavior in E. coli.

PubMed

Hoynes-O'Connor, Allison; Moon, Tae Seok

2016-12-16

A key driver of synthetic biology is the development of designable genetic parts with predictable behaviors that can be quickly implemented in complex genetic systems. However, the intrinsic complexity of gene regulation can make the rational design of genetic parts challenging. This challenge is apparent in the design of antisense RNA (asRNA) regulators. Though asRNAs are well-known regulators, the literature governing their design is conflicting and leaves the synthetic biology community without clear asRNA design rules. The goal of this study is to perform a comprehensive experimental characterization and statistical analysis of 121 unique asRNA regulators in order to resolve the conflicts that currently exist in the literature. asRNAs usually consist of two regions, the Hfq binding site and the target binding region (TBR). First, the behaviors of several high-performing Hfq binding sites were compared, in terms of their ability to improve repression efficiencies and their orthogonality. Next, a large-scale analysis of TBR design parameters identified asRNA length, the thermodynamics of asRNA-mRNA complex formation, and the percent of target mismatch as key parameters for TBR design. These parameters were used to develop simple asRNA design rules. Finally, these design rules were applied to construct both a simple and a complex genetic circuit containing different asRNAs, and predictable behavior was observed in both circuits. The results presented in this study will drive synthetic biology forward by providing useful design guidelines for the construction of asRNA regulators with predictable behaviors.

Autonomous dexterous end-effectors for space robotics

NASA Technical Reports Server (NTRS)

Bekey, George A.; Iberall, Thea; Liu, Huan

1989-01-01

The development of a knowledge-based controller is summarized for the Belgrade/USC robot hand, a five-fingered end effector, designed for maximum autonomy. The biological principles of the hand and its architecture are presented. The conceptual and software aspects of the grasp selection system are discussed, including both the effects of the geometry of the target object and the task to be performed. Some current research issues are presented.

Navy Virginia (SSN-774) Class Attack Submarine Procurement: Background and Issues for Congress

DTIC Science & Technology

2010-07-08

current and future Virginia Class submarines once they mature—advanced electromagnetic signature reduction (AESR), a conformal acoustic velocity sensor...WAA is a sensor array that is designed to detect the vibrations and acoustic signatures of targets. The Navy has stated that CAVES WAA could save...Active Shaft Grounding System, Circuit D, Ship Service Turbine Generator magnetic levitation bearings / throttle control system, etc.); • Special

Evolving phage vectors for cell targeted gene delivery.

PubMed

Larocca, David; Burg, Michael A; Jensen-Pergakes, Kristen; Ravey, Edward Prenn; Gonzalez, Ana Maria; Baird, Andrew

2002-03-01

We adapted filamentous phage vectors for targeted gene delivery to mammalian cells by inserting a mammalian reporter gene expression cassette (GFP) into the vector backbone and fusing the pIII coat protein to a cell targeting ligand (i.e. FGF2, EGF). Like transfection with animal viral vectors, targeted phage gene delivery is concentration, time, and ligand dependent. Importantly, targeted phage particles are specific for the appropriate target cell surface receptor. Phage have distinct advantages over existing gene therapy vectors because they are simple, economical to produce at high titer, have no intrinsic tropism for mammalian cells, and are relatively simple to genetically modify and evolve. Initially transduction by targeted phage particles was low resulting in foreign gene expression in 1-2% of transfected cells. We increased transduction efficiency by modifying both the transfection protocol and vector design. For example, we stabilized the display of the targeting ligand to create multivalent phagemid-based vectors with transduction efficiencies of up to 45% in certain cell lines when combined with genotoxic treatment. Taken together, these studies establish that the efficiency of phage-mediated gene transfer can be significantly improved through genetic modification. We are currently evolving phage vectors with enhanced cell targeting, increased stability, reduced immunogenicity and other properties suitable for gene therapy.

To exploit the tumor microenvironment: Since the EPR effect fails in the clinic, what is the future of nanomedicine?

PubMed

Danhier, F

2016-12-28

Tumor targeting by nanomedicine-based therapeutics has emerged as a promising approach to overcome the lack of specificity of conventional chemotherapeutic agents and to provide clinicians the ability to overcome shortcomings of current cancer treatment. The major underlying mechanism of the design of nanomedicines was the Enhanced Permeability and Retention (EPR) effect, considered as the "royal gate" in the drug delivery field. However, after the publication of thousands of research papers, the verdict has been handed down: the EPR effect works in rodents but not in humans! Thus the basic rationale of the design and development of nanomedicines in cancer therapy is failing making it necessary to stop claiming efficacy gains via the EPR effect, while tumor targeting cannot be proved in the clinic. It is probably time to dethrone the EPR effect and to ask the question: what is the future of nanomedicines without the EPR effect? The aim of this review is to provide a general overview on (i) the current state of the EPR effect, (ii) the future of nanomedicine and (iii) the strategies of modulation of the tumor microenvironment to improve the delivery of nanomedicine. Copyright © 2016 Elsevier B.V. All rights reserved.

Under the radar--how the tobacco industry targets youth in Australia.

PubMed

Harper, Todd A; Martin, Jane E

2002-12-01

Tobacco consumption has been declining in Australia since the 1970s when controls on advertising were first introduced. Since this time, legislation has been progressively introduced, severely restricting tobacco advertising and promotion in the mainstream media. This has resulted in limited opportunities for the tobacco industry to reach new smokers, particularly young people. This paper outlines marketing strategies used by tobacco companies and their advertising agencies to reach this group; it examines how the industry exploits loopholes in current legislation and identifies new promotional opportunities. Increasingly, the industry has targeted young people through film, dance parties, nightclubs, fashion shows, e-mail and the internet. The industry is also capitalizing on promoting pack design elements and enhancing them through event promotion. Unless restrictions on tobacco marketing and promotion are comprehensive they undermine the effectiveness of those already in place and will continue to be exploited by the tobacco industry. The recent announcement by the Federal government to reassess the current legislative restrictions in light of these new marketing trends is welcome. The removal of all incentives to promote tobacco products, including imagery associated with the pack and its design, is essential in removing one of the key factors influencing the uptake and prevalence of smoking in youth.

The Current Crisis in Emergency Care and the Impact on Disaster Preparedness

PubMed Central

Cherry, Robert A; Trainer, Marcia

2008-01-01

Background The Homeland Security Act (HSA) of 2002 provided for the designation of a critical infrastructure protection program. This ultimately led to the designation of emergency services as a targeted critical infrastructure. In the context of an evolving crisis in hospital-based emergency care, the extent to which federal funding has addressed disaster preparedness will be examined. Discussion After 9/11, federal plans, procedures and benchmarks were mandated to assure a unified, comprehensive disaster response, ranging from local to federal activation of resources. Nevertheless, insufficient federal funding has contributed to a long-standing counter-trend which has eroded emergency medical care. The causes are complex and multifactorial, but they have converged to present a severely overburdened system that regularly exceeds emergency capacity and capabilities. This constant acute overcrowding, felt in communities all across the country, indicates a nation at risk. Federal funding has not sufficiently prioritized the improvements necessary for an emergency care infrastructure that is critical for an all hazards response to disaster and terrorist emergencies. Summary Currently, the nation is unable to meet presidential preparedness mandates for emergency and disaster care. Federal funding strategies must therefore be re-prioritized and targeted in a way that reasonably and consistently follows need. PMID:18452615

[Clinical and health economic challenges of personalized medicine].

PubMed

Brüggenjürgen, B; Kornbluth, L; Ferrara, J V; Willich, S N

2012-05-01

Healthcare systems across the globe are currently challenged by aging populations, increases in chronic diseases and the difficult task of managing a healthcare budget. In this health economic climate, personalized medicine promises not only an improvement in healthcare delivery but also the possibility of more cost-effective therapies. It is important to remember, however, that personalized medicine has the potential to both increase and decrease costs. Each targeted therapy must be evaluated individually. However, standard clinical trial design is not suitable for personalized therapies. Therefore, both scientists and regulatory authorities will need to accept innovative study designs in order to validate personalized therapies. Hence correct economic evaluations are difficult to carry out due to lack of clear clinical evidence, longitudinal accounting and experience with patient/clinician behavior in the context of personalized medicine. In terms of reimbursement, payers, pharmaceutical companies and companion diagnostic manufacturers will also need to explore creative risk-sharing concepts. Germany is no exception to the challenges that face personalized medicine and for personalized medicine to really become the future of medicine many health economic challenges first need to be overcome. The health economic implications of personalized medicine remain unclear but it is certain that the expansion of targeted therapies in current healthcare systems will create a host of challenges.

Driving Toward Precision Medicine for Acute Leukemias: Are We There Yet?

PubMed

Chung, Clement; Ma, Hilary

2017-09-01

Despite recent progress in the understanding of the molecular basis of acute leukemias, treatment options for these diseases have not changed significantly over the last few decades. We present a nonexhaustive summary of the current cytogenetic and molecular changes associated with acute leukemias in disease prognostication and potential targeted therapies. An emerging paradigm is that many genetic or molecular alterations target similar signal transduction, transcriptional, and epigenetic pathways. Some of these targets may be used as predictive biomarkers for the development of novel targeted therapies that depart significantly from conventional chemotherapy, the current mainstay for the treatment of acute leukemias. Established leukemia-specific predictive biomarkers for precision medicine include those genetic lesions such as BCR-ABL1 for Philadelphia-positive acute lymphoblastic leukemia and PML-RARα for acute promyelocytic leukemia. Evidence indicates that targeted therapy for FLT-ITD gene mutations with small-molecule tyrosine kinase inhibitors can extend its use from relapsed disease to up-front induction therapy. Core-binding factor acute myeloid leukemia in adults predicts benefit with high-dose cytarabine in the absence of KIT mutation. Although risk-adapted therapy based on genetic abnormalities in acute leukemias has allowed the beginning of personalized treatment and selective use of hematopoietic stem cell transplantation, the prognostic and/or predictive value of many novel mutations of the acute leukemic genome is yet to be elucidated. Many challenges lie ahead in targeted therapies due to overlapping of chromosomal and molecular lesions as well as other limiting factors. Future work should focus on the understanding of pathogenetic changes that lead to leukemogenesis, which may guide the rational design of new targeted therapies and make the drive toward precision medicine for acute leukemias one step closer. © 2017 Pharmacotherapy Publications, Inc.

On the utility of within-participant research design when working with patients with neurocognitive disorders

PubMed Central

Steingrimsdottir, Hanna Steinunn; Arntzen, Erik

2015-01-01

Within-participant research designs are frequently used within the field of behavior analysis to document changes in behavior before, during, and after treatment. The purpose of the present article is to show the utility of within-participant research designs when working with older adults with neurocognitive disorders. The reason for advocating for these types of experimental designs is that they provide valid information about whether the changes that are observed in the dependent variable are caused by manipulations of the independent variable, or whether the change may be due to other variables. We provide examples from published papers where within-participant research design has been used with patients with neurocognitive disorders. The examples vary somewhat, demonstrating possible applications. It is our suggestion that the within-participant research design may be used more often with the targeted client group than is documented in the literature at the current date. PMID:26229453

On the utility of within-participant research design when working with patients with neurocognitive disorders.

PubMed

Steingrimsdottir, Hanna Steinunn; Arntzen, Erik

2015-01-01

Within-participant research designs are frequently used within the field of behavior analysis to document changes in behavior before, during, and after treatment. The purpose of the present article is to show the utility of within-participant research designs when working with older adults with neurocognitive disorders. The reason for advocating for these types of experimental designs is that they provide valid information about whether the changes that are observed in the dependent variable are caused by manipulations of the independent variable, or whether the change may be due to other variables. We provide examples from published papers where within-participant research design has been used with patients with neurocognitive disorders. The examples vary somewhat, demonstrating possible applications. It is our suggestion that the within-participant research design may be used more often with the targeted client group than is documented in the literature at the current date.

National Launch System Space Transportation Main Engine

NASA Technical Reports Server (NTRS)

Hoodless, Ralph M., Jr.; Monk, Jan C.; Cikanek, Harry A., III

1991-01-01

The present liquid-oxygen/liquid-hydrogen engine is described as meeting the specific requirements of the National Launch System (NLS) Program including cost-effectiveness and robustness. An overview of the NLS and its objectives is given which indicates that the program aims to develop a flexible launch system to meet security, civil, and commercial needs. The Space Transportation Main Engine (STME) provides core and boost propulsion for the 1.5-stage vehicle and core propulsion for the solid booster vehicle. The design incorporates step-throttling, order-of-magnitude reductions in welds, and configuration targets designed to optimize robustness. The STME is designed to provide adaptable and dependable propulsion while minimizing recurring costs and is designed to meet the needs of NLS and other typical space-transportation programs currently being planned.

Space Launch Systems Block 1B Preliminary Navigation System Design

NASA Technical Reports Server (NTRS)

Oliver, T. Emerson; Park, Thomas; Anzalone, Evan; Smith, Austin; Strickland, Dennis; Patrick, Sean

2018-01-01

NASA is currently building the Space Launch Systems (SLS) Block 1 launch vehicle for the Exploration Mission 1 (EM-1) test flight. In parallel, NASA is also designing the Block 1B launch vehicle. The Block 1B vehicle is an evolution of the Block 1 vehicle and extends the capability of the NASA launch vehicle. This evolution replaces the Interim Cryogenic Propulsive Stage (ICPS) with the Exploration Upper Stage (EUS). As the vehicle evolves to provide greater lift capability, increased robustness for manned missions, and the capability to execute more demanding missions so must the SLS Integrated Navigation System evolved to support those missions. This paper describes the preliminary navigation systems design for the SLS Block 1B vehicle. The evolution of the navigation hard-ware and algorithms from an inertial-only navigation system for Block 1 ascent flight to a tightly coupled GPS-aided inertial navigation system for Block 1B is described. The Block 1 GN&C system has been designed to meet a LEO insertion target with a specified accuracy. The Block 1B vehicle navigation system is de-signed to support the Block 1 LEO target accuracy as well as trans-lunar or trans-planetary injection accuracy. Additionally, the Block 1B vehicle is designed to support human exploration and thus is designed to minimize the probability of Loss of Crew (LOC) through high-quality inertial instruments and robust algorithm design, including Fault Detection, Isolation, and Recovery (FDIR) logic.

Broadband Liner Optimization for the Source Diagnostic Test Fan

NASA Technical Reports Server (NTRS)

Nark, Douglas M.; Jones, Michael G.

2012-01-01

The broadband component of fan noise has grown in relevance with the utilization of increased bypass ratio and advanced fan designs. Thus, while the attenuation of fan tones remains paramount, the ability to simultaneously reduce broadband fan noise levels has become more appealing. This paper describes a broadband acoustic liner optimization study for the scale model Source Diagnostic Test fan. Specifically, in-duct attenuation predictions with a statistical fan source model are used to obtain optimum impedance spectra over a number of flow conditions for three liner locations in the bypass duct. The predicted optimum impedance information is then used with acoustic liner modeling tools to design liners aimed at producing impedance spectra that most closely match the predicted optimum values. Design selection is based on an acceptance criterion that provides the ability to apply increased weighting to specific frequencies and/or operating conditions. Typical tonal liner designs targeting single frequencies at one operating condition are first produced to provide baseline performance information. These are followed by multiple broadband design approaches culminating in a broadband liner targeting the full range of frequencies and operating conditions. The broadband liner is found to satisfy the optimum impedance objectives much better than the tonal liner designs. In addition, the broadband liner is found to provide better attenuation than the tonal designs over the full range of frequencies and operating conditions considered. Thus, the current study successfully establishes a process for the initial design and evaluation of novel broadband liner concepts for complex engine configurations.

Insect odorant receptors are molecular targets of the insect repellent DEET.

PubMed

Ditzen, Mathias; Pellegrino, Maurizio; Vosshall, Leslie B

2008-03-28

DEET (N,N-diethyl-meta-toluamide) is the world's most widely used topical insect repellent, with broad effectiveness against most insects. Its mechanism of action and molecular target remain unknown. Here, we show that DEET blocks electrophysiological responses of olfactory sensory neurons to attractive odors in Anopheles gambiae and Drosophila melanogaster. DEET inhibits behavioral attraction to food odors in Drosophila, and this inhibition requires the highly conserved olfactory co-receptor OR83b. DEET inhibits odor-evoked currents mediated by the insect odorant receptor complex, comprising a ligand-binding subunit and OR83b. We conclude that DEET masks host odor by inhibiting subsets of heteromeric insect odorant receptors that require the OR83b co-receptor. The identification of candidate molecular targets for the action of DEET may aid in the design of safer and more effective insect repellents.

Advances in Targeted Pesticides with Environmentally Responsive Controlled Release by Nanotechnology

PubMed Central

Huang, Bingna; Chen, Feifei; Shen, Yue; Wang, Yan; Sun, Changjiao; Zhao, Xiang; Cui, Bo; Gao, Fei; Zeng, Zhanghua; Cui, Haixin

2018-01-01

Pesticides are the basis for defending against major biological disasters and important for ensuring national food security. Biocompatible, biodegradable, intelligent, and responsive materials are currently an emerging area of interest in the field of efficient, safe, and green pesticide formulation. Using nanotechnology to design and prepare targeted pesticides with environmentally responsive controlled release via compound and chemical modifications has also shown great potential in creating novel formulations. In this review, special attention has been paid to intelligent pesticides with precise controlled release modes that can respond to micro-ecological environment changes such as light-sensitivity, thermo-sensitivity, humidity sensitivity, soil pH, and enzyme activity. Moreover, establishing intelligent and controlled pesticide release technologies using nanomaterials are reported. These technologies could increase pesticide-loading, improve the dispersibility and stability of active ingredients, and promote target ability. PMID:29439498

The “curved lead pathway” method to enable a single lead to reach any two intracranial targets

NASA Astrophysics Data System (ADS)

Ding, Chen-Yu; Yu, Liang-Hong; Lin, Yuan-Xiang; Chen, Fan; Lin, Zhang-Ya; Kang, De-Zhi

2017-01-01

Deep brain stimulation is an effective way to treat movement disorders, and a powerful research tool for exploring brain functions. This report proposes a “curved lead pathway” method for lead implantation, such that a single lead can reach in sequence to any two intracranial targets. A new type of stereotaxic system for implanting a curved lead to the brain of human/primates was designed, the auxiliary device needed for this method to be used in rat/mouse was fabricated and verified in rat, and the Excel algorithm used for automatically calculating the necessary parameters was implemented. This “curved lead pathway” method of lead implantation may complement the current method, make lead implantation for multiple targets more convenient, and expand the experimental techniques of brain function research.

Design and Implementation of the Automated Rendezvous Targeting Algorithms for Orion

NASA Technical Reports Server (NTRS)

DSouza, Christopher; Weeks, Michael

2010-01-01

The Orion vehicle will be designed to perform several rendezvous missions: rendezvous with the ISS in Low Earth Orbit (LEO), rendezvous with the EDS/Altair in LEO, a contingency rendezvous with the ascent stage of the Altair in Low Lunar Orbit (LLO) and a contingency rendezvous in LLO with the ascent and descent stage in the case of an aborted lunar landing. Therefore, it is not difficult to realize that each of these scenarios imposes different operational, timing, and performance constraints on the GNC system. To this end, a suite of on-board guidance and targeting algorithms have been designed to meet the requirement to perform the rendezvous independent of communications with the ground. This capability is particularly relevant for the lunar missions, some of which may occur on the far side of the moon. This paper will describe these algorithms which are designed to be structured and arranged in such a way so as to be flexible and able to safely perform a wide variety of rendezvous trajectories. The goal of the algorithms is not to merely fly one specific type of canned rendezvous profile. Conversely, it was designed from the start to be general enough such that any type of trajectory profile can be flown.(i.e. a coelliptic profile, a stable orbit rendezvous profile, and a expedited LLO rendezvous profile, etc) all using the same rendezvous suite of algorithms. Each of these profiles makes use of maneuver types which have been designed with dual goals of robustness and performance. They are designed to converge quickly under dispersed conditions and they are designed to perform many of the functions performed on the ground today. The targeting algorithms consist of a phasing maneuver (NC), an altitude adjust maneuver (NH), and plane change maneuver (NPC), a coelliptic maneuver (NSR), a Lambert targeted maneuver, and several multiple-burn targeted maneuvers which combine one of more of these algorithms. The derivation and implementation of each of these algorithms will be discussed in detail, as well and the Rendezvous Targeting "wrapper" which will sequentially tie them all together into a single onboard targeting tool which can produce a final integrated rendezvous trajectory. In a similar fashion, the various guidance modes available for flying out each of these maneuvers will be discussed as well. This paradigm of having the onboard guidance & targeting capability described above is different than the way the Space Shuttle has operated thus far. As a result, a discussion of these differences in terms of operations and ground and crew intervention will also be discussed. However, the general framework of how the mission designers on the ground first perform all mission design and planning functions, and then uplink that burn plan to the vehicle ensures that the ground will be involved to ensure safety and reliability. The only real difference is which of these functions will be done onboard vs. on the ground as done currently. Finally, this paper will describe the performance of each of these algorithms individually as well as the entire suite of algorithms as applied to the Orion ISS and EDS/Altair rendezvous missions in LEO. These algorithms have been incorporated in both a Linear Covariance environment and a Monte Carlo environment and the results of these dispersion analyses will be presented in the paper as well.

Molecular targets for flavivirus drug discovery

PubMed Central

Sampath, Aruna; Padmanabhan, R.

2009-01-01

Flaviviruses are a major cause of infectious disease in humans. Dengue virus causes an estimated 50 million cases of febrile illness each year, including an increasing number of cases of hemorrhagic fever. West Nile virus, which recently spread from the Mediterranean basin to the Western Hemisphere, now causes thousands of sporadic cases of encephalitis annually. Despite the existence of licensed vaccines, yellow fever, Japanese encephalitis and tick-borne encephalitis also claim many thousands of victims each year across their vast endemic areas. Antiviral therapy could potentially reduce morbidity and mortality from flavivirus infections, but no effective drugs are currently available. This article introduces a collection of papers in Antiviral Research on molecular targets for flavivirus antiviral drug design and murine models of dengue virus disease that aims to encourage drug development efforts. After reviewing the flavivirus replication cycle, we discuss the envelope glycoprotein, NS3 protease, NS3 helicase, NS5 methyltransferase and NS5 RNA-dependent RNA polymerase as potential drug targets, with special attention being given to the viral protease. The other viral proteins are the subject of individual articles in the journal. Together, these papers highlight current status of drug discovery efforts for flavivirus diseases and suggest promising areas for further research. PMID:18796313

Gene therapy to target ER stress in brain diseases.

PubMed

Valenzuela, Vicente; Martínez, Gabriela; Duran-Aniotz, Claudia; Hetz, Claudio

2016-10-01

Gene therapy based on the use of Adeno-associated viruses (AAVs) is emerging as a safe and stable strategy to target molecular pathways involved in a variety of brain diseases. Endoplasmic reticulum (ER) stress is proposed as a transversal feature of most animal models and clinical samples from patients affected with neurodegenerative diseases. Manipulation of the unfolded protein response (UPR), a major homeostatic reaction under ER stress conditions, had proved beneficial in diverse models of neurodegeneration. Although increasing number of drugs are available to target ER stress, the use of small molecules to treat chronic brain diseases is challenging because of poor blood brain barrier permeability and undesirable side effects due to the role of the UPR in the physiology of peripheral organs. Gene therapy is currently considered a possible future alternative to circumvent these problems by the delivery of therapeutic agents to selective regions and cell types of the nervous system. Here we discuss current efforts to design gene therapy strategies to alleviate ER stress on a disease context. This article is part of a Special Issue entitled SI:ER stress. Copyright © 2016 Elsevier B.V. All rights reserved.

An overview of the therapeutic potential of regenerative medicine in cutaneous wound healing.

PubMed

Pang, Calver; Ibrahim, Amel; Bulstrode, Neil W; Ferretti, Patrizia

2017-06-01

The global burden of disease associated with wounds is an increasingly significant public health concern. Current treatments are often expensive, time-consuming and limited in their efficacy in chronic wounds. The challenge of overcoming current barriers associated with wound care requires innovative management techniques. Regenerative medicine is an emerging field of research that focuses on the repair, replacement or regeneration of cells, tissues or organs to restore impaired function. This article provides an overview of the pathophysiology of wound healing and reviews the latest evidence on the application of the principal components of regenerative medicine (growth factors, stem cell transplantation, biomaterials and tissue engineering) as therapeutic targets. Improved knowledge and understanding of the pathophysiology of wound healing has pointed to new therapeutic targets. Regenerative medicine has the potential to underpin the design of specific target therapies in acute and chronic wound healing. This personalised approach could eventually reduce the burden of disease associated with wound healing. Further evidence is required in the form of large animal studies and clinical trials to assess long-term efficacy and safety of these new treatments. © 2017 Medicalhelplines.com Inc and John Wiley & Sons Ltd.

Conceptual design of the EU DEMO EC-system: main developments and R&D achievements

NASA Astrophysics Data System (ADS)

Granucci, G.; Aiello, G.; Alberti, S.; Avramidis, K. A.; Braunmüller, F.; Bruschi, A.; Chelis, J.; Franck, J.; Figini, L.; Gantenbein, G.; Garavaglia, S.; Grossetti, G.; Illy, S.; Ioannidis, Z.; Jelonnek, J.; Kalaria, P.; Latsas, G.; Moro, A.; Pagonakis, I. Gr.; Peponis, D.; Poli, E.; Rispoli, N.; Rzesnicki, T.; Scherer, T.; Strauss, D.; Thumm, M.; Tigelis, I.; Tsironis, C.; Wu, C.; Franke, T.; Tran, M. Q.

2017-11-01

For the development of a DEMOnstration Fusion Power Plant the design of auxiliary heating systems is a key activity in order to achieve controlled burning plasma. The present heating mix considers electron cyclotron resonance heating (ECRH), neutral beam injection (NBI) and ion cyclotron resonance heating (ICRH) with a target power to the plasma of about 50 MW for each system. The main tasks assigned to the EC system are plasma breakdown and assisted start-up, heating to L-H transition and plasma current ramp up to burn, MHD stability control and assistance in plasma current ramp down. The consequent requirements are used for the conceptual design of the EC system, from the RF source to the launcher, with an extensive R&D program focused on relevant technologies to be developed. Gyrotron: the R&D and Advanced Developments on EC RF sources are targeting for gyrotrons operating at 240 GHz, considered as optimum EC Current Drive frequency in case of higher magnetic field than for the 2015 EU DEMO1 baseline. Multi-purpose (multi-frequency) and frequency step-tunable gyrotrons are under investigation to increase the flexibility of the system. As main targets an output power of significantly above 1 MW (target: 2 MW) and a total efficiency higher than 60% are set. The principle feasibility at limits of a 236 GHz, conventional-cavity and, alternatively, of a 238 GHz coaxial-cavity gyrotron are under investigation together with the development of a synthetic diamond Brewster-angle window technology. Advanced developments are on-going in the field of multi-stage depressed collector technologies. Transmission line (TL): different TL options are under investigation and a preliminary study of an evacuated quasi-optical multiple-beam TL, considered for a hybrid solution, is presented and discussed in terms of layout, dimensions and theoretical losses. Launcher: remote steering antennas have been considered as a possible launcher solution especially under the constraints to avoid movable mirrors close to the plasma. With dedicated beam tracing calculations, the deposition locations coverage and the wave absorption efficiency have been investigated, considering a selection of frequencies, injection angles and launching points. An option for the EC system structure is proposed in clusters, in order to allow the necessary redundancy and flexibility to guarantee the required EC power in the different phases of the plasma pulse. Number and composition of the clusters are analysed to have high availability and therefore maximum reliability with a minimum number of components.

Integration of the real-time tracking gradiometer (RTG) aboard the autonomous underwater vehicle (AUV) Morpheus

NASA Astrophysics Data System (ADS)

Allen, George I.; Matthews, Robert; Wynn, Michael

2001-10-01

In keeping with the Navy's policy to remove humans from harms way, the Autonomous Underwater Vehicle (AUV) is replacing human divers for many missions. The Advanced Marine Systems Lab at Florida Atlantic University (FAU) has developed a small, magnetically friendly, modular plastic AUV called Morpheus designed for coastal applications and especially suited for very shallow water (VSW) mine reconnaissance. Currently employed sensor technologies on AUVs have certain deficiencies and limitations when used across the wide gamut of naval targets and environments, and a strong requirement exists for a sensor or sensors to fill these niches. The Real-time Tracking Gradiometer (RTG) selected for this integration is truly such a niche sensor because its capabilities are not degraded by media interfaces or environmental conditions. It is an experimental prototype fluxgate magnetometer array developed by Quantum Magnetics for the Coastal Systems Station (CSS) and was designed to be man portable and self contained. While limited by physics in detection range, it is capable of detecting ferrous targets under the worst environmental conditions, even when the target is buried. While not having the range of sonar, the RTG does not respond to the false alarms that are indicated by sonar, and since it is capable of also providing range and bearing information, it provides an invaluable niche filling classification tool. The placing of any magnetic sensing system on a conventional AUV is a non-trivial problem. The standard AUV is designed around materials and components that were selected to maximize performance without regard to the magnetic properties of the materials used in its fabrication. To minimize the degradation of sensor performance caused by the platform, several steps must be taken. These include; the substitution of nonferrous components for ferrous, maximizing the separation between the sensor and magnetic field sources, minimizing current loops and using auxiliary current and field sensors capable of generating noise canceling signals. To maximize utility, the magnetic sensor systems should also provide range, bearing and magnetic target strength. While all data and results contained in this paper have been obtained with land-based testing, they are easily adapted to the underwater environment of the AUV. The RTG was recently attached to the Morpheus, and data collected with the unmodified Morpheus powered and undergoing simulated sea motion table. These tests indicate that integration, while not trivial, is indeed feasible, and work is continuing toward mounting the sensor internal to the AUV and implementing the required noise mitigation solutions.

Design and Testing of an Educational Water Tunnel

NASA Astrophysics Data System (ADS)

Kosaraju, Srinivas

2017-11-01

A new water tunnel is designed and tested for educational and research purposes at Northern Arizona University. The university currently owns an educational wind tunnel with a test section of 12in X 12in X 24in. However, due to limited size of test section and range of Reynolds numbers, its application is currently limited to very few experiments. In an effort to expand the educational and research capabilities, a student team is tasked to design, build and test a water tunnel as a Capstone Senior Design project. The water tunnel is designed to have a test section of 8in X 8in X 36in. and be able to test up to Re = 50E3. Multiple numerical models are used to optimize the flow field inside the test section before building the physical apparatus. The water tunnel is designed to accommodate multiple experiments for drag and lift studies. The built-in die system can deliver up to three different colors to study the streamlines and vortex shedding from the surfaces. During the first phase, a low discharge pump is used to achieve Re = 4E3 to test laminar flows. In the second phase, a high discharge pump will be used to achieve targeted Re = 50E3 to study turbulent flows.

Advancing Porous Silicon Biosensor Technology for Use in Clinical Diagnostics

NASA Astrophysics Data System (ADS)

Bonanno, Lisa Marie

Inexpensive and robust analytical techniques for detecting molecular recognition events are in great demand in healthcare, food safety, and environmental monitoring. Despite vast research in this area, challanges remain to develop practical biomolecular platforms that, meet the rigorous demands of real-world applications. This includes maintaining low-cost devices that are sensitive and specific in complex test specimens, are stable after storage, have short assay time, and possess minimal complexity of instrumentation for readout. Nanostructured porous silicon (PSi) material has been identified as an ideal candidate towards achieving these goals and the past decade has seen diverse proof-of-principle studies developing optical-based sensing techniques. In Part 1 of this thesis, the impact of surface chemistry and PSi morphology on detection sensitivity of target molecules is investigated. Initial proof-of-concept that PSi devices facilitate detection of protein in whole blood is demonstrated. This work highlights the importance of material stability and blocking chemistry for sensor use in real world biological samples. In addition, the intrinisic filtering capability of the 3-D PSi morphology is shown as an advantage in complex solutions, such as whole blood. Ultimately, this initial work identified a need to improve detection sensitivity of the PSI biosensor technique to facilitate clinical diagnostic use over relevant target concentration ranges. The second part of this thesis, builds upon sensitivity challenges that are highlighted in the first part of the thesis and development of a surface-bound competitive inhibition immunoassay facilitated improved detection sensitivity of small molecular weight targets (opiates) over a relevant clinical concentration range. In addition, optimization of assay protocol addressed issues of maintaining stability of sensors after storage. Performance of the developed assay (specificity and sensitivity) was then validated in a blind clinical study that screened real patient urine samples (n=70) for opiates in collaboration with Strong Memorial Hospital Clinical Toxicology Laboratory. PSI sensor results showed improved clinical specificity over current commercial opiate immunoassay techniques and therefore, identified potential for a reduction in false-negative and false-positive screening results. Here, we demonstrate for the first time, successful clinical capability of a PSi sensor to detect opiates as a model target in real-world patient samples. The final part of this thesis explores novel sensor designs to leverage the tunable optical properties of PSi photonic devices and facilitate colorimetric readout of molecular recognition events by the unaided eye. Such a design is ideal for uncomplicated diagnostic screening at point-of-care as no instrumentation is needed for result readout. The photonic PSi transducers were integrated with target analyte-responsive hydrogels (TRAP-gels) that upon exposure to a target solution would swell and dissolute, inducing material property changes that were optically detected by the incorporated PSi transducer. This strategy extends target detection throughout the 3-ll internal volume of the PSi, improving upon current techniques that limit detection to the surface area (2-ll) of PSi. Work to acheive this approach involved design of TRAP-gel networks, polymer synthesis and characterization techniques, and optical characterization of the hybrid hydrogel-PSi material sensor. Successful implementation of a hybrid sensor design was exhibited for a. model chemical target (reducing agent), in which visual colorimetric change from red to green was observed for above-threshold exposure to the chemical target. In addition, initial proof-of-concept of an opiate responsive TRAP-gel is also demonstrated where cross-links are formed between antibody-antigen interactions and exposure to opiates induces bulk gel dissolution.

Beam heating of thick targets for on-line mass separators

NASA Astrophysics Data System (ADS)

Eaton, T. W.; Ravn, H. L.; Isolde Collaboration

1987-05-01

Energy deposition computations have been made on a variety of target materials utilized for the production of radioisotopes by means of 600-MeV protons. Results have shown that, when a proton current of 100 μA is assumed, dispersed target materials, such as uranium carbide powder and magnesium oxide, are best able to withstand the energy absorption and consequent beam heating without the need of additional cooling. Modified foil targets of titanium, zirconium and tantalum also appear capable of withstanding a full beam current, whilst liquid metal targets in their present form appear to have limitations in terms of the maximum allowable beam current. A redesign of the target container is proposed which allows higher proton currents to be used with these targets also.

Neutron generator for BNCT based on high current ECR ion source with gyrotron plasma heating.

PubMed

Skalyga, V; Izotov, I; Golubev, S; Razin, S; Sidorov, A; Maslennikova, A; Volovecky, A; Kalvas, T; Koivisto, H; Tarvainen, O

2015-12-01

BNCT development nowadays is constrained by a progress in neutron sources design. Creation of a cheap and compact intense neutron source would significantly simplify trial treatments avoiding use of expensive and complicated nuclear reactors and accelerators. D-D or D-T neutron generator is one of alternative types of such sources for. A so-called high current quasi-gasdynamic ECR ion source with plasma heating by millimeter wave gyrotron radiation is suggested to be used in a scheme of D-D neutron generator in the present work. Ion source of that type was developed in the Institute of Applied Physics of Russian Academy of Sciences (Nizhny Novgorod, Russia). It can produce deuteron ion beams with current density up to 700-800 mA/cm(2). Generation of the neutron flux with density at the level of 7-8·10(10) s(-1) cm(-2) at the target surface could be obtained in case of TiD2 target bombardment with deuteron beam accelerated to 100 keV. Estimations show that it is enough for formation of epithermal neutron flux with density higher than 10(9) s(-1) cm(-2) suitable for BNCT. Important advantage of described approach is absence of Tritium in the scheme. First experiments performed in pulsed regime with 300 mA, 45 kV deuteron beam directed to D2O target demonstrated 10(9) s(-1) neutron flux. This value corresponds to theoretical estimations and proofs prospects of neutron generator development based on high current quasi-gasdynamic ECR ion source. Copyright © 2015 Elsevier Ltd. All rights reserved.

Three-Dimensional Hydrodynamic Simulations of OMEGA Implosions

NASA Astrophysics Data System (ADS)

Igumenshchev, I. V.

2016-10-01

The effects of large-scale (with Legendre modes less than 30) asymmetries in OMEGA direct-drive implosions caused by laser illumination nonuniformities (beam-power imbalance and beam mispointing and mistiming) and target offset, mount, and layers nonuniformities were investigated using three-dimensional (3-D) hydrodynamic simulations. Simulations indicate that the performance degradation in cryogenic implosions is caused mainly by the target offsets ( 10 to 20 μm), beampower imbalance (σrms 10 %), and initial target asymmetry ( 5% ρRvariation), which distort implosion cores, resulting in a reduced hot-spot confinement and an increased residual kinetic energy of the stagnated target. The ion temperature inferred from the width of simulated neutron spectra are influenced by bulk fuel motion in the distorted hot spot and can result in up to 2-keV apparent temperature increase. Similar temperature variations along different lines of sight are observed. Simulated x-ray images of implosion cores in the 4- to 8-keV energy range show good agreement with experiments. Demonstrating hydrodynamic equivalence to ignition designs on OMEGA requires reducing large-scale target and laser-imposed nonuniformities, minimizing target offset, and employing high-efficient mid-adiabat (α = 4) implosion designs that mitigate cross-beam energy transfer (CBET) and suppress short-wavelength Rayleigh-Taylor growth. These simulations use a new low-noise 3-D Eulerian hydrodynamic code ASTER. Existing 3-D hydrodynamic codes for direct-drive implosions currently miss CBET and noise-free ray-trace laser deposition algorithms. ASTER overcomes these limitations using a simplified 3-D laser-deposition model, which includes CBET and is capable of simulating the effects of beam-power imbalance, beam mispointing, mistiming, and target offset. This material is based upon work supported by the Department of Energy National Nuclear Security Administration under Award Number DE-NA0001944.

A novel neural network based image reconstruction model with scale and rotation invariance for target identification and classification for Active millimetre wave imaging

NASA Astrophysics Data System (ADS)

Agarwal, Smriti; Bisht, Amit Singh; Singh, Dharmendra; Pathak, Nagendra Prasad

2014-12-01

Millimetre wave imaging (MMW) is gaining tremendous interest among researchers, which has potential applications for security check, standoff personal screening, automotive collision-avoidance, and lot more. Current state-of-art imaging techniques viz. microwave and X-ray imaging suffers from lower resolution and harmful ionizing radiation, respectively. In contrast, MMW imaging operates at lower power and is non-ionizing, hence, medically safe. Despite these favourable attributes, MMW imaging encounters various challenges as; still it is very less explored area and lacks suitable imaging methodology for extracting complete target information. Keeping in view of these challenges, a MMW active imaging radar system at 60 GHz was designed for standoff imaging application. A C-scan (horizontal and vertical scanning) methodology was developed that provides cross-range resolution of 8.59 mm. The paper further details a suitable target identification and classification methodology. For identification of regular shape targets: mean-standard deviation based segmentation technique was formulated and further validated using a different target shape. For classification: probability density function based target material discrimination methodology was proposed and further validated on different dataset. Lastly, a novel artificial neural network based scale and rotation invariant, image reconstruction methodology has been proposed to counter the distortions in the image caused due to noise, rotation or scale variations. The designed neural network once trained with sample images, automatically takes care of these deformations and successfully reconstructs the corrected image for the test targets. Techniques developed in this paper are tested and validated using four different regular shapes viz. rectangle, square, triangle and circle.

Safety testing of monoclonal antibodies in non-human primates: Case studies highlighting their impact on human risk assessment.

PubMed

Brennan, Frank R; Cavagnaro, Joy; McKeever, Kathleen; Ryan, Patricia C; Schutten, Melissa M; Vahle, John; Weinbauer, Gerhard F; Marrer-Berger, Estelle; Black, Lauren E

2018-01-01

Monoclonal antibodies (mAbs) are improving the quality of life for patients suffering from serious diseases due to their high specificity for their target and low potential for off-target toxicity. The toxicity of mAbs is primarily driven by their pharmacological activity, and therefore safety testing of these drugs prior to clinical testing is performed in species in which the mAb binds and engages the target to a similar extent to that anticipated in humans. For highly human-specific mAbs, this testing often requires the use of non-human primates (NHPs) as relevant species. It has been argued that the value of these NHP studies is limited because most of the adverse events can be predicted from the knowledge of the target, data from transgenic rodents or target-deficient humans, and other sources. However, many of the mAbs currently in development target novel pathways and may comprise novel scaffolds with multi-functional domains; hence, the pharmacological effects and potential safety risks are less predictable. Here, we present a total of 18 case studies, including some of these novel mAbs, with the aim of interrogating the value of NHP safety studies in human risk assessment. These studies have identified mAb candidate molecules and pharmacological pathways with severe safety risks, leading to candidate or target program termination, as well as highlighting that some pathways with theoretical safety concerns are amenable to safe modulation by mAbs. NHP studies have also informed the rational design of safer drug candidates suitable for human testing and informed human clinical trial design (route, dose and regimen, patient inclusion and exclusion criteria and safety monitoring), further protecting the safety of clinical trial participants.

Specialized Color Targets for Spectral Reflectance Reconstruction of Magnified Images

NASA Astrophysics Data System (ADS)

Kruschwitz, Jennifer D. T.

Digital images are used almost exclusively instead of film to capture visual information across many scientific fields. The colorimetric color representation within these digital images can be relayed from the digital counts produced by the camera with the use of a known color target. In image capture of magnified images, there is currently no reliable color target that can be used at multiple magnifications and give the user a solid understanding of the color ground truth within those images. The first part of this dissertation included the design, fabrication, and testing of a color target produced with optical interference coated microlenses for use in an off-axis illumination, compound microscope. An ideal target was designed to increase the color gamut for colorimetric imaging and provide the necessary "Block Dye" spectral reflectance profiles across the visible spectrum to reduce the number of color patches necessary for multiple filter imaging systems that rely on statistical models for spectral reflectance reconstruction. There are other scientific disciplines that can benefit from a specialized color target to determine the color ground truth in their magnified images and perform spectral estimation. Not every discipline has the luxury of having a multi-filter imaging system. The second part of this dissertation developed two unique ways of using an interference coated color mirror target: one that relies on multiple light-source angles, and one that leverages a dynamic color change with time. The source multi-angle technique would be used for the microelectronic discipline where the reconstructed spectral reflectance would be used to determine a dielectric film thickness on a silicon substrate, and the time varying technique would be used for a biomedical example to determine the thickness of human tear film.

Emerging science and therapies in non-small-cell lung cancer: targeting the MET pathway.

PubMed

Kris, Mark G; Arenberg, Douglas A; Herbst, Roy S; Riely, Gregory J

2014-11-01

During this enduring, learner-driven, interactive CME webseries, lung cancer specialists will address the science and targeted therapies for the MET pathway in non-small cell lung cancer. Over the past decade, research has evolved in the science of identifying targeted biological changes in DNA and individual cancer cells. Along with the advanced understanding of lung cancer mutations, has come the development of specific targeted therapies that improve patient outcomes. The first step in treating a patient with lung cancer is proper diagnosis and staging, applying to the principles of personalize medicine. Our current understanding of lung cancer is that of a collection of diseases individualized through specific mutations. This CME activity reviews the role of the pulmonologist and pathologist in proper tissue acquisition and analysis. This new era of personalized medicine and clinical research advances has changed the way clinicians evaluate and treat patients with lung cancer. The data on lung cancer cell mutations and newer targeted therapies have improved the progression free survival and quality of life of lung cancer patients. This CME activity is designed to present a practical overview of recent evidenced based data of MET targeted therapies for patients with lung cancer. As research continues to evolve, we continue to advance our understanding in the science of lung cancers involving the MET pathway. Evidenced based data supporting newer targeted therapeutics provides insight on applying treatment for optimal outcomes. This CME activity will focus on the individualized treatment strategies using practical decision making for patients with MET expression. This activity has been designed to meet the educational needs of medical oncologists, pathologists, radiation oncologists, surgeons, pulmonologists, internists, and other healthcare clinicians responsible for the care of patients with lung cancer. Online access:http://www.elseviercme.com/516/.

Optical monitoring of ion beam Y-Ba-Cu-O sputtering

NASA Astrophysics Data System (ADS)

Klein, J. D.; Yen, A.

1990-11-01

The emission spectra resulting from ion beam sputtering a Y-Ba-Cu-O target were observed as a function of beam voltage and beam current. The spectra were relatively clean with several peaks readily attributed to each of Y, Ba, and Ar. Monitoring of copper and oxygen was more difficult with a single CuO peak and one O peak evident. The intensities of the cation peaks were linear with respect to beam voltage above 400 V. Since target current was found not to be directly proportional to beam current, target power was defined as the product of beam voltage and target current. The response of cation peak height to changes in target power was linear and similar for variations of either beam voltage or target current.

Compact VLSI neural computer integrated with active pixel sensor for real-time ATR applications

NASA Astrophysics Data System (ADS)

Fang, Wai-Chi; Udomkesmalee, Gabriel; Alkalai, Leon

1997-04-01

A compact VLSI neural computer integrated with an active pixel sensor has been under development to mimic what is inherent in biological vision systems. This electronic eye- brain computer is targeted for real-time machine vision applications which require both high-bandwidth communication and high-performance computing for data sensing, synergy of multiple types of sensory information, feature extraction, target detection, target recognition, and control functions. The neural computer is based on a composite structure which combines Annealing Cellular Neural Network (ACNN) and Hierarchical Self-Organization Neural Network (HSONN). The ACNN architecture is a programmable and scalable multi- dimensional array of annealing neurons which are locally connected with their local neurons. Meanwhile, the HSONN adopts a hierarchical structure with nonlinear basis functions. The ACNN+HSONN neural computer is effectively designed to perform programmable functions for machine vision processing in all levels with its embedded host processor. It provides a two order-of-magnitude increase in computation power over the state-of-the-art microcomputer and DSP microelectronics. A compact current-mode VLSI design feasibility of the ACNN+HSONN neural computer is demonstrated by a 3D 16X8X9-cube neural processor chip design in a 2-micrometers CMOS technology. Integration of this neural computer as one slice of a 4'X4' multichip module into the 3D MCM based avionics architecture for NASA's New Millennium Program is also described.

Analytical Quality by Design Approach in RP-HPLC Method Development for the Assay of Etofenamate in Dosage Forms

PubMed Central

Peraman, R.; Bhadraya, K.; Reddy, Y. Padmanabha; Reddy, C. Surayaprakash; Lokesh, T.

2015-01-01

By considering the current regulatory requirement for an analytical method development, a reversed phase high performance liquid chromatographic method for routine analysis of etofenamate in dosage form has been optimized using analytical quality by design approach. Unlike routine approach, the present study was initiated with understanding of quality target product profile, analytical target profile and risk assessment for method variables that affect the method response. A liquid chromatography system equipped with a C18 column (250×4.6 mm, 5 μ), a binary pump and photodiode array detector were used in this work. The experiments were conducted based on plan by central composite design, which could save time, reagents and other resources. Sigma Tech software was used to plan and analyses the experimental observations and obtain quadratic process model. The process model was used for predictive solution for retention time. The predicted data from contour diagram for retention time were verified actually and it satisfied with actual experimental data. The optimized method was achieved at 1.2 ml/min flow rate of using mobile phase composition of methanol and 0.2% triethylamine in water at 85:15, % v/v, pH adjusted to 6.5. The method was validated and verified for targeted method performances, robustness and system suitability during method transfer. PMID:26997704

Spectral and temporal characteristics of target current and electromagnetic pulse induced by nanosecond laser ablation

NASA Astrophysics Data System (ADS)

Krása, J.; De Marco, M.; Cikhardt, J.; Pfeifer, M.; Velyhan, A.; Klír, D.; Řezáč, K.; Limpouch, J.; Krouský, E.; Dostál, J.; Ullschmied, J.; Dudžák, R.

2017-06-01

The current balancing the target charging and the emission of transient electromagnetic pulses (EMP) driven by the interaction of a focused 1.315 μm iodine 300 ps PALS laser with metallic and plastic targets were measured with the use of inductive probes. It is experimentally proven that the duration of return target currents and EMPs is much longer than the duration of laser-target interaction. The laser-produced plasma is active after the laser-target interaction. During this phase, the target acts as a virtual cathode and the plasma-target interface expands. A double exponential function is used in order to obtain the temporal characteristics of EMP. The rise time of EMPs fluctuates in the range up to a few tens of nanoseconds. Frequency spectra of EMP and target currents are modified by resonant frequencies of the interaction chamber.

BrainStorm: a psychosocial game suite design for non-invasive cross-generational cognitive capabilities data collection

NASA Astrophysics Data System (ADS)

Ahmad, Faizan; Chen, Yiqiang; Hu, Lisha; Wang, Shuangquan; Wang, Jindong; Chen, Zhenyu; Jiang, Xinlong; Shen, Jianfei

2017-11-01

Currently available traditional as well as videogame-based cognitive assessment techniques are inappropriate due to several reasons. This paper presents a novel psychosocial game suite, BrainStorm, for non-invasive cross-generational cognitive capabilities data collection, which additionally provides cross-generational social support. A motivation behind the development of presented game suite is to provide an entertaining and exciting platform for its target users in order to collect gameplay-based cognitive capabilities data in a non-invasive manner. An extensive evaluation of the presented game suite demonstrated high acceptability and attraction for its target users. Besides, the data collection process is successfully reported as transparent and non-invasive.