Multi probes measurements at the PALS Facility Research Centre during high intense laser pulse interactions with various target materials

NASA Astrophysics Data System (ADS)

De Marco, Massimo; Krása, Josef; Cikhardt, Jakub; Consoli, Fabrizio; De Angelis, Riccardo; Pfeifer, Miroslav; Krůs, Miroslav; Dostál, Jan; Margarone, Daniele; Picciotto, Antonino; Velyhan, Andriy; Klír, Daniel; Dudžák, Roman; Limpouch, Jiří; Korn, Georg

2018-01-01

During the interaction of high intense laser pulse with solid target, a large amount of hot electrons is produced and a giant Electromagnetic Pulse (EMP) is generated due to the current flowing into the system target-target holder, as well as due to the escaping charged particles in vacuum. EMP production for different target materials is investigated inside and outside the target chamber, using monopole antenna, super wide-band microstrip antenna and Moebius antenna. The EMP consists in a fast transient magnetic field lasting hundreds of nanosecond with frequencies ranging from MHz to tens of GHz. Measurements of magnetic field and return target current in the range of kA were carried out by an inductive target probe (Cikhardt J. et al. Rev. Sci. Instrum. 85 (2014) 103507).

Predicting Drug-Target Interactions With Multi-Information Fusion.

PubMed

Peng, Lihong; Liao, Bo; Zhu, Wen; Li, Zejun; Li, Keqin

2017-03-01

Identifying potential associations between drugs and targets is a critical prerequisite for modern drug discovery and repurposing. However, predicting these associations is difficult because of the limitations of existing computational methods. Most models only consider chemical structures and protein sequences, and other models are oversimplified. Moreover, datasets used for analysis contain only true-positive interactions, and experimentally validated negative samples are unavailable. To overcome these limitations, we developed a semi-supervised based learning framework called NormMulInf through collaborative filtering theory by using labeled and unlabeled interaction information. The proposed method initially determines similarity measures, such as similarities among samples and local correlations among the labels of the samples, by integrating biological information. The similarity information is then integrated into a robust principal component analysis model, which is solved using augmented Lagrange multipliers. Experimental results on four classes of drug-target interaction networks suggest that the proposed approach can accurately classify and predict drug-target interactions. Part of the predicted interactions are reported in public databases. The proposed method can also predict possible targets for new drugs and can be used to determine whether atropine may interact with alpha1B- and beta1- adrenergic receptors. Furthermore, the developed technique identifies potential drugs for new targets and can be used to assess whether olanzapine and propiomazine may target 5HT2B. Finally, the proposed method can potentially address limitations on studies of multitarget drugs and multidrug targets.

Predicting drug-target interaction for new drugs using enhanced similarity measures and super-target clustering.

PubMed

Shi, Jian-Yu; Yiu, Siu-Ming; Li, Yiming; Leung, Henry C M; Chin, Francis Y L

2015-07-15

Predicting drug-target interaction using computational approaches is an important step in drug discovery and repositioning. To predict whether there will be an interaction between a drug and a target, most existing methods identify similar drugs and targets in the database. The prediction is then made based on the known interactions of these drugs and targets. This idea is promising. However, there are two shortcomings that have not yet been addressed appropriately. Firstly, most of the methods only use 2D chemical structures and protein sequences to measure the similarity of drugs and targets respectively. However, this information may not fully capture the characteristics determining whether a drug will interact with a target. Secondly, there are very few known interactions, i.e. many interactions are "missing" in the database. Existing approaches are biased towards known interactions and have no good solutions to handle possibly missing interactions which affect the accuracy of the prediction. In this paper, we enhance the similarity measures to include non-structural (and non-sequence-based) information and introduce the concept of a "super-target" to handle the problem of possibly missing interactions. Based on evaluations on real data, we show that our similarity measure is better than the existing measures and our approach is able to achieve higher accuracy than the two best existing algorithms, WNN-GIP and KBMF2K. Our approach is available at http://web.hku.hk/∼liym1018/projects/drug/drug.html or http://www.bmlnwpu.org/us/tools/PredictingDTI_S2/METHODS.html. Copyright © 2015 Elsevier Inc. All rights reserved.

Presenting the Rain-Sea Interaction Facility

NASA Technical Reports Server (NTRS)

Bliven, Larry F.; Elfouhaily, Tonas M.

1993-01-01

The new Rain-Sea Interaction Facility (RSIF) was established at GSFC/WFF and the first finds are presented. The unique feature of this laboratory is the ability to systematically study microwave scattering from a water surface roughened by artificial rain, for which the droplets are at terminal velocity. The fundamental instruments and systems (e.g., the rain simulator, scatterometers, and surface elevation probes) were installed and evaluated during these first experiments - so the majority of the data were obtained with the rain simulator at 1 m above the water tank. From these initial experiments, three new models were proposed: the square-root function for NCS vs. R, the log Gaussian model for ring-wave elevation frequency spectrum, and the Erland probability density distribution for back scattered power. Rain rate is the main input for these models, although the coefficients may be dependent upon other factors (drop-size distribution, fall velocity, radar configuration, etc.). The facility is functional and we foresee collaborative studies with investigators who are engaged in measuring and modeling rain-sea interaction processes.

Implementation of a solid target production facility

NASA Astrophysics Data System (ADS)

Tochon-Danguy, H. J.; Poniger, S. S.; Sachinidis, J. I.; Panopoulos, H. P.; Scott, A. M.

2012-12-01

The desire to utilize long-lived PET isotopes in Australia has significantly increased over the years and several research projects for labelling of peptides, proteins and biomolecules, including labelling of recombinant antibodies has been restricted due to the limited availability of suitable isotopes. This need has led to the recent installation and commissioning of a new facility dedicated to fully automated solid target isotope production, including 24I, 64Cu, 89Zr and 86Y at the Austin Health Centre for PET.

Drug-target interaction prediction via class imbalance-aware ensemble learning.

PubMed

Ezzat, Ali; Wu, Min; Li, Xiao-Li; Kwoh, Chee-Keong

2016-12-22

Multiple computational methods for predicting drug-target interactions have been developed to facilitate the drug discovery process. These methods use available data on known drug-target interactions to train classifiers with the purpose of predicting new undiscovered interactions. However, a key challenge regarding this data that has not yet been addressed by these methods, namely class imbalance, is potentially degrading the prediction performance. Class imbalance can be divided into two sub-problems. Firstly, the number of known interacting drug-target pairs is much smaller than that of non-interacting drug-target pairs. This imbalance ratio between interacting and non-interacting drug-target pairs is referred to as the between-class imbalance. Between-class imbalance degrades prediction performance due to the bias in prediction results towards the majority class (i.e. the non-interacting pairs), leading to more prediction errors in the minority class (i.e. the interacting pairs). Secondly, there are multiple types of drug-target interactions in the data with some types having relatively fewer members (or are less represented) than others. This variation in representation of the different interaction types leads to another kind of imbalance referred to as the within-class imbalance. In within-class imbalance, prediction results are biased towards the better represented interaction types, leading to more prediction errors in the less represented interaction types. We propose an ensemble learning method that incorporates techniques to address the issues of between-class imbalance and within-class imbalance. Experiments show that the proposed method improves results over 4 state-of-the-art methods. In addition, we simulated cases for new drugs and targets to see how our method would perform in predicting their interactions. New drugs and targets are those for which no prior interactions are known. Our method displayed satisfactory prediction performance and was

Drug-target interaction prediction from PSSM based evolutionary information.

PubMed

Mousavian, Zaynab; Khakabimamaghani, Sahand; Kavousi, Kaveh; Masoudi-Nejad, Ali

2016-01-01

The labor-intensive and expensive experimental process of drug-target interaction prediction has motivated many researchers to focus on in silico prediction, which leads to the helpful information in supporting the experimental interaction data. Therefore, they have proposed several computational approaches for discovering new drug-target interactions. Several learning-based methods have been increasingly developed which can be categorized into two main groups: similarity-based and feature-based. In this paper, we firstly use the bi-gram features extracted from the Position Specific Scoring Matrix (PSSM) of proteins in predicting drug-target interactions. Our results demonstrate the high-confidence prediction ability of the Bigram-PSSM model in terms of several performance indicators specifically for enzymes and ion channels. Moreover, we investigate the impact of negative selection strategy on the performance of the prediction, which is not widely taken into account in the other relevant studies. This is important, as the number of non-interacting drug-target pairs are usually extremely large in comparison with the number of interacting ones in existing drug-target interaction data. An interesting observation is that different levels of performance reduction have been attained for four datasets when we change the sampling method from the random sampling to the balanced sampling. Copyright © 2015 Elsevier Inc. All rights reserved.

Design and Fabrication of Opacity Targets for the National Ignition Facility

DOE PAGES

Cardenas, Tana; Schmidt, Derek William; Dodd, Evan S.; ...

2017-12-22

Accurate models for opacity of partially ionized atoms are important for modeling and understanding stellar interiors and other high-energy-density phenomena such as inertial confinement fusion. Lawrence Livermore National Laboratory is leading a multilaboratory effort to conduct experiments on the National Ignition Facility (NIF) to try to reproduce recent opacity tests at the Sandia National Laboratory Z-facility. Since 2015, the NIF effort has evolved several hohlraum designs that consist of multiple pieces joined together. The target also has three components attached to the main stalk over a long distance with high tolerances that have resulted in several design iterations. The targetmore » has made use of rapid prototyped features to attach a capsule and collimator under the hohlraum while avoiding interference with the beams. Furthermore, this paper discusses the evolution of the hohlraum and overall target design and the challenges involved with fabricating and assembling these targets.« less

Design and Fabrication of Opacity Targets for the National Ignition Facility

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

Cardenas, Tana; Schmidt, Derek William; Dodd, Evan S.

Accurate models for opacity of partially ionized atoms are important for modeling and understanding stellar interiors and other high-energy-density phenomena such as inertial confinement fusion. Lawrence Livermore National Laboratory is leading a multilaboratory effort to conduct experiments on the National Ignition Facility (NIF) to try to reproduce recent opacity tests at the Sandia National Laboratory Z-facility. Since 2015, the NIF effort has evolved several hohlraum designs that consist of multiple pieces joined together. The target also has three components attached to the main stalk over a long distance with high tolerances that have resulted in several design iterations. The targetmore » has made use of rapid prototyped features to attach a capsule and collimator under the hohlraum while avoiding interference with the beams. Furthermore, this paper discusses the evolution of the hohlraum and overall target design and the challenges involved with fabricating and assembling these targets.« less

Drug-Target Interaction Prediction through Label Propagation with Linear Neighborhood Information.

PubMed

Zhang, Wen; Chen, Yanlin; Li, Dingfang

2017-11-25

Interactions between drugs and target proteins provide important information for the drug discovery. Currently, experiments identified only a small number of drug-target interactions. Therefore, the development of computational methods for drug-target interaction prediction is an urgent task of theoretical interest and practical significance. In this paper, we propose a label propagation method with linear neighborhood information (LPLNI) for predicting unobserved drug-target interactions. Firstly, we calculate drug-drug linear neighborhood similarity in the feature spaces, by considering how to reconstruct data points from neighbors. Then, we take similarities as the manifold of drugs, and assume the manifold unchanged in the interaction space. At last, we predict unobserved interactions between known drugs and targets by using drug-drug linear neighborhood similarity and known drug-target interactions. The experiments show that LPLNI can utilize only known drug-target interactions to make high-accuracy predictions on four benchmark datasets. Furthermore, we consider incorporating chemical structures into LPLNI models. Experimental results demonstrate that the model with integrated information (LPLNI-II) can produce improved performances, better than other state-of-the-art methods. The known drug-target interactions are an important information source for computational predictions. The usefulness of the proposed method is demonstrated by cross validation and the case study.

The accomplishments of lithium target and test facility validation activities in the IFMIF/EVEDA phase

NASA Astrophysics Data System (ADS)

Arbeiter, Frederik; Baluc, Nadine; Favuzza, Paolo; Gröschel, Friedrich; Heidinger, Roland; Ibarra, Angel; Knaster, Juan; Kanemura, Takuji; Kondo, Hiroo; Massaut, Vincent; Saverio Nitti, Francesco; Miccichè, Gioacchino; O'hira, Shigeru; Rapisarda, David; Sugimoto, Masayoshi; Wakai, Eiichi; Yokomine, Takehiko

2018-01-01

As part of the engineering validation and engineering design activities (EVEDA) phase for the international fusion materials irradiation facility IFMIF, major elements of a lithium target facility and the test facility were designed, prototyped and validated. For the lithium target facility, the EVEDA lithium test loop was built at JAEA and used to test the stability (waves and long term) of the lithium flow in the target, work out the startup procedures, and test lithium purification and analysis. It was confirmed by experiments in the Lifus 6 plant at ENEA that lithium corrosion on ferritic martensitic steels is acceptably low. Furthermore, complex remote handling procedures for the remote maintenance of the target in the test cell environment were successfully practiced. For the test facility, two variants of a high flux test module were prototyped and tested in helium loops, demonstrating their good capabilities of maintaining the material specimens at the desired temperature with a low temperature spread. Irradiation tests were performed for heated specimen capsules and irradiation instrumentation in the BR2 reactor at SCK-CEN. The small specimen test technique, essential for obtaining material test results with limited irradiation volume, was advanced by evaluating specimen shape and test technique influences.

Calculations of high-power production target and beamdump for the GSI future Super-FRS for a fast extraction scheme at the FAIR Facility

NASA Astrophysics Data System (ADS)

Tahir, N. A.; Weick, H.; Iwase, H.; Geissel, H.; Hoffmann, D. H. H.; Kindler, B.; Lommel, B.; Radon, T.; Münzenberg, G.; Shutov, A.; Sümmerer, K.; Winkler, M.

2005-06-01

A superconducting fragment separator (Super-FRS) is being designed for the production and separation of radioactive isotopes at the future FAIR (Facility for Antiprotons and Ion Research) facility at Darmstadt. This paper discusses various aspects and requirements for the high-power production target that will be used in the Super-FRS experiments. The production target must survive over an extended period of time as it will be used during the course of many experiments. The specific power deposited by the high intensity beam that will be generated at the future FAIR facility will be high enough to destroy the target in most of the cases as a result of a single shot from the new heavy ion synchrotrons SIS100/300. By using an appropriate beam intensity and focal spot parameters, the target would survive after being irradiated once. However, the heat should be dissipated efficiently before the same target area is irradiated again. We have considered a wheel shaped solid carbon target that rotates around its axis so that different areas of the target are irradiated successively. This allows for cooling of the beam heated region by thermal conduction before the same part of the target is irradiated a second time. Another attractive option is to use a liquid jet target at the Super-FRS. First calculations of a possible liquid lithium target are also presented in this paper. One of the advantages of using lithium as a target is that it will survive even if one uses a smaller focal spot, which has half the area of that used for a solid carbon target. This will significantly improve the isotope resolution. A similar problem associated with these experiments will be safe deposition of the beam energy in a beamdump after its interaction with the production target. We also present calculations to study the suitability of a proposed beamdump.

Gadolinium-148 and other spallation production cross section measurements for accelerator target facilities

NASA Astrophysics Data System (ADS)

Kelley, Karen Corzine

At the Los Alamos Neutron Science Center accelerator complex, protons are accelerated to 800 MeV and directed to two tungsten targets, Target 4 at the Weapons Neutron Research facility and the 1L target at the Lujan Center. The Department of Energy requires hazard classification analyses to be performed on these targets and places limits on certain radionuclide inventories in the targets to avoid characterizing the facilities as "nuclear facilities." Gadolinium-148 is a radionuclide created from the spallation of tungsten. Allowed isotopic inventories are particularly low for this isotope because it is an alpha-particle emitter with a 75-year half-life. The activity level of Gadolinium-148 is low, but it encompasses almost two-thirds of the total dose burden for the two tungsten targets based on present yield estimates. From a hazard classification standpoint, this severely limits the lifetime of these tungsten targets. The cross section is not well-established experimentally and this is the motivation for measuring the Gadolinium-148 production cross section from tungsten. In a series of experiments at the Weapons Neutron Research facility, Gadolinium-148 production was measured for 600- and 800-MeV protons on tungsten, tantalum, and gold. These experiments used 3 mum thin tungsten, tantalum, and gold foils and 10 mum thin aluminum activation foils. In addition, spallation yields were determined for many short-lived and long-lived spallation products with these foils using gamma and alpha spectroscopy and compared with predictions of the Los Alamos National Laboratory codes CEM2k+GEM2 and MCNPX. The cumulative Gadolinium-148 production cross section measured from tantalum, tungsten, and gold for incident 600-MeV protons were 15.2 +/- 4.0, 8.31 +/- 0.92, and 0.591 +/- 0.155, respectively. The average production cross sections measured at 800 MeV were 28.6 +/- 3.5, 19.4 +/- 1.8, and 3.69 +/- 0.50 for tantalum, tungsten, and gold, respectively. These cumulative

Nail-like targets for laser plasma interaction experiments

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

Pasley, J; Wei, M; Shipton, E

2007-12-18

The interaction of ultra-high power picosecond laser pulses with solid targets is of interest both for benchmarking the results of hybrid particle in cell (PIC) codes and also for applications to re-entrant cone guided fast ignition. We describe the construction of novel targets in which copper/titanium wires are formed into 'nail-like' objects by a process of melting and micromachining, so that energy can be reliably coupled to a 24 {micro}m diameter wire. An extreme-ultraviolet image of the interaction of the Titan laser with such a target is shown.

Predicting drug-target interactions using restricted Boltzmann machines.

PubMed

Wang, Yuhao; Zeng, Jianyang

2013-07-01

In silico prediction of drug-target interactions plays an important role toward identifying and developing new uses of existing or abandoned drugs. Network-based approaches have recently become a popular tool for discovering new drug-target interactions (DTIs). Unfortunately, most of these network-based approaches can only predict binary interactions between drugs and targets, and information about different types of interactions has not been well exploited for DTI prediction in previous studies. On the other hand, incorporating additional information about drug-target relationships or drug modes of action can improve prediction of DTIs. Furthermore, the predicted types of DTIs can broaden our understanding about the molecular basis of drug action. We propose a first machine learning approach to integrate multiple types of DTIs and predict unknown drug-target relationships or drug modes of action. We cast the new DTI prediction problem into a two-layer graphical model, called restricted Boltzmann machine, and apply a practical learning algorithm to train our model and make predictions. Tests on two public databases show that our restricted Boltzmann machine model can effectively capture the latent features of a DTI network and achieve excellent performance on predicting different types of DTIs, with the area under precision-recall curve up to 89.6. In addition, we demonstrate that integrating multiple types of DTIs can significantly outperform other predictions either by simply mixing multiple types of interactions without distinction or using only a single interaction type. Further tests show that our approach can infer a high fraction of novel DTIs that has been validated by known experiments in the literature or other databases. These results indicate that our approach can have highly practical relevance to DTI prediction and drug repositioning, and hence advance the drug discovery process. Software and datasets are available on request. Supplementary data are

Laser-Plasma Interactions on NIKE and the Fusion Test Facility

NASA Astrophysics Data System (ADS)

Phillips, Lee; Weaver, James

2008-11-01

Recent proposed designs for a Fusion Test Facility (FTF) (Obenchain et al., Phys. Plasmas 13 056320 (2006)) for direct-drive ICF targets for energy applications involve high implosion velocities combined with higher laser irradiances. The use of high irradiances increases the likelihood of deleterious laser plasma instabilities (LPI) but the proposed use of a 248 nm KrF laser to drive these targets is expected to minimize the LPI risk. We examine, using simulation results from NRL's FAST hydrocode, the proposed operational regimes of the FTF in relation to the thresholds for the SRS, SBS, and 2-plasmon instabilities. Simulations are also used to help design and interpret ongoing experiments being conducted at NRL's NIKE facility for the purpose of generating and studying LPI. Target geometries and laser pulseshapes were devised in order to create plasma conditions with long scalelengths and low electron temperatures that allow the growth of parametric instabilities. These simulations include the effects of finite beam angles through the use of raytracing.

The National Ignition Facility: Transition to a User Facility

NASA Astrophysics Data System (ADS)

Moses, E. I.; Atherton, J.; Lagin, L.; Larson, D.; Keane, C.; MacGowan, B.; Patterson, R.; Spaeth, M.; Van Wonterghem, B.; Wegner, P.; Kauffman, R.

2016-03-01

The National Ignition Facility (NIF) at Lawrence Livermore National Laboratory (LLNL) has been operational since March 2009 and has been transitioning to a user facility supporting ignition science, high energy density science (HEDS), national security applications, and fundamental science. The facility has achieved its design goal of 1.8 MJ and 500 TW of 3ω light on target, and has performed target experiments with 1.9 MJ at peak powers of 410 TW. The facility is on track to perform over 200 target shots this year in support of all of its user communities. The facility has nearly 60 diagnostic systems operational and has shown flexibility in laser pulse shape and performance to meet the requirements of its multiple users. Progress continues on its goal of demonstrating thermonuclear burn in the laboratory. It has performed over 40 indirect-drive experiments with cryogenic-layered capsules. New platforms are being developed for HEDS and fundamental science. Equation-of-state and material strength experiments have been done on a number of materials with pressures of over 50 MBars obtained in diamond, conditions never previously encountered in the laboratory and similar to those found in planetary interiors. Experiments are also in progress investigating radiation transport, hydrodynamic instabilities, and direct drive implosions. NIF continues to develop as an experimental facility. Advanced Radiographic Capability (ARC) is now being installed on NIF for producing high-energy radiographs of the imploded cores of ignition targets and for short pulse laser-plasma interaction experiments. One NIF beam is planned for conversion to two picosecond beams in 2014. Other new diagnostics such as x-ray Thomson scattering, low energy neutron spectrometer, and multi-layer reflecting x-ray optics are also planned. Incremental improvements in laser performance such as improved optics damage performance, beam balance, and back reflection control are being pursued.

Investigation into the electromagnetic impulses from long-pulse laser illuminating solid targets inside a laser facility

NASA Astrophysics Data System (ADS)

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

2016-09-01

Emission of the electromagnetic pulses (EMP) due to laser-target interaction in laser facility had been evaluated using a cone antenna in this work. The microwave in frequencies ranging from several hundreds of MHz to 2 GHz was recorded when long-pulse lasers with several thousands of joules illuminated the solid targets, meanwhile the voltage signals from 1 V to 4 V were captured as functions of laser energy and backlight laser, where the corresponding electric field strengths were obtained by simulating the cone antenna in combination with conducting a mathematical process (Tiknohov Regularization with L curve). All the typical coupled voltage oscillations displayed multiple peaks and had duration of up to 80 ns before decaying into noise and mechanisms of the EMP generation was schematically interpreted in basis of the practical measuring environments. The resultant data were expected to offer basic know-how to achieve inertial confinement fusion.

Evolution of Gas Cell Targets for Magnetized Liner Inertial Fusion Experiments at the Sandia National Laboratories PECOS Test Facility

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

Paguio, R. R.; Smith, G. E.; Taylor, J. L.

Z-Beamlet (ZBL) experiments conducted at the PECOS test facility at Sandia National Laboratories (SNL) investigated the nonlinear processes in laser plasma interaction (or laserplasma instabilities LPI) that complicate the deposition of laser energy by enhanced absorption, backscatter, filamentation and beam-spray that can occur in large-scale laser-heated gas cell targets. These targets and experiments were designed to provide better insight into the physics of the laser preheat stage of the Magnetized Liner Inertial Fusion (MagLIF) scheme being tested on the SNL Z-machine. The experiments aim to understand the tradeoffs between laser spot size, laser pulse shape, laser entrance hole (LEH) windowmore » thickness, and fuel density for laser preheat. Gas cell target design evolution and fabrication adaptations to accommodate the evolving experiment and scientific requirements are also described in this paper.« less

Evolution of Gas Cell Targets for Magnetized Liner Inertial Fusion Experiments at the Sandia National Laboratories PECOS Test Facility

DOE PAGES

Paguio, R. R.; Smith, G. E.; Taylor, J. L.; ...

2017-12-04

Z-Beamlet (ZBL) experiments conducted at the PECOS test facility at Sandia National Laboratories (SNL) investigated the nonlinear processes in laser plasma interaction (or laserplasma instabilities LPI) that complicate the deposition of laser energy by enhanced absorption, backscatter, filamentation and beam-spray that can occur in large-scale laser-heated gas cell targets. These targets and experiments were designed to provide better insight into the physics of the laser preheat stage of the Magnetized Liner Inertial Fusion (MagLIF) scheme being tested on the SNL Z-machine. The experiments aim to understand the tradeoffs between laser spot size, laser pulse shape, laser entrance hole (LEH) windowmore » thickness, and fuel density for laser preheat. Gas cell target design evolution and fabrication adaptations to accommodate the evolving experiment and scientific requirements are also described in this paper.« less

Comprehensive peptidomimetic libraries targeting protein-protein interactions.

PubMed

Whitby, Landon R; Boger, Dale L

2012-10-16

Transient protein-protein interactions (PPIs) are essential components in cellular signaling pathways as well as in important processes such as viral infection, replication, and immune suppression. The unknown or uncharacterized PPIs involved in such interaction networks often represent compelling therapeutic targets for drug discovery. To date, however, the main strategies for discovery of small molecule modulators of PPIs are typically limited to structurally characterized targets. Recent developments in molecular scaffolds that mimic the side chain display of peptide secondary structures have yielded effective designs, but few screening libraries of such mimetics are available to interrogate PPI targets. We initiated a program to prepare a comprehensive small molecule library designed to mimic the three major recognition motifs that mediate PPIs (α-helix, β-turn, and β-strand). Three libraries would be built around templates designed to mimic each such secondary structure and substituted with all triplet combinations of groups representing the 20 natural amino acid side chains. When combined, the three libraries would contain a member capable of mimicking the key interaction and recognition residues of most targetable PPIs. In this Account, we summarize the results of the design, synthesis, and validation of an 8000 member α-helix mimetic library and a 4200 member β-turn mimetic library. We expect that the screening of these libraries will not only provide lead structures against α-helix- or β-turn-mediated protein-protein or peptide-receptor interactions, even if the nature of the interaction is unknown, but also yield key insights into the recognition motif (α-helix or β-turn) and identify the key residues mediating the interaction. Consistent with this expectation, the screening of the libraries against p53/MDM2 and HIV-1 gp41 (α-helix mimetic library) or the opioid receptors (β-turn mimetic library) led to the discovery of library members expected

Drug-target interaction prediction using ensemble learning and dimensionality reduction.

PubMed

Ezzat, Ali; Wu, Min; Li, Xiao-Li; Kwoh, Chee-Keong

2017-10-01

Experimental prediction of drug-target interactions is expensive, time-consuming and tedious. Fortunately, computational methods help narrow down the search space for interaction candidates to be further examined via wet-lab techniques. Nowadays, the number of attributes/features for drugs and targets, as well as the amount of their interactions, are increasing, making these computational methods inefficient or occasionally prohibitive. This motivates us to derive a reduced feature set for prediction. In addition, since ensemble learning techniques are widely used to improve the classification performance, it is also worthwhile to design an ensemble learning framework to enhance the performance for drug-target interaction prediction. In this paper, we propose a framework for drug-target interaction prediction leveraging both feature dimensionality reduction and ensemble learning. First, we conducted feature subspacing to inject diversity into the classifier ensemble. Second, we applied three different dimensionality reduction methods to the subspaced features. Third, we trained homogeneous base learners with the reduced features and then aggregated their scores to derive the final predictions. For base learners, we selected two classifiers, namely Decision Tree and Kernel Ridge Regression, resulting in two variants of ensemble models, EnsemDT and EnsemKRR, respectively. In our experiments, we utilized AUC (Area under ROC Curve) as an evaluation metric. We compared our proposed methods with various state-of-the-art methods under 5-fold cross validation. Experimental results showed EnsemKRR achieving the highest AUC (94.3%) for predicting drug-target interactions. In addition, dimensionality reduction helped improve the performance of EnsemDT. In conclusion, our proposed methods produced significant improvements for drug-target interaction prediction. Copyright © 2017 Elsevier Inc. All rights reserved.

TargetNet: a web service for predicting potential drug-target interaction profiling via multi-target SAR models.

PubMed

Yao, Zhi-Jiang; Dong, Jie; Che, Yu-Jing; Zhu, Min-Feng; Wen, Ming; Wang, Ning-Ning; Wang, Shan; Lu, Ai-Ping; Cao, Dong-Sheng

2016-05-01

Drug-target interactions (DTIs) are central to current drug discovery processes and public health fields. Analyzing the DTI profiling of the drugs helps to infer drug indications, adverse drug reactions, drug-drug interactions, and drug mode of actions. Therefore, it is of high importance to reliably and fast predict DTI profiling of the drugs on a genome-scale level. Here, we develop the TargetNet server, which can make real-time DTI predictions based only on molecular structures, following the spirit of multi-target SAR methodology. Naïve Bayes models together with various molecular fingerprints were employed to construct prediction models. Ensemble learning from these fingerprints was also provided to improve the prediction ability. When the user submits a molecule, the server will predict the activity of the user's molecule across 623 human proteins by the established high quality SAR model, thus generating a DTI profiling that can be used as a feature vector of chemicals for wide applications. The 623 SAR models related to 623 human proteins were strictly evaluated and validated by several model validation strategies, resulting in the AUC scores of 75-100 %. We applied the generated DTI profiling to successfully predict potential targets, toxicity classification, drug-drug interactions, and drug mode of action, which sufficiently demonstrated the wide application value of the potential DTI profiling. The TargetNet webserver is designed based on the Django framework in Python, and is freely accessible at http://targetnet.scbdd.com .

TargetNet: a web service for predicting potential drug-target interaction profiling via multi-target SAR models

NASA Astrophysics Data System (ADS)

Yao, Zhi-Jiang; Dong, Jie; Che, Yu-Jing; Zhu, Min-Feng; Wen, Ming; Wang, Ning-Ning; Wang, Shan; Lu, Ai-Ping; Cao, Dong-Sheng

2016-05-01

Drug-target interactions (DTIs) are central to current drug discovery processes and public health fields. Analyzing the DTI profiling of the drugs helps to infer drug indications, adverse drug reactions, drug-drug interactions, and drug mode of actions. Therefore, it is of high importance to reliably and fast predict DTI profiling of the drugs on a genome-scale level. Here, we develop the TargetNet server, which can make real-time DTI predictions based only on molecular structures, following the spirit of multi-target SAR methodology. Naïve Bayes models together with various molecular fingerprints were employed to construct prediction models. Ensemble learning from these fingerprints was also provided to improve the prediction ability. When the user submits a molecule, the server will predict the activity of the user's molecule across 623 human proteins by the established high quality SAR model, thus generating a DTI profiling that can be used as a feature vector of chemicals for wide applications. The 623 SAR models related to 623 human proteins were strictly evaluated and validated by several model validation strategies, resulting in the AUC scores of 75-100 %. We applied the generated DTI profiling to successfully predict potential targets, toxicity classification, drug-drug interactions, and drug mode of action, which sufficiently demonstrated the wide application value of the potential DTI profiling. The TargetNet webserver is designed based on the Django framework in Python, and is freely accessible at http://targetnet.scbdd.com.

Target design optimization for an electron accelerator driven subcritical facility with circular and square beam profiles.

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

Gohar, M. Y. A; Sofu, T.; Zhong, Z.

2008-10-30

A subcritical facility driven by an electron accelerator is planned at the Kharkov Institute of Physics and Technology (KIPT) in Ukraine for medical isotope production, materials research, training, and education. The conceptual design of the facility is being pursued through collaborations between ANL and KIPT. As part of the design effort, the high-fidelity analyses of various target options are performed with formulations to reflect the realistic configuration and the three dimensional geometry of each design. This report summarizes the results of target design optimization studies for electron beams with two different beam profiles. The target design optimization is performed viamore » the sequential neutronic, thermal-hydraulic, and structural analyses for a comprehensive assessment of each configuration. First, a target CAD model is developed with proper emphasis on manufacturability to provide a basis for separate but consistent models for subsequent neutronic, thermal-hydraulic, and structural analyses. The optimizations are pursued for maximizing the neutron yield, streamlining the flow field to avoid hotspots, and minimizing the thermal stresses to increase the durability. In addition to general geometric modifications, the inlet/outlet channel configurations, target plate partitioning schemes, flow manipulations and rates, electron beam diameter/width options, and cladding material choices are included in the design optimizations. The electron beam interactions with the target assembly and the neutronic response of the subcritical facility are evaluated using the MCNPX code. the results for the electron beam energy deposition, neutron generation, and utilization in the subcritical pile are then used to characterize the axisymmetric heat generation profiles in the target assembly with explicit simulations of the beam tube, the coolant, the clad, and the target materials. Both tungsten and uranium are considered as target materials. Neutron spectra from

Strong electromagnetic pulses generated in high-intensity short-pulse laser interactions with thin foil targets

NASA Astrophysics Data System (ADS)

Rączka, P.; Dubois, J.-L.; Hulin, S.; Tikhonchuk, V.; Rosiński, M.; Zaraś-Szydłowska, A.; Badziak, J.

2017-12-01

Measurements are reported of the target neutralization current, the target charge, and the tangential component of the magnetic field generated as a result of laser-target interaction by pulses with the energy in the range of 45 mJ to 92 mJ on target and the pulse duration from 39 fs to 1000 fs. The experiment was performed at the Eclipse facility in CELIA, Bordeaux. The aim of the experiment was to extend investigations performed for the thick (mm scale) targets to the case of thin (micrometer thickness) targets in a way that would allow for a straightforward comparison of the results. We found that thin foil targets tend to generate 20 to 50 percent higher neutralization current and the target charge than the thick targets. The measurement of the tangential component of the magnetic field had shown that the initial spike is dominated by the 1 ns pulse consistent with the 1 ns pulse of the neutralization current, but there are some differences between targets of different type on sub-ns scale, which is an effect going beyond a simple picture of the target acting as an antenna. The sub-ns structure appears to be reproducible to surprising degree. We found that there is in general a linear correlation between the maximum value of the magnetic field and the maximum neutralization current, which supports the target-antenna picture, except for pulses hundreds of fs long.

The Nike KrF laser facility: Performance and initial target experiments

NASA Astrophysics Data System (ADS)

Obenschain, S. P.; Bodner, S. E.; Colombant, D.; Gerber, K.; Lehmberg, R. H.; McLean, E. A.; Mostovych, A. N.; Pronko, M. S.; Pawley, C. J.; Schmitt, A. J.; Sethian, J. D.; Serlin, V.; Stamper, J. A.; Sullivan, C. A.; Dahlburg, J. P.; Gardner, J. H.; Chan, Y.; Deniz, A. V.; Hardgrove, J.; Lehecka, T.; Klapisch, M.

1996-05-01

Krypton-fluoride (KrF) lasers are of interest to laser fusion because they have both the large bandwidth capability (≳THz) desired for rapid beam smoothing and the short laser wavelength (1/4 μm) needed for good laser-target coupling. Nike is a recently completed 56-beam KrF laser and target facility at the Naval Research Laboratory. Because of its bandwidth of 1 THz FWHM (full width at half-maximum), Nike produces more uniform focal distributions than any other high-energy ultraviolet laser. Nike was designed to study the hydrodynamic instability of ablatively accelerated planar targets. First results show that Nike has spatially uniform ablation pressures (Δp/p<2%). Targets have been accelerated for distances sufficient to study hydrodynamic instability while maintaining good planarity. In this review we present the performance of the Nike laser in producing uniform illumination, and its performance in correspondingly uniform acceleration of targets.

Optimizing prognosis-related key miRNA-target interactions responsible for cancer metastasis.

PubMed

Zhao, Hongying; Yuan, Huating; Hu, Jing; Xu, Chaohan; Liao, Gaoming; Yin, Wenkang; Xu, Liwen; Wang, Li; Zhang, Xinxin; Shi, Aiai; Li, Jing; Xiao, Yun

2017-12-12

Increasing evidence suggests that the abnormality of microRNAs (miRNAs) and their downstream targets is frequently implicated in the pathogenesis of human cancers, however, the clinical benefit of causal miRNA-target interactions has been seldom studied. Here, we proposed a computational method to optimize prognosis-related key miRNA-target interactions by combining transcriptome and clinical data from thousands of TCGA tumors across 16 cancer types. We obtained a total of 1,956 prognosis-related key miRNA-target interactions between 112 miRNAs and 1,443 their targets. Interestingly, these key target genes are specifically involved in tumor progression-related functions, such as 'cell adhesion' and 'cell migration'. Furthermore, they are most significantly correlated with 'tissue invasion and metastasis', a hallmark of metastasis, in ten distinct types of cancer through the hallmark analysis. These results implicated that the prognosis-related key miRNA-target interactions were highly associated with cancer metastasis. Finally, we observed that the combination of these key miRNA-target interactions allowed to distinguish patients with good prognosis from those with poor prognosis both in most TCGA cancer types and independent validation sets, highlighting their roles in cancer metastasis. We provided a user-friendly database named miRNATarget (freely available at http://biocc.hrbmu.edu.cn/miRNATar/), which provides an overview of the prognosis-related key miRNA-target interactions across 16 cancer types.

Hot-spot analysis for drug discovery targeting protein-protein interactions.

PubMed

Rosell, Mireia; Fernández-Recio, Juan

2018-04-01

Protein-protein interactions are important for biological processes and pathological situations, and are attractive targets for drug discovery. However, rational drug design targeting protein-protein interactions is still highly challenging. Hot-spot residues are seen as the best option to target such interactions, but their identification requires detailed structural and energetic characterization, which is only available for a tiny fraction of protein interactions. Areas covered: In this review, the authors cover a variety of computational methods that have been reported for the energetic analysis of protein-protein interfaces in search of hot-spots, and the structural modeling of protein-protein complexes by docking. This can help to rationalize the discovery of small-molecule inhibitors of protein-protein interfaces of therapeutic interest. Computational analysis and docking can help to locate the interface, molecular dynamics can be used to find suitable cavities, and hot-spot predictions can focus the search for inhibitors of protein-protein interactions. Expert opinion: A major difficulty for applying rational drug design methods to protein-protein interactions is that in the majority of cases the complex structure is not available. Fortunately, computational docking can complement experimental data. An interesting aspect to explore in the future is the integration of these strategies for targeting PPIs with large-scale mutational analysis.

Debris and shrapnel assessments for National Ignition Facility targets and diagnostics

NASA Astrophysics Data System (ADS)

Masters, N. D.; Fisher, A.; Kalantar, D.; Stölken, J.; Smith, C.; Vignes, R.; Burns, S.; Doeppner, T.; Kritcher, A.; Park, H.-S.

2016-05-01

High-energy laser experiments at the National Ignition Facility (NIF) can create debris and shrapnel capable of damaging laser optics and diagnostic instruments. The size, composition and location of target components and sacrificial shielding (e.g., disposable debris shields, or diagnostic filters) and the protection they provide is constrained by many factors, including: chamber and diagnostic geometries, experimental goals and material considerations. An assessment of the generation, nature and velocity of shrapnel and debris and their potential threats is necessary prior to fielding targets or diagnostics. These assessments may influence target and shielding design, filter configurations and diagnostic selection. This paper will outline the approach used to manage the debris and shrapnel risk associated with NIF targets and diagnostics and present some aspects of two such cases: the Material Strength Rayleigh- Taylor campaign and the Mono Angle Crystal Spectrometer (MACS).

Laser-Plasma Interaction Experiments at Direct-Drive Ignition-Relevant Plasma Conditions at the National Ignition Facility

NASA Astrophysics Data System (ADS)

Solodov, A. A.; Rosenberg, M. J.; Myatt, J. F.; Shaw, J. G.; Seka, W.; Epstein, R.; Short, R. W.; Follett, R. K.; Regan, S. P.; Froula, D. H.; Radha, P. B.; Michel, P.; Chapman, T.; Hohenberger, M.

2017-10-01

Laser-plasma interaction (LPI) instabilities, such as stimulated Raman scattering (SRS) and two-plasmon decay, can be detrimental for direct-drive inertial confinement fusion because of target preheat by the high-energy electrons they generate. The radiation-hydrodynamic code DRACO was used to design planar-target experiments at the National Ignition Facility that generated plasma and interaction conditions relevant to ignition direct-drive designs (IL 1015W/cm2 , Te > 3 keV, density gradient scale lengths of Ln 600 μm). Laser-energy conversion efficiency to hot electrons of 0.5% to 2.5% with temperature of 45 to 60 keV was inferred from the experiment when the laser intensity at the quarter-critical surface increased from 6 to 15 ×1014W/cm2 . LPI was dominated by SRS, as indicated by the measured scattered-light spectra. Simulations of SRS using the LPI code LPSE have been performed and compared with predictions of theoretical models. Implications for ignition-scale direct-drive experiments will be discussed. This material is based upon work supported by the Department of Energy National Nuclear Security Administration under Award Number DE-NA0001944.

Predicting Drug-Target Interactions for New Drug Compounds Using a Weighted Nearest Neighbor Profile.

PubMed

van Laarhoven, Twan; Marchiori, Elena

2013-01-01

In silico discovery of interactions between drug compounds and target proteins is of core importance for improving the efficiency of the laborious and costly experimental determination of drug-target interaction. Drug-target interaction data are available for many classes of pharmaceutically useful target proteins including enzymes, ion channels, GPCRs and nuclear receptors. However, current drug-target interaction databases contain a small number of drug-target pairs which are experimentally validated interactions. In particular, for some drug compounds (or targets) there is no available interaction. This motivates the need for developing methods that predict interacting pairs with high accuracy also for these 'new' drug compounds (or targets). We show that a simple weighted nearest neighbor procedure is highly effective for this task. We integrate this procedure into a recent machine learning method for drug-target interaction we developed in previous work. Results of experiments indicate that the resulting method predicts true interactions with high accuracy also for new drug compounds and achieves results comparable or better than those of recent state-of-the-art algorithms. Software is publicly available at http://cs.ru.nl/~tvanlaarhoven/drugtarget2013/.

Nanoparticle-blood interactions: the implications on solid tumour targeting.

PubMed

Lazarovits, James; Chen, Yih Yang; Sykes, Edward A; Chan, Warren C W

2015-02-18

Nanoparticles are suitable platforms for cancer targeting and diagnostic applications. Typically, less than 10% of all systemically administered nanoparticles accumulate in the tumour. Here we explore the interactions of blood components with nanoparticles and describe how these interactions influence solid tumour targeting. In the blood, serum proteins adsorb onto nanoparticles to form a protein corona in a manner dependent on nanoparticle physicochemical properties. These serum proteins can block nanoparticle tumour targeting ligands from binding to tumour cell receptors. Additionally, serum proteins can also encourage nanoparticle uptake by macrophages, which decreases nanoparticle availability in the blood and limits tumour accumulation. The formation of this protein corona will also increase the nanoparticle hydrodynamic size or induce aggregation, which makes nanoparticles too large to enter into the tumour through pores of the leaky vessels, and prevents their deep penetration into tumours for cell targeting. Recent studies have focused on developing new chemical strategies to reduce or eliminate serum protein adsorption, and rescue the targeting potential of nanoparticles to tumour cells. An in-depth and complete understanding of nanoparticle-blood interactions is key to designing nanoparticles with optimal physicochemical properties with high tumour accumulation. The purpose of this review article is to describe how the protein corona alters the targeting of nanoparticles to solid tumours and explains current solutions to solve this problem.

Interactive target tracking for persistent wide-area surveillance

NASA Astrophysics Data System (ADS)

Ersoy, Ilker; Palaniappan, Kannappan; Seetharaman, Guna S.; Rao, Raghuveer M.

2012-06-01

Persistent aerial surveillance is an emerging technology that can provide continuous, wide-area coverage from an aircraft-based multiple-camera system. Tracking targets in these data sets is challenging for vision algorithms due to large data (several terabytes), very low frame rate, changing viewpoint, strong parallax and other imperfections due to registration and projection. Providing an interactive system for automated target tracking also has additional challenges that require online algorithms that are seamlessly integrated with interactive visualization tools to assist the user. We developed an algorithm that overcomes these challenges and demonstrated it on data obtained from a wide-area imaging platform.

Target-projectile interaction during impact melting at Kamil Crater, Egypt

NASA Astrophysics Data System (ADS)

Fazio, Agnese; D'Orazio, Massimo; Cordier, Carole; Folco, Luigi

2016-05-01

In small meteorite impacts, the projectile may survive through fragmentation; in addition, it may melt, and chemically and physically interact with both shocked and melted target rocks. However, the mixing/mingling between projectile and target melts is a process still not completely understood. Kamil Crater (45 m in diameter; Egypt), generated by the hypervelocity impact of the Gebel Kamil Ni-rich ataxite on sandstone target, allows to study the target-projectile interaction in a simple and fresh geological setting. We conducted a petrographic and geochemical study of macroscopic impact melt lapilli and bombs ejected from the crater, which were collected during our geophysical campaign in February 2010. Two types of glasses constitute the impact melt lapilli and bombs: a white glass and a dark glass. The white glass is mostly made of SiO2 and it is devoid of inclusions. Its negligible Ni and Co contents suggest derivation from the target rocks without interaction with the projectile (<0.1 wt% of projectile contamination). The dark glass is a silicate melt with variable contents of Al2O3 (0.84-18.7 wt%), FeOT (1.83-61.5 wt%), and NiO (<0.01-10.2 wt%). The dark glass typically includes fragments (from few μm to several mm in size) of shocked sandstone, diaplectic glass, lechatelierite, and Ni-Fe metal blebs. The metal blebs are enriched in Ni compared to the Gebel Kamil meteorite. The dark glass is thus a mixture of target and projectile melts (11-12 wt% of projectile contamination). Based on recently proposed models for target-projectile interaction and for impact glass formation, we suggest a scenario for the glass formation at Kamil. During the transition from the contact and compression stage and the excavation stage, projectile and target liquids formed at their interface and chemically interact in a restricted zone. Projectile contamination affected only a shallow portion of the target rocks. The SiO2 melt that eventually solidified as white glass behaved as

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.

Both Patient and Facility Contribute to Achieving the Centers for Medicare and Medicaid Services' Pay-for-Performance Target for Dialysis Adequacy

PubMed Central

Tighiouart, Hocine; Meyer, Klemens B.; Miskulin, Dana C.

2011-01-01

The Centers for Medicare and Medicaid Services (CMS) designated the achieved urea reduction ratio (URR) as a pay-for-performance measure, but to what extent this measure reflects patient characteristics and adherence instead of its intent to reflect facility performance is unknown. Here, we quantified the contributions of patient case-mix and adherence to the variability in achieving URR targets across dialysis facilities. We found that 92% of 10,069 hemodialysis patients treated at 173 facilities during the last quarter of 2004 achieved the target URR ≥65%. Mixed-effect models with random intercept for dialysis facility revealed a significant facility effect: 11.5% of the variation in achievement of target URR was attributable to the facility level. Adjusting for patient case-mix reduced the proportion of variation attributable to the facility level to 6.7%. Patient gender, body surface area, dialysis access, and adherence with treatment strongly associated with achievement of the URR target. We could not identify specific facility characteristics that explained the remaining variation between facilities. These data suggest that if adherence is not a modifiable patient characteristic, providers could be unfairly penalized for caring for these patients under current CMS policy. These penalties may have unintended consequences. PMID:22025629

Visualization and Analysis of MiRNA-Targets Interactions Networks.

PubMed

León, Luis E; Calligaris, Sebastián D

2017-01-01

MicroRNAs are a class of small, noncoding RNA molecules of 21-25 nucleotides in length that regulate the gene expression by base-pairing with the target mRNAs, mainly leading to down-regulation or repression of the target genes. MicroRNAs are involved in diverse regulatory pathways in normal and pathological conditions. In this context, it is highly important to identify the targets of specific microRNA in order to understand the mechanism of its regulation and consequently its involvement in disease. However, the microRNA target identification is experimentally laborious and time-consuming. The in silico prediction of microRNA targets is an extremely useful approach because you can identify potential mRNA targets, reduce the number of possibilities and then, validate a few microRNA-mRNA interactions in an in vitro experimental model. In this chapter, we describe, in a simple way, bioinformatics guidelines to use miRWalk database and Cytoscape software for analyzing microRNA-mRNA interactions through their visualization as a network.

SELF-BLM: Prediction of drug-target interactions via self-training SVM.

PubMed

Keum, Jongsoo; Nam, Hojung

2017-01-01

Predicting drug-target interactions is important for the development of novel drugs and the repositioning of drugs. To predict such interactions, there are a number of methods based on drug and target protein similarity. Although these methods, such as the bipartite local model (BLM), show promise, they often categorize unknown interactions as negative interaction. Therefore, these methods are not ideal for finding potential drug-target interactions that have not yet been validated as positive interactions. Thus, here we propose a method that integrates machine learning techniques, such as self-training support vector machine (SVM) and BLM, to develop a self-training bipartite local model (SELF-BLM) that facilitates the identification of potential interactions. The method first categorizes unlabeled interactions and negative interactions among unknown interactions using a clustering method. Then, using the BLM method and self-training SVM, the unlabeled interactions are self-trained and final local classification models are constructed. When applied to four classes of proteins that include enzymes, G-protein coupled receptors (GPCRs), ion channels, and nuclear receptors, SELF-BLM showed the best performance for predicting not only known interactions but also potential interactions in three protein classes compare to other related studies. The implemented software and supporting data are available at https://github.com/GIST-CSBL/SELF-BLM.

Relativistic-electron-beam/target interaction in plasma channels

NASA Astrophysics Data System (ADS)

Halbleib, J. A., Sr.; Wright, T. P.

1980-08-01

A model describing the transport of relativistic electron beams in plasma channels and their subsequent interaction with solid targets is developed and applied to single-beam and multiple-beam configurations. For single beams the targets consist of planar tantalum foils and, in some cases, cusp fields on the transmission side of the foils are employed to improve beam/target coupling efficiency. In the multi-beam configurations, several beams are arranged in wagon-wheel fashion so as to converge upon cylindrical targets, consisting of either hollow tantalum or solid graphite cylinders, located at the hub. For 0.3-cm beam radii that are less than or equal to the channel radii, mean specific power depositions up to about 17 TW/g per MA of injected beam current are obtained for single beams; 12-beam results are typically an order-of-magnitude less. The corresponding enhancements are up to five times the collisional stopping power for either single or multiple beams. Substantial improvement is predicted for the multi-beam interaction should future channel technology permit transport at higher current densities in smaller channels.

Development and use of interactive displays in real-time ground support research facilities

NASA Technical Reports Server (NTRS)

Rhea, Donald C.; Hammons, Kvin R.; Malone, Jacqueline C.; Nesel, Michael C.

1989-01-01

The NASA Western Aeronautical Test Range (WATR) is one of the world's most advanced aeronautical research flight test support facilities. A variety of advanced and often unique real-time interactive displays has been developed for use in the mission control centers (MCC) to support research flight and ground testing. These dispalys consist of applications operating on systems described as real-time interactive graphics super workstations and real-time interactive PC/AT compatible workstations. This paper reviews these two types of workstations and the specific applications operating on each display system. The applications provide examples that demonstrate overall system capability applicable for use in other ground-based real-time research/test facilities.

High energy density physics effects predicted in simulations of the CERN HiRadMat beam-target interaction experiments

NASA Astrophysics Data System (ADS)

Tahir, N. A.; Burkart, F.; Schmidt, R.; Shutov, A.; Wollmann, D.; Piriz, A. R.

2016-12-01

Experiments have been done at the CERN HiRadMat (High Radiation to Materials) facility in which large cylindrical copper targets were irradiated with 440 GeV proton beam generated by the Super Proton Synchrotron (SPS). The primary purpose of these experiments was to confirm the existence of hydrodynamic tunneling of ultra-relativistic protons and their hadronic shower in solid materials, that was predicted by previous numerical simulations. The experimental measurements have shown very good agreement with the simulation results. This provides confidence in our simulations of the interaction of the 7 TeV LHC (Large Hadron Collider) protons and the 50 TeV Future Circular Collider (FCC) protons with solid materials, respectively. This work is important from the machine protection point of view. The numerical simulations have also shown that in the HiRadMat experiments, a significant part of thetarget material is be converted into different phases of High Energy Density (HED) matter, including two-phase solid-liquid mixture, expanded as well as compressed hot liquid phases, two-phase liquid-gas mixture and gaseous state. The HiRadMat facility is therefore a unique ion beam facility worldwide that is currently available for studying the thermophysical properties of HED matter. In the present paper we discuss the numerical simulation results and present a comparison with the experimental measurements.

Method to Reduce Target Motion Through Needle-Tissue Interactions.

PubMed

Oldfield, Matthew J; Leibinger, Alexander; Seah, Tian En Timothy; Rodriguez Y Baena, Ferdinando

2015-11-01

During minimally invasive surgical procedures, it is often important to deliver needles to particular tissue volumes. Needles, when interacting with a substrate, cause deformation and target motion. To reduce reliance on compensatory intra-operative imaging, a needle design and novel delivery mechanism is proposed. Three-dimensional finite element simulations of a multi-segment needle inserted into a pre-existing crack are presented. The motion profiles of the needle segments are varied to identify methods that reduce target motion. Experiments are then performed by inserting a needle into a gelatine tissue phantom and measuring the internal target motion using digital image correlation. Simulations indicate that target motion is reduced when needle segments are stroked cyclically and utilise a small amount of retraction instead of being held stationary. Results are confirmed experimentally by statistically significant target motion reductions of more than 8% during cyclic strokes and 29% when also incorporating retraction, with the same net insertion speed. By using a multi-segment needle and taking advantage of frictional interactions on the needle surface, it is demonstrated that target motion ahead of an advancing needle can be substantially reduced.

Identification of chemogenomic features from drug–target interaction networks using interpretable classifiers

PubMed Central

Tabei, Yasuo; Pauwels, Edouard; Stoven, Véronique; Takemoto, Kazuhiro; Yamanishi, Yoshihiro

2012-01-01

Motivation: Drug effects are mainly caused by the interactions between drug molecules and their target proteins including primary targets and off-targets. Identification of the molecular mechanisms behind overall drug–target interactions is crucial in the drug design process. Results: We develop a classifier-based approach to identify chemogenomic features (the underlying associations between drug chemical substructures and protein domains) that are involved in drug–target interaction networks. We propose a novel algorithm for extracting informative chemogenomic features by using L1 regularized classifiers over the tensor product space of possible drug–target pairs. It is shown that the proposed method can extract a very limited number of chemogenomic features without loosing the performance of predicting drug–target interactions and the extracted features are biologically meaningful. The extracted substructure–domain association network enables us to suggest ligand chemical fragments specific for each protein domain and ligand core substructures important for a wide range of protein families. Availability: Softwares are available at the supplemental website. Contact: yamanishi@bioreg.kyushu-u.ac.jp Supplementary Information: Datasets and all results are available at http://cbio.ensmp.fr/~yyamanishi/l1binary/ . PMID:22962471

A time-of-flight system for the external target facility

NASA Astrophysics Data System (ADS)

Zhang, Xue-Heng; Yu, Yu-Hong; Sun, Zhi-Yu; Mao, Rui-Shi; Wang, Shi-Tao; Zhou, Yong; Yan, Duo; Liu, Long-Xiang

2013-05-01

A time-of-flight system with a plastic scintillator coupled to photomultipliers is developed for the external target facility (ETF). This system can satisfy the requirement of an ultrahigh vacuum (~10-9 mbar), a high counting rate (~106 particles per second) and a magnetic field environment. In the beam test experiment, a total time resolution of 580 ps FWHM was obtained for the whole system, and nuclei with a mass of up to 80 could be identified using this system.

The Human Kinome Targeted by FDA Approved Multi-Target Drugs and Combination Products: A Comparative Study from the Drug-Target Interaction Network Perspective.

PubMed

Li, Ying Hong; Wang, Pan Pan; Li, Xiao Xu; Yu, Chun Yan; Yang, Hong; Zhou, Jin; Xue, Wei Wei; Tan, Jun; Zhu, Feng

2016-01-01

The human kinome is one of the most productive classes of drug target, and there is emerging necessity for treating complex diseases by means of polypharmacology (multi-target drugs and combination products). However, the advantages of the multi-target drugs and the combination products are still under debate. A comparative analysis between FDA approved multi-target drugs and combination products, targeting the human kinome, was conducted by mapping targets onto the phylogenetic tree of the human kinome. The approach of network medicine illustrating the drug-target interactions was applied to identify popular targets of multi-target drugs and combination products. As identified, the multi-target drugs tended to inhibit target pairs in the human kinome, especially the receptor tyrosine kinase family, while the combination products were able to against targets of distant homology relationship. This finding asked for choosing the combination products as a better solution for designing drugs aiming at targets of distant homology relationship. Moreover, sub-networks of drug-target interactions in specific disease were generated, and mechanisms shared by multi-target drugs and combination products were identified. In conclusion, this study performed an analysis between approved multi-target drugs and combination products against the human kinome, which could assist the discovery of next generation polypharmacology.

Drug-target interaction prediction: A Bayesian ranking approach.

PubMed

Peska, Ladislav; Buza, Krisztian; Koller, Júlia

2017-12-01

In silico prediction of drug-target interactions (DTI) could provide valuable information and speed-up the process of drug repositioning - finding novel usage for existing drugs. In our work, we focus on machine learning algorithms supporting drug-centric repositioning approach, which aims to find novel usage for existing or abandoned drugs. We aim at proposing a per-drug ranking-based method, which reflects the needs of drug-centric repositioning research better than conventional drug-target prediction approaches. We propose Bayesian Ranking Prediction of Drug-Target Interactions (BRDTI). The method is based on Bayesian Personalized Ranking matrix factorization (BPR) which has been shown to be an excellent approach for various preference learning tasks, however, it has not been used for DTI prediction previously. In order to successfully deal with DTI challenges, we extended BPR by proposing: (i) the incorporation of target bias, (ii) a technique to handle new drugs and (iii) content alignment to take structural similarities of drugs and targets into account. Evaluation on five benchmark datasets shows that BRDTI outperforms several state-of-the-art approaches in terms of per-drug nDCG and AUC. BRDTI results w.r.t. nDCG are 0.929, 0.953, 0.948, 0.897 and 0.690 for G-Protein Coupled Receptors (GPCR), Ion Channels (IC), Nuclear Receptors (NR), Enzymes (E) and Kinase (K) datasets respectively. Additionally, BRDTI significantly outperformed other methods (BLM-NII, WNN-GIP, NetLapRLS and CMF) w.r.t. nDCG in 17 out of 20 cases. Furthermore, BRDTI was also shown to be able to predict novel drug-target interactions not contained in the original datasets. The average recall at top-10 predicted targets for each drug was 0.762, 0.560, 1.000 and 0.404 for GPCR, IC, NR, and E datasets respectively. Based on the evaluation, we can conclude that BRDTI is an appropriate choice for researchers looking for an in silico DTI prediction technique to be used in drug

The effects of return current and target charging in short pulse high intensity laser interactions

NASA Astrophysics Data System (ADS)

Beg, Farhat

2003-10-01

Since the introduction of the technique of chirped pulse amplification (CPA), peak laser intensities have increased dramatically. It is now possible to perform laser-plasma interaction experiments at intensities approaching 1021 Wcm-2. The electrons in the field of such lasers are highly relativistic (gamma 31) and the temperature of the hot electron distribution produced in a plasma at such extreme intensities can exceed 10 MeV. Since the resulting beam current exceeds the Alfvén limit, a neutralizing return current of cold plasma electrons moving in the opposite direction is produced. Another source of return current is that due to the escape of very energetic electrons from the target, which then creates a large electrostatic potential due to charge separation. These return currents can cause significant ohmic heating. We present results from experiments performed at Rutherford Appleton Laboratory using the VULCAN laser facility (I> 5 x1019 Wcm-2). Single wire targets were used and in some shots a secondary wire or foil was placed near the target. Three main observations were made: (i) generation of a Z-pinch in the wire due to the return current, (ii) optical transition radiation at 2w and (iii) proton emission from both the primary wire target and the secondary wire or foil. The Z-pinch was observed to be m=0 unstable. The current was estimated to be about 0.8 MA using simple energy balance considerations. Intense second harmonic emission due to coherent optical transition radiation from both the primary target and secondary objects was observed and is likely due to electron bunches accelerated by the ponderomotive jxB force of the laser. The proton emission from the secondary wire or foil was likely due to field emission of electrons from the these objects in response to the large potential produced from charging of the primary target. Results of simulations to model these interactions will also be presented.

Tertiary structure-based analysis of microRNA–target interactions

PubMed Central

Gan, Hin Hark; Gunsalus, Kristin C.

2013-01-01

Current computational analysis of microRNA interactions is based largely on primary and secondary structure analysis. Computationally efficient tertiary structure-based methods are needed to enable more realistic modeling of the molecular interactions underlying miRNA-mediated translational repression. We incorporate algorithms for predicting duplex RNA structures, ionic strength effects, duplex entropy and free energy, and docking of duplex–Argonaute protein complexes into a pipeline to model and predict miRNA–target duplex binding energies. To ensure modeling accuracy and computational efficiency, we use an all-atom description of RNA and a continuum description of ionic interactions using the Poisson–Boltzmann equation. Our method predicts the conformations of two constructs of Caenorhabditis elegans let-7 miRNA–target duplexes to an accuracy of ∼3.8 Å root mean square distance of their NMR structures. We also show that the computed duplex formation enthalpies, entropies, and free energies for eight miRNA–target duplexes agree with titration calorimetry data. Analysis of duplex–Argonaute docking shows that structural distortions arising from single-base-pair mismatches in the seed region influence the activity of the complex by destabilizing both duplex hybridization and its association with Argonaute. Collectively, these results demonstrate that tertiary structure-based modeling of miRNA interactions can reveal structural mechanisms not accessible with current secondary structure-based methods. PMID:23417009

Inferring protein domains associated with drug side effects based on drug-target interaction network.

PubMed

Iwata, Hiroaki; Mizutani, Sayaka; Tabei, Yasuo; Kotera, Masaaki; Goto, Susumu; Yamanishi, Yoshihiro

2013-01-01

Most phenotypic effects of drugs are involved in the interactions between drugs and their target proteins, however, our knowledge about the molecular mechanism of the drug-target interactions is very limited. One of challenging issues in recent pharmaceutical science is to identify the underlying molecular features which govern drug-target interactions. In this paper, we make a systematic analysis of the correlation between drug side effects and protein domains, which we call "pharmacogenomic features," based on the drug-target interaction network. We detect drug side effects and protein domains that appear jointly in known drug-target interactions, which is made possible by using classifiers with sparse models. It is shown that the inferred pharmacogenomic features can be used for predicting potential drug-target interactions. We also discuss advantages and limitations of the pharmacogenomic features, compared with the chemogenomic features that are the associations between drug chemical substructures and protein domains. The inferred side effect-domain association network is expected to be useful for estimating common drug side effects for different protein families and characteristic drug side effects for specific protein domains.

Neutron measurements from beam-target reactions at the ELISE neutral beam test facility

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

Xufei, X., E-mail: xiexufei@pku.edu.cn; Fan, T.; Nocente, M.

2014-11-15

Measurements of 2.5 MeV neutron emission from beam-target reactions performed at the ELISE neutral beam test facility are presented in this paper. The measurements are used to study the penetration of a deuterium beam in a copper dump, based on the observation of the time evolution of the neutron counting rate from beam-target reactions with a liquid scintillation detector. A calculation based on a local mixing model of deuterium deposition in the target up to a concentration of 20% at saturation is used to evaluate the expected neutron yield for comparison with data. The results are of relevance to understandmore » neutron emission associated to beam penetration in a solid target, with applications to diagnostic systems for the SPIDER and MITICA Neutral Beam Injection prototypes.« less

Inferring protein domains associated with drug side effects based on drug-target interaction network

PubMed Central

2013-01-01

Background Most phenotypic effects of drugs are involved in the interactions between drugs and their target proteins, however, our knowledge about the molecular mechanism of the drug-target interactions is very limited. One of challenging issues in recent pharmaceutical science is to identify the underlying molecular features which govern drug-target interactions. Results In this paper, we make a systematic analysis of the correlation between drug side effects and protein domains, which we call "pharmacogenomic features," based on the drug-target interaction network. We detect drug side effects and protein domains that appear jointly in known drug-target interactions, which is made possible by using classifiers with sparse models. It is shown that the inferred pharmacogenomic features can be used for predicting potential drug-target interactions. We also discuss advantages and limitations of the pharmacogenomic features, compared with the chemogenomic features that are the associations between drug chemical substructures and protein domains. Conclusion The inferred side effect-domain association network is expected to be useful for estimating common drug side effects for different protein families and characteristic drug side effects for specific protein domains. PMID:24565527

Simulations of beam-matter interaction experiments at the CERN HiRadMat facility and prospects of high-energy-density physics research.

PubMed

Tahir, N A; Burkart, F; Shutov, A; Schmidt, R; Wollmann, D; Piriz, A R

2014-12-01

In a recent publication [Schmidt et al., Phys. Plasmas 21, 080701 (2014)], we reported results on beam-target interaction experiments that have been carried out at the CERN HiRadMat (High Radiation to Materials) facility using extended solid copper cylindrical targets that were irradiated with a 440-GeV proton beam delivered by the Super Proton Synchrotron (SPS). On the one hand, these experiments confirmed the existence of hydrodynamic tunneling of the protons that leads to substantial increase in the range of the protons and the corresponding hadron shower in the target, a phenomenon predicted by our previous theoretical investigations [Tahir et al., Phys. Rev. ST Accel. Beams 25, 051003 (2012)]. On the other hand, these experiments demonstrated that the beam heated part of the target is severely damaged and is converted into different phases of high energy density (HED) matter, as suggested by our previous theoretical studies [Tahir et al., Phys. Rev. E 79, 046410 (2009)]. The latter confirms that the HiRadMat facility can be used to study HED physics. In the present paper, we give details of the numerical simulations carried out to understand the experimental measurements. These include the evolution of the physical parameters, for example, density, temperature, pressure, and the internal energy in the target, during and after the irradiation. This information is important in order to determine the region of the HED phase diagram that can be accessed in such experiments. These simulations have been done using the energy deposition code fluka and a two-dimensional hydrodynamic code, big2, iteratively.

Predicting Drug-Target Interactions Based on Small Positive Samples.

PubMed

Hu, Pengwei; Chan, Keith C C; Hu, Yanxing

2018-01-01

A basic task in drug discovery is to find new medication in the form of candidate compounds that act on a target protein. In other words, a drug has to interact with a target and such drug-target interaction (DTI) is not expected to be random. Significant and interesting patterns are expected to be hidden in them. If these patterns can be discovered, new drugs are expected to be more easily discoverable. Currently, a number of computational methods have been proposed to predict DTIs based on their similarity. However, such as approach does not allow biochemical features to be directly considered. As a result, some methods have been proposed to try to discover patterns in physicochemical interactions. Since the number of potential negative DTIs are very high both in absolute terms and in comparison to that of the known ones, these methods are rather computationally expensive and they can only rely on subsets, rather than the full set, of negative DTIs for training and validation. As there is always a relatively high chance for negative DTIs to be falsely identified and as only partial subset of such DTIs is considered, existing approaches can be further improved to better predict DTIs. In this paper, we present a novel approach, called ODT (one class drug target interaction prediction), for such purpose. One main task of ODT is to discover association patterns between interacting drugs and proteins from the chemical structure of the former and the protein sequence network of the latter. ODT does so in two phases. First, the DTI-network is transformed to a representation by structural properties. Second, it applies a oneclass classification algorithm to build a prediction model based only on known positive interactions. We compared the best AUROC scores of the ODT with several state-of-art approaches on Gold standard data. The prediction accuracy of the ODT is superior in comparison with all the other methods at GPCRs dataset and Ion channels dataset. Performance

A free-piston Stirling engine/linear alternator controls and load interaction test facility

NASA Technical Reports Server (NTRS)

Rauch, Jeffrey S.; Kankam, M. David; Santiago, Walter; Madi, Frank J.

1992-01-01

A test facility at LeRC was assembled for evaluating free-piston Stirling engine/linear alternator control options, and interaction with various electrical loads. This facility is based on a 'SPIKE' engine/alternator. The engine/alternator, a multi-purpose load system, a digital computer based load and facility control, and a data acquisition system with both steady-periodic and transient capability are described. Preliminary steady-periodic results are included for several operating modes of a digital AC parasitic load control. Preliminary results on the transient response to switching a resistive AC user load are discussed.

D 2 and D-T Liquid-Layer Target Shots at the National Ignition Facility

DOE PAGES

Walters, Curtis; Alger, Ethan; Bhandarkar, Suhas; ...

2018-01-19

Experiments at the National Ignition Facility (NIF) using targets containing a deuterium-tritium (D-T) fuel layer have, until recently, required that a high-quality layer of solid D-T (herein referred to as an ice layer) be formed in the capsule. The development of a process to line the inner surface of a target capsule with a foam layer of a thickness that is typical of ice layers has resulted in the ability to field targets with liquid layers wetting the foam. Successful fielding of liquid-layer targets on NIF required not only a foam-lined capsule but also changes to the capsule filling processmore » and the manner with which the inventory is maintained in the capsule. Additionally, changes to target heater power and the temperature drops across target components were required in order to achieve the desired range of shot temperatures. Finally, these changes and the target’s performance during four target shots on NIF are discussed.« less

D 2 and D-T Liquid-Layer Target Shots at the National Ignition Facility

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

Walters, Curtis; Alger, Ethan; Bhandarkar, Suhas

Experiments at the National Ignition Facility (NIF) using targets containing a deuterium-tritium (D-T) fuel layer have, until recently, required that a high-quality layer of solid D-T (herein referred to as an ice layer) be formed in the capsule. The development of a process to line the inner surface of a target capsule with a foam layer of a thickness that is typical of ice layers has resulted in the ability to field targets with liquid layers wetting the foam. Successful fielding of liquid-layer targets on NIF required not only a foam-lined capsule but also changes to the capsule filling processmore » and the manner with which the inventory is maintained in the capsule. Additionally, changes to target heater power and the temperature drops across target components were required in order to achieve the desired range of shot temperatures. Finally, these changes and the target’s performance during four target shots on NIF are discussed.« less

Protein-protein interactions and cancer: targeting the central dogma.

PubMed

Garner, Amanda L; Janda, Kim D

2011-01-01

Between 40,000 and 200,000 protein-protein interactions have been predicted to exist within the human interactome. As these interactions are of a critical nature in many important cellular functions and their dysregulation is causal of disease, the modulation of these binding events has emerged as a leading, yet difficult therapeutic arena. In particular, the targeting of protein-protein interactions relevant to cancer is of fundamental importance as the tumor-promoting function of several aberrantly expressed proteins in the cancerous state is directly resultant of its ability to interact with a protein-binding partner. Of significance, these protein complexes play a crucial role in each of the steps of the central dogma of molecular biology, the fundamental processes of genetic transmission. With the many important discoveries being made regarding the mechanisms of these genetic process, the identification of new chemical probes are needed to better understand and validate the druggability of protein-protein interactions related to the central dogma. In this review, we provide an overview of current small molecule-based protein-protein interaction inhibitors for each stage of the central dogma: transcription, mRNA splicing and translation. Importantly, through our analysis we have uncovered a lack of necessary probes targeting mRNA splicing and translation, thus, opening up the possibility for expansion of these fields.

Targeting RNA–Protein Interactions within the Human Immunodeficiency Virus Type 1 Lifecycle

PubMed Central

2013-01-01

RNA–protein interactions are vital throughout the HIV-1 life cycle for the successful production of infectious virus particles. One such essential RNA–protein interaction occurs between the full-length genomic viral RNA and the major structural protein of the virus. The initial interaction is between the Gag polyprotein and the viral RNA packaging signal (psi or Ψ), a highly conserved RNA structural element within the 5′-UTR of the HIV-1 genome, which has gained attention as a potential therapeutic target. Here, we report the application of a target-based assay to identify small molecules, which modulate the interaction between Gag and Ψ. We then demonstrate that one such molecule exhibits potent inhibitory activity in a viral replication assay. The mode of binding of the lead molecules to the RNA target was characterized by 1H NMR spectroscopy. PMID:24358934

Drug Target Protein-Protein Interaction Networks: A Systematic Perspective

PubMed Central

2017-01-01

The identification and validation of drug targets are crucial in biomedical research and many studies have been conducted on analyzing drug target features for getting a better understanding on principles of their mechanisms. But most of them are based on either strong biological hypotheses or the chemical and physical properties of those targets separately. In this paper, we investigated three main ways to understand the functional biomolecules based on the topological features of drug targets. There are no significant differences between targets and common proteins in the protein-protein interactions network, indicating the drug targets are neither hub proteins which are dominant nor the bridge proteins. According to some special topological structures of the drug targets, there are significant differences between known targets and other proteins. Furthermore, the drug targets mainly belong to three typical communities based on their modularity. These topological features are helpful to understand how the drug targets work in the PPI network. Particularly, it is an alternative way to predict potential targets or extract nontargets to test a new drug target efficiently and economically. By this way, a drug target's homologue set containing 102 potential target proteins is predicted in the paper. PMID:28691014

Computation of shock wave/target interaction

NASA Technical Reports Server (NTRS)

Mark, A.; Kutler, P.

1983-01-01

Computational results of shock waves impinging on targets and the ensuing diffraction flowfield are presented. A number of two-dimensional cases are computed with finite difference techniques. The classical case of a shock wave/cylinder interaction is compared with shock tube data and shows the quality of the computations on a pressure-time plot. Similar results are obtained for a shock wave/rectangular body interaction. Here resolution becomes important and the use of grid clustering techniques tend to show good agreement with experimental data. Computational results are also compared with pressure data resulting from shock impingement experiments for a complicated truck-like geometry. Here of significance are the grid generation and clustering techniques used. For these very complicated bodies, grids are generated by numerically solving a set of elliptic partial differential equations.

New Equilibrium Models of Drug-Receptor Interactions Derived from Target-Mediated Drug Disposition.

PubMed

Peletier, Lambertus A; Gabrielsson, Johan

2018-05-14

In vivo analyses of pharmacological data are traditionally based on a closed system approach not incorporating turnover of target and ligand-target kinetics, but mainly focussing on ligand-target binding properties. This study incorporates information about target and ligand-target kinetics parallel to binding. In a previous paper, steady-state relationships between target- and ligand-target complex versus ligand exposure were derived and a new expression of in vivo potency was derived for a circulating target. This communication is extending the equilibrium relationships and in vivo potency expression for (i) two separate targets competing for one ligand, (ii) two different ligands competing for a single target and (iii) a single ligand-target interaction located in tissue. The derived expressions of the in vivo potencies will be useful both in drug-related discovery projects and mechanistic studies. The equilibrium states of two targets and one ligand may have implications in safety assessment, whilst the equilibrium states of two competing ligands for one target may cast light on when pharmacodynamic drug-drug interactions are important. The proposed equilibrium expressions for a peripherally located target may also be useful for small molecule interactions with extravascularly located targets. Including target turnover, ligand-target complex kinetics and binding properties in expressions of potency and efficacy will improve our understanding of within and between-individual (and across species) variability. The new expressions of potencies highlight the fact that the level of drug-induced target suppression is very much governed by target turnover properties rather than by the target expression level as such.

Initiated chemical vapor deposited nanoadhesive for bonding National Ignition Facility's targets

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

Lee, Tom

Currently, the target fabrication scientists in National Ignition Facility Directorate at Lawrence Livermore National Laboratory (LLNL) is studying the propagation force resulted from laser impulses impacting a target. To best study this, they would like the adhesive used to glue the target substrates to be as thin as possible. The main objective of this research project is to create adhesive glue bonds for NIF’s targets that are ≤ 1 μm thick. Polyglycidylmethacrylate (PGMA) thin films were coated on various substrates using initiated chemical vapor deposition (iCVD). Film quality studies using white light interferometry reveal that the iCVD PGMA films weremore » smooth. The coated substrates were bonded at 150 °C under vacuum, with low inflow of Nitrogen. Success in bonding most of NIF’s mock targets at thicknesses ≤ 1 μm indicates that our process is feasible in bonding the real targets. Key parameters that are required for successful bonding were concluded from the bonding results. They include inert bonding atmosphere, sufficient contact between the PGMA films, and smooth substrates. Average bond strength of 0.60 MPa was obtained from mechanical shearing tests. The bonding failure mode of the sheared interfaces was observed to be cohesive. Future work on this project will include reattempt to bond silica aerogel to iCVD PGMA coated substrates, stabilize carbon nanotube forests with iCVD PGMA coating, and kinetics study of PGMA thermal crosslinking.« less

Mathematical description of drug-target interactions: application to biologics that bind to targets with two binding sites.

PubMed

Gibiansky, Leonid; Gibiansky, Ekaterina

2018-02-01

The emerging discipline of mathematical pharmacology occupies the space between advanced pharmacometrics and systems biology. A characteristic feature of the approach is application of advance mathematical methods to study the behavior of biological systems as described by mathematical (most often differential) equations. One of the early application of mathematical pharmacology (that was not called this name at the time) was formulation and investigation of the target-mediated drug disposition (TMDD) model and its approximations. The model was shown to be remarkably successful, not only in describing the observed data for drug-target interactions, but also in advancing the qualitative and quantitative understanding of those interactions and their role in pharmacokinetic and pharmacodynamic properties of biologics. The TMDD model in its original formulation describes the interaction of the drug that has one binding site with the target that also has only one binding site. Following the framework developed earlier for drugs with one-to-one binding, this work aims to describe a rigorous approach for working with similar systems and to apply it to drugs that bind to targets with two binding sites. The quasi-steady-state, quasi-equilibrium, irreversible binding, and Michaelis-Menten approximations of the model are also derived. These equations can be used, in particular, to predict concentrations of the partially bound target (RC). This could be clinically important if RC remains active and has slow internalization rate. In this case, introduction of the drug aimed to suppress target activity may lead to the opposite effect due to RC accumulation.

Overview of Progress on the LANSCE Accelerator and Target Facilities Improvement Program

NASA Astrophysics Data System (ADS)

Macek, R. J.; Brun, T.; Donahue, J. B.; Fitzgerald, D. H.

1997-05-01

Three projects to improve the performance of the accelerator and target facilities for the Los Alamos Neutron Science Center have been initiated since 1994. The LANSCE Reliability Improvement Project was separated into two phases. Phase I, completed in 1995, was targeted at near-term improvements to beam availability that could be completed in a year. Phase II, now underway, consists of two projects: 1) converting the beam injection into the Proton Storage Ring (PSR) from the present two-step process H^- to H^0 to H^+) to direct injection of H^- beam in one step (H^- to H^+), and 2) an upgrade of the spallation neutron production target which will reduce the target change-out time from about a year to about three weeks. The third project, the SPSS Enhancement Project, is aimed at increasing the PSR output beam current from the present 70 μA at 20 Hz to 200 μA at 30 Hz, plus implementing seven new neutron scattering instruments. Objectives, plans, results and progress to date will be summarized.

Plant model of KIPT neutron source facility simulator

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

Cao, Yan; Wei, Thomas Y.; Grelle, Austin L.

2016-02-01

Argonne National Laboratory (ANL) of the United States and Kharkov Institute of Physics and Technology (KIPT) of Ukraine are collaborating on constructing a neutron source facility at KIPT, Kharkov, Ukraine. The facility has 100-kW electron beam driving a subcritical assembly (SCA). The electron beam interacts with a natural uranium target or a tungsten target to generate neutrons, and deposits its power in the target zone. The total fission power generated in SCA is about 300 kW. Two primary cooling loops are designed to remove 100-kW and 300-kW from the target zone and the SCA, respectively. A secondary cooling system ismore » coupled with the primary cooling system to dispose of the generated heat outside the facility buildings to the atmosphere. In addition, the electron accelerator has a low efficiency for generating the electron beam, which uses another secondary cooling loop to remove the generated heat from the accelerator primary cooling loop. One of the main functions the KIPT neutron source facility is to train young nuclear specialists; therefore, ANL has developed the KIPT Neutron Source Facility Simulator for this function. In this simulator, a Plant Control System and a Plant Protection System were developed to perform proper control and to provide automatic protection against unsafe and improper operation of the facility during the steady-state and the transient states using a facility plant model. This report focuses on describing the physics of the plant model and provides several test cases to demonstrate its capabilities. The plant facility model uses the PYTHON script language. It is consistent with the computer language of the plant control system. It is easy to integrate with the simulator without an additional interface, and it is able to simulate the transients of the cooling systems with system control variables changing on real-time.« less

Comparisons of social interaction and activities of daily living between long-term care facility and community-dwelling stroke patients.

PubMed

Yoon, Jeong-Ae; Park, Se-Gwan; Roh, Hyo-Lyun

2015-10-01

[Purpose] This study was conducted to compare the correlation between social interaction and activities of daily living (ADL) between community-dwelling and long-term care facility stroke patients. [Subjects and Methods] The Subjects were 65 chronic stroke patients (32 facility-residing, 33 community-dwelling). The Evaluation Social Interaction (ESI) tool was used to evaluate social interaction and the Assessment of Motor and Process Skills (AMPS) measure was used to evaluate ADL. [Results] Both social interaction and ADL were higher in community-dwelling than facility-residing stroke patients. There was a correlation between ESI and ADL for both motor and process skills among facility-residing patients, while only ADL process skills and ESI correlated among community-dwelling patients. In a partial correlation analysis using ADL motor and process skills as control variables, only process skills correlated with ESI. [Conclusion] For rehabilitation of stroke patients, an extended treatment process that combines ADL and social activities is likely to be required. Furthermore, treatment programs and institutional systems that can improve social interaction and promote health maintenance for community-dwelling and facility-residing chronic stroke patients are needed throughout the rehabilitation process.

Dynamic interactions between visual working memory and saccade target selection

PubMed Central

Schneegans, Sebastian; Spencer, John P.; Schöner, Gregor; Hwang, Seongmin; Hollingworth, Andrew

2014-01-01

Recent psychophysical experiments have shown that working memory for visual surface features interacts with saccadic motor planning, even in tasks where the saccade target is unambiguously specified by spatial cues. Specifically, a match between a memorized color and the color of either the designated target or a distractor stimulus influences saccade target selection, saccade amplitudes, and latencies in a systematic fashion. To elucidate these effects, we present a dynamic neural field model in combination with new experimental data. The model captures the neural processes underlying visual perception, working memory, and saccade planning relevant to the psychophysical experiment. It consists of a low-level visual sensory representation that interacts with two separate pathways: a spatial pathway implementing spatial attention and saccade generation, and a surface feature pathway implementing color working memory and feature attention. Due to bidirectional coupling between visual working memory and feature attention in the model, the working memory content can indirectly exert an effect on perceptual processing in the low-level sensory representation. This in turn biases saccadic movement planning in the spatial pathway, allowing the model to quantitatively reproduce the observed interaction effects. The continuous coupling between representations in the model also implies that modulation should be bidirectional, and model simulations provide specific predictions for complementary effects of saccade target selection on visual working memory. These predictions were empirically confirmed in a new experiment: Memory for a sample color was biased toward the color of a task-irrelevant saccade target object, demonstrating the bidirectional coupling between visual working memory and perceptual processing. PMID:25228628

Time Critical Targeting Concept of Operations (CONOPS) Interactions

DTIC Science & Technology

2011-05-01

range of topics in force development and employment. Carl has participated in projects examining the interdiction of armoured ground forces , long...Critical Targeting Concept of Operations (CONOPS) Interactions Executive Summary In 2003, RAND Project Air Force examined the...Attack. ____________________ ________________________________________________ Carl Rhodes Project Air Force , RAND Corporation Carl Rhodes is the

The drift chamber array at the external target facility in HIRFL-CSR

NASA Astrophysics Data System (ADS)

Sun, Y. Z.; Sun, Z. Y.; Wang, S. T.; Duan, L. M.; Sun, Y.; Yan, D.; Tang, S. W.; Yang, H. R.; Lu, C. G.; Ma, P.; Yu, Y. H.; Zhang, X. H.; Yue, K.; Fang, F.; Su, H.

2018-06-01

A drift chamber array at the External Target Facility in HIRFL-CSR has been constructed for three-dimensional particle tracking in high-energy radioactive ion beam experiments. The design, readout, track reconstruction program and calibration procedures for the detector are described. The drift chamber array was tested in a 311 AMeV 40Ar beam experiment. The detector performance based on the measurements of the beam test is presented. A spatial resolution of 230 μm is achieved.

AlphaSpace: Fragment-Centric Topographical Mapping To Target Protein–Protein Interaction Interfaces

PubMed Central

2016-01-01

Inhibition of protein–protein interactions (PPIs) is emerging as a promising therapeutic strategy despite the difficulty in targeting such interfaces with drug-like small molecules. PPIs generally feature large and flat binding surfaces as compared to typical drug targets. These features pose a challenge for structural characterization of the surface using geometry-based pocket-detection methods. An attractive mapping strategy—that builds on the principles of fragment-based drug discovery (FBDD)—is to detect the fragment-centric modularity at the protein surface and then characterize the large PPI interface as a set of localized, fragment-targetable interaction regions. Here, we introduce AlphaSpace, a computational analysis tool designed for fragment-centric topographical mapping (FCTM) of PPI interfaces. Our approach uses the alpha sphere construct, a geometric feature of a protein’s Voronoi diagram, to map out concave interaction space at the protein surface. We introduce two new features—alpha-atom and alpha-space—and the concept of the alpha-atom/alpha-space pair to rank pockets for fragment-targetability and to facilitate the evaluation of pocket/fragment complementarity. The resulting high-resolution interfacial map of targetable pocket space can be used to guide the rational design and optimization of small molecule or biomimetic PPI inhibitors. PMID:26225450

Wavefront correction by target-phase-locking technology in a 500 TW laser facility

NASA Astrophysics Data System (ADS)

Wang, D. E.; Dai, W. J.; Zhou, K. N.; Su, J. Q.; Xue, Q.; Yuan, Q.; Zhang, X.; Deng, X. W.; Yang, Y.; Wang, Y. C.; Xie, N.; Sun, L.; Hu, D. X.; Zhu, Q. H.

2017-03-01

We demonstrate a novel approach termed target-phase-locking that could improve the entire beam wavefront quality of a 500 TW Nd3+:phosphate glass laser facility. The thermal and static wavefront from front-end to target is corrected by using one deformable mirror that receives feedback from both the focal-spot sensor and wavefront sensor, and only the main laser of the laser system is employed in the correction process, with auxiliary calibration light no longer necessary. As a result, a static focal spot with full width at half maximum of 8.87  ×  5.74 µm is achieved, the thermal wavefront induced by flash-lamp-pumped Nd3+:phosphate glass is compensated with PV from 3.54-0.43 µm, and a dynamic focal spot with intensity exceeding 1020 W cm-2 is precisely predicted at the target with such an approach.

Fuzzy Neural Network-Based Interacting Multiple Model for Multi-Node Target Tracking Algorithm

PubMed Central

Sun, Baoliang; Jiang, Chunlan; Li, Ming

2016-01-01

An interacting multiple model for multi-node target tracking algorithm was proposed based on a fuzzy neural network (FNN) to solve the multi-node target tracking problem of wireless sensor networks (WSNs). Measured error variance was adaptively adjusted during the multiple model interacting output stage using the difference between the theoretical and estimated values of the measured error covariance matrix. The FNN fusion system was established during multi-node fusion to integrate with the target state estimated data from different nodes and consequently obtain network target state estimation. The feasibility of the algorithm was verified based on a network of nine detection nodes. Experimental results indicated that the proposed algorithm could trace the maneuvering target effectively under sensor failure and unknown system measurement errors. The proposed algorithm exhibited great practicability in the multi-node target tracking of WSNs. PMID:27809271

Druggable orthosteric and allosteric hot spots to target protein-protein interactions.

PubMed

Ma, Buyong; Nussinov, Ruth

2014-01-01

Drug designing targeting protein-protein interactions is challenging. Because structural elucidation and computational analysis have revealed the importance of hot spot residues in stabilizing these interactions, there have been on-going efforts to develop drugs which bind the hot spots and out-compete the native protein partners. The question arises as to what are the key 'druggable' properties of hot spots in protein-protein interactions and whether these mimic the general hot spot definition. Identification of orthosteric (at the protein- protein interaction site) and allosteric (elsewhere) druggable hot spots is expected to help in discovering compounds that can more effectively modulate protein-protein interactions. For example, are there any other significant features beyond their location in pockets in the interface? The interactions of protein-protein hot spots are coupled with conformational dynamics of protein complexes. Currently increasing efforts focus on the allosteric drug discovery. Allosteric drugs bind away from the native binding site and can modulate the native interactions. We propose that identification of allosteric hot spots could similarly help in more effective allosteric drug discovery. While detection of allosteric hot spots is challenging, targeting drugs to these residues has the potential of greatly increasing the hot spot and protein druggability.

Assessment and Mitigation of Diagnostic-Generated Electromagnetic Interference at the National Ignition Facility

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

Brown, C G; Ayers, M J; Felker, B

2012-04-20

Electromagnetic interference (EMI) is an ever-present challenge at laser facilities such as the National Ignition Facility (NIF). The major source of EMI at such facilities is laser-target interaction that can generate intense electromagnetic fields within, and outside of, the laser target chamber. In addition, the diagnostics themselves can be a source of EMI, even interfering with themselves. In this paper we describe EMI generated by ARIANE and DIXI, present measurements, and discuss effects of the diagnostic-generated EMI on ARIANE's CCD and on a PMT nearby DIXI. Finally we present some of the efforts we have made to mitigate the effectsmore » of diagnostic-generated EMI on NIF diagnostics.« less

Interactive object recognition assistance: an approach to recognition starting from target objects

NASA Astrophysics Data System (ADS)

Geisler, Juergen; Littfass, Michael

1999-07-01

Recognition of target objects in remotely sensed imagery required detailed knowledge about the target object domain as well as about mapping properties of the sensing system. The art of object recognition is to combine both worlds appropriately and to provide models of target appearance with respect to sensor characteristics. Common approaches to support interactive object recognition are either driven from the sensor point of view and address the problem of displaying images in a manner adequate to the sensing system. Or they focus on target objects and provide exhaustive encyclopedic information about this domain. Our paper discusses an approach to assist interactive object recognition based on knowledge about target objects and taking into account the significance of object features with respect to characteristics of the sensed imagery, e.g. spatial and spectral resolution. An `interactive recognition assistant' takes the image analyst through the interpretation process by indicating step-by-step the respectively most significant features of objects in an actual set of candidates. The significance of object features is expressed by pregenerated trees of significance, and by the dynamic computation of decision relevance for every feature at each step of the recognition process. In the context of this approach we discuss the question of modeling and storing the multisensorial/multispectral appearances of target objects and object classes as well as the problem of an adequate dynamic human-machine-interface that takes into account various mental models of human image interpretation.

Network Understanding of Herb Medicine via Rapid Identification of Ingredient-Target Interactions

NASA Astrophysics Data System (ADS)

Zhang, Hai-Ping; Pan, Jian-Bo; Zhang, Chi; Ji, Nan; Wang, Hao; Ji, Zhi-Liang

2014-01-01

Today, herb medicines have become the major source for discovery of novel agents in countermining diseases. However, many of them are largely under-explored in pharmacology due to the limitation of current experimental approaches. Therefore, we proposed a computational framework in this study for network understanding of herb pharmacology via rapid identification of putative ingredient-target interactions in human structural proteome level. A marketing anti-cancer herb medicine in China, Yadanzi (Brucea javanica), was chosen for mechanistic study. Total 7,119 ingredient-target interactions were identified for thirteen Yadanzi active ingredients. Among them, about 29.5% were estimated to have better binding affinity than their corresponding marketing drug-target interactions. Further Bioinformatics analyses suggest that simultaneous manipulation of multiple proteins in the MAPK signaling pathway and the phosphorylation process of anti-apoptosis may largely answer for Yadanzi against non-small cell lung cancers. In summary, our strategy provides an efficient however economic solution for systematic understanding of herbs' power.

Network understanding of herb medicine via rapid identification of ingredient-target interactions.

PubMed

Zhang, Hai-Ping; Pan, Jian-Bo; Zhang, Chi; Ji, Nan; Wang, Hao; Ji, Zhi-Liang

2014-01-16

Today, herb medicines have become the major source for discovery of novel agents in countermining diseases. However, many of them are largely under-explored in pharmacology due to the limitation of current experimental approaches. Therefore, we proposed a computational framework in this study for network understanding of herb pharmacology via rapid identification of putative ingredient-target interactions in human structural proteome level. A marketing anti-cancer herb medicine in China, Yadanzi (Brucea javanica), was chosen for mechanistic study. Total 7,119 ingredient-target interactions were identified for thirteen Yadanzi active ingredients. Among them, about 29.5% were estimated to have better binding affinity than their corresponding marketing drug-target interactions. Further Bioinformatics analyses suggest that simultaneous manipulation of multiple proteins in the MAPK signaling pathway and the phosphorylation process of anti-apoptosis may largely answer for Yadanzi against non-small cell lung cancers. In summary, our strategy provides an efficient however economic solution for systematic understanding of herbs' power.

Learning in human-dolphin interactions at zoological facilities

NASA Astrophysics Data System (ADS)

Sweeney, Diane L.

This research aimed to better understand learning in zoological settings, particularly learning about marine mammals, by investigating the research question, what do people learn through interacting with dolphins in zoological facilities? Sociocultural situated learning theory, specifically a Community of Practice (CoP) model of learning (Lave & Wenger, 1991), was the theoretical framework. The CoP model allowed for diversity of knowledge, interest, motivations, and goals that existed among the community of animal enthusiasts at three commercial zoological facilities, and also for peripheral to more central types of participation. I collected data through interviews of spectators, visitors, and trainers (n=51), observations (n=16), and an online questionnaire of past-visitors (n=933). Data were coded, categorized, and analyzed based on the National Science Foundation's (Friedman, 2008) and the National Research Council's (2009) frameworks for informal science education. Five principal findings answered the research question. First, all participants gained new knowledge within three broad categories: (a) dolphin physiology and natural history, (b) care and training of dolphins, and (c) conservation. Second, all participants constructed personal meanings by connecting the activity to experiences, beliefs, and practices outside the interaction context. Almost all participants made associations with conservation. Third, most participants shifted their attitudes and gained a sense of personal agency about beginning or increasing stewardship actions. Fourth, visitors learned interspecies etiquette skills; trainers learned skills in dolphin training and management, people management, and teaching. Fifth, visitors had long-lasting memories of the experience that occurred eight months to 18 years in the past. Popular cultural ideas about dolphins and the ways the dolphins were represented influenced visitors' expectations and the types of learning. Potential physical

Predicting Drug-Target Interaction Networks Based on Functional Groups and Biological Features

PubMed Central

Shi, Xiao-He; Hu, Le-Le; Kong, Xiangyin; Cai, Yu-Dong; Chou, Kuo-Chen

2010-01-01

Background Study of drug-target interaction networks is an important topic for drug development. It is both time-consuming and costly to determine compound-protein interactions or potential drug-target interactions by experiments alone. As a complement, the in silico prediction methods can provide us with very useful information in a timely manner. Methods/Principal Findings To realize this, drug compounds are encoded with functional groups and proteins encoded by biological features including biochemical and physicochemical properties. The optimal feature selection procedures are adopted by means of the mRMR (Maximum Relevance Minimum Redundancy) method. Instead of classifying the proteins as a whole family, target proteins are divided into four groups: enzymes, ion channels, G-protein- coupled receptors and nuclear receptors. Thus, four independent predictors are established using the Nearest Neighbor algorithm as their operation engine, with each to predict the interactions between drugs and one of the four protein groups. As a result, the overall success rates by the jackknife cross-validation tests achieved with the four predictors are 85.48%, 80.78%, 78.49%, and 85.66%, respectively. Conclusion/Significance Our results indicate that the network prediction system thus established is quite promising and encouraging. PMID:20300175

Nanoparticle-macrophage interactions: A balance between clearance and cell-specific targeting

PubMed Central

Rattan, Rahul; Bhattacharjee, Somnath; Zong, Hong; Swain, Corban; Siddiqui, Muneeb A.; Visovatti, Scott H.; Kanthi, Yogendra; Desai, Sajani; Pinsky, David J.; Goonewardena, Sascha N.

2017-01-01

The surface properties of nanoparticles (NPs) are a major factor that influences how these nanomaterials interact with biological systems. Interactions between NPs and macrophages of the reticuloendothelial system (RES) can reduce the efficacy of NP diagnostics and therapeutics. Traditionally, to limit NP clearance by the RES system, the NP surface is neutralized with molecules like poly(ethylene glycol) (PEG) which are known to resist protein adsorption and RES clearance. Unfortunately, PEG modification is not without drawbacks including difficulties with the synthesis and associations with immune reactions. To overcome some of these obstacles, we neutralized the NP surface by acetylation and compared this modification to PEGylation for RES clearance and tumor-specific targeting. We found that acetylation was comparable to PEGylation in reducing RES clearance. Additionally, we found that dendrimer acetylation did not impact folic acid (FA)-mediated targeting of tumor cells whereas PEG surface modification reduced the targeting ability of the NP. These results clarify the impact of different NP surface modifications on RES clearance and cell-specific targeting and provide insights into the design of more effective NPs. PMID:28705434

Characterizing the interaction among bullet, body armor, and human and surrogate targets.

PubMed

Shen, Weixin; Niu, Yuqing; Bykanova, Lucy; Laurence, Peter; Link, Norman

2010-12-01

This study used a combined experimental and modeling approach to characterize and quantify the interaction among bullet, body armor, and human surrogate targets during the 10-1000 μs range that is crucial to evaluating the protective effectiveness of body armor against blunt injuries. Ballistic tests incorporating high-speed flash X-ray measurements were performed to acquire the deformations of bullets and body armor samples placed against ballistic clay and gelatin targets with images taken between 10 μs and 1 ms of the initial impact. Finite element models (FEMs) of bullet, armor, and gelatin and clay targets were developed with material parameters selected to best fit model calculations to the test measurements. FEMs of bullet and armor interactions were then assembled with a FEM of a human torso and FEMs of clay and gelatin blocks in the shape of a human torso to examine the effects of target material and geometry on the interaction. Test and simulation results revealed three distinct loading phases during the interaction. In the first phase, the bullet was significantly slowed in about 60 μs as it transferred a major portion of its energy into the body armor. In the second phase, fibers inside the armor were pulled toward the point of impact and kept on absorbing energy until about 100 μs after the initial impact when energy absorption reached its peak. In the third phase, the deformation on the armor's back face continued to grow and energies inside both armor and targets redistributed through wave propagation. The results indicated that armor deformation and energy absorption in the second and third phases were significantly affected by the material properties (density and stiffness) and geometrical characteristics (curvature and gap at the armor-target interface) of the targets. Valid surrogate targets for testing the ballistic resistance of the armor need to account for these factors and produce the same armor deformation and energy absorption as on a

The physics basis for ignition using indirect-drive targets on the National Ignition Facility

NASA Astrophysics Data System (ADS)

Lindl, John D.; Amendt, Peter; Berger, Richard L.; Glendinning, S. Gail; Glenzer, Siegfried H.; Haan, Steven W.; Kauffman, Robert L.; Landen, Otto L.; Suter, Laurence J.

2004-02-01

The 1990 National Academy of Science final report of its review of the Inertial Confinement Fusion Program recommended completion of a series of target physics objectives on the 10-beam Nova laser at the Lawrence Livermore National Laboratory as the highest-priority prerequisite for proceeding with construction of an ignition-scale laser facility, now called the National Ignition Facility (NIF). These objectives were chosen to demonstrate that there was sufficient understanding of the physics of ignition targets that the laser requirements for laboratory ignition could be accurately specified. This research on Nova, as well as additional research on the Omega laser at the University of Rochester, is the subject of this review. The objectives of the U.S. indirect-drive target physics program have been to experimentally demonstrate and predictively model hohlraum characteristics, as well as capsule performance in targets that have been scaled in key physics variables from NIF targets. To address the hohlraum and hydrodynamic constraints on indirect-drive ignition, the target physics program was divided into the Hohlraum and Laser-Plasma Physics (HLP) program and the Hydrodynamically Equivalent Physics (HEP) program. The HLP program addresses laser-plasma coupling, x-ray generation and transport, and the development of energy-efficient hohlraums that provide the appropriate spectral, temporal, and spatial x-ray drive. The HEP experiments address the issues of hydrodynamic instability and mix, as well as the effects of flux asymmetry on capsules that are scaled as closely as possible to ignition capsules (hydrodynamic equivalence). The HEP program also addresses other capsule physics issues associated with ignition, such as energy gain and energy loss to the fuel during implosion in the absence of alpha-particle deposition. The results from the Nova and Omega experiments approach the NIF requirements for most of the important ignition capsule parameters, including

Electron Shock Ignition of Inertial Fusion Targets

DOE PAGES

Shang, W. L.; Betti, R.; Hu, S. X.; ...

2017-11-07

Here, it is shown that inertial fusion targets designed with low implosion velocities can be shock ignited using laser–plasma interaction generated hot electrons (hot-e) to obtain high-energy gains. These designs are robust to multimode asymmetries and are predicted to ignite even for significantly distorted implosions. Electron shock ignition requires tens of kilojoules of hot-e, which can only be produced on a large laser facility like the National Ignition Facility, with the laser to hot-e conversion efficiency greater than 10% at laser intensities ~10 16 W/cm 2.

Electron Shock Ignition of Inertial Fusion Targets

NASA Astrophysics Data System (ADS)

Shang, W. L.; Betti, R.; Hu, S. X.; Woo, K.; Hao, L.; Ren, C.; Christopherson, A. R.; Bose, A.; Theobald, W.

2017-11-01

It is shown that inertial confinement fusion targets designed with low implosion velocities can be shock-ignited using laser-plasma interaction generated hot electrons (hot-e 's) to obtain high energy gains. These designs are robust to multimode asymmetries and are predicted to ignite even for significantly distorted implosions. Electron shock ignition requires tens of kilojoules of hot-e 's which can be produced only at a large laser facility like the National Ignition Facility, with the laser-to-hot-e conversion efficiency greater than 10% at laser intensities ˜1016 W /cm2 .

Electron Shock Ignition of Inertial Fusion Targets.

PubMed

Shang, W L; Betti, R; Hu, S X; Woo, K; Hao, L; Ren, C; Christopherson, A R; Bose, A; Theobald, W

2017-11-10

It is shown that inertial confinement fusion targets designed with low implosion velocities can be shock-ignited using laser-plasma interaction generated hot electrons (hot-e's) to obtain high energy gains. These designs are robust to multimode asymmetries and are predicted to ignite even for significantly distorted implosions. Electron shock ignition requires tens of kilojoules of hot-e's which can be produced only at a large laser facility like the National Ignition Facility, with the laser-to-hot-e conversion efficiency greater than 10% at laser intensities ∼10^{16}  W/cm^{2}.

Spectra, composition, and interactions of nuclei with magnet interaction chambers

NASA Astrophysics Data System (ADS)

Parnell, T. A.; Burnett, T. H.; Cherry, M. C.; Dake, S.; Derrickson, J. H.; Fountain, W. F.; Fuki, M.; Gregory, J. C.; Hayashi, T.; Holynski, R.; Iwai, J.; Jurak, A.; Lord, J. J.; Miyamura, O.; Niwa, K.; Oda, H.; Ogata, T.; Roberts, F. E.; Shibata, T.; Strausz, S. C.; Tabuki, T.; Taira, T.; Takahashi, Y.; Tominaga, T.; Watts, J. W.; Wefel, J. P.; Wilczynska, B.; Wilczynski, H.; Wilkes, R. J.; Wolter, W.; Wosiek, T.; Yamamoto, A.; Yokomi, H.; Yuda, T.

1990-03-01

Emulsion chambers will be flown in the Astromag Facility to measure the cosmic ray composition and spectra to 10 exp 15 eV total energy and to definitively study the characteristics of nucleus-nucleus interactions above 10 exp 12 eV/n. Two configurations of emulsion chambers will be flown in the SCIN/MAGIC experiment. One chamber has an emulsion target and a calorimeter similar to those recently flown on balloons for composition and spectra measurements. The other has an identical calorimeter and a low-density target section optimized for performing rigidity measurements on charged particles produced in interactions. The transverse momenta of charged and neutral mesons, direct hadronic pairs from resonance decays and interference effects, and possible charge clustering in high-density states of matter will be studied.

ORION laser target diagnostics.

PubMed

Bentley, C D; Edwards, R D; Andrew, J E; James, S F; Gardner, M D; Comley, A J; Vaughan, K; Horsfield, C J; Rubery, M S; Rothman, S D; Daykin, S; Masoero, S J; Palmer, J B; Meadowcroft, A L; Williams, B M; Gumbrell, E T; Fyrth, J D; Brown, C R D; Hill, M P; Oades, K; Wright, M J; Hood, B A; Kemshall, P

2012-10-01

The ORION laser facility is one of the UK's premier laser facilities which became operational at AWE in 2010. Its primary mission is one of stockpile stewardship, ORION will extend the UK's experimental plasma physics capability to the high temperature, high density regime relevant to Atomic Weapons Establishment's (AWE) program. The ORION laser combines ten laser beams operating in the ns regime with two sub ps short pulse chirped pulse amplification beams. This gives the UK a unique combined long pulse/short pulse laser capability which is not only available to AWE personnel but also gives access to our international partners and visiting UK academia. The ORION laser facility is equipped with a comprehensive suite of some 45 diagnostics covering optical, particle, and x-ray diagnostics all able to image the laser target interaction point. This paper focuses on a small selection of these diagnostics.

Interactions between Impacting Particles and Target in Two-Phase Flow

NASA Astrophysics Data System (ADS)

Kang, Sang-Wook; Chow, Tze-Show

1996-11-01

The time-dependent interaction phenomena between a target and the incident solid particles borne by supersonic gas-jet stream have been numerically analyzed. In particular, the analysis dealt with particles such as aluminum, copper, and uranium ipinging on aluminum, copper, or uranium targets at various impact velocities ranging from 200 m/s to 1,000 m/s. Typical particle sizes were 50 to 100 micrometers. Results show considerable deformation of both the incident particles and the target when the velocity is greater than 500 m/s. Experiments performed on copper particles impacting an aluminum target demonstrate that under certain conditions (such as a supersonic gas jet issuing from a nozzle carrying solid particles) the impacts not only deform but also cause deposition of the particles on the surface. The present analysis shows the plausibility of such behavior when the particles impact the target at high velocities.

Monitoring System for the Gold Target by Radiation Detectors in Hadron Experimental Facility at J-PARC

NASA Astrophysics Data System (ADS)

Muto, Ryotaro; Agari, Keizo; Aoki, Kazuya; Bessho, Kotaro; Hagiwara, Masayuki; Hirose, Erina; Ieiri, Masaharu; Iwasaki, Ruri; Katoh, Yohji; Kitagawa, Jun-ichi; Minakawa, Michifumi; Morino, Yuhei; Saito, Kiwamu; Sato, Yoshinori; Sawada, Shin'ya; Shirakabe, Yoshihisa; Suzuki, Yoshihiro; Takahashi, Hitoshi; Tanaka, Kazuhiro; Toyoda, Akihisa; Watanabe, Hiroaki; Yamanoi, Yutaka

2017-09-01

At the Hadron Experimental Facility in J-PARC, we inject a 30-GeV proton beam into a gold target to produce secondary particle beams required for various particle and nuclear physics experiments. The gold target is placed in a hermetic chamber, and helium gas is circulated in the chamber to monitor the soundness of the target. The radioactivity in helium gas is continuously monitored by gamma-ray detectors such as a germanium detector and a NaI(Tl) detector. Beam operations with those target-monitoring systems were successfully performed from April to June and October to December 2015, and from May to June 2016. In this paper, the details of the helium gas circulation system and gamma-ray detectors and the analysis results of the obtained gamma-ray spectra are reported.

Setting realistic recovery targets for two interacting endangered species, sea otter and northern abalone.

PubMed

Chadès, Iadine; Curtis, Janelle M R; Martin, Tara G

2012-12-01

Failure to account for interactions between endangered species may lead to unexpected population dynamics, inefficient management strategies, waste of scarce resources, and, at worst, increased extinction risk. The importance of species interactions is undisputed, yet recovery targets generally do not account for such interactions. This shortcoming is a consequence of species-centered legislation, but also of uncertainty surrounding the dynamics of species interactions and the complexity of modeling such interactions. The northern sea otter (Enhydra lutris kenyoni) and one of its preferred prey, northern abalone (Haliotis kamtschatkana), are endangered species for which recovery strategies have been developed without consideration of their strong predator-prey interactions. Using simulation-based optimization procedures from artificial intelligence, namely reinforcement learning and stochastic dynamic programming, we combined sea otter and northern abalone population models with functional-response models and examined how different management actions affect population dynamics and the likelihood of achieving recovery targets for each species through time. Recovery targets for these interacting species were difficult to achieve simultaneously in the absence of management. Although sea otters were predicted to recover, achieving abalone recovery targets failed even when threats to abalone such as predation and poaching were reduced. A management strategy entailing a 50% reduction in the poaching of northern abalone was a minimum requirement to reach short-term recovery goals for northern abalone when sea otters were present. Removing sea otters had a marginally positive effect on the abalone population but only when we assumed a functional response with strong predation pressure. Our optimization method could be applied more generally to any interacting threatened or invasive species for which there are multiple conservation objectives. © 2012 Society for

IFPTarget: A Customized Virtual Target Identification Method Based on Protein-Ligand Interaction Fingerprinting Analyses.

PubMed

Li, Guo-Bo; Yu, Zhu-Jun; Liu, Sha; Huang, Lu-Yi; Yang, Ling-Ling; Lohans, Christopher T; Yang, Sheng-Yong

2017-07-24

Small-molecule target identification is an important and challenging task for chemical biology and drug discovery. Structure-based virtual target identification has been widely used, which infers and prioritizes potential protein targets for the molecule of interest (MOI) principally via a scoring function. However, current "universal" scoring functions may not always accurately identify targets to which the MOI binds from the retrieved target database, in part due to a lack of consideration of the important binding features for an individual target. Here, we present IFPTarget, a customized virtual target identification method, which uses an interaction fingerprinting (IFP) method for target-specific interaction analyses and a comprehensive index (Cvalue) for target ranking. Evaluation results indicate that the IFP method enables substantially improved binding pose prediction, and Cvalue has an excellent performance in target ranking for the test set. When applied to screen against our established target library that contains 11,863 protein structures covering 2842 unique targets, IFPTarget could retrieve known targets within the top-ranked list and identified new potential targets for chemically diverse drugs. IFPTarget prediction led to the identification of the metallo-β-lactamase VIM-2 as a target for quercetin as validated by enzymatic inhibition assays. This study provides a new in silico target identification tool and will aid future efforts to develop new target-customized methods for target identification.

Pion emission in α-particle interactions with various targets of nuclear emulsion detector

NASA Astrophysics Data System (ADS)

Abdelsalam, A.; Abou-Moussa, Z.; Rashed, N.; M. Badawy, B.; A. Amer, H.; Osman, W.; M. El-Ashmawy, M.; Abdallah, N.

2015-09-01

The behavior of relativistic hadron multiplicity for 4He-nucleus interactions is investigated. The experiment is carried out at 2.1 A and 3.7 A GeV (Dubna energy) to search for the incident energy effect on the interactions inside different emulsion target nuclei. Data are presented in terms of the number of emitted relativistic hadrons in both forward and backward angular zones. The dependence on the target size is presented. For this purpose the statistical events are discriminated into groups according to the interactions with H, CNO, Em, and AgBr target nuclei. The separation of events, into the mentioned groups, is executed based on Glauber's multiple scattering theory approach. Features suggestive of a decay mechanism seem to be a characteristic of the backward emission of relativistic hadrons. The results strongly support the assumption that the relativistic hadrons may already be emitted during the de-excitation of the excited target nucleus, in a behavior like that of compound-nucleus disintegration. Regarding the limiting fragmentation hypothesis beyond 1 A GeV, the target size is the main parameter affecting the backward production of the relativistic hadron. The incident energy is a principal factor responsible for the forward relativistic hadron production, implying that this system of particle production is a creation system. However, the target size is an effective parameter as well as the projectile size considering the geometrical concept regarded in the nuclear fireball model. The data are analyzed in the framework of the FRITIOF model.

Quantitative and Systems Pharmacology. 1. In Silico Prediction of Drug-Target Interactions of Natural Products Enables New Targeted Cancer Therapy.

PubMed

Fang, Jiansong; Wu, Zengrui; Cai, Chuipu; Wang, Qi; Tang, Yun; Cheng, Feixiong

2017-11-27

Natural products with diverse chemical scaffolds have been recognized as an invaluable source of compounds in drug discovery and development. However, systematic identification of drug targets for natural products at the human proteome level via various experimental assays is highly expensive and time-consuming. In this study, we proposed a systems pharmacology infrastructure to predict new drug targets and anticancer indications of natural products. Specifically, we reconstructed a global drug-target network with 7,314 interactions connecting 751 targets and 2,388 natural products and built predictive network models via a balanced substructure-drug-target network-based inference approach. A high area under receiver operating characteristic curve of 0.96 was yielded for predicting new targets of natural products during cross-validation. The newly predicted targets of natural products (e.g., resveratrol, genistein, and kaempferol) with high scores were validated by various literature studies. We further built the statistical network models for identification of new anticancer indications of natural products through integration of both experimentally validated and computationally predicted drug-target interactions of natural products with known cancer proteins. We showed that the significantly predicted anticancer indications of multiple natural products (e.g., naringenin, disulfiram, and metformin) with new mechanism-of-action were validated by various published experimental evidence. In summary, this study offers powerful computational systems pharmacology approaches and tools for the development of novel targeted cancer therapies by exploiting the polypharmacology of natural products.

Thick-target transmission method for excitation functions of interaction cross sections

NASA Astrophysics Data System (ADS)

Aikawa, M.; Ebata, S.; Imai, S.

2016-09-01

We propose a method, called as thick-target transmission (T3) method, to obtain an excitation function of interaction cross sections. In an ordinal experiment to measure the excitation function of interaction cross sections by the transmission method, we need to change the beam energy for each cross section. In the T3 method, the excitation function is derived from the beam attenuations measured at the targets of different thicknesses without changing the beam energy. The advantage of the T3 method is the simplicity and availability for radioactive beams. To confirm the availability, we perform a simulation for the 12C + 27Al system with the PHITS code instead of actual experiments. Our results have large uncertainties but well reproduce the tendency of the experimental data.

Hospital to Post-Acute Care Facility Transfers: Identifying Targets for Information Exchange Quality Improvement.

PubMed

Jones, Christine D; Cumbler, Ethan; Honigman, Benjamin; Burke, Robert E; Boxer, Rebecca S; Levy, Cari; Coleman, Eric A; Wald, Heidi L

2017-01-01

Information exchange is critical to high-quality care transitions from hospitals to post-acute care (PAC) facilities. We conducted a survey to evaluate the completeness and timeliness of information transfer and communication between a tertiary-care academic hospital and its related PAC facilities. This was a cross-sectional Web-based 36-question survey of 110 PAC clinicians and staff representing 31 PAC facilities conducted between October and December 2013. We received responses from 71 of 110 individuals representing 29 of 31 facilities (65% and 94% response rates). We collapsed 4-point Likert responses into dichotomous variables to reflect completeness (sufficient vs insufficient) and timeliness (timely vs not timely) for information transfer and communication. Among respondents, 32% reported insufficient information about discharge medical conditions and management plan, and 83% reported at least occasionally encountering problems directly related to inadequate information from the hospital. Hospital clinician contact information was the most common insufficient domain. With respect to timeliness, 86% of respondents desired receipt of a discharge summary on or before the day of discharge, but only 58% reported receiving the summary within this time frame. Through free-text responses, several participants expressed the need for paper prescriptions for controlled pain medications to be sent with patients at the time of transfer. Staff and clinicians at PAC facilities perceive substantial deficits in content and timeliness of information exchange between the hospital and facilities. Such deficits are particularly relevant in the context of the increasing prevalence of bundled payments for care across settings as well as forthcoming readmissions penalties for PAC facilities. Targets identified for quality improvement include structuring discharge summary information to include information identified as deficient by respondents, completion of discharge summaries

Exploring drug-target interaction networks of illicit drugs.

PubMed

Atreya, Ravi V; Sun, Jingchun; Zhao, Zhongming

2013-01-01

Drug addiction is a complex and chronic mental disease, which places a large burden on the American healthcare system due to its negative effects on patients and their families. Recently, network pharmacology is emerging as a promising approach to drug discovery by integrating network biology and polypharmacology, allowing for a deeper understanding of molecular mechanisms of drug actions at the systems level. This study seeks to apply this approach for investigation of illicit drugs and their targets in order to elucidate their interaction patterns and potential secondary drugs that can aid future research and clinical care. In this study, we extracted 188 illicit substances and their related information from the DrugBank database. The data process revealed 86 illicit drugs targeting a total of 73 unique human genes, which forms an illicit drug-target network. Compared to the full drug-target network from DrugBank, illicit drugs and their target genes tend to cluster together and form four subnetworks, corresponding to four major medication categories: depressants, stimulants, analgesics, and steroids. External analysis of Anatomical Therapeutic Chemical (ATC) second sublevel classifications confirmed that the illicit drugs have neurological functions or act via mechanisms of stimulants, opioids, and steroids. To further explore other drugs potentially having associations with illicit drugs, we constructed an illicit-extended drug-target network by adding the drugs that have the same target(s) as illicit drugs to the illicit drug-target network. After analyzing the degree and betweenness of the network, we identified hubs and bridge nodes, which might play important roles in the development and treatment of drug addiction. Among them, 49 non-illicit drugs might have potential to be used to treat addiction or have addictive effects, including some results that are supported by previous studies. This study presents the first systematic review of the network

Exploring drug-target interaction networks of illicit drugs

PubMed Central

2013-01-01

Background Drug addiction is a complex and chronic mental disease, which places a large burden on the American healthcare system due to its negative effects on patients and their families. Recently, network pharmacology is emerging as a promising approach to drug discovery by integrating network biology and polypharmacology, allowing for a deeper understanding of molecular mechanisms of drug actions at the systems level. This study seeks to apply this approach for investigation of illicit drugs and their targets in order to elucidate their interaction patterns and potential secondary drugs that can aid future research and clinical care. Results In this study, we extracted 188 illicit substances and their related information from the DrugBank database. The data process revealed 86 illicit drugs targeting a total of 73 unique human genes, which forms an illicit drug-target network. Compared to the full drug-target network from DrugBank, illicit drugs and their target genes tend to cluster together and form four subnetworks, corresponding to four major medication categories: depressants, stimulants, analgesics, and steroids. External analysis of Anatomical Therapeutic Chemical (ATC) second sublevel classifications confirmed that the illicit drugs have neurological functions or act via mechanisms of stimulants, opioids, and steroids. To further explore other drugs potentially having associations with illicit drugs, we constructed an illicit-extended drug-target network by adding the drugs that have the same target(s) as illicit drugs to the illicit drug-target network. After analyzing the degree and betweenness of the network, we identified hubs and bridge nodes, which might play important roles in the development and treatment of drug addiction. Among them, 49 non-illicit drugs might have potential to be used to treat addiction or have addictive effects, including some results that are supported by previous studies. Conclusions This study presents the first systematic

Interacting multiple model forward filtering and backward smoothing for maneuvering target tracking

NASA Astrophysics Data System (ADS)

Nandakumaran, N.; Sutharsan, S.; Tharmarasa, R.; Lang, Tom; McDonald, Mike; Kirubarajan, T.

2009-08-01

The Interacting Multiple Model (IMM) estimator has been proven to be effective in tracking agile targets. Smoothing or retrodiction, which uses measurements beyond the current estimation time, provides better estimates of target states. Various methods have been proposed for multiple model smoothing in the literature. In this paper, a new smoothing method, which involves forward filtering followed by backward smoothing while maintaining the fundamental spirit of the IMM, is proposed. The forward filtering is performed using the standard IMM recursion, while the backward smoothing is performed using a novel interacting smoothing recursion. This backward recursion mimics the IMM estimator in the backward direction, where each mode conditioned smoother uses standard Kalman smoothing recursion. Resulting algorithm provides improved but delayed estimates of target states. Simulation studies are performed to demonstrate the improved performance with a maneuvering target scenario. The comparison with existing methods confirms the improved smoothing accuracy. This improvement results from avoiding the augmented state vector used by other algorithms. In addition, the new technique to account for model switching in smoothing is a key in improving the performance.

Thin and thick targets for radioactive ion beam production at SPIRAL1 facility

NASA Astrophysics Data System (ADS)

Jardin, P.; Bajeat, O.; Delahaye, P.; Dubois, M.; Kuchi, V.; Maunoury, L.

2018-05-01

The upgrade of the Système de Production d'Ions Radioactifs Accélérés en Ligne (SPIRAL1) facility will deliver its new Radioactive Ion Beams (RIB) by summer 2017. The goal of the upgrade is an improvement of the performances of the installation in terms of isotopes species and ion charge states [1]. Ion beams are produced using the Isotope Separator On Line Method, consisting in an association of a primary beam of stable ions, a hot target and an ion source. The primary beam impinges on the material of the target. Radioactive isotopes are produced by nuclear reactions and propagate up to the source, where they are ionized and accelerated to create a RIB. One advantage of SPIRAL1 driver is the variety of its available primary beams, from carbon to uranium with energies up to 95 MeV/A. Within the SPIRAL1 upgrade, they will be combined with targets made of a large choice of materials, extending in this way the number of possible nuclear reactions (fusion-evaporation, transfer, fragmentation) for producing a wider range of isotopes, up to regions of the nuclide chart still scarcely explored. Depending on the reaction process, on the collision energy and on the primary beam power, thin and thick targets are used. As their functions can be different, their design must cope with specific constraints which will be described. After a presentation of the goals of present and future SPIRAL1 Target Ion Source System, the main target features, studies and designs under progress are presented.

Laser Irradiated Foam Targets: Absorption and Radiative Properties

NASA Astrophysics Data System (ADS)

Salvadori, Martina; Luigi Andreoli, Pier; Cipriani, Mattia; Consoli, Fabrizio; Cristofari, Giuseppe; De Angelis, Riccardo; di Giorgio, Giorgio; Giulietti, Danilo; Ingenito, Francesco; Gus'kov, Sergey Yu.; Rupasov, Alexander A.

2018-01-01

An experimental campaign to characterize the laser radiation absorption of foam targets and the subsequent emission of radiation from the produced plasma was carried out in the ABC facility of the ENEA Research Center in Frascati (Rome). Different targets have been used: plastic in solid or foam state and aluminum targets. The activated different diagnostics allowed to evaluate the plasma temperature, the density distribution, the fast particle spectrum and the yield of the X-Ray radiation emitted by the plasma for the different targets. These results confirm the foam homogenization action on laser-plasma interaction, mainly attributable to the volume absorption of the laser radiation propagating in such structured materials. These results were compared with simulation absorption models of the laser propagating into a foam target.

The Methodology of Interactive Parametric Modelling of Construction Site Facilities in BIM Environment

NASA Astrophysics Data System (ADS)

Kozlovská, Mária; Čabala, Jozef; Struková, Zuzana

2014-11-01

Information technology is becoming a strong tool in different industries, including construction. The recent trend of buildings designing is leading up to creation of the most comprehensive virtual building model (Building Information Model) in order to solve all the problems relating to the project as early as in the designing phase. Building information modelling is a new way of approaching to the design of building projects documentation. Currently, the building site layout as a part of the building design documents has a very little support in the BIM environment. Recently, the research of designing the construction process conditions has centred on improvement of general practice in planning and on new approaches to construction site layout planning. The state of art in field of designing the construction process conditions indicated an unexplored problem related to connection of knowledge system with construction site facilities (CSF) layout through interactive modelling. The goal of the paper is to present the methodology for execution of 3D construction site facility allocation model (3D CSF-IAM), based on principles of parametric and interactive modelling.

Simulations of bremsstrahlung emission in ultra-intense laser interactions with foil targets

NASA Astrophysics Data System (ADS)

Vyskočil, Jiří; Klimo, Ondřej; Weber, Stefan

2018-05-01

Bremsstrahlung emission from interactions of short ultra-intense laser pulses with solid foils is studied using particle-in-cell (PIC) simulations. A module for simulating bremsstrahlung has been implemented in the PIC loop to self-consistently account for the dynamics of the laser–plasma interaction, plasma expansion, and the emission of gamma ray photons. This module made it possible to study emission from thin targets, where refluxing of hot electrons plays an important role. It is shown that the angular distribution of the emitted photons exhibits a four-directional structure with the angle of emission decreasing with the increase of the width of the target. Additionally, a collimated forward flash consisting of high energy photons has been identified in thin targets. The conversion efficiency of the energy of the laser pulse to the energy of the gamma rays rises with both the driving pulse intensity, and the thickness of the target. The amount of gamma rays also increases with the atomic number of the target material, despite a lower absorption of the driving laser pulse. The angular spectrum of the emitted gamma rays is directly related to the increase of hot electron divergence during their refluxing and its measurement can be used in experiments to study this process.

Plant microRNA-Target Interaction Identification Model Based on the Integration of Prediction Tools and Support Vector Machine

PubMed Central

Meng, Jun; Shi, Lin; Luan, Yushi

2014-01-01

Background Confident identification of microRNA-target interactions is significant for studying the function of microRNA (miRNA). Although some computational miRNA target prediction methods have been proposed for plants, results of various methods tend to be inconsistent and usually lead to more false positive. To address these issues, we developed an integrated model for identifying plant miRNA–target interactions. Results Three online miRNA target prediction toolkits and machine learning algorithms were integrated to identify and analyze Arabidopsis thaliana miRNA-target interactions. Principle component analysis (PCA) feature extraction and self-training technology were introduced to improve the performance. Results showed that the proposed model outperformed the previously existing methods. The results were validated by using degradome sequencing supported Arabidopsis thaliana miRNA-target interactions. The proposed model constructed on Arabidopsis thaliana was run over Oryza sativa and Vitis vinifera to demonstrate that our model is effective for other plant species. Conclusions The integrated model of online predictors and local PCA-SVM classifier gained credible and high quality miRNA-target interactions. The supervised learning algorithm of PCA-SVM classifier was employed in plant miRNA target identification for the first time. Its performance can be substantially improved if more experimentally proved training samples are provided. PMID:25051153

Computational-experimental approach to drug-target interaction mapping: A case study on kinase inhibitors

PubMed Central

Ravikumar, Balaguru; Parri, Elina; Timonen, Sanna; Airola, Antti; Wennerberg, Krister

2017-01-01

Due to relatively high costs and labor required for experimental profiling of the full target space of chemical compounds, various machine learning models have been proposed as cost-effective means to advance this process in terms of predicting the most potent compound-target interactions for subsequent verification. However, most of the model predictions lack direct experimental validation in the laboratory, making their practical benefits for drug discovery or repurposing applications largely unknown. Here, we therefore introduce and carefully test a systematic computational-experimental framework for the prediction and pre-clinical verification of drug-target interactions using a well-established kernel-based regression algorithm as the prediction model. To evaluate its performance, we first predicted unmeasured binding affinities in a large-scale kinase inhibitor profiling study, and then experimentally tested 100 compound-kinase pairs. The relatively high correlation of 0.77 (p < 0.0001) between the predicted and measured bioactivities supports the potential of the model for filling the experimental gaps in existing compound-target interaction maps. Further, we subjected the model to a more challenging task of predicting target interactions for such a new candidate drug compound that lacks prior binding profile information. As a specific case study, we used tivozanib, an investigational VEGF receptor inhibitor with currently unknown off-target profile. Among 7 kinases with high predicted affinity, we experimentally validated 4 new off-targets of tivozanib, namely the Src-family kinases FRK and FYN A, the non-receptor tyrosine kinase ABL1, and the serine/threonine kinase SLK. Our sub-sequent experimental validation protocol effectively avoids any possible information leakage between the training and validation data, and therefore enables rigorous model validation for practical applications. These results demonstrate that the kernel-based modeling approach

Backscattering from targets residing in caustics resulting from ocean boundary interactions

NASA Astrophysics Data System (ADS)

Dzikowicz, Benjamin R.; Marston, Philip L.

2005-04-01

Detection of targets by backscatter in shallow water can be enhanced by interactions with ocean boundaries. A laboratory experiment is performed where a spherical target passes through an Airy caustic formed by a curved surface. When the target resides in the insonified region of the caustic there are two sets of multi-path rays: two pairs reflecting once off the surface (either to or from the target), and three reflecting twice off the surface (to and from the target). When a target moves across the caustic the singly reflected rays merge, as do the doubly reflected. With a longer tone burst the rays in each set overlap and the backscatter is greatly enhanced as the target moves into the insonified region. For a point target the singly reflected backscatter scales as an Airy function [B. R. Dzikowicz and P. L. Marston, J. Acoust. Soc. Am. 116, 2751-2757 (2004)], and the doubly reflected as the square of an Airy function. For a finite target the doubly reflected backscatter unfolds into a hyperbolic umbilic function. The arguments of the Airy and Hyperbolic Umbilic functions are calculated using the relative echo times of transient pulses. [Work supported by ONR.

The physical environment, activity and interaction in residential care facilities for older people: a comparative case study.

PubMed

Nordin, Susanna; McKee, Kevin; Wallinder, Maria; von Koch, Lena; Wijk, Helle; Elf, Marie

2017-12-01

The physical environment is of particular importance for supporting activities and interactions among older people living in residential care facilities (RCFs) who spend most of their time inside the facility. More knowledge is needed regarding the complex relationships between older people and environmental aspects in long-term care. The present study aimed to explore how the physical environment influences resident activities and interactions at two RCFs by using a mixed-method approach. Environmental assessments were conducted via the Swedish version of the Sheffield Care Environment Assessment Matrix (S-SCEAM), and resident activities, interactions and locations were assessed through an adapted version of the Dementia Care Mapping (DCM). The Observed Emotion Rating Scale (OERS) was used to assess residents' affective states. Field notes and walk-along interviews were also used. Findings indicate that the design of the physical environment influenced the residents' activities and interactions. Private apartments and dining areas showed high environmental quality at both RCFs, whereas the overall layout had lower quality. Safety was highly supported. Despite high environmental quality in general, several factors restricted resident activities. To optimise care for older people, the design process must clearly focus on accessible environments that provide options for residents to use the facility independently. © 2016 The Authors. Scandinavian Journal of Caring Sciences published by John Wiley & Sons Ltd on behalf of Nordic College of Caring Science.

Complex interactions between phytochemicals. The multi-target therapeutic concept of phytotherapy.

PubMed

Efferth, Thomas; Koch, Egon

2011-01-01

Drugs derived from natural resources represent a significant segment of the pharmaceutical market as compared to randomly synthesized compounds. It is a goal of drug development programs to design selective ligands that act on single disease targets to obtain highly effective and safe drugs with low side effects. Although this strategy was successful for many new therapies, there is a marked decline in the number of new drugs introduced into clinical practice over the past decades. One reason for this failure may be due to the fact that the pathogenesis of many diseases is rather multi-factorial in nature and not due to a single cause. Phytotherapy, whose therapeutic efficacy is based on the combined action of a mixture of constituents, offers new treatment opportunities. Because of their biological defence function, plant secondary metabolites act by targeting and disrupting the cell membrane, by binding and inhibiting specific proteins or they adhere to or intercalate into RNA or DNA. Phytotherapeutics may exhibit pharmacological effects by the synergistic or antagonistic interaction of many phytochemicals. Mechanistic reasons for interactions are bioavailability, interference with cellular transport processes, activation of pro-drugs or deactivation of active compounds to inactive metabolites, action of synergistic partners at different points of the same signalling cascade (multi-target effects) or inhibition of binding to target proteins. "-Omics" technologies and systems biology may facilitate unravelling synergistic effects of herbal mixtures.

DrugECs: An Ensemble System with Feature Subspaces for Accurate Drug-Target Interaction Prediction

PubMed Central

Jiang, Jinjian; Wang, Nian; Zhang, Jun

2017-01-01

Background Drug-target interaction is key in drug discovery, especially in the design of new lead compound. However, the work to find a new lead compound for a specific target is complicated and hard, and it always leads to many mistakes. Therefore computational techniques are commonly adopted in drug design, which can save time and costs to a significant extent. Results To address the issue, a new prediction system is proposed in this work to identify drug-target interaction. First, drug-target pairs are encoded with a fragment technique and the software “PaDEL-Descriptor.” The fragment technique is for encoding target proteins, which divides each protein sequence into several fragments in order and encodes each fragment with several physiochemical properties of amino acids. The software “PaDEL-Descriptor” creates encoding vectors for drug molecules. Second, the dataset of drug-target pairs is resampled and several overlapped subsets are obtained, which are then input into kNN (k-Nearest Neighbor) classifier to build an ensemble system. Conclusion Experimental results on the drug-target dataset showed that our method performs better and runs faster than the state-of-the-art predictors. PMID:28744468

The Alto Tandem and Isol Facility at IPN Orsay

NASA Astrophysics Data System (ADS)

Franchoo, Serge

Alto is an infrastructure for experimental nuclear physics in France that comprises both an on-line isotope-separation facility based on the photofission of uranium and a stable-ion beam facility based on a 14.5-MV tandem accelerator. The isotope-separation on-line section of Alto is dedicated to the production of neutron-rich radioactive ion beams (RIB) from the interaction of the γ-flux induced by a 50-MeV 10-µA electron beam in a uranium-carbide target. It is dimensioned for 1011 fissions per second. The RIB facility is exploited in alternating mode with the tandem-based section of Alto, capable of accelerating both light ions for nuclear astrophysics and heavy ions for γ-spectroscopy. The facility thereby offers the opportunity to deliver beams to a large range of physics programmes from nuclear to interdisciplinary physics. In this article, we present the Alto facility as well as some of the highlights and prospects of the experimental programme.

Present status of the liquid lithium target facility in the international fusion materials irradiation facility (IFMIF)

NASA Astrophysics Data System (ADS)

Nakamura, Hiroo; Riccardi, B.; Loginov, N.; Ara, K.; Burgazzi, L.; Cevolani, S.; Dell'Orco, G.; Fazio, C.; Giusti, D.; Horiike, H.; Ida, M.; Ise, H.; Kakui, H.; Matsui, H.; Micciche, G.; Muroga, T.; Nakamura, Hideo; Shimizu, K.; Sugimoto, M.; Suzuki, A.; Takeuchi, H.; Tanaka, S.; Yoneoka, T.

2004-08-01

During the three year key element technology phase of the International Fusion Materials Irradiation Facility (IFMIF) project, completed at the end of 2002, key technologies have been validated. In this paper, these results are summarized. A water jet experiment simulating Li flow validated stable flow up to 20 m/s with a double reducer nozzle. In addition, a small Li loop experiment validated stable Li flow up to 14 m/s. To control the nitrogen content in Li below 10 wppm will require surface area of a V-Ti alloy getter of 135 m 2. Conceptual designs of diagnostics have been carried out. Moreover, the concept of a remote handling system to replace the back wall based on `cut and reweld' and `bayonet' options has been established. Analysis by FMEA showed safe operation of the target system. Recent activities in the transition phase, started in 2003, and plan for the next phase are also described.

Flyer Target Acceleration and Energy Transfer at its Collision with Massive Targets

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

Borodziuk, S.; Kasperczuk, A.; Pisarczyk, T.

2006-01-15

Numerical modelling was aimed at simulation of successive events resulting from interaction of laser beam-single and double targets. It was performed by means of the 2D Lagrangian hydrodynamics code ATLANT-HE. This code is based on one-fluid and two-temperature model of plasma with electron and ion heat conductivity considerations. The code has an advanced treatment of laser light propagation and absorption. This numerical modelling corresponds to the experiment, which was carried out with the use of the PALS facility. Two types of planar solid targets, i.e. single massive Al slabs and double targets consisting of 6 {mu}m thick Al foil andmore » Al slab were applied. The targets were irradiated by the iodine laser pulses of two wavelengths: 1.315 and 0.438 {mu}m. A pulse duration of 0.4 ns and a focal spot diameter of 250 {mu}m at a laser energy of 130 J were used. The numerical modelling allowed us to obtain a more detailed description of shock wave propagation and crater formation.« less

Membrane nanotubes facilitate long-distance interactions between natural killer cells and target cells

PubMed Central

Chauveau, Anne; Aucher, Anne; Eissmann, Philipp; Vivier, Eric; Davis, Daniel M.

2010-01-01

Membrane nanotubes are membranous tethers that physically link cell bodies over long distances. Here, we present evidence that nanotubes allow human natural killer (NK) cells to interact functionally with target cells over long distances. Nanotubes were formed when NK cells contacted target cells and moved apart. The frequency of nanotube formation was dependent on the number of receptor/ligand interactions and increased on NK cell activation. Most importantly, NK cell nanotubes contained a submicron scale junction where proteins accumulated, including DAP10, the signaling adaptor that associates with the activating receptor NKG2D, and MHC class I chain-related protein A (MICA), a cognate ligand for NKG2D, as occurs at close intercellular synapses between NK cells and target cells. Quantitative live-cell fluorescence imaging suggested that MICA accumulated at small nanotube synapses in sufficient numbers to trigger cell activation. In addition, tyrosine-phosphorylated proteins and Vav-1 accumulated at such junctions. Functionally, nanotubes could aid the lysis of distant target cells either directly or by moving target cells along the nanotube path into close contact for lysis via a conventional immune synapse. Target cells moving along the nanotube path were commonly polarized such that their uropods faced the direction of movement. This is the opposite polarization than for normal cell migration, implying that nanotubes can specifically drive target cell movement. Finally, target cells that remained connected to an NK cell by a nanotube were frequently lysed, whereas removing the nanotube using a micromanipulator reduced lysis of these target cells. PMID:20212116

Computational approach for elucidating interactions of cross-species miRNAs and their targets in Flaviviruses.

PubMed

Shinde, Santosh P; Banerjee, Amit Kumar; Arora, Neelima; Murty, U S N; Sripathi, Venkateswara Rao; Pal-Bhadra, Manika; Bhadra, Utpal

2015-03-01

Combating viral diseases has been a challenging task since time immemorial. Available molecular approaches are limited and not much effective for this daunting task. MicroRNA based therapies have shown promise in recent times. MicroRNAs are tiny non-coding RNAs that regulate translational repression of target mRNA in highly specific manner. In this study, we have determined the target regions for human and viral microRNAs in the conserved genomic regions of selected viruses of Flaviviridae family using miRanda and performed a comparative target selectivity analysis among them. Specific target regions were determined and they were compared extensively among themselves by exploring their position to determine the vicinity. Based on the multiplicity and cooperativity analysis, interaction maps were developed manually to represent the interactions between top-ranking miRNAs and genomes of the viruses considered in this study. Self-organizing map (SOM) was used to cluster the best-ranked microRNAs based on the vital physicochemical properties. This study will provide deep insight into the interrelation of the viral and human microRNAs interactions with the selected Flaviviridae genomes and will help to identify cross-species microRNA targets on the viral genome.

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

NASA Astrophysics Data System (ADS)

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

2018-01-01

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

Wave-current interactions at the FloWave Ocean Energy Research Facility

NASA Astrophysics Data System (ADS)

Noble, Donald; Davey, Thomas; Steynor, Jeffrey; Bruce, Tom; Smith, Helen; Kaklis, Panagiotis

2015-04-01

Physical scale model testing is an important part of the marine renewable energy development process, allowing the study of forces and device behaviour in a controlled environment prior to deployment at sea. FloWave is a new state-of-the-art ocean energy research facility, designed to provide large scale physical modelling services to the tidal and wave sector. It has the unique ability to provide complex multi-directional waves that can be combined with currents from any direction in the 25m diameter circular tank. The facility is optimised for waves around 2s period and 0.4m height, and is capable of generating currents upwards of 1.6m/s. This offers the ability to model metocean conditions suitable for most renewable energy devices at a typical scale of between 1:10 and 1:40. The test section is 2m deep, which can be classed as intermediate-depth for most waves of interest, thus the full dispersion equation must be solved as the asymptotic simplifications do not apply. The interaction between waves and currents has been studied in the tank. This has involved producing in the tank sets of regular waves, focussed wave groups, and random sea spectra including multi-directional sea states. These waves have been both inline-with and opposing the current, as well as investigating waves at arbitrary angles to the current. Changes in wave height and wavelength have been measured, and compared with theoretical results. Using theoretical wave-current interaction models, methods have been explored to "correct" the wave height in the central test area of the tank when combined with a steady current. This allows the wave height with current to be set equal to that without a current. Thus permitting, for example, direct comparison of device motion response between tests with and without current. Alternatively, this would also permit a specific wave height and current combination to be produced in the tank, reproducing recorded conditions at a particular site of interest. The

Micro-Environmental Signature of The Interactions between Druggable Target Protein, Dipeptidyl Peptidase-IV, and Anti-Diabetic Drugs.

PubMed

Chakraborty, Chiranjib; Mallick, Bidyut; Sharma, Ashish Ranjan; Sharma, Garima; Jagga, Supriya; Doss, C George Priya; Nam, Ju-Suk; Lee, Sang-Soo

2017-01-01

Druggability of a target protein depends on the interacting micro-environment between the target protein and drugs. Therefore, a precise knowledge of the interacting micro-environment between the target protein and drugs is requisite for drug discovery process. To understand such micro-environment, we performed in silico interaction analysis between a human target protein, Dipeptidyl Peptidase-IV (DPP-4), and three anti-diabetic drugs (saxagliptin, linagliptin and vildagliptin). During the theoretical and bioinformatics analysis of micro-environmental properties, we performed drug-likeness study, protein active site predictions, docking analysis and residual interactions with the protein-drug interface. Micro-environmental landscape properties were evaluated through various parameters such as binding energy, intermolecular energy, electrostatic energy, van der Waals'+H-bond+desolvo energy (E VHD ) and ligand efficiency (LE) using different in silico methods. For this study, we have used several servers and software, such as Molsoft prediction server, CASTp server, AutoDock software and LIGPLOT server. Through micro-environmental study, highest log P value was observed for linagliptin (1.07). Lowest binding energy was also observed for linagliptin with DPP-4 in the binding plot. We also identified the number of H-bonds and residues involved in the hydrophobic interactions between the DPP-4 and the anti-diabetic drugs. During interaction, two H-bonds and nine residues, two H-bonds and eleven residues as well as four H-bonds and nine residues were found between the saxagliptin, linagliptin as well as vildagliptin cases and DPP-4, respectively. Our in silico data obtained for drug-target interactions and micro-environmental signature demonstrates linagliptin as the most stable interacting drug among the tested anti-diabetic medicines.

Optimized hydrophobic interactions and hydrogen bonding at the target-ligand interface leads the pathways of drug-designing.

PubMed

Patil, Rohan; Das, Suranjana; Stanley, Ashley; Yadav, Lumbani; Sudhakar, Akulapalli; Varma, Ashok K

2010-08-16

Weak intermolecular interactions such as hydrogen bonding and hydrophobic interactions are key players in stabilizing energetically-favored ligands, in an open conformational environment of protein structures. However, it is still poorly understood how the binding parameters associated with these interactions facilitate a drug-lead to recognize a specific target and improve drugs efficacy. To understand this, comprehensive analysis of hydrophobic interactions, hydrogen bonding and binding affinity have been analyzed at the interface of c-Src and c-Abl kinases and 4-amino substituted 1H-pyrazolo [3, 4-d] pyrimidine compounds. In-silico docking studies were performed, using Discovery Studio software modules LigandFit, CDOCKER and ZDOCK, to investigate the role of ligand binding affinity at the hydrophobic pocket of c-Src and c-Abl kinase. Hydrophobic and hydrogen bonding interactions of docked molecules were compared using LigPlot program. Furthermore, 3D-QSAR and MFA calculations were scrutinized to quantify the role of weak interactions in binding affinity and drug efficacy. The in-silico method has enabled us to reveal that a multi-targeted small molecule binds with low affinity to its respective targets. But its binding affinity can be altered by integrating the conformationally favored functional groups at the active site of the ligand-target interface. Docking studies of 4-amino-substituted molecules at the bioactive cascade of the c-Src and c-Abl have concluded that 3D structural folding at the protein-ligand groove is also a hallmark for molecular recognition of multi-targeted compounds and for predicting their biological activity. The results presented here demonstrate that hydrogen bonding and optimized hydrophobic interactions both stabilize the ligands at the target site, and help alter binding affinity and drug efficacy.

Optimized Hydrophobic Interactions and Hydrogen Bonding at the Target-Ligand Interface Leads the Pathways of Drug-Designing

PubMed Central

Stanley, Ashley; Yadav, Lumbani; Sudhakar, Akulapalli; Varma, Ashok K.

2010-01-01

Background Weak intermolecular interactions such as hydrogen bonding and hydrophobic interactions are key players in stabilizing energetically-favored ligands, in an open conformational environment of protein structures. However, it is still poorly understood how the binding parameters associated with these interactions facilitate a drug-lead to recognize a specific target and improve drugs efficacy. To understand this, comprehensive analysis of hydrophobic interactions, hydrogen bonding and binding affinity have been analyzed at the interface of c-Src and c-Abl kinases and 4-amino substituted 1H-pyrazolo [3, 4-d] pyrimidine compounds. Methodology In-silico docking studies were performed, using Discovery Studio software modules LigandFit, CDOCKER and ZDOCK, to investigate the role of ligand binding affinity at the hydrophobic pocket of c-Src and c-Abl kinase. Hydrophobic and hydrogen bonding interactions of docked molecules were compared using LigPlot program. Furthermore, 3D-QSAR and MFA calculations were scrutinized to quantify the role of weak interactions in binding affinity and drug efficacy. Conclusions The in-silico method has enabled us to reveal that a multi-targeted small molecule binds with low affinity to its respective targets. But its binding affinity can be altered by integrating the conformationally favored functional groups at the active site of the ligand-target interface. Docking studies of 4-amino-substituted molecules at the bioactive cascade of the c-Src and c-Abl have concluded that 3D structural folding at the protein-ligand groove is also a hallmark for molecular recognition of multi-targeted compounds and for predicting their biological activity. The results presented here demonstrate that hydrogen bonding and optimized hydrophobic interactions both stabilize the ligands at the target site, and help alter binding affinity and drug efficacy. PMID:20808434

The Target Model of Strategic Interaction of Kazan Federal University and the Region in the Field of Education

ERIC Educational Resources Information Center

Gabdulchakov, Valerian F.

2016-01-01

The subject of the study in the article is conceptual basis of construction of the target model of interaction between University and region. Hence the topic of the article "the Target model of strategic interaction between the University and the region in the field of education." The objective was to design a target model of this…

Protein-Protein Interactions of Viroporins in Coronaviruses and Paramyxoviruses: New Targets for Antivirals?

PubMed Central

Torres, Jaume; Surya, Wahyu; Li, Yan; Liu, Ding Xiang

2015-01-01

Viroporins are members of a rapidly growing family of channel-forming small polypeptides found in viruses. The present review will be focused on recent structural and protein-protein interaction information involving two viroporins found in enveloped viruses that target the respiratory tract; (i) the envelope protein in coronaviruses and (ii) the small hydrophobic protein in paramyxoviruses. Deletion of these two viroporins leads to viral attenuation in vivo, whereas data from cell culture shows involvement in the regulation of stress and inflammation. The channel activity and structure of some representative members of these viroporins have been recently characterized in some detail. In addition, searches for protein-protein interactions using yeast-two hybrid techniques have shed light on possible functional roles for their exposed cytoplasmic domains. A deeper analysis of these interactions should not only provide a more complete overview of the multiple functions of these viroporins, but also suggest novel strategies that target protein-protein interactions as much needed antivirals. These should complement current efforts to block viroporin channel activity. PMID:26053927

Dynamic model of target charging by short laser pulse interactions

NASA Astrophysics Data System (ADS)

Poyé, A.; Dubois, J.-L.; Lubrano-Lavaderci, F.; D'Humières, E.; Bardon, M.; Hulin, S.; Bailly-Grandvaux, M.; Ribolzi, J.; Raffestin, D.; Santos, J. J.; Nicolaï, Ph.; Tikhonchuk, V.

2015-10-01

A model providing an accurate estimate of the charge accumulation on the surface of a metallic target irradiated by a high-intensity laser pulse of fs-ps duration is proposed. The model is confirmed by detailed comparisons with specially designed experiments. Such a model is useful for understanding the electromagnetic pulse emission and the quasistatic magnetic field generation in laser-plasma interaction experiments.

Dynamic model of target charging by short laser pulse interactions.

PubMed

Poyé, A; Dubois, J-L; Lubrano-Lavaderci, F; D'Humières, E; Bardon, M; Hulin, S; Bailly-Grandvaux, M; Ribolzi, J; Raffestin, D; Santos, J J; Nicolaï, Ph; Tikhonchuk, V

2015-10-01

A model providing an accurate estimate of the charge accumulation on the surface of a metallic target irradiated by a high-intensity laser pulse of fs-ps duration is proposed. The model is confirmed by detailed comparisons with specially designed experiments. Such a model is useful for understanding the electromagnetic pulse emission and the quasistatic magnetic field generation in laser-plasma interaction experiments.

Learner Agency and Its Effect on Spoken Interaction Time in the Target Language

ERIC Educational Resources Information Center

Knight, Janine; Barberà, Elena

2017-01-01

This paper presents the results of how four dyads in an online task-based synchronous computer-mediated (TB-SCMC) interaction event use their agency to carry out speaking tasks, and how their choices and actions affect time spent interacting in the target language. A case study approach was employed to analyse the language functions and cognitive…

A Systematic Prediction of Drug-Target Interactions Using Molecular Fingerprints and Protein Sequences.

PubMed

Huang, Yu-An; You, Zhu-Hong; Chen, Xing

2018-01-01

Drug-Target Interactions (DTI) play a crucial role in discovering new drug candidates and finding new proteins to target for drug development. Although the number of detected DTI obtained by high-throughput techniques has been increasing, the number of known DTI is still limited. On the other hand, the experimental methods for detecting the interactions among drugs and proteins are costly and inefficient. Therefore, computational approaches for predicting DTI are drawing increasing attention in recent years. In this paper, we report a novel computational model for predicting the DTI using extremely randomized trees model and protein amino acids information. More specifically, the protein sequence is represented as a Pseudo Substitution Matrix Representation (Pseudo-SMR) descriptor in which the influence of biological evolutionary information is retained. For the representation of drug molecules, a novel fingerprint feature vector is utilized to describe its substructure information. Then the DTI pair is characterized by concatenating the two vector spaces of protein sequence and drug substructure. Finally, the proposed method is explored for predicting the DTI on four benchmark datasets: Enzyme, Ion Channel, GPCRs and Nuclear Receptor. The experimental results demonstrate that this method achieves promising prediction accuracies of 89.85%, 87.87%, 82.99% and 81.67%, respectively. For further evaluation, we compared the performance of Extremely Randomized Trees model with that of the state-of-the-art Support Vector Machine classifier. And we also compared the proposed model with existing computational models, and confirmed 15 potential drug-target interactions by looking for existing databases. The experiment results show that the proposed method is feasible and promising for predicting drug-target interactions for new drug candidate screening based on sizeable features. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Study of the hydrodynamics of the formation of flows caused by the interaction of a shock wave with two-dimensional density perturbations on the Iskra-5 laser facility

NASA Astrophysics Data System (ADS)

Babanov, A. V.; Barinov, M. A.; Barinov, S. P.; Garanin, R. V.; Zhidkov, N. V.; Kalmykov, N. A.; Kovalenko, V. P.; Kokorin, S. N.; Pinegin, A. V.; Solomatina, E. Yu.; Solomatin, I. I.; Suslov, N. A.

2017-03-01

The hydrodynamics of the flow formation due to the interaction of a shock wave with two-dimensional density perturbations is experimentally investigated on the Iskra-5 laser facility. Shadow images of a jet arising as a result of the impact of a shock wave (formed by a soft X-ray pulse from a target-illuminator) on a flat aluminium target with a blind cylindrical cavity are recorded in experiments with point-like X-ray backlighting having a photon energy of ~4.5 keV. The sizes and mass of the jet ejected from the aluminium cavity by this shock wave are estimated. The experimental data are compared with the results of numerical simulation of the jet formation and dynamics according to the two-dimensional MID-ND2D code.

The Tn7 transposition regulator TnsC interacts with the transposase subunit TnsB and target selector TnsD

PubMed Central

Choi, Ki Young; Spencer, Jeanelle M.; Craig, Nancy L.

2014-01-01

The excision of transposon Tn7 from a donor site and its insertion into its preferred target site, attachment site attTn7, is mediated by four Tn7-encoded transposition proteins: TnsA, TnsB, TnsC, and TnsD. Transposition requires the assembly of a nucleoprotein complex containing all four Tns proteins and the DNA substrates, the donor site containing Tn7, and the preferred target site attTn7. TnsA and TnsB together form the heteromeric Tn7 transposase, and TnsD is a target-selecting protein that binds specifically to attTn7. TnsC is the key regulator of transposition, interacting with both the TnsAB transposase and TnsD-attTn7. We show here that TnsC interacts directly with TnsB, and identify the specific region of TnsC involved in the TnsB–TnsC interaction during transposition. We also show that a TnsC mutant defective in interaction with TnsB is defective for Tn7 transposition both in vitro and in vivo. Tn7 displays cis-acting target immunity, which blocks Tn7 insertion into a target DNA that already contains Tn7. We provide evidence that the direct TnsB–TnsC interaction that we have identified also mediates cis-acting Tn7 target immunity. We also show that TnsC interacts directly with the target selector protein TnsD. PMID:24982178

Strategic interaction among hospitals and nursing facilities: the efficiency effects of payment systems and vertical integration.

PubMed

Banks, D; Parker, E; Wendel, J

2001-03-01

Rising post-acute care expenditures for Medicare transfer patients and increasing vertical integration between hospitals and nursing facilities raise questions about the links between payment system structure, the incentive for vertical integration and the impact on efficiency. In the United States, policy-makers are responding to these concerns by initiating prospective payments to nursing facilities, and are exploring the bundling of payments to hospitals. This paper develops a static profit-maximization model of the strategic interaction between the transferring hospital and a receiving nursing facility. This model suggests that the post-1984 system of prospective payment for hospital care, coupled with nursing facility payments that reimburse for services performed, induces inefficient under-provision of hospital services and encourages vertical integration. It further indicates that the extension of prospective payment to nursing facilities will not eliminate the incentive to vertically integrate, and will not result in efficient production unless such integration takes place. Bundling prospective payments for hospitals and nursing facilities will neither remove the incentive for vertical integration nor induce production efficiency without such vertical integration. However, bundled payment will induce efficient production, with or without vertical integration, if nursing facilities are reimbursed for services performed. Copyright 2001 John Wiley & Sons, Ltd.

miRTarBase update 2018: a resource for experimentally validated microRNA-target interactions.

PubMed

Chou, Chih-Hung; Shrestha, Sirjana; Yang, Chi-Dung; Chang, Nai-Wen; Lin, Yu-Ling; Liao, Kuang-Wen; Huang, Wei-Chi; Sun, Ting-Hsuan; Tu, Siang-Jyun; Lee, Wei-Hsiang; Chiew, Men-Yee; Tai, Chun-San; Wei, Ting-Yen; Tsai, Tzi-Ren; Huang, Hsin-Tzu; Wang, Chung-Yu; Wu, Hsin-Yi; Ho, Shu-Yi; Chen, Pin-Rong; Chuang, Cheng-Hsun; Hsieh, Pei-Jung; Wu, Yi-Shin; Chen, Wen-Liang; Li, Meng-Ju; Wu, Yu-Chun; Huang, Xin-Yi; Ng, Fung Ling; Buddhakosai, Waradee; Huang, Pei-Chun; Lan, Kuan-Chun; Huang, Chia-Yen; Weng, Shun-Long; Cheng, Yeong-Nan; Liang, Chao; Hsu, Wen-Lian; Huang, Hsien-Da

2018-01-04

MicroRNAs (miRNAs) are small non-coding RNAs of ∼ 22 nucleotides that are involved in negative regulation of mRNA at the post-transcriptional level. Previously, we developed miRTarBase which provides information about experimentally validated miRNA-target interactions (MTIs). Here, we describe an updated database containing 422 517 curated MTIs from 4076 miRNAs and 23 054 target genes collected from over 8500 articles. The number of MTIs curated by strong evidence has increased ∼1.4-fold since the last update in 2016. In this updated version, target sites validated by reporter assay that are available in the literature can be downloaded. The target site sequence can extract new features for analysis via a machine learning approach which can help to evaluate the performance of miRNA-target prediction tools. Furthermore, different ways of browsing enhance user browsing specific MTIs. With these improvements, miRTarBase serves as more comprehensively annotated, experimentally validated miRNA-target interactions databases in the field of miRNA related research. miRTarBase is available at http://miRTarBase.mbc.nctu.edu.tw/. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

Basic features of electromagnetic pulse generated in a laser-target chamber at 3-TW laser facility PALS

NASA Astrophysics Data System (ADS)

De Marco, M.; Pfeifer, M.; Krousky, E.; Krasa, J.; Cikhardt, J.; Klir, D.; Nassisi, V.

2014-04-01

We describe the radiofrequency emission taking place when 300 ps laser pulses irradiate various solid targets with an intensity of 1016 W/cm2. The emission of intense electromagnetic pulses was observed outside the laser target chamber by two loop antennas up to 1 GHz. Electromagnetic pulses can be 800 MHz transients, which decay from a peak electromagnetic field of E0 ≊ 7 kV/m and H0 ≊ 15 A/m. The occurrence of these electromagnetic pulses is associated with generation of hard x-rays with photon energies extending beyond 1 MeV. This contribution reports the first observation of this effect at the PALS facility.

Network Analysis of Drug-target Interactions: A Study on FDA-approved New Molecular Entities Between 2000 to 2015.

PubMed

Lin, Hui-Heng; Zhang, Le-Le; Yan, Ru; Lu, Jin-Jian; Hu, Yuanjia

2017-09-25

The U.S. Food and Drug Administration (FDA) approves new drugs every year. Drug targets are some of the most important interactive molecules for drugs, as they have a significant impact on the therapeutic effects of drugs. In this work, we thoroughly analyzed the data of small molecule drugs approved by the U.S. FDA between 2000 and 2015. Specifically, we focused on seven classes of new molecular entity (NME) classified by the anatomic therapeutic chemical (ATC) classification system. They were NMEs and their corresponding targets for the cardiovascular system, respiratory system, nerve system, general anti-infective systemic, genito-urinary system and sex hormones, alimentary tract and metabolisms, and antineoplastic and immunomodulating agents. To study the drug-target interaction on the systems level, we employed network topological analysis and multipartite network projections. As a result, the drug-target relations of different kinds of drugs were comprehensively characterized and global pictures of drug-target, drug-drug, and target-target interactions were visualized and analyzed from the perspective of network models.

Atomic Force Microscopy Probing of Receptor–Nanoparticle Interactions for Riboflavin Receptor Targeted Gold–Dendrimer Nanocomposites

PubMed Central

2015-01-01

Riboflavin receptors are overexpressed in malignant cells from certain human breast and prostate cancers, and they constitute a group of potential surface markers important for cancer targeted delivery of therapeutic agents and imaging molecules. Here we report on the fabrication and atomic force microscopy (AFM) characterization of a core–shell nanocomposite consisting of a gold nanoparticle (AuNP) coated with riboflavin receptor-targeting poly(amido amine) dendrimer. We designed this nanocomposite for potential applications such as a cancer targeted imaging material based on its surface plasmon resonance properties conferred by AuNP. We employed AFM as a technique for probing the binding interaction between the nanocomposite and riboflavin binding protein (RfBP) in solution. AFM enabled precise measurement of the AuNP height distribution before (13.5 nm) and after chemisorption of riboflavin-conjugated dendrimer (AuNP–dendrimer; 20.5 nm). Binding of RfBP to the AuNP–dendrimer caused a height increase to 26.7 nm, which decreased to 22.8 nm when coincubated with riboflavin as a competitive ligand, supporting interaction of AuNP–dendrimer and its target protein. In summary, physical determination of size distribution by AFM imaging can serve as a quantitative approach to monitor and characterize the nanoscale interaction between a dendrimer-covered AuNP and target protein molecules in vitro. PMID:24571134

Chemical projectile-target interaction during hypervelocity cratering experiments (MEMIN project).

NASA Astrophysics Data System (ADS)

Ebert, M.; Hecht, L.; Deutsch, A.; Kenkmann, T.

2012-04-01

The detection and identification of meteoritic components in impact-derived rocks are of great value for confirming an impact origin and reconstructing the type of extraterrestrial material that repeatedly stroke the Earth during geologic evolution [1]. However, little is known about processes that control the projectile distribution into the various impactites that originate during the cratering and excavation process, and inter-element fractionation between siderophile elements during impact cratering. In the context of the MEMIN project, cratering experiments have been performed using spheres of Cr-V-Co-Mo-W-rich steel and of the iron meteorite Campo del Cielo (IAB) as projectiles accelerated to about 5 km/s, and blocks of Seeberger sandstone as target. The experiments were carried out at the two-stage acceleration facilities of the Fraunhofer Ernst-Mach-Institute (Freiburg). Our results are based on geochemical analyses of highly shocked ejecta material. The ejecta show various shock features including multiple sets of planar deformations features (PDF) in quartz, diaplectic quartz, and partial melting of the sandstone. Melting is concentrated in the phyllosilicate-bearing sandstone matrix but involves quartz, too. Droplets of molten projectile have entered the low-viscosity sandstone melt but not quartz glass. Silica-rich sandstone melts are enriched in the elements that are used to trace the projectile, like Fe, Ni, Cr, Co, and V (but no or little W and Mo). Inter-element ratios of these "projectile" tracer elements within the contaminated sandstone melt may be strongly modified from the original ratios in the projectiles. This fractionation most likely result from variation in the lithophile or siderophile character and/or from differences in reactivity of these tracer elements with oxygen [2] during interaction of metal melt with silicate melt. The shocked quartz with PDF is also enriched in Fe and Ni (experiment with a meteorite iron projectile) and in Fe

Obtaining control of cell surface functionalizations via Pre-targeting and Supramolecular host guest interactions

NASA Astrophysics Data System (ADS)

Rood, Mark T. M.; Spa, Silvia J.; Welling, Mick M.; Ten Hove, Jan Bart; van Willigen, Danny M.; Buckle, Tessa; Velders, Aldrik H.; van Leeuwen, Fijs W. B.

2017-01-01

The use of mammalian cells for therapeutic applications is finding its way into modern medicine. However, modification or “training” of cells to make them suitable for a specific application remains complex. By envisioning a chemical toolbox that enables specific, but straight-forward and generic cellular functionalization, we investigated how membrane-receptor (pre)targeting could be combined with supramolecular host-guest interactions based on β-cyclodextrin (CD) and adamantane (Ad). The feasibility of this approach was studied in cells with membranous overexpression of the chemokine receptor 4 (CXCR4). By combining specific targeting of CXCR4, using an adamantane (Ad)-functionalized Ac-TZ14011 peptide (guest; KD = 56 nM), with multivalent host molecules that entailed fluorescent β-CD-Poly(isobutylene-alt-maleic-anhydride)-polymers with different fluorescent colors and number of functionalities, host-guest cell-surface modifications could be studied in detail. A second set of Ad-functionalized entities enabled introduction of additional surface functionalities. In addition, the attraction between CD and Ad could be used to drive cell-cell interactions. Combined we have shown that supramolecular interactions, that are based on specific targeting of an overexpressed membrane-receptor, allow specific and stable, yet reversible, surface functionalization of viable cells and how this approach can be used to influence the interaction between cells and their surroundings.

IRIS : A reaction spectroscopy facility with solid H2 /D2 target

NASA Astrophysics Data System (ADS)

Holl, Matthias; Kanungo, Ritu; Alcorta, Martin; Andreoiu, Corina; Bidaman, Harris; Burbadge, Christina; Burke, Devin; Chen, Alan; Davids, Barry; Diaz Varela, Alejandra; Garrett, Paul; Hackman, Greg; Ishimoto, Shigeru; Kaur, Satbir; Keefe, Matthew; Kruecken, Reiner; Mansour, Iymad; Randhawa, Jaspreet; Sanetullaev, Alisher; Shotter, Alan; Smith, Jenna; Tanaka, Junki; Tanihata, Isao; Turko, Joseph; Workman, Orry

2016-09-01

The charged particle reaction spectroscopy station IRIS at TRIUMF is designed to allow studies of inelastic scattering and transfer reactions for low intensity beams. To do so, a novel solid H2 /D2 target is used in combination with a low pressure ionization chamber for the identification of incoming beam particles. The light ejectiles are measured using a ΔE - E telescope consisting of an annular silicon detector followed by CsI(Tl) array. Another ΔE - E telescope, consisting of two segmented silicon detectors, is used to identify the heavy outgoing particles. An overview of the faciltity will be given and examples from recent experiments that illustrate that facility's capability for reaction studies of exotic nuclei will be shown. Support from Canada Foundation for Innovation, Nova Scotia Research and Innovation Trust and NSERC.

Assessment of the significance of patent-derived information for the early identification of compound-target interaction hypotheses.

PubMed

Senger, Stefan

2017-04-21

Patents are an important source of information for effective decision making in drug discovery. Encouragingly, freely accessible patent-chemistry databases are now in the public domain. However, at present there is still a wide gap between relatively low coverage-high quality manually-curated data sources and high coverage data sources that use text mining and automated extraction of chemical structures. To secure much needed funding for further research and an improved infrastructure, hard evidence is required to demonstrate the significance of patent-derived information in drug discovery. Surprisingly little such evidence has been reported so far. To address this, the present study attempts to quantify the relevance of patents for formulating and substantiating hypotheses for compound-target interactions. A manually-curated set of 130 compound-target interaction pairs annotated with what are considered to be the earliest patent and publication has been produced. The analysis of this set revealed that in stark contrast to what has been reported for novel chemical structures, only about 10% of the compound-target interaction pairs could be found in publications in the scientific literature within one year of being reported in patents. The average delay across all interaction pairs is close to 4 years. In an attempt to benchmark current capabilities, it was also examined how much of the benefit of using patent-derived information can be retained when a bioannotated version of SureChEMBL is used as secondary source for the patent literature. Encouragingly, this approach found the patents in the annotated set for 72% of the compound-target interaction pairs. Similarly, the effect of using the bioactivity database ChEMBL as secondary source for the scientific literature was studied. Here, the publications from the annotated set were only found for 46% of the compound-target interaction pairs. Patent-derived information is a significant enabler for formulating compound-target

Curcumin targets fibroblast–tumor cell interactions in oral squamous cell carcinoma

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

Dudás, József, E-mail: jozsef.dudas@i-med.ac.at; Fullár, Alexandra, E-mail: fullarsz@gmail.com; 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, 1085 Budapest

Co-culture of periodontal ligament fibroblasts (PDLs) and SCC-25 oral squamous carcinoma cells (OSCC) results in conversion of PDLs into carcinoma-associated fibroblasts (CAFs) and induces epithelial-to mesenchymal transition (EMT) of OSCC tumor cells. We hypothesized that Curcumin targets this dynamic mutual interaction between CAFs and tumor cells. Normal and 2 μM Curcumin-treated co-culture were performed for 4 days, followed by analysis of tumor cell invasivity, mRNA/protein expression of EMT-markers and mediators, activity measure of matrix metalloproteinase 9 (MMP-9), and western blot analysis of signal transduction in tumor cells and fibroblasts. In Curcumin-treated co-culture, in tumor cells, the levels of nuclear factormore » κB (NFκBα) and early response kinase (ERK)—decreased, in fibroblasts, integrin αv protein synthesis decreased compared to corresponding cells in normal co-culture. The signal modulatory changes induced by Curcumin caused decreased release of EMT-mediators in CAFs and reversal of EMT in tumor cells, which was associated with decreased invasion. These data confirm the palliative potential of Curcumin in clinical application. - Graphical abstract: Co-culture of periodontal ligament fibroblasts (PDLs) and SCC-25 oral squamous carcinoma cells (OSCC) results in conversion of PDLs into carcinoma-associated fibroblasts (CAFs) and induces epithelial-to mesenchymal transition (EMT) of tumor cells. Curcumin targets this dynamic mutual interaction between CAFs and tumor cells by inhibiting the production of EMT mediators in CAFs and by modification of intracellular signaling in tumor cells. This causes less invasivity and reversal of EMT in tumor cells. Highlights: ► Curcumin targets tumor–fibroblast interaction in head and neck cancer. ► Curcumin suppresses mediators of epithelial–mesenchymal transition. ► Curcumin decreases the invasivity of tumor cells.« less

Efficient monoenergetic proton beam from ultra-fast laser interaction with nanostructured targets

NASA Astrophysics Data System (ADS)

Fazeli, R.

2018-03-01

The broad energy spectrum of laser-accelerated proton beams is the most important difficulty associated with such particle sources on the way to future applications such as medical therapy, proton imaging, inertial fusion, and high-energy physics. The generation of proton beams with enhanced monoenergetic features through an ultra-intense laser interaction with optimized nanostructured targets is reported. Targets were irradiated by 40 fs laser pulses of intensity 5.5 ×1020 W c m -2 and wavelength 1 μm. The results of multi-parametric Particle-in-Cell calculations showed that proton beams with considerably reduced energy spread can be obtained by using the proposed nanostructured target. At optimized target dimensions, the proton spectrum was found to exhibit a narrow peak at about 63 MeV with a relative energy spread of ΔE /Epeak˜ 5 % which is efficiently lower than what is expected for unstructured double layer targets (˜70%).

Bypassing Protein Corona Issue on Active Targeting: Zwitterionic Coatings Dictate Specific Interactions of Targeting Moieties and Cell Receptors.

PubMed

Safavi-Sohi, Reihaneh; Maghari, Shokoofeh; Raoufi, Mohammad; Jalali, Seyed Amir; Hajipour, Mohammad J; Ghassempour, Alireza; Mahmoudi, Morteza

2016-09-07

Surface functionalization strategies for targeting nanoparticles (NP) to specific organs, cells, or organelles, is the foundation for new applications of nanomedicine to drug delivery and biomedical imaging. Interaction of NPs with biological media leads to the formation of a biomolecular layer at the surface of NPs so-called as "protein corona". This corona layer can shield active molecules at the surface of NPs and cause mistargeting or unintended scavenging by the liver, kidney, or spleen. To overcome this corona issue, we have designed biotin-cysteine conjugated silica NPs (biotin was employed as a targeting molecule and cysteine was used as a zwitterionic ligand) to inhibit corona-induced mistargeting and thus significantly enhance the active targeting capability of NPs in complex biological media. To probe the targeting yield of our engineered NPs, we employed both modified silicon wafer substrates with streptavidin (i.e., biotin receptor) to simulate a target and a cell-based model platform using tumor cell lines that overexpress biotin receptors. In both cases, after incubation with human plasma (thus forming a protein corona), cellular uptake/substrate attachment of the targeted NPs with zwitterionic coatings were significantly higher than the same NPs without zwitterionic coating. Our results demonstrated that NPs with a zwitterionic surface can considerably facilitate targeting yield of NPs and provide a promising new type of nanocarriers in biological applications.

Pair production by high intensity picosecond laser interacting with thick solid target at XingGuangIII

NASA Astrophysics Data System (ADS)

Wu, Yuchi; Dong, Kegong; Yan, Yonghong; Zhu, Bin; Zhang, Tiankui; Chen, Jia; Yu, Minghai; Tan, Fang; Wang, Shaoyi; Han, Dan; Lu, Feng; Gu, Yuqiu

2017-06-01

An experiment for pair production by high intensity laser irradiating thick solid targets is present. The experiment used picosecond beam of the XingGuangIII laser facility, with intensities up to several 1019 W/cm2, pulse durations about 0.8 ps and laser energies around 120 J. Pairs were generated from 1 mm-thick tantalum disk targets with different diameters from 1 mm to 10 mm. Energy spectra of hot electron from targetrear surface represent a Maxwellian distribution and obey a scaling of ∼(Iλ2)0.5. Large quantity of positrons were observed at the target rear normal direction with a yield up to 2.8 × 109 e+/sr. Owing to the target rear surface sheath field, the positrons behave as a quasi-monoenergetic beam with peak energy of several MeV. Our experiment shows that the peak energy of positron beam is inversely proportional to the target diameter.

The interactive astronomical data analysis facility - image enhancement techniques to Comet Halley

NASA Astrophysics Data System (ADS)

Klinglesmith, D. A.

1981-10-01

PDP 11/40 computer is at the heart of a general purpose interactive data analysis facility designed to permit easy access to data in both visual imagery and graphic representations. The major components consist of: the 11/40 CPU and 256 K bytes of 16-bit memory; two TU10 tape drives; 20 million bytes of disk storage; three user terminals; and the COMTAL image processing display system. The application of image enhancement techniques to two sequences of photographs of Comet Halley taken in Egypt in 1910 provides evidence for eruptions from the comet's nucleus.

Narrow Energy Spread Protons and Ions from High-Intensity, High-Contrast Laser Solid Target Interactions

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

Dollar, Franklin; Matsuoka, Takeshi; McGuffey, Christopher

2010-11-04

Recent simulations show that an idealized, high intensity, short pulse laser can generate quasi-monoenergetic proton beams with energies over 100 MeV in an interaction with a thin film. However, most short pulse laser facilities with sufficient intensity have difficulty controlling the nanosecond and picosecond contrast necessary to realize such a regime. Experiments were performed to investigate proton and ion acceleration from a high contrast, short pulse laser by employing dual plasma mirrors along with a deformable mirror at the HERCULES laser facility at the Center for Ultrafast Optical Sciences, University of Michigan. Plasma mirrors were characterized, allowing a 50% throughputmore » with an intensity contrast increase of 105. The focal spot quality was also exceptional, showing a 1.1 micron full width at half maximum (FWHM) focal diameter. Experiments were done using temporally cleaned 30 TW, 32 fs pulses to achieve an intensity of up to 10{sup 21} Wcm{sup -2} on Si{sub 3}N{sub 4} and Mylar targets with thicknesses ranging 50 nm to 13 microns. Proton beams with energy spreads below 2 MeV were observed from all thicknesses, peaking with energies up to 10.3 MeV and an energy spread of 0.8 MeV. Similar narrow energy spreads were observed for oxygen, nitrogen, and carbon at the silicon nitride thickness of 50 nm with energies up to 24 MeV with an energy spread of 3 MeV, whereas the energy spread is greatly increased at a larger thickness. Maximum energies were confirmed with CR39 track detectors, while a Thomson ion spectrometer was used to gauge the monoenergetic nature of the beam.« less

Intermolecular interaction of thiosemicarbazone derivatives to solvents and a potential Aedes aegypti target

NASA Astrophysics Data System (ADS)

da Silva, João Bosco P.; Hallwass, Fernando; da Silva, Aluizio G.; Moreira, Diogo Rodrigo; Ramos, Mozart N.; Espíndola, José Wanderlan P.; de Oliveira, Ana Daura T.; Brondani, Dalci José; Leite, Ana Cristina L.; Merz, Kenneth M.

2015-08-01

DFT calculations were used to access information about structure, energy and electronic properties of series of phenyl- and phenoxymethyl-(thio)semicarbazone derivatives with demonstrated activity against the larvae of Aedes aegypti in stage L4. The way as the thiosemicarbazone derivatives can interact with solvents like DMSO and water were analyzed from the comparison between calculated and experimental 1H NMR chemical shifts. The evidences of thiosemicarbazone derivatives making H-bond interaction to solvent have provide us insights on how they can interact with a potential A. aegypti's biological target, the Sterol Carrier Protein-2.

Interaction of Myosin Phosphatase Target Subunit (MYPT1) with Myosin Phosphatase-RhoA Interacting Protein (MRIP): A Role of Glutamic Acids in the Interaction.

PubMed

Lee, Eunhee; Stafford, Walter F

2015-01-01

Scaffold proteins bind to and functionally link protein members of signaling pathways. Interaction of the scaffold proteins, myosin phosphatase target subunit (MYPT1) and myosin phosphatase-RhoA interacting protein (MRIP), causes co-localization of myosin phosphatase and RhoA to actomyosin. To examine biophysical properties of interaction of MYPT1 with MRIP, we employed analytical ultracentrifugation and surface plasmon resonance. In regard to MRIP, its residues 724-837 are sufficient for the MYPT1/MRIP interaction. Moreover, MRIP binds to MYPT1 as either a monomer or a dimer. With respect to MYPT1, its leucine repeat region, LR (residues 991-1030) is sufficient to account for the MYPT1/MRIP interaction. Furthermore, point mutations that replace glutamic acids 998-1000 within LR reduced the binding affinity toward MRIP. This suggests that the glutamic acids of MYPT1 play an important role in the interaction.

Use of a spatial scan statistic to identify clusters of births occurring outside Ghanaian health facilities for targeted intervention.

PubMed

Bosomprah, Samuel; Dotse-Gborgbortsi, Winfred; Aboagye, Patrick; Matthews, Zoe

2016-11-01

To identify and evaluate clusters of births that occurred outside health facilities in Ghana for targeted intervention. A retrospective study was conducted using a convenience sample of live births registered in Ghanaian health facilities from January 1 to December 31, 2014. Data were extracted from the district health information system. A spatial scan statistic was used to investigate clusters of home births through a discrete Poisson probability model. Scanning with a circular spatial window was conducted only for clusters with high rates of such deliveries. The district was used as the geographic unit of analysis. The likelihood P value was estimated using Monte Carlo simulations. Ten statistically significant clusters with a high rate of home birth were identified. The relative risks ranged from 1.43 ("least likely" cluster; P=0.001) to 1.95 ("most likely" cluster; P=0.001). The relative risks of the top five "most likely" clusters ranged from 1.68 to 1.95; these clusters were located in Ashanti, Brong Ahafo, and the Western, Eastern, and Greater regions of Accra. Health facility records, geospatial techniques, and geographic information systems provided locally relevant information to assist policy makers in delivering targeted interventions to small geographic areas. Copyright © 2016 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

Comprehensive description of the Orion laser facility

NASA Astrophysics Data System (ADS)

Hopps, Nicholas; Oades, Kevin; Andrew, Jim; Brown, Colin; Cooper, Graham; Danson, Colin; Daykin, Simon; Duffield, Stuart; Edwards, Ray; Egan, David; Elsmere, Stephen; Gales, Steve; Girling, Mark; Gumbrell, Edward; Harvey, Ewan; Hillier, David; Hoarty, David; Horsfield, Colin; James, Steven; Leatherland, Alex; Masoero, Stephen; Meadowcroft, Anthony; Norman, Michael; Parker, Stefan; Rothman, Stephen; Rubery, Michael; Treadwell, Paul; Winter, David; Bett, Thomas

2015-06-01

The Orion laser facility at the atomic weapons establishment (AWE) in the UK has been operational since April 2013, fielding experiments that require both its long and short pulse capability. This paper provides a full description of the facility in terms of laser performance, target systems and diagnostics currently available. Inevitably, this is a snapshot of current capability—the available diagnostics and the laser capability are evolving continuously. The laser systems consist of ten beams, optimised around 1 ns pulse duration, which each provide a nominal 500 J at a wavelength of 351 nm. There are also two short pulse beams, which each provide 500 J in 0.5 ps at 1054 nm. There are options for frequency doubling one short pulse beam to enhance the pulse temporal contrast. More recently, further contrast enhancement, based on optical parametric amplification (OPA) in the front end with a pump pulse duration of a few ps, has been installed. An extensive suite of diagnostics are available for users, probing the optical emission, x-rays and particles produced in laser-target interactions. Optical probe diagnostics are also available. A description of the diagnostics is provided.

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.

Overview of the Neutron experimental facilities at LANSCE

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

Mocko, Michal

2016-06-30

This presentation gives an overview of the neutron experimental facilities at LANSCE. The layout is mentioned in detail, with a map of the south-side experimental facilities, information on Target-4 and the Lujan Center. Then it goes into detail about neutron sources, specifically continuous versus pulsed. Target 4 is then discussed. In conclusion, we have introduced the south-side experimental facilities in operation at LANSCE. 1L target and Target 4 provide complementary neutron energy spectra. Two spallation neutron sources taken together cover more than 11 orders of magnitude in neutron energy.

Secondary neutron-production cross sections from heavy-ion interactions in composite targets

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

Heilbronn, L.; Iwata, Y.; Murakami, T.

Secondary neutron-production cross sections have been measured from interactions of 290 MeV/nucleon C and 600 MeV/nucleon Ne in a target composed of simulated Martian regolith and polyethylene, and from 400 MeV/nucleon Ne interactions in wall material from the International Space Station. The data were measured between 5 deg. and 80 deg. in the laboratory. We report the double-differential cross sections, angular distributions, and total neutron-production cross sections from all three systems. The spectra from all three systems exhibit behavior previously reported in other heavy-ion neutron-production experiments, namely, a peak at forward angles near the energy corresponding to the beam velocity,more » with the remaining spectra generated by pre-equilibrium and equilibrium processes. The double-differential cross sections are fitted with a moving-source parametrization. Also reported are the data without corrections for neutron flux attenuation in the target and other intervening materials and for neutron production in nontarget materials near the target position. These uncorrected spectra are compared with SHIELD-HIT and PHITS transport model calculations. The transport model calculations reproduce the spectral shapes well but, on average, underestimate the magnitudes of the cross sections.« less

SPES and the neutron facilities at Laboratori Nazionali di Legnaro

NASA Astrophysics Data System (ADS)

Silvestrin, L.; Bisello, D.; Esposito, J.; Mastinu, P.; Prete, G.; Wyss, J.

2016-03-01

The SPES Radioactive Ion Beam (RIB) facility, now in the construction phase at INFN-LNL, has the aim to provide high-intensity and high-quality beams of neutron-rich nuclei for nuclear physics research as well as to develop an interdisciplinary research center based on the cyclotron proton beam. The SPES system is based on a dual-exit high-current cyclotron, with tunable proton beam energy 35-70MeV and 0.20-0.75mA. The first exit is used as proton driver to supply an ISOL system with an UCx Direct Target able to sustain a power of 10kW. The expected fission rate in the target is of the order of 10^{13} fissions per second. The exotic isotopes will be re-accelerated by the ALPI superconducting LINAC at energies of 10 A MeV and higher, for masses around A=130 amu, with an expected beam intensity of 10^7 - 10^9 pps. The second exit will be used for applied physics: radioisotope production for medicine and neutrons for material studies. Fast neutron spectra will be produced by the proton beam interaction with a conversion target. A production rate in excess of 10^{14} n/s can be achieved: this opens up the prospect of a high-flux neutron irradiation facility (NEPIR) to produce both discrete and continuous energy neutrons. A direct proton beam line is also envisaged. NEPIR and the direct proton line would dramatically increase the wide range of irradiation facilities presently available at LNL. We also present LENOS, a proposed project dedicated to accurate neutron cross-sections measurements using intense, well-characterized, broad energy neutron beams. Other activities already in operation at LNL are briefly reviewed: the SIRAD facility for proton and heavy-ion irradiation at the TANDEM-ALPI accelerator and the BELINA test facility at CN van de Graaff accelerator.

RISC-Target Interaction: Cleavage and Translational Suppression

PubMed Central

van den Berg, Arjen; Mols, Johann; Han, Jiahuai

2008-01-01

Summary Small RNA molecules have been known and utilized to suppress gene expression for more than a decade. The discovery that these small RNA molecules are endogenously expressed in many organisms and have a critical role in controlling gene expression have led to the arising of a whole new field of research. Termed small interfering RNA (siRNA) or microRNA (miRNA) these ~22 nt RNA molecules have the capability to suppress gene expression through various mechanisms once they are incorporated in the multi-protein RNA-Induced Silencing Complex (RISC) and interact with their target mRNA. This review introduces siRNAs and microRNAs in a historical perspective and focuses on the key molecules in RISC, structural properties and mechanisms underlying the process of small RNA regulated post-transcriptional suppression of gene expression. PMID:18692607

Phosphorylation regulates the Star-PAP-PIPKIα interaction and directs specificity toward mRNA targets

PubMed Central

Mohan, Nimmy; AP, Sudheesh; Francis, Nimmy; Anderson, Richard; Laishram, Rakesh S.

2015-01-01

Star-PAP is a nuclear non-canonical poly(A) polymerase (PAP) that shows specificity toward mRNA targets. Star-PAP activity is stimulated by lipid messenger phosphatidyl inositol 4,5 bisphoshate (PI4,5P2) and is regulated by the associated Type I phosphatidylinositol-4-phosphate 5-kinase that synthesizes PI4,5P2 as well as protein kinases. These associated kinases act as coactivators of Star-PAP that regulates its activity and specificity toward mRNAs, yet the mechanism of control of these interactions are not defined. We identified a phosphorylated residue (serine 6, S6) on Star-PAP in the zinc finger region, the domain required for PIPKIα interaction. We show that S6 is phosphorylated by CKIα within the nucleus which is required for Star-PAP nuclear retention and interaction with PIPKIα. Unlike the CKIα mediated phosphorylation at the catalytic domain, Star-PAP S6 phosphorylation is insensitive to oxidative stress suggesting a signal mediated regulation of CKIα activity. S6 phosphorylation together with coactivator PIPKIα controlled select subset of Star-PAP target messages by regulating Star-PAP-mRNA association. Our results establish a novel role for phosphorylation in determining Star-PAP target mRNA specificity and regulation of 3′-end processing. PMID:26138484

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

Legislative, educational, policy and other interventions targeting physicians' interaction with pharmaceutical companies: a systematic review.

PubMed

Alkhaled, Lina; Kahale, Lara; Nass, Hala; Brax, Hneine; Fadlallah, Racha; Badr, Kamal; Akl, Elie A

2014-07-01

Pharmaceutical company representatives likely influence the prescribing habits and professional behaviour of physicians. The objective of this study was to systematically review the effects of interventions targeting practising physicians' interactions with pharmaceutical companies. We included observational studies, non-randomised controlled trials (non-RCTs) and RCTs evaluating legislative, educational, policy or other interventions targeting the interactions between physicians and pharmaceutical companies. The search strategy included an electronic search of MEDLINE and EMBASE. Two reviewers performed duplicate and independent study selection, data abstraction and assessment of risk of bias. We assessed the risk of bias in each included study. We summarised the findings narratively because the nature of the data did not allow a meta-analysis to be conducted. We assessed the quality of evidence by outcome using the GRADE methodology. Of 11 189 identified citations, one RCT and three observational studies met the eligibility criteria. All four studies specifically targeted one type of interaction with pharmaceutical companies, that is, interactions with drug representatives. The RCT provided moderate quality evidence of no effect of a 'collaborative approach' between the pharmaceutical industry and a health authority. The three observational studies provided low quality evidence suggesting a positive effect of policies aiming to reduce interaction between physicians and pharmaceutical companies (by restricting free samples, promotional material, and meetings with pharmaceutical company representatives) on prescription behaviour. We identified too few studies to allow strong conclusions. Available evidence suggests a potential impact of policies aiming to reduce interaction between physicians and drug representatives on physicians' prescription behaviour. We found no evidence concerning interventions affecting other types of interaction with pharmaceutical

Assessment of personal airborne exposures and surface contamination from x-ray vaporization of beryllium targets at the National Ignition Facility.

PubMed

Paik, Samuel Y; Epperson, Patrick M; Kasper, Kenneth M

2017-06-01

This article presents air and surface sampling data collected over the first two years since beryllium was introduced as a target material at the National Ignition Facility. Over this time, 101 experiments with beryllium-containing targets were executed. The data provides an assessment of current conditions in the facility and a baseline for future impacts as new, reduced regulatory limits for beryllium are being proposed by both the Occupational Safety and Health Administration and Department of Energy. This study also investigates how beryllium deposits onto exposed surfaces as a result of x-ray vaporization and the effectiveness of simple decontamination measures in reducing the amount of removable beryllium from a surface. Based on 1,961 surface wipe samples collected from entrant components (equipment directly exposed to target debris) and their surrounding work areas during routine reconfiguration activities, only one result was above the beryllium release limit of 0.2 µg/100 cm 2 and 27 results were above the analytical reporting limit of 0.01 µg/100 cm 2 , for a beryllium detection rate of 1.4%. Surface wipe samples collected from the internal walls of the NIF target chamber, however, showed higher levels of beryllium, with beryllium detected on 73% and 87% of the samples during the first and second target chamber entries (performed annually), respectively, with 23% of the samples above the beryllium release limit during the second target chamber entry. The analysis of a target chamber wall panel exposed during the first 30 beryllium-containing experiments (cumulatively) indicated that 87% of the beryllium contamination remains fixed onto the surface after wet wiping the surface and 92% of the non-fixed contamination was removed by decontaminating the surface using a dry wipe followed by a wet wipe. Personal airborne exposures assessed during access to entrant components and during target chamber entry indicated that airborne beryllium was not present

Predicting drug-target interactions by dual-network integrated logistic matrix factorization

NASA Astrophysics Data System (ADS)

Hao, Ming; Bryant, Stephen H.; Wang, Yanli

2017-01-01

In this work, we propose a dual-network integrated logistic matrix factorization (DNILMF) algorithm to predict potential drug-target interactions (DTI). The prediction procedure consists of four steps: (1) inferring new drug/target profiles and constructing profile kernel matrix; (2) diffusing drug profile kernel matrix with drug structure kernel matrix; (3) diffusing target profile kernel matrix with target sequence kernel matrix; and (4) building DNILMF model and smoothing new drug/target predictions based on their neighbors. We compare our algorithm with the state-of-the-art method based on the benchmark dataset. Results indicate that the DNILMF algorithm outperforms the previously reported approaches in terms of AUPR (area under precision-recall curve) and AUC (area under curve of receiver operating characteristic) based on the 5 trials of 10-fold cross-validation. We conclude that the performance improvement depends on not only the proposed objective function, but also the used nonlinear diffusion technique which is important but under studied in the DTI prediction field. In addition, we also compile a new DTI dataset for increasing the diversity of currently available benchmark datasets. The top prediction results for the new dataset are confirmed by experimental studies or supported by other computational research.

A Global Survey and Interactive Map Suite of Deep Underground Facilities; Examples of Geotechnical and Engineering Capabilities, Achievements, Challenges: (Mines, Shafts, Tunnels, Boreholes, Sites and Underground Facilities for Nuclear Waste and Physics R&D)

NASA Astrophysics Data System (ADS)

Tynan, M. C.; Russell, G. P.; Perry, F.; Kelley, R.; Champenois, S. T.

2017-12-01

This global survey presents a synthesis of some notable geotechnical and engineering information reflected in four interactive layer maps for selected: 1) deep mines and shafts; 2) existing, considered or planned radioactive waste management deep underground studies, sites, or disposal facilities; 3) deep large diameter boreholes, and 4) physics underground laboratories and facilities from around the world. These data are intended to facilitate user access to basic information and references regarding deep underground "facilities", history, activities, and plans. In general, the interactive maps and database [http://gis.inl.gov/globalsites/] provide each facility's approximate site location, geology, and engineered features (e.g.: access, geometry, depth, diameter, year of operations, groundwater, lithology, host unit name and age, basin; operator, management organization, geographic data, nearby cultural features, other). Although the survey is not all encompassing, it is a comprehensive review of many of the significant existing and historical underground facilities discussed in the literature addressing radioactive waste management and deep mined geologic disposal safety systems. The global survey is intended to support and to inform: 1) interested parties and decision makers; 2) radioactive waste disposal and siting option evaluations, and 3) safety case development as a communication tool applicable to any mined geologic disposal facility as a demonstration of historical and current engineering and geotechnical capabilities available for use in deep underground facility siting, planning, construction, operations and monitoring.

In Silico Identification of Proteins Associated with Drug-induced Liver Injury Based on the Prediction of Drug-target Interactions.

PubMed

Ivanov, Sergey; Semin, Maxim; Lagunin, Alexey; Filimonov, Dmitry; Poroikov, Vladimir

2017-07-01

Drug-induced liver injury (DILI) is the leading cause of acute liver failure as well as one of the major reasons for drug withdrawal from clinical trials and the market. Elucidation of molecular interactions associated with DILI may help to detect potentially hazardous pharmacological agents at the early stages of drug development. The purpose of our study is to investigate which interactions with specific human protein targets may cause DILI. Prediction of interactions with 1534 human proteins was performed for the dataset with information about 699 drugs, which were divided into three categories of DILI: severe (178 drugs), moderate (310 drugs) and without DILI (211 drugs). Based on the comparison of drug-target interactions predicted for different drugs' categories and interpretation of those results using clustering, Gene Ontology, pathway and gene expression analysis, we identified 61 protein targets associated with DILI. Most of the revealed proteins were linked with hepatocytes' death caused by disruption of vital cellular processes, as well as the emergence of inflammation in the liver. It was found that interaction of a drug with the identified targets is the essential molecular mechanism of the severe DILI for the most of the considered pharmaceuticals. Thus, pharmaceutical agents interacting with many of the identified targets may be considered as candidates for filtering out at the early stages of drug research. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Interacting with target tracking algorithms in a gaze-enhanced motion video analysis system

NASA Astrophysics Data System (ADS)

Hild, Jutta; Krüger, Wolfgang; Heinze, Norbert; Peinsipp-Byma, Elisabeth; Beyerer, Jürgen

2016-05-01

Motion video analysis is a challenging task, particularly if real-time analysis is required. It is therefore an important issue how to provide suitable assistance for the human operator. Given that the use of customized video analysis systems is more and more established, one supporting measure is to provide system functions which perform subtasks of the analysis. Recent progress in the development of automated image exploitation algorithms allow, e.g., real-time moving target tracking. Another supporting measure is to provide a user interface which strives to reduce the perceptual, cognitive and motor load of the human operator for example by incorporating the operator's visual focus of attention. A gaze-enhanced user interface is able to help here. This work extends prior work on automated target recognition, segmentation, and tracking algorithms as well as about the benefits of a gaze-enhanced user interface for interaction with moving targets. We also propose a prototypical system design aiming to combine both the qualities of the human observer's perception and the automated algorithms in order to improve the overall performance of a real-time video analysis system. In this contribution, we address two novel issues analyzing gaze-based interaction with target tracking algorithms. The first issue extends the gaze-based triggering of a target tracking process, e.g., investigating how to best relaunch in the case of track loss. The second issue addresses the initialization of tracking algorithms without motion segmentation where the operator has to provide the system with the object's image region in order to start the tracking algorithm.

Target material dependence of positron generation from high intensity laser-matter interactions

DOE PAGES

Williams, G. J.; Barnak, D.; Fiksel, G.; ...

2016-12-06

Here, the effective scaling of positron-electron pair production by direct, ultraintense laser-matter interaction is investigated for a range of target materials and thicknesses. An axial magnetic field, acting as a focusing lens, was employed to measure positron signals for targets with atomic numbers as low as copper (Z – 29). The pair production yield was found to be consistent with the Bethe-Heitler mechanism, where the number of positrons emitted into a 1 steradian cone angle from the target rear was found to be proportional to Z 2. The unexpectedly low scaling results from Coulomb collisions that act to stop ormore » scatter positrons into high angles. Monte Carlo simulations support the experimental results, providing a comprehensive power-law scaling relationship for all elemental materials and densities.« less

DrugE-Rank: improving drug–target interaction prediction of new candidate drugs or targets by ensemble learning to rank

PubMed Central

Yuan, Qingjun; Gao, Junning; Wu, Dongliang; Zhang, Shihua; Mamitsuka, Hiroshi; Zhu, Shanfeng

2016-01-01

Motivation: Identifying drug–target interactions is an important task in drug discovery. To reduce heavy time and financial cost in experimental way, many computational approaches have been proposed. Although these approaches have used many different principles, their performance is far from satisfactory, especially in predicting drug–target interactions of new candidate drugs or targets. Methods: Approaches based on machine learning for this problem can be divided into two types: feature-based and similarity-based methods. Learning to rank is the most powerful technique in the feature-based methods. Similarity-based methods are well accepted, due to their idea of connecting the chemical and genomic spaces, represented by drug and target similarities, respectively. We propose a new method, DrugE-Rank, to improve the prediction performance by nicely combining the advantages of the two different types of methods. That is, DrugE-Rank uses LTR, for which multiple well-known similarity-based methods can be used as components of ensemble learning. Results: The performance of DrugE-Rank is thoroughly examined by three main experiments using data from DrugBank: (i) cross-validation on FDA (US Food and Drug Administration) approved drugs before March 2014; (ii) independent test on FDA approved drugs after March 2014; and (iii) independent test on FDA experimental drugs. Experimental results show that DrugE-Rank outperforms competing methods significantly, especially achieving more than 30% improvement in Area under Prediction Recall curve for FDA approved new drugs and FDA experimental drugs. Availability: http://datamining-iip.fudan.edu.cn/service/DrugE-Rank Contact: zhusf@fudan.edu.cn Supplementary information: Supplementary data are available at Bioinformatics online. PMID:27307615

DrugE-Rank: improving drug-target interaction prediction of new candidate drugs or targets by ensemble learning to rank.

PubMed

Yuan, Qingjun; Gao, Junning; Wu, Dongliang; Zhang, Shihua; Mamitsuka, Hiroshi; Zhu, Shanfeng

2016-06-15

Identifying drug-target interactions is an important task in drug discovery. To reduce heavy time and financial cost in experimental way, many computational approaches have been proposed. Although these approaches have used many different principles, their performance is far from satisfactory, especially in predicting drug-target interactions of new candidate drugs or targets. Approaches based on machine learning for this problem can be divided into two types: feature-based and similarity-based methods. Learning to rank is the most powerful technique in the feature-based methods. Similarity-based methods are well accepted, due to their idea of connecting the chemical and genomic spaces, represented by drug and target similarities, respectively. We propose a new method, DrugE-Rank, to improve the prediction performance by nicely combining the advantages of the two different types of methods. That is, DrugE-Rank uses LTR, for which multiple well-known similarity-based methods can be used as components of ensemble learning. The performance of DrugE-Rank is thoroughly examined by three main experiments using data from DrugBank: (i) cross-validation on FDA (US Food and Drug Administration) approved drugs before March 2014; (ii) independent test on FDA approved drugs after March 2014; and (iii) independent test on FDA experimental drugs. Experimental results show that DrugE-Rank outperforms competing methods significantly, especially achieving more than 30% improvement in Area under Prediction Recall curve for FDA approved new drugs and FDA experimental drugs. http://datamining-iip.fudan.edu.cn/service/DrugE-Rank zhusf@fudan.edu.cn Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press.

Recommendation Techniques for Drug-Target Interaction Prediction and Drug Repositioning.

PubMed

Alaimo, Salvatore; Giugno, Rosalba; Pulvirenti, Alfredo

2016-01-01

The usage of computational methods in drug discovery is a common practice. More recently, by exploiting the wealth of biological knowledge bases, a novel approach called drug repositioning has raised. Several computational methods are available, and these try to make a high-level integration of all the knowledge in order to discover unknown mechanisms. In this chapter, we review drug-target interaction prediction methods based on a recommendation system. We also give some extensions which go beyond the bipartite network case.

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.

Multidrug-resistant organisms in a community living facility: tracking patient interactions and time spent in common areas.

PubMed

Bowen, Mary Elizabeth; Craighead, Jeffrey D; Klanchar, S Angelina; Nieves-Garcia, Veronica

2012-09-01

Contact precautions in community living facilities (CLF) are used to reduce the transmission of multidrug-resistant organisms (MDRO). However, this policy does not address the contamination of shared spaces, devices (eg, wheelchairs), and interactions with other patients. Using a real-time surveillance system, this study examines the time MDRO-positive patients spend interacting with others in communal areas. The findings from this study may be used to tailor MDRO policies and practices to the specific needs of CLF. Published by Mosby, Inc.

Investigation on target normal sheath acceleration through measurements of ions energy distribution

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

Tudisco, S., E-mail: tudisco@lns.infn.it; Cirrone, G. A. P.; Mascali, D.

2016-02-15

An experimental campaign aiming at investigating the ion acceleration mechanisms through laser-matter interaction in femtosecond domain has been carried out at the Intense Laser Irradiation Laboratory facility with a laser intensity of up to 2 × 10{sup 19} W/cm{sup 2}. A Thomson parabola spectrometer was used to obtain the spectra of the ions of the different species accelerated. Here, we show the energy spectra of light-ions and we discuss their dependence on structural characteristics of the target and the role of surface and target bulk in the acceleration process.

Phosphorylation regulates the Star-PAP-PIPKIα interaction and directs specificity toward mRNA targets.

PubMed

Mohan, Nimmy; Sudheesh, A P; Francis, Nimmy; Anderson, Richard; Laishram, Rakesh S

2015-08-18

Star-PAP is a nuclear non-canonical poly(A) polymerase (PAP) that shows specificity toward mRNA targets. Star-PAP activity is stimulated by lipid messenger phosphatidyl inositol 4,5 bisphoshate (PI4,5P2) and is regulated by the associated Type I phosphatidylinositol-4-phosphate 5-kinase that synthesizes PI4,5P2 as well as protein kinases. These associated kinases act as coactivators of Star-PAP that regulates its activity and specificity toward mRNAs, yet the mechanism of control of these interactions are not defined. We identified a phosphorylated residue (serine 6, S6) on Star-PAP in the zinc finger region, the domain required for PIPKIα interaction. We show that S6 is phosphorylated by CKIα within the nucleus which is required for Star-PAP nuclear retention and interaction with PIPKIα. Unlike the CKIα mediated phosphorylation at the catalytic domain, Star-PAP S6 phosphorylation is insensitive to oxidative stress suggesting a signal mediated regulation of CKIα activity. S6 phosphorylation together with coactivator PIPKIα controlled select subset of Star-PAP target messages by regulating Star-PAP-mRNA association. Our results establish a novel role for phosphorylation in determining Star-PAP target mRNA specificity and regulation of 3'-end processing. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

Effect of target composition on proton acceleration in ultraintense laser-thin foil interaction

NASA Astrophysics Data System (ADS)

Liu, Qingcao; Liu, Meng; Yu, Tongpu; Ding, Pengji; Liu, Zuoye; Sun, Shaohua; Liu, Xiaoliang; Lu, Xing; Guo, Zeqin; Hu, Bitao

2012-09-01

The interactions of ultraintense circularly polarized laser pulses with a mixed solid target and a double-layer target are studied by two-dimensional particle-in-cell simulations. Different carbon and proton compositions in the targets are used in the simulations. It is shown that the proton acceleration mechanisms in both targets are very sensitive to the ion density ratios between protons and carbon ions. For a mixed solid target, a relatively low proton density gives rise to monoenergetic peaks in the proton energy spectrum while a high proton density leads to a large cut-off energy and wide energy spread. With the increase of the ratio, the so-called directed-Coulomb-explosion becomes dominated over the radiation pressure. Surprisingly, for a double-layer target with a front proton layer and an ultrathin rear carbon layer, a highly monoenergetic proton beam with a peak energy of 1.7 GeV/u, an energy spread of ˜4%, and a divergency angle of 2° can be obtained, which might have diverse applications in medical therepy and proton imaging in future.

Mechanism of MicroRNA-Target Interaction: Molecular Dynamics Simulations and Thermodynamics Analysis

PubMed Central

Wang, Yonghua; Li, Yan; Ma, Zhi; Yang, Wei; Ai, Chunzhi

2010-01-01

MicroRNAs (miRNAs) are endogenously produced ∼21-nt riboregulators that associate with Argonaute (Ago) proteins to direct mRNA cleavage or repress the translation of complementary RNAs. Capturing the molecular mechanisms of miRNA interacting with its target will not only reinforce the understanding of underlying RNA interference but also fuel the design of more effective small-interfering RNA strands. To address this, in the present work the RNA-bound (Ago-miRNA, Ago-miRNA-target) and RNA-free Ago forms were analyzed by performing both molecular dynamics simulations and thermodynamic analysis. Based on the principal component analysis results of the simulation trajectories as well as the correlation analysis in fluctuations of residues, we discover that: 1) three important (PAZ, Mid and PIWI) domains exist in Argonaute which define the global dynamics of the protein; 2) the interdomain correlated movements are so crucial for the interaction of Ago-RNAs that they not only facilitate the relaxation of the interactions between residues surrounding the RNA binding channel but also induce certain conformational changes; and 3) it is just these conformational changes that expand the cavity of the active site and open putative pathways for both the substrate uptake and product release. In addition, by thermodynamic analysis we also discover that for both the guide RNA 5′-end recognition and the facilitated site-specific cleavage of the target, the presence of two metal ions (of Mg2+) plays a predominant role, and this conclusion is consistent with the observed enzyme catalytic cleavage activity in the ternary complex (Ago-miRNA-mRNA). Our results find that it is the set of arginine amino acids concentrated in the nucleotide-binding channel in Ago, instead of the conventionally-deemed seed base-paring, that makes greater contributions in stabilizing the binding of the nucleic acids to Ago. PMID:20686687

Hydrodynamic interactions for complex-shaped nanocarriers in targeted drug delivery

NASA Astrophysics Data System (ADS)

Wang, Yaohong; Eckmann, David; Radhakrishnan, Ravi; Ayyaswamy, Portonovo

2014-11-01

Nanocarrier motion in a blood vessel involves hydrodynamic and Brownian interactions, which collectively dictate the efficacy in targeted drug delivery. The shape of nanocarriers plays a crucial role in drug delivery. In order to quantify the flow and association properties of elliptical nanoparticles, we have developed an arbitrary Lagrangian-Eulerian framework with capabilities to simulate the hydrodynamic motion of nanoparticles of arbitrary shapes. We introduce the quaternions for rotational motion, and two collision models, namely, (a) an impulse-based model for wall-particle collision, and (b) the short-range repulsive Gay-Berne potential for particle-particle collision. We also study the red blood cell and nanocarrier (such as ellipsoid) interactions. We compare our results with those obtained for a hard sphere model for both RBCs and nanocarriers. Supported by NIH through grant U01-EB016027.

Extracting sets of chemical substructures and protein domains governing drug-target interactions.

PubMed

Yamanishi, Yoshihiro; Pauwels, Edouard; Saigo, Hiroto; Stoven, Véronique

2011-05-23

The identification of rules governing molecular recognition between drug chemical substructures and protein functional sites is a challenging issue at many stages of the drug development process. In this paper we develop a novel method to extract sets of drug chemical substructures and protein domains that govern drug-target interactions on a genome-wide scale. This is made possible using sparse canonical correspondence analysis (SCCA) for analyzing drug substructure profiles and protein domain profiles simultaneously. The method does not depend on the availability of protein 3D structures. From a data set of known drug-target interactions including enzymes, ion channels, G protein-coupled receptors, and nuclear receptors, we extract a set of chemical substructures shared by drugs able to bind to a set of protein domains. These two sets of extracted chemical substructures and protein domains form components that can be further exploited in a drug discovery process. This approach successfully clusters protein domains that may be evolutionary unrelated but that bind a common set of chemical substructures. As shown in several examples, it can also be very helpful for predicting new protein-ligand interactions and addressing the problem of ligand specificity. The proposed method constitutes a contribution to the recent field of chemogenomics that aims to connect the chemical space with the biological space.

Genome scale enzyme–metabolite and drug–target interaction predictions using the signature molecular descriptor

DOE PAGES

Faulon, Jean-Loup; Misra, Milind; Martin, Shawn; ...

2007-11-23

Motivation: Identifying protein enzymatic or pharmacological activities are important areas of research in biology and chemistry. Biological and chemical databases are increasingly being populated with linkages between protein sequences and chemical structures. Additionally, there is now sufficient information to apply machine-learning techniques to predict interactions between chemicals and proteins at a genome scale. Current machine-learning techniques use as input either protein sequences and structures or chemical information. We propose here a method to infer protein–chemical interactions using heterogeneous input consisting of both protein sequence and chemical information. Results: Our method relies on expressing proteins and chemicals with a common cheminformaticsmore » representation. We demonstrate our approach by predicting whether proteins can catalyze reactions not present in training sets. We also predict whether a given drug can bind a target, in the absence of prior binding information for that drug and target. Lastly, such predictions cannot be made with current machine-learning techniques requiring binding information for individual reactions or individual targets.« less

Moderator Demonstration Facility Design and Optimization

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

McClanahan, Tucker C.; Gallmeier, Franz X.; Iverson, Erik B.

2017-02-01

The Spallation Neutron Source (SNS) facility at Oak Ridge National Laboratory (ORNL) is implementing a Moderator Demonstration Facility (MDF) to demonstrate the performance characteristics of advanced moderators central to the Second Target Station (STS) for SNS. The MDF will use the "spare" front-end installation within the SNS accelerator support complex – an ion source, radio-frequency quadrupole (RFQ) accelerator, and medium-energy beam transport (MEBT) chopper - to provide a 2.5 MeV proton beam of peak current 50 mA and maximum pulse length of less than 10 s at a repetition rate of no more than 60 Hz to a suitable neutron-producingmore » target to demonstrate those aspects of moderator performance necessary to meet the goals of the STS design e ort. The accelerator beam parameters are not open to variation beyond that described above - they are fixed by the nature of the spare front-end installation (the Integrated Test Stand Facility; ITSF). Accordingly, there are some neutronic challenges in developing prototypic moderator illumination from a very non-prototypic primary neutron source; the spallation source we are attempting to mimic has an extended neutron source volume approximately 40 cm long (in the direction of the proton beam), approximately 10 cm wide (horizontally transverse to the proton beam) and approximately 5 cm high (vertically transverse to the proton beam), and an isotropic evaporation energy spectrum with mean energy above 1 MeV. In contrast, the primary neutron source available from the 7Li(p,n) reaction (the most prolific at 2.5 MeV proton energy by more than an order of magnitude) is strongly anisotropic, with an energy spectrum that is both strongly dependent on emission angle and kinematically limited to less than 700 keV, and the interaction zone between the incident protons and any target material (neutron-producing or not) is intrinsically limited to a few tens of microns. The MDF will be unique and innovative amongst the world�

Observation of anisotropic interactions between metastable atoms and target molecules by two-dimensional collisional ionization electron spectroscopy

NASA Astrophysics Data System (ADS)

Kishimoto, Naoki; Ohno, Koichi

Excited metastable atoms colliding with target molecules can sensitively probe outer properties of molecules by chemi-ionization (Penning ionization) from molecular orbitals in the outer region, since metastable atoms cannot penetrate into the repulsive interaction wall around the molecules. By means of two-dimensional measurements using kinetic energy analysis of electrons combined with a velocity-resolved metastable beam, one can obtain information on the anisotropic interaction between the colliding particles without any control of orientation or alignment of target molecules. We have developed a classical trajectory method to calculate the collision energy dependence of partial ionization cross-sections (CEDPICS) on the anisotropic interaction potential energy surface, which has enabled us to study stereodynamics between metastable atoms and target molecules as well as the spatial distribution of molecular orbitals and electron ejection functions which have a relation with entrance and exit channels of the reaction. Based on the individual CEDPICS, the electronic structure of molecules can also be elucidated.

Synaptic activity induces input-specific rearrangements in a targeted synaptic protein interaction network.

PubMed

Lautz, Jonathan D; Brown, Emily A; VanSchoiack, Alison A Williams; Smith, Stephen E P

2018-05-27

Cells utilize dynamic, network level rearrangements in highly interconnected protein interaction networks to transmit and integrate information from distinct signaling inputs. Despite the importance of protein interaction network dynamics, the organizational logic underlying information flow through these networks is not well understood. Previously, we developed the quantitative multiplex co-immunoprecipitation platform, which allows for the simultaneous and quantitative measurement of the amount of co-association between large numbers of proteins in shared complexes. Here, we adapt quantitative multiplex co-immunoprecipitation to define the activity dependent dynamics of an 18-member protein interaction network in order to better understand the underlying principles governing glutamatergic signal transduction. We first establish that immunoprecipitation detected by flow cytometry can detect activity dependent changes in two known protein-protein interactions (Homer1-mGluR5 and PSD-95-SynGAP). We next demonstrate that neuronal stimulation elicits a coordinated change in our targeted protein interaction network, characterized by the initial dissociation of Homer1 and SynGAP-containing complexes followed by increased associations among glutamate receptors and PSD-95. Finally, we show that stimulation of distinct glutamate receptor types results in different modular sets of protein interaction network rearrangements, and that cells activate both modules in order to integrate complex inputs. This analysis demonstrates that cells respond to distinct types of glutamatergic input by modulating different combinations of protein co-associations among a targeted network of proteins. Our data support a model of synaptic plasticity in which synaptic stimulation elicits dissociation of preexisting multiprotein complexes, opening binding slots in scaffold proteins and allowing for the recruitment of additional glutamatergic receptors. This article is protected by copyright. All

Strategic targeting of essential host-pathogen interactions in chlamydial disease.

PubMed

Coombes, B K; Johnson, D L; Mahony, J B

2002-09-01

The chlamydiae are obligate intracellular gram-negative bacteria that are exquisitely adapted for exploitation of their hosts and contribute to a wide range of acute and chronic human diseases. Acute infections treated with non-cidal antibiotics can lead to the development of persistent, non-replicating bacteria with the corollary that these persistent (yet viable) chlamydiae can resist eradication by further antimicrobial treatment and cause chronic disease. These findings highlight an urgent need for therapeutics that are effective against persistent infections and call for creative approaches to identify potential drug targets. The C. pneumoniae and C. trachomatis genome projects have greatly expanded our knowledge of chlamydial pathogenesis and have provided an enormous potential for the identification and characterization of unknown genes and potential virulence factors in these bacteria. As intracellular pathogens, chlamydiae rely on host cells for all aspects of their survival, from the initial attachment with host cell membranes, to cellular invasion, acquisition of host cell metabolites and intracellular replication. As such, the molecules participating in interactions with the host could be attractive targets for therapeutic intervention. This review describes recent advances in chlamydial genomics, proteomics and cell biology that have cast light on host-pathogen relations that are essential for chlamydial survival. Using this knowledge, we discuss how strategically interfering with essential interactions between chlamydiae and the host cell could be exploited to develop an innovative, and potentially more relevant arsenal of therapeutic compounds.

The interaction of facility design with management goals.

PubMed

Lindeman, W E

1991-01-01

While medical groups have different goals based on their mission, size and market, they all seek to propagate and maintain a financially sound enterprise. Author William Lindeman, AIA, writes that a primary factor in achieving this goal is excellent facility design. While facility design is no guarantee for success, exceptionally poor design can make success all but impossible.

Synthesis of mouse centromere-targeted polyamides and physico-chemical studies of their interaction with the target double-stranded DNA.

PubMed

Nozeret, Karine; Bonan, Marc; Yarmoluk, Serguiy M; Novopashina, Darya S; Boutorine, Alexandre S

2015-09-01

Synthetic minor groove-binding pyrrole-imidazole polyamides labeled by fluorophores are promising candidates for fluorescence imaging of double-stranded DNA in isolated chromosomes or fixed and living cells. We synthesized nine hairpin and two head-to-head tandem polyamides targeting repeated sequences from mouse major satellites. Their interaction with synthetic target dsDNA has been studied by physico-chemical methods in vitro before and after coupling to various fluorophores. Great variability in affinities and fluorescence properties reveals a conclusion that these properties do not only rely on recognition rules, but also on other known and unknown structural factors. Individual testing of each probe is needed before cellular applications. Copyright © 2015 Elsevier Ltd. All rights reserved.

Interactive Parallel Data Analysis within Data-Centric Cluster Facilities using the IPython Notebook

NASA Astrophysics Data System (ADS)

Pascoe, S.; Lansdowne, J.; Iwi, A.; Stephens, A.; Kershaw, P.

2012-12-01

The data deluge is making traditional analysis workflows for many researchers obsolete. Support for parallelism within popular tools such as matlab, IDL and NCO is not well developed and rarely used. However parallelism is necessary for processing modern data volumes on a timescale conducive to curiosity-driven analysis. Furthermore, for peta-scale datasets such as the CMIP5 archive, it is no longer practical to bring an entire dataset to a researcher's workstation for analysis, or even to their institutional cluster. Therefore, there is an increasing need to develop new analysis platforms which both enable processing at the point of data storage and which provides parallelism. Such an environment should, where possible, maintain the convenience and familiarity of our current analysis environments to encourage curiosity-driven research. We describe how we are combining the interactive python shell (IPython) with our JASMIN data-cluster infrastructure. IPython has been specifically designed to bridge the gap between the HPC-style parallel workflows and the opportunistic curiosity-driven analysis usually carried out using domain specific languages and scriptable tools. IPython offers a web-based interactive environment, the IPython notebook, and a cluster engine for parallelism all underpinned by the well-respected Python/Scipy scientific programming stack. JASMIN is designed to support the data analysis requirements of the UK and European climate and earth system modeling community. JASMIN, with its sister facility CEMS focusing the earth observation community, has 4.5 PB of fast parallel disk storage alongside over 370 computing cores provide local computation. Through the IPython interface to JASMIN, users can make efficient use of JASMIN's multi-core virtual machines to perform interactive analysis on all cores simultaneously or can configure IPython clusters across multiple VMs. Larger-scale clusters can be provisioned through JASMIN's batch scheduling system

Toward Small-Molecule Inhibition of Protein-Protein Interactions: General Aspects and Recent Progress in Targeting Costimulatory and Coinhibitory (Immune Checkpoint) Interactions.

PubMed

Bojadzic, Damir; Buchwald, Peter

2018-05-30

Protein-protein interactions (PPIs) that are part of the costimulatory and coinhibitory (immune checkpoint) signaling are critical for adequate T cell response and are important therapeutic targets for immunomodulation. Biologics targeting them have already achieved considerable clinical success in the treatment of autoimmune diseases or transplant recipients (e.g., abatacept, belatacept, and belimumab) as well as cancer (e.g., ipilimumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab). In view of such progress, there have been only relatively limited efforts toward developing small-molecule PPI inhibitors (SMPPIIs) targeting these cosignaling interactions, possibly because they, as all other PPIs, are difficult to target by small molecules and were not considered druggable. Nevertheless, substantial progress has been achieved during the last decade. SMPPIIs proving the feasibility of such approaches have been identified through various strategies for a number of cosignaling interactions including CD40-CD40L, OX40-OX40L, BAFFR-BAFF, CD80-CD28, and PD-1-PD-L1s. Here, after an overview of the general aspects and challenges of SMPPII-focused drug discovery, we review them briefly together with relevant structural, immune-signaling, physicochemical, and medicinal chemistry aspects. While so far only a few of these SMPPIIs have shown activity in animal models (DRI-C21045 for CD40-D40L, KR33426 for BAFFR-BAFF) or reached clinical development (RhuDex for CD80-CD28, CA-170 for PD-1-PD-L1), there is proof-of-principle evidence for the feasibility of such approaches in immunomodulation. They can result in products that are easier to develop/manufacture and are less likely to be immunogenic or encounter postmarket safety events than corresponding biologics, and, contrary to them, can even become orally bioavailable. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Application of an atomic oxygen beam facility to the investigation of shuttle glow chemistry

NASA Technical Reports Server (NTRS)

Arnold, G. S.; Peplinski, D. R.

1985-01-01

A facility for the investigation of the interactions of energetic atomic oxygen with solids is described. The facility is comprised of a four chambered, differentially pumped molecular beam apparatus which can be equipped with one of a variety of sources of atomic oxygen. The primary source is a dc arc heated supersonic nozzle source which produces a flux of atomic oxygen in excess of 10 to the 15th power sq cm/sec at the target, at a velocity of 3.5 km/sec. Results of applications of this facility to the study of the reactions of atomic oxygen with carbon and polyimide films are briefly reviewed and compared to data obtained on various flights of the space shuttle. A brief discussion of possible application of this facility to investigation of chemical reactions which might contribute to atmosphere induced vehicle glow is presented.

Allelic Interactions among Pto-MIR475b and Its Four Target Genes Potentially Affect Growth and Wood Properties in Populus

PubMed Central

Xiao, Liang; Quan, Mingyang; Du, Qingzhang; Chen, Jinhui; Xie, Jianbo; Zhang, Deqiang

2017-01-01

MicroRNAs (miRNAs) play crucial roles in plant growth and development, but few studies have illuminated the allelic interactions among miRNAs and their targets in perennial plants. Here, we combined analysis of expression patterns and single-nucleotide polymorphism (SNP)-based association studies to explore the interactions between Pto-MIR475b and its four target genes (Pto-PPR1, Pto-PPR2, Pto-PPR3, and Pto-PPR4) in 435 unrelated individuals of Populus tomentosa. Expression patterns showed a significant negative correlation (r = -0.447 to -0.411, P < 0.01) between Pto-MIR475b and its four targets in eight tissues of P. tomentosa, suggesting that Pto-miR475b may negatively regulate the four targets. Single SNP-based association studies identified 93 significant associations (P < 0.01, Q < 0.1) representing associations of 80 unique SNPs in Pto-MIR475b and its four targets with nine traits, revealing their potential roles in tree growth and wood formation. Moreover, one common SNP in the precursor region significantly altered the secondary structure of the pre-Pto-miR475b and changed the expression level of Pto-MIR475b. Analysis of epistatic interactions identified 115 significant SNP–SNP associations (P < 0.01) representing 45 unique SNPs from Pto-MIR475b and its four targets for 10 traits, revealing that genetic interactions between Pto-MIR475b and its targets influence quantitative traits of perennial plants. Our study provided a feasible strategy to study population genetics in forest trees and enhanced our understanding of miRNAs by dissecting the allelic interactions between this miRNA and its targets in P. tomentosa. PMID:28680433

Assessment of personal airborne exposures and surface contamination from x-ray vaporization of beryllium targets at the National Ignition Facility

DOE PAGES

Paik, Samuel Y.; Epperson, Patrick M.; Kasper, Kenneth M.

2017-02-28

Here, this article presents air and surface sampling data collected over the first two years since beryllium was introduced as a target material at the National Ignition Facility. Over this time, 101 experiments with beryllium-containing targets were executed. The data provides an assessment of current conditions in the facility and a baseline for future impacts as new, reduced regulatory limits for beryllium are being proposed by both the Occupational Safety and Health Administration and Department of Energy. This study also investigates how beryllium deposits onto exposed surfaces as a result of x-ray vaporization and the effectiveness of simple decontamination measuresmore » in reducing the amount of removable beryllium from a surface. Based on 1,961 surface wipe samples collected from entrant components (equipment directly exposed to target debris) and their surrounding work areas during routine reconfiguration activities, only one result was above the beryllium release limit of 0.2 µg/100 cm 2 and 27 results were above the analytical reporting limit of 0.01 µg/100 cm 2, for a beryllium detection rate of 1.4%. Surface wipe samples collected from the internal walls of the NIF target chamber, however, showed higher levels of beryllium, with beryllium detected on 73% and 87% of the samples during the first and second target chamber entries (performed annually), respectively, with 23% of the samples above the beryllium release limit during the second target chamber entry. The analysis of a target chamber wall panel exposed during the first 30 beryllium-containing experiments (cumulatively) indicated that 87% of the beryllium contamination remains fixed onto the surface after wet wiping the surface and 92% of the non-fixed contamination was removed by decontaminating the surface using a dry wipe followed by a wet wipe. Personal airborne exposures assessed during access to entrant components and during target chamber entry indicated that airborne beryllium was

RFDT: A Rotation Forest-based Predictor for Predicting Drug-Target Interactions Using Drug Structure and Protein Sequence Information.

PubMed

Wang, Lei; You, Zhu-Hong; Chen, Xing; Yan, Xin; Liu, Gang; Zhang, Wei

2018-01-01

Identification of interaction between drugs and target proteins plays an important role in discovering new drug candidates. However, through the experimental method to identify the drug-target interactions remain to be extremely time-consuming, expensive and challenging even nowadays. Therefore, it is urgent to develop new computational methods to predict potential drugtarget interactions (DTI). In this article, a novel computational model is developed for predicting potential drug-target interactions under the theory that each drug-target interaction pair can be represented by the structural properties from drugs and evolutionary information derived from proteins. Specifically, the protein sequences are encoded as Position-Specific Scoring Matrix (PSSM) descriptor which contains information of biological evolutionary and the drug molecules are encoded as fingerprint feature vector which represents the existence of certain functional groups or fragments. Four benchmark datasets involving enzymes, ion channels, GPCRs and nuclear receptors, are independently used for establishing predictive models with Rotation Forest (RF) model. The proposed method achieved the prediction accuracy of 91.3%, 89.1%, 84.1% and 71.1% for four datasets respectively. In order to make our method more persuasive, we compared our classifier with the state-of-theart Support Vector Machine (SVM) classifier. We also compared the proposed method with other excellent methods. Experimental results demonstrate that the proposed method is effective in the prediction of DTI, and can provide assistance for new drug research and development. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Design of the LBNF Beamline Target Station

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

Tariq, S.; Ammigan, K.; Anderson, K.

2016-10-01

The Long Baseline Neutrino Facility (LBNF) project will build a beamline located at Fermilab to create and aim an intense neutrino beam of appropriate energy range toward the DUNE detectors at the SURF facility in Lead, South Dakota. Neutrino production starts in the Target Station, which consists of a solid target, magnetic focusing horns, and the associated sub-systems and shielding infrastructure. Protons hit the target producing mesons which are then focused by the horns into a helium-filled decay pipe where they decay into muons and neutrinos. The target and horns are encased in actively cooled steel and concrete shielding inmore » a chamber called the target chase. The reference design chase is filled with air, but nitrogen and helium are being evaluated as alternatives. A replaceable beam window separates the decay pipe from the target chase. The facility is designed for initial operation at 1.2 MW, with the ability to upgrade to 2.4 MW, and is taking advantage of the experience gained by operating Fermilab’s NuMI facility. We discuss here the design status, associated challenges, and ongoing R&D and physics-driven component optimization of the Target Station.« less

Ultra-intense laser interaction with specially-designed targets as a source of energetic protons

NASA Astrophysics Data System (ADS)

Psikal, J.; Matys, M.

2017-05-01

In this contribution, we discuss the optimization of laser driven proton acceleration efficiency by nanostructured targets, interpret the experimental results showing the manipulation of proton beam profiles by nanosctructured rear surface of the targets and investigate the acceleration of protons from hydrogen solid ribbon by PW-class lasers, with the help of multidimensional particle-in-cell simulations. Microstructured hollow targets are proposed to enhance the absorption of the laser pulse energy while keeping the target thickness to minimum, which is both favorable for enhanced efficiency of the acceleration of protons. Thin targets with grating structures of various configurations on their rear sides stretch the proton beams in the perpendicular direction to the grating orientation due to transverse electric fields generated inside the target grooves and can reduce the proton beam divergence in the parallel direction to the grating due to a lower density of the stretched beam compared with flat foils. Finally, it is shown that when multiPW laser pulse interacts with hydrogen solid ribbon, hole boring radiation pressure acceleration (RPA) dominates over the target normal sheath acceleration (TNSA).

Specificity in the interaction of natural products with their target proteins--a biochemical and structural insight.

PubMed

Venkatraman, Prasanna

2010-06-01

Natural products are an abundant source of anti cancer agents. They act as cytotoxic drugs, and inhibitors of apoptosis, transcription, cell proliferation and angiogenesis. While pathways targeted by natural products have been well studied, there is paucity of information about the in vivo molecular target/s of these compounds. This review summarizes some of the natural compounds for which the molecular targets, mechanism of action and structural basis of specificity have been well documented. These examples illustrate that 'off target' binding can be explained on the basis of diversity inherent to biomolecular interactions. There is enough evidence to suggest that natural compounds are potent and versatile warheads that can be optimized for a multi targeted therapeutic intervention in cancer.

Targeting protein-protein interactions in hematologic malignancies: still a challenge or a great opportunity for future therapies?

PubMed Central

Cierpicki, Tomasz; Grembecka, Jolanta

2015-01-01

Summary Over the past several years, there has been an increasing research effort focused on inhibition of protein-protein interactions (PPIs) to develop novel therapeutic approaches for cancer, including hematologic malignancies. These efforts have led to development of small molecule inhibitors of PPIs, some of which already advanced to the stage of clinical trials while others are at different stages of pre-clinical optimization, emphasizing PPIs as an emerging and attractive class of drug targets. Here, we review several examples of recently developed inhibitors of protein-protein interactions highly relevant to hematologic cancers. We address the existing skepticism about feasibility of targeting PPIs and emphasize potential therapeutic benefit from blocking PPIs in hematologic malignancies. We then use these examples to discuss the approaches for successful identification of PPI inhibitors and provide analysis of the protein-protein interfaces, with the goal to address ‘druggability’ of new PPIs relevant to hematology. We discuss lessons learned to improve the success of targeting new protein-protein interactions and evaluate prospects and limits of the research in this field. We conclude that not all PPIs are equally tractable for blocking by small molecules, and detailed analysis of PPI interfaces is critical for selection of those with the highest chance of success. Together, our analysis uncovers patterns that should help to advance drug discovery in hematologic malignancies by successful targeting of new protein-protein interactions. PMID:25510283

Intercellular communications-redox interactions in radiation toxicity; potential targets for radiation mitigation.

PubMed

Farhood, Bagher; Goradel, Nasser Hashemi; Mortezaee, Keywan; Khanlarkhani, Neda; Salehi, Ensieh; Nashtaei, Maryam Shabani; Shabeeb, Dheyauldeen; Musa, Ahmed Eleojo; Fallah, Hengameh; Najafi, Masoud

2018-06-17

Nowadays, using ionizing radiation (IR) is necessary for clinical, agricultural, nuclear energy or industrial applications. Accidental exposure to IR after a radiation terror or disaster poses a threat to human. In contrast to the old dogma of radiation toxicity, several experiments during the last two recent decades have revealed that intercellular signaling and communications play a key role in this procedure. Elevated level of cytokines and other intercellular signals increase oxidative damage and inflammatory responses via reduction/oxidation interactions (redox system). Intercellular signals induce production of free radicals and inflammatory mediators by some intermediate enzymes such as cyclooxygenase-2 (COX-2), nitric oxide synthase (NOS), NADPH oxidase, and also via triggering mitochondrial ROS. Furthermore, these signals facilitate cell to cell contact and increasing cell toxicity via cohort effect. Nitric oxide is a free radical with ability to act as an intercellular signal that induce DNA damage and changes in some signaling pathways in irradiated as well as non-irradiated adjacent cells. Targeting of these mediators by some anti-inflammatory agents or via antioxidants such as mitochondrial ROS scavengers opens a window to mitigate radiation toxicity after an accidental exposure. Experiments which have been done so far suggests that some cytokines such as IL-1β, TNF-α, TGF-β, IL-4 and IL-13 are some interesting targets that depend on irradiated organs and may help mitigate radiation toxicity. Moreover, animal experiments in recent years indicated that targeting of toll like receptors (TLRs) may be more useful for radioprotection and mitigation. In this review, we aimed to describe the role of intercellular interactions in oxidative injury, inflammation, cell death and killing effects of IR. Moreover, we described evidence on potential mitigation of radiation injury via targeting of these mediators.

The radioactive beam facility ALTO

NASA Astrophysics Data System (ADS)

Essabaa, Saïd; Barré-Boscher, Nicole; Cheikh Mhamed, Maher; Cottereau, Evelyne; Franchoo, Serge; Ibrahim, Fadi; Lau, Christophe; Roussière, Brigitte; Saïd, Abdelhakim; Tusseau-Nenez, Sandrine; Verney, David

2013-12-01

The Transnational Access facility ALTO (TNA07-ENSAR/FP7) has been commissioned and received from the French safety authorities, the operation license. It is allowed to run at nominal intensity to produce 1011 fissions/s in a thick uranium carbide target by photo-fission using a 10 μA, 50 MeV electron beam. In addition the recent success in operating the selective laser ion source broadens the physics program with neutron-rich nuclear beams possible at this facility installed at IPN Orsay. The facility also aims at being a test bench for the SPIRAL2 project. In that framework an ambitious R&D program on the target ion source system is being developed.

Excluded Facility Financial Status and Options for Payment System Modification

PubMed Central

Schneider, John E.; Cromwell, Jerry; McGuire, Thomas P.

1993-01-01

Psychiatric, rehabilitation, long-term care, and children's facilities have remained under the reimbursement system established under the Tax Equity and Fiscal Responsibility Act (TEFRA) of 1982 (Public Law 97-248). The number of TEFRA facilities and discharges has been increasing while their average profit rates have been steadily declining. Modifying TEFRA would require either rebasing the target amount or adjusting cost sharing for facilities exceeding their cost target. Based on our simulations of alternative payment systems, we recommend rebasing facilities' target amounts using a 50/50 blend of own costs and national average costs. Cost sharing above the target amount could be increased to include more government sharing of losses. PMID:10135345

A systems biology perspective on plant-microbe interactions: biochemical and structural targets of pathogen effectors.

PubMed

Pritchard, Leighton; Birch, Paul

2011-04-01

Plants have biochemical defences against stresses from predators, parasites and pathogens. In this review we discuss the interaction of plant defences with microbial pathogens such as bacteria, fungi and oomycetes, and viruses. We examine principles of complex dynamic networks that allow identification of network components that are differentially and predictably sensitive to perturbation, thus making them likely effector targets. We relate these principles to recent developments in our understanding of known effector targets in plant-pathogen systems, and propose a systems-level framework for the interpretation and modelling of host-microbe interactions mediated by effectors. We describe this framework briefly, and conclude by discussing useful experimental approaches for populating this framework. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Targeted proteomics coming of age - SRM, PRM and DIA performance evaluated from a core facility perspective.

PubMed

Kockmann, Tobias; Trachsel, Christian; Panse, Christian; Wahlander, Asa; Selevsek, Nathalie; Grossmann, Jonas; Wolski, Witold E; Schlapbach, Ralph

2016-08-01

Quantitative mass spectrometry is a rapidly evolving methodology applied in a large number of omics-type research projects. During the past years, new designs of mass spectrometers have been developed and launched as commercial systems while in parallel new data acquisition schemes and data analysis paradigms have been introduced. Core facilities provide access to such technologies, but also actively support the researchers in finding and applying the best-suited analytical approach. In order to implement a solid fundament for this decision making process, core facilities need to constantly compare and benchmark the various approaches. In this article we compare the quantitative accuracy and precision of current state of the art targeted proteomics approaches single reaction monitoring (SRM), parallel reaction monitoring (PRM) and data independent acquisition (DIA) across multiple liquid chromatography mass spectrometry (LC-MS) platforms, using a readily available commercial standard sample. All workflows are able to reproducibly generate accurate quantitative data. However, SRM and PRM workflows show higher accuracy and precision compared to DIA approaches, especially when analyzing low concentrated analytes. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Interactions of dendrimers with biological drug targets: reality or mystery - a gap in drug delivery and development research.

PubMed

Ahmed, Shaimaa; Vepuri, Suresh B; Kalhapure, Rahul S; Govender, Thirumala

2016-07-21

Dendrimers have emerged as novel and efficient materials that can be used as therapeutic agents/drugs or as drug delivery carriers to enhance therapeutic outcomes. Molecular dendrimer interactions are central to their applications and realising their potential. The molecular interactions of dendrimers with drugs or other materials in drug delivery systems or drug conjugates have been extensively reported in the literature. However, despite the growing application of dendrimers as biologically active materials, research focusing on the mechanistic analysis of dendrimer interactions with therapeutic biological targets is currently lacking in the literature. This comprehensive review on dendrimers over the last 15 years therefore attempts to identify the reasons behind the apparent lack of dendrimer-receptor research and proposes approaches to address this issue. The structure, hierarchy and applications of dendrimers are briefly highlighted, followed by a review of their various applications, specifically as biologically active materials, with a focus on their interactions at the target site. It concludes with a technical guide to assist researchers on how to employ various molecular modelling and computational approaches for research on dendrimer interactions with biological targets at a molecular level. This review highlights the impact of a mechanistic analysis of dendrimer interactions on a molecular level, serves to guide and optimise their discovery as medicinal agents, and hopes to stimulate multidisciplinary research between scientific, experimental and molecular modelling research teams.

Interacting Multiple Model (IMM) Fifth-Degree Spherical Simplex-Radial Cubature Kalman Filter for Maneuvering Target Tracking

PubMed Central

Liu, Hua; Wu, Wen

2017-01-01

For improving the tracking accuracy and model switching speed of maneuvering target tracking in nonlinear systems, a new algorithm named the interacting multiple model fifth-degree spherical simplex-radial cubature Kalman filter (IMM5thSSRCKF) is proposed in this paper. The new algorithm is a combination of the interacting multiple model (IMM) filter and the fifth-degree spherical simplex-radial cubature Kalman filter (5thSSRCKF). The proposed algorithm makes use of Markov process to describe the switching probability among the models, and uses 5thSSRCKF to deal with the state estimation of each model. The 5thSSRCKF is an improved filter algorithm, which utilizes the fifth-degree spherical simplex-radial rule to improve the filtering accuracy. Finally, the tracking performance of the IMM5thSSRCKF is evaluated by simulation in a typical maneuvering target tracking scenario. Simulation results show that the proposed algorithm has better tracking performance and quicker model switching speed when disposing maneuver models compared with the interacting multiple model unscented Kalman filter (IMMUKF), the interacting multiple model cubature Kalman filter (IMMCKF) and the interacting multiple model fifth-degree cubature Kalman filter (IMM5thCKF). PMID:28608843

Interacting Multiple Model (IMM) Fifth-Degree Spherical Simplex-Radial Cubature Kalman Filter for Maneuvering Target Tracking.

PubMed

Liu, Hua; Wu, Wen

2017-06-13

For improving the tracking accuracy and model switching speed of maneuvering target tracking in nonlinear systems, a new algorithm named the interacting multiple model fifth-degree spherical simplex-radial cubature Kalman filter (IMM5thSSRCKF) is proposed in this paper. The new algorithm is a combination of the interacting multiple model (IMM) filter and the fifth-degree spherical simplex-radial cubature Kalman filter (5thSSRCKF). The proposed algorithm makes use of Markov process to describe the switching probability among the models, and uses 5thSSRCKF to deal with the state estimation of each model. The 5thSSRCKF is an improved filter algorithm, which utilizes the fifth-degree spherical simplex-radial rule to improve the filtering accuracy. Finally, the tracking performance of the IMM5thSSRCKF is evaluated by simulation in a typical maneuvering target tracking scenario. Simulation results show that the proposed algorithm has better tracking performance and quicker model switching speed when disposing maneuver models compared with the interacting multiple model unscented Kalman filter (IMMUKF), the interacting multiple model cubature Kalman filter (IMMCKF) and the interacting multiple model fifth-degree cubature Kalman filter (IMM5thCKF).

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.

First experimental evidence of hydrodynamic tunneling of ultra–relativistic protons in extended solid copper target at the CERN HiRadMat facility

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

Schmidt, R.; Grenier, D.; Wollmann, D.

2014-08-15

A novel experiment has been performed at the CERN HiRadMat test facility to study the impact of the 440 GeV proton beam generated by the Super Proton Synchrotron on extended solid copper cylindrical targets. Substantial hydrodynamic tunneling of the protons in the target material has been observed that leads to significant lengthening of the projectile range, which confirms our previous theoretical predictions [N. A. Tahir et al., Phys. Rev. Spec. Top.-Accel. Beams 15, 051003 (2012)]. Simulation results show very good agreement with the experimental measurements. These results have very important implications on the machine protection design for powerful machines like themore » Large Hadron Collider (LHC), the future High Luminosity LHC, and the proposed huge 80 km circumference Future Circular Collider, which is currently being discussed at CERN. Another very interesting outcome of this work is that one may also study the field of High Energy Density Physics at this test facility.« less

First experimental evidence of hydrodynamic tunneling of ultra-relativistic protons in extended solid copper target at the CERN HiRadMat facility

NASA Astrophysics Data System (ADS)

Schmidt, R.; Blanco Sancho, J.; Burkart, F.; Grenier, D.; Wollmann, D.; Tahir, N. A.; Shutov, A.; Piriz, A. R.

2014-08-01

A novel experiment has been performed at the CERN HiRadMat test facility to study the impact of the 440 GeV proton beam generated by the Super Proton Synchrotron on extended solid copper cylindrical targets. Substantial hydrodynamic tunneling of the protons in the target material has been observed that leads to significant lengthening of the projectile range, which confirms our previous theoretical predictions [N. A. Tahir et al., Phys. Rev. Spec. Top.-Accel. Beams 15, 051003 (2012)]. Simulation results show very good agreement with the experimental measurements. These results have very important implications on the machine protection design for powerful machines like the Large Hadron Collider (LHC), the future High Luminosity LHC, and the proposed huge 80 km circumference Future Circular Collider, which is currently being discussed at CERN. Another very interesting outcome of this work is that one may also study the field of High Energy Density Physics at this test facility.

Above scaling short-pulse ion acceleration from flat foil and ``Pizza-top Cone'' targets at the Trident laser facility

NASA Astrophysics Data System (ADS)

Flippo, Kirk; Hegelich, B. Manuel; Cort Gautier, D.; Johnson, J. Randy; Kline, John L.; Shimada, Tsutomu; Fernández, Juan C.; Gaillard, Sandrine; Rassuchine, Jennifer; Le Galloudec, Nathalie; Cowan, Thomas E.; Malekos, Steve; Korgan, Grant

2006-10-01

Ion-driven Fast Ignition (IFI) has certain advantages over electron-driven FI due to a possible large reduction in the amount of energy required. Recent experiments at the Los Alamos National Laboratory's Trident facility have yielded ion energies and efficiencies many times in excess of recent published scaling laws, leading to even more potential advantages of IFI. Proton energies in excess of 35 MeV have been observed from targets produced by the University of Nevada, Reno - dubbed ``Pizza-top Cone'' targets - at intensities of only 1x10^19 W/cm^2 with 20 joules in 600 fs. Energies in excess of 24 MeV were observed from simple flat foil targets as well. The observed energies, above any published scaling laws, are attributed to target production, preparation, and shot to shot monitoring of many laser parameters, especially the laser ASE prepulse level and laser pulse duration. The laser parameters are monitored in real-time to keep the laser in optimal condition throughout the run providing high quality, reproducible shots.

Impact of fluid-structure interaction on direct tumor-targeting in a representative hepatic artery system.

PubMed

Childress, Emily M; Kleinstreuer, Clement

2014-03-01

Direct targeting of solid tumors with chemotherapeutic drugs and/or radioactive microspheres can be a treatment option which minimizes side-effects and reduces cost. Briefly, computational analysis generates particle release maps (PRMs) which visually link upstream particle injection regions in the main artery with associated exit branches, some connected to tumors. The overall goal is to compute patient-specific PRMs realistically, accurately, and cost-effectively, which determines the suitable radial placement of a micro-catheter for optimal particle injection. Focusing in this paper on new steps towards realism and accuracy, the impact of fluid-structure interaction on direct drug-targeting is evaluated, using a representative hepatic artery system with liver tumor as a test bed. Specifically, the effect of arterial wall motion was demonstrated by modeling a two-way fluid-structure interaction analysis with Lagrangian particle tracking in the bifurcating arterial system. Clearly, rapid computational evaluation of optimal catheter location for tumor-targeting in a clinical application is very important. Hence, rigid-wall cases were also compared to the flexible scenario to establish whether PRMs generated when based on simplifying assumptions could provide adequate guidance towards ideal catheter placement. It was found that the best rigid (i.e., time-averaged) geometry is the physiological one that occurs during the diastolic targeting interval.

Interaction of Herbal Compounds with Biological Targets: A Case Study with Berberine

PubMed Central

Chen, Xiao-Wu; Di, Yuan Ming; Zhang, Jian; Zhou, Zhi-Wei; Li, Chun Guang; Zhou, Shu-Feng

2012-01-01

Berberine is one of the main alkaloids found in the Chinese herb Huang lian (Rhizoma Coptidis), which has been reported to have multiple pharmacological activities. This study aimed to analyze the molecular targets of berberine based on literature data followed by a pathway analysis using the PANTHER program. PANTHER analysis of berberine targets showed that the most classes of molecular functions include receptor binding, kinase activity, protein binding, transcription activity, DNA binding, and kinase regulator activity. Based on the biological process classification of in vitro berberine targets, those targets related to signal transduction, intracellular signalling cascade, cell surface receptor-linked signal transduction, cell motion, cell cycle control, immunity system process, and protein metabolic process are most frequently involved. In addition, berberine was found to interact with a mixture of biological pathways, such as Alzheimer's disease-presenilin and -secretase pathways, angiogenesis, apoptosis signalling pathway, FAS signalling pathway, Hungtington disease, inflammation mediated by chemokine and cytokine signalling pathways, interleukin signalling pathway, and p53 pathways. We also explored the possible mechanism of action for the anti-diabetic effect of berberine. Further studies are warranted to elucidate the mechanisms of action of berberine using systems biology approach. PMID:23213296

Prediction of Drug-Target Interactions and Drug Repositioning via Network-Based Inference

PubMed Central

Jiang, Jing; Lu, Weiqiang; Li, Weihua; Liu, Guixia; Zhou, Weixing; Huang, Jin; Tang, Yun

2012-01-01

Drug-target interaction (DTI) is the basis of drug discovery and design. It is time consuming and costly to determine DTI experimentally. Hence, it is necessary to develop computational methods for the prediction of potential DTI. Based on complex network theory, three supervised inference methods were developed here to predict DTI and used for drug repositioning, namely drug-based similarity inference (DBSI), target-based similarity inference (TBSI) and network-based inference (NBI). Among them, NBI performed best on four benchmark data sets. Then a drug-target network was created with NBI based on 12,483 FDA-approved and experimental drug-target binary links, and some new DTIs were further predicted. In vitro assays confirmed that five old drugs, namely montelukast, diclofenac, simvastatin, ketoconazole, and itraconazole, showed polypharmacological features on estrogen receptors or dipeptidyl peptidase-IV with half maximal inhibitory or effective concentration ranged from 0.2 to 10 µM. Moreover, simvastatin and ketoconazole showed potent antiproliferative activities on human MDA-MB-231 breast cancer cell line in MTT assays. The results indicated that these methods could be powerful tools in prediction of DTIs and drug repositioning. PMID:22589709

Activation loop targeting strategy for design of receptor-interacting protein kinase 2 (RIPK2) inhibitors.

PubMed

Suebsuwong, Chalada; Pinkas, Daniel M; Ray, Soumya S; Bufton, Joshua C; Dai, Bing; Bullock, Alex N; Degterev, Alexei; Cuny, Gregory D

2018-02-15

Development of selective kinase inhibitors remains a challenge due to considerable amino acid sequence similarity among family members particularly in the ATP binding site. Targeting the activation loop might offer improved inhibitor selectivity since this region of kinases is less conserved. However, the strategy presents difficulties due to activation loop flexibility. Herein, we report the design of receptor-interacting protein kinase 2 (RIPK2) inhibitors based on pan-kinase inhibitor regorafenib that aim to engage basic activation loop residues Lys169 or Arg171. We report development of CSR35 that displayed >10-fold selective inhibition of RIPK2 versus VEGFR2, the target of regorafenib. A co-crystal structure of CSR35 with RIPK2 revealed a resolved activation loop with an ionic interaction between the carboxylic acid installed in the inhibitor and the side-chain of Lys169. Our data provides principle feasibility of developing activation loop targeting type II inhibitors as a complementary strategy for achieving improved selectivity. Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Evaluation of seismic spatial interaction effects through an impact testing program

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

Thomas, B.D.; Driesen, G.E.

The consequences of non-seismically qualified objects falling and striking essential, seismically qualified objects is an analytically difficult problem to assess. Analytical solutions to impact problems are conservative and only available for simple situations. In a nuclear facility, the numerous ``sources`` and ``targets`` requiring evaluation often have complex geometric configurations, which makes calculations and computer modeling difficult. Few industry or regulatory rules are available for this specialized assessment. A drop test program was recently conducted to ``calibrate`` the judgment of seismic qualification engineers who perform interaction evaluations and to further develop seismic interaction criteria. Impact tests on varying combinations of sourcesmore » and targets were performed by dropping the sources from various heights onto targets that were connected to instruments. This paper summarizes the scope, test configurations, and some results of the drop test program. Force and acceleration time history data and general observations are presented on the ruggedness of various targets when subjected to impacts from different types of sources.« less

Evaluation of seismic spatial interaction effects through an impact testing program

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

Thomas, B.D.; Driesen, G.E.

The consequences of non-seismically qualified objects falling and striking essential, seismically qualified objects is an analytically difficult problem to assess. Analytical solutions to impact problems are conservative and only available for simple situations. In a nuclear facility, the numerous sources'' and targets'' requiring evaluation often have complex geometric configurations, which makes calculations and computer modeling difficult. Few industry or regulatory rules are available for this specialized assessment. A drop test program was recently conducted to calibrate'' the judgment of seismic qualification engineers who perform interaction evaluations and to further develop seismic interaction criteria. Impact tests on varying combinations of sourcesmore » and targets were performed by dropping the sources from various heights onto targets that were connected to instruments. This paper summarizes the scope, test configurations, and some results of the drop test program. Force and acceleration time history data and general observations are presented on the ruggedness of various targets when subjected to impacts from different types of sources.« less

Setup of a Biomedical Facility to Study Physiologically Relevant Flow-Structure Interactions

NASA Astrophysics Data System (ADS)

Mehdi, Faraz; Sheng, Jian

2013-11-01

The design and implementation of a closed loop biomedical facility to study arterial flows is presented. The facility has a test section of 25 inches, and is capable of generating both steady and pulsatile flows via a centrifugal and a dual piston pump respectively. The Reynolds and Womersley numbers occurring in major blood vessels can be matched. The working fluid is a solution of NaI that allows refractive index matching with both rigid glass and compliant polymer models to facilitate tomographic PIV and holographic PIV. The combination of these two techniques allows us to study both large scale flow features as well as flows very close to the wall. The polymer models can be made with different modulus of elasticity and can be pre-stressed using a 5-axis stage. Radially asymmetric patches can also be pre-fabricated and incorporated in the tube during the manufacturing process to simulate plaque formation in arteries. These tubes are doped with tracer particles allowing for the measurement of wall deformation. Preliminary flow data over rigid and compliant walls is presented. One of the aims of this study is to characterize the changes in flow as the compliancy of blood vessels change due to age or disease, and explore the fluid interactions with an evolving surface boundary.

National Biomedical Tracer Facility: Project definition study

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

Heaton, R.; Peterson, E.; Smith, P.

The Los Alamos National Laboratory is an ideal institution and New Mexico is an ideal location for siting the National Biomedical Tracer Facility (NBTF). The essence of the Los Alamos proposal is the development of two complementary irradiation facilities that combined with our existing radiochemical processing hot cell facilities and waste handling and disposal facilities provide a low cost alternative to other proposals that seek to satisfy the objectives of the NBTF. We propose the construction of a 30 MeV cyclotron facility at the site of the radiochemical facilities, and the construction of a 100 MeV target station at LAMPFmore » to satisfy the requirements and objectives of the NBTF. We do not require any modifications to our existing radiochemical processing hot cell facilities or our waste treatment and disposal facilities to accomplish the objectives of the NBTF. The total capital cost for the facility defined by the project definition study is $15.2 M. This cost estimate includes $9.9 M for the cyclotron and associated facility, $2.0 M for the 100 MeV target station at LAMPF, and $3.3 M for design.« less

An Improved Interacting Multiple Model Filtering Algorithm Based on the Cubature Kalman Filter for Maneuvering Target Tracking.

PubMed

Zhu, Wei; Wang, Wei; Yuan, Gannan

2016-06-01

In order to improve the tracking accuracy, model estimation accuracy and quick response of multiple model maneuvering target tracking, the interacting multiple models five degree cubature Kalman filter (IMM5CKF) is proposed in this paper. In the proposed algorithm, the interacting multiple models (IMM) algorithm processes all the models through a Markov Chain to simultaneously enhance the model tracking accuracy of target tracking. Then a five degree cubature Kalman filter (5CKF) evaluates the surface integral by a higher but deterministic odd ordered spherical cubature rule to improve the tracking accuracy and the model switch sensitivity of the IMM algorithm. Finally, the simulation results demonstrate that the proposed algorithm exhibits quick and smooth switching when disposing different maneuver models, and it also performs better than the interacting multiple models cubature Kalman filter (IMMCKF), interacting multiple models unscented Kalman filter (IMMUKF), 5CKF and the optimal mode transition matrix IMM (OMTM-IMM).

Interaction of prime and target in the subliminal affective priming effect.

PubMed

Haneda, Kaoruko; Nomura, Michio; Iidaka, Tetsuya; Ohira, Hideki

2003-04-01

It has been found that an emotional stimulus such as a facial expression presented subliminally can affect subsequent information processing and behavior, usually by shifting evaluation of a subsequent stimulus to a valence congruent with the previous stimulus. This phenomenon is called subliminal affective priming. The present study was conducted to replicate and expand previous findings by investigating interaction of primes and targets in the affective priming effect. Two conditions were used. Prime (subliminal presentation 35 msec.) of an angry face of a woman and a No Prime control condition. Just after presentation of the prime, an ambiguous angry face or an emotionally neutral face was presented above the threshold of awareness (500 msec.). 12 female undergraduate women judged categories of facial expressions (Anger, Neutral, or Happiness) for the target faces. Analysis indicated that the Anger primes significantly facilitated judgment of anger for the ambiguous angry faces; however, the priming effect of the Anger primes was not observed for neutral faces. Consequently, the present finding suggested that a subliminal affective priming effect should be more prominent when affective valence of primes and targets is congruent.

An Innovative Approach for Decreasing Fall Trauma Admissions from Geriatric Living Facilities: Preliminary Investigation.

PubMed

Evans, Tracy; Gross, Brian; Rittenhouse, Katelyn; Harnish, Carissa; Vellucci, Ashley; Bupp, Katherine; Horst, Michael; Miller, Jo Ann; Baier, Ron; Chandler, Roxanne; Rogers, Frederick B

2015-12-01

Geriatric living facilities have been associated with a high rate of falls. We sought to develop an innovative intervention approach targeting geriatric living facilities that would reduce geriatric fall admissions to our Level II trauma center. In 2011, a Trauma Prevention Taskforce visited 5 of 28 local geriatric living facilities to present a fall prevention protocol composed of three sections: fall education, risk factor identification, and fall prevention strategies. To determine the impact of the intervention, the trauma registry was queried for all geriatric fall admissions attributed to patients living at local geriatric living facilities. The fall admission rate (total fall admissions/total beds) of the pre-intervention period (2010-2011) was compared with that of the postintervention period (2012-2013) at the 5 intervention and 23 control facilities. A P value < 0.05 was considered statistically significant. From 2010 to 2013, there were 487 fall admissions attributed to local geriatric living facilities (intervention: 179 fall admissions; control: 308 fall admissions). The unadjusted fall rate decreased at intervention facilities from 8.9 fall admissions/bed pre-intervention to 8.1 fall admissions/bed postintervention, whereas fall admission rates increased at control sites from 5.9 to 7.7 fall admissions/bed during the same period [control/intervention odds ratio (OR), 95% confidence interval (CI) = 1.32, 1.05-1.67; period OR, 95%CI = 1.55, 1.18-2.04, P = 0.002; interaction of control/intervention group and period OR 95% CI = 0.68, 0.46-1.00, P = 0.047]. An aggressive intervention program targeting high-risk geriatric living facilities resulted in a statistically significant decrease in geriatric fall admissions to our Level II trauma center.

A Small-molecule Inhibitor, 5′-O-Tritylthymidine, targets FAK and Mdm-2 Interaction, and Blocks Breast and Colon Tumorigenesis in vivo

PubMed Central

Golubovskaya, Vita; Palma, Nadia L.; Zheng, Min; Ho, Baotran; Magis, Andrew; Ostrov, David; Cance, William G.

2013-01-01

Focal Adhesion Kinase (FAK) is overexpressed in many types of tumors and plays an important role in survival. We developed a novel approach, targeting FAK-protein interactions by computer modeling and screening of NCI small molecule drug database. In this report we targeted FAK and Mdm-2 protein interaction to decrease tumor growth. By macromolecular modeling we found a model of FAK and Mdm-2 interaction and performed screening of >200,000 small molecule compounds from NCI database with drug-like characteristics, targeting the FAK-Mdm-2 interaction. We identified 5′-O-Tritylthymidine, called M13 compound that significantly decreased viability in different cancer cells. M13 was docked into the pocket of FAK and Mdm-2 interaction and was directly bound to the FAK-N terminal domain by ForteBio Octet assay. In addition, M13 compound affected FAK and Mdm-2 levels and decreased complex of FAK and Mdm-2 proteins in breast and colon cancer cells. M13 re-activated p53 activity inhibited by FAK with Mdm-2 promoter. M13 decreased viability, clonogenicity, increased detachment and apoptosis in a dose-dependent manner in BT474 breast and in HCT116 colon cancer cells in vitro. M13 decreased FAK, activated p53 and caspase-8 in both cell lines. In addition, M13 decreased breast and colon tumor growth in vivo. M13 activated p53 and decreased FAK in tumor samples consistent with decreased tumor growth. The data demonstrate a novel approach for targeting FAK and Mdm-2 protein interaction, provide a model of FAK and Mdm-2 interaction, identify M13 compound targeting this interaction and decreasing tumor growth that is critical for future targeted therapeutics. PMID:22292771

Protein-protein interaction networks identify targets which rescue the MPP+ cellular model of Parkinson’s disease

NASA Astrophysics Data System (ADS)

Keane, Harriet; Ryan, Brent J.; Jackson, Brendan; Whitmore, Alan; Wade-Martins, Richard

2015-11-01

Neurodegenerative diseases are complex multifactorial disorders characterised by the interplay of many dysregulated physiological processes. As an exemplar, Parkinson’s disease (PD) involves multiple perturbed cellular functions, including mitochondrial dysfunction and autophagic dysregulation in preferentially-sensitive dopamine neurons, a selective pathophysiology recapitulated in vitro using the neurotoxin MPP+. Here we explore a network science approach for the selection of therapeutic protein targets in the cellular MPP+ model. We hypothesised that analysis of protein-protein interaction networks modelling MPP+ toxicity could identify proteins critical for mediating MPP+ toxicity. Analysis of protein-protein interaction networks constructed to model the interplay of mitochondrial dysfunction and autophagic dysregulation (key aspects of MPP+ toxicity) enabled us to identify four proteins predicted to be key for MPP+ toxicity (P62, GABARAP, GBRL1 and GBRL2). Combined, but not individual, knockdown of these proteins increased cellular susceptibility to MPP+ toxicity. Conversely, combined, but not individual, over-expression of the network targets provided rescue of MPP+ toxicity associated with the formation of autophagosome-like structures. We also found that modulation of two distinct proteins in the protein-protein interaction network was necessary and sufficient to mitigate neurotoxicity. Together, these findings validate our network science approach to multi-target identification in complex neurological diseases.

Electromagnetic pulse (EMP) radiation by laser interaction with a solid H2 ribbon

NASA Astrophysics Data System (ADS)

De Marco, M.; Krása, J.; Cikhardt, J.; Velyhan, A.; Pfeifer, M.; Dudžák, R.; Dostál, J.; Krouský, E.; Limpouch, J.; Pisarczyk, T.; Kalinowska, Z.; Chodukowski, T.; Ullschmied, J.; Giuffrida, L.; Chatain, D.; Perin, J.-P.; Margarone, D.

2017-08-01

The electromagnetic pulses (EMPs) generated during the interaction of a focused 1.315-μm sub-nanosecond laser pulse with a solid hydrogen ribbon were measured. The strength and temporal characteristics of EMPs were found to be dependent on the target density. If a low density target is ionized during the interaction with the laser, and the plasma does not physically touch the target holder, the EMP is weaker in strength and shorter in time duration. It is shown that during the H2 target experiment, the EMP does not strongly affect the response of fast electronic devices. The measurements of the EMP were carried out by Rohde&Schwarz B-Probes, particularly sensitive in the frequency range from 30 MHz and 1 GHz. Numerical simulations of resonant frequencies of the target chamber used in the experiment at the Prague Asterix Laser System kJ-class laser facility elucidate the peaked structure of EMP frequency spectra in the GHz domain.

Cartilage-targeting drug delivery: can electrostatic interactions help?

PubMed

Bajpayee, Ambika G; Grodzinsky, Alan J

2017-03-01

Current intra-articular drug delivery methods do not guarantee sufficient drug penetration into cartilage tissue to reach cell and matrix targets at the concentrations necessary to elicit the desired biological response. Here, we provide our perspective on the utilization of charge-charge (electrostatic) interactions to enhance drug penetration and transport into cartilage, and to enable sustained binding of drugs within the tissue's highly negatively charged extracellular matrix. By coupling drugs to positively charged nanocarriers that have optimal size and charge, cartilage can be converted from a drug barrier into a drug reservoir for sustained intra-tissue delivery. Alternatively, a wide variety of drugs themselves can be made cartilage-penetrating by functionalizing them with specialized positively charged protein domains. Finally, we emphasize that appropriate animal models, with cartilage thickness similar to that of humans, must be used for the study of drug transport and retention in cartilage.

Discovery: an interactive resource for the rational selection and comparison of putative drug target proteins in malaria

PubMed Central

Joubert, Fourie; Harrison, Claudia M; Koegelenberg, Riaan J; Odendaal, Christiaan J; de Beer, Tjaart AP

2009-01-01

Background Up to half a billion human clinical cases of malaria are reported each year, resulting in about 2.7 million deaths, most of which occur in sub-Saharan Africa. Due to the over-and misuse of anti-malarials, widespread resistance to all the known drugs is increasing at an alarming rate. Rational methods to select new drug target proteins and lead compounds are urgently needed. The Discovery system provides data mining functionality on extensive annotations of five malaria species together with the human and mosquito hosts, enabling the selection of new targets based on multiple protein and ligand properties. Methods A web-based system was developed where researchers are able to mine information on malaria proteins and predicted ligands, as well as perform comparisons to the human and mosquito host characteristics. Protein features used include: domains, motifs, EC numbers, GO terms, orthologs, protein-protein interactions, protein-ligand interactions and host-pathogen interactions among others. Searching by chemical structure is also available. Results An in silico system for the selection of putative drug targets and lead compounds is presented, together with an example study on the bifunctional DHFR-TS from Plasmodium falciparum. Conclusion The Discovery system allows for the identification of putative drug targets and lead compounds in Plasmodium species based on the filtering of protein and chemical properties. PMID:19642978

The enemy within: Targeting host-parasite interaction for antileishmanial drug discovery.

PubMed

Lamotte, Suzanne; Späth, Gerald F; Rachidi, Najma; Prina, Eric

2017-06-01

The state of antileishmanial chemotherapy is strongly compromised by the emergence of drug-resistant Leishmania. The evolution of drug-resistant phenotypes has been linked to the parasites' intrinsic genome instability, with frequent gene and chromosome amplifications causing fitness gains that are directly selected by environmental factors, including the presence of antileishmanial drugs. Thus, even though the unique eukaryotic biology of Leishmania and its dependence on parasite-specific virulence factors provide valid opportunities for chemotherapeutical intervention, all strategies that target the parasite in a direct fashion are likely prone to select for resistance. Here, we review the current state of antileishmanial chemotherapy and discuss the limitations of ongoing drug discovery efforts. We finally propose new strategies that target Leishmania viability indirectly via mechanisms of host-parasite interaction, including parasite-released ectokinases and host epigenetic regulation, which modulate host cell signaling and transcriptional regulation, respectively, to establish permissive conditions for intracellular Leishmania survival.

Splitter target for controlling magnetic reconnection in relativistic laser plasma interactions

NASA Astrophysics Data System (ADS)

Gu, Y. J.; Bulanov, S. S.; Korn, G.; Bulanov, S. V.

2018-04-01

The utilization of a conical target irradiated by a high power laser is proposed to study fast magnetic reconnection in relativistic plasma interactions. Such target, placed in front of the near critical density gas jet, splits the laser pulse, forming two parallel laser pulses in the 2D case and a donut shaped pulse in the 3D case. The magnetic annihilation and reconnection occur in the density downramp region of the subsequent gas jet. The magnetic field energy is converted into the particle kinetic energy. As a result, a backward accelerated electron beam is obtained as a signature of reconnection. The above mechanisms are demonstrated using particle-in-cell simulations in both 2D and 3D cases. Facilitating the synchronization of two laser beams, the proposed approach can be used in designing the corresponding experiments on studying fundamental problems of relativistic plasma physics.

Simulation study of 3-5 keV x-ray conversion efficiency from Ar K-shell vs. Ag L-shell targets on the National Ignition Facility laser

NASA Astrophysics Data System (ADS)

Kemp, G. E.; Colvin, J. D.; Fournier, K. B.; May, M. J.; Barrios, M. A.; Patel, M. V.; Scott, H. A.; Marinak, M. M.

2015-05-01

Tailored, high-flux, multi-keV x-ray sources are desirable for studying x-ray interactions with matter for various civilian, space and military applications. For this study, we focus on designing an efficient laser-driven non-local thermodynamic equilibrium 3-5 keV x-ray source from photon-energy-matched Ar K-shell and Ag L-shell targets at sub-critical densities (˜nc/10) to ensure supersonic, volumetric laser heating with minimal losses to kinetic energy, thermal x rays and laser-plasma instabilities. Using Hydra, a multi-dimensional, arbitrary Lagrangian-Eulerian, radiation-hydrodynamics code, we performed a parameter study by varying initial target density and laser parameters for each material using conditions readily achievable on the National Ignition Facility (NIF) laser. We employ a model, benchmarked against Kr data collected on the NIF, that uses flux-limited Lee-More thermal conductivity and multi-group implicit Monte-Carlo photonics with non-local thermodynamic equilibrium, detailed super-configuration accounting opacities from Cretin, an atomic-kinetics code. While the highest power laser configurations produced the largest x-ray yields, we report that the peak simulated laser to 3-5 keV x-ray conversion efficiencies of 17.7% and 36.4% for Ar and Ag, respectively, occurred at lower powers between ˜100-150 TW. For identical initial target densities and laser illumination, the Ag L-shell is observed to have ≳10× higher emissivity per ion per deposited laser energy than the Ar K-shell. Although such low-density Ag targets have not yet been demonstrated, simulations of targets fabricated using atomic layer deposition of Ag on silica aerogels (˜20% by atomic fraction) suggest similar performance to atomically pure metal foams and that either fabrication technique may be worth pursuing for an efficient 3-5 keV x-ray source on NIF.

Estimation of marginal costs at existing waste treatment facilities.

PubMed

Martinez-Sanchez, Veronica; Hulgaard, Tore; Hindsgaul, Claus; Riber, Christian; Kamuk, Bettina; Astrup, Thomas F

2016-04-01

This investigation aims at providing an improved basis for assessing economic consequences of alternative Solid Waste Management (SWM) strategies for existing waste facilities. A bottom-up methodology was developed to determine marginal costs in existing facilities due to changes in the SWM system, based on the determination of average costs in such waste facilities as function of key facility and waste compositional parameters. The applicability of the method was demonstrated through a case study including two existing Waste-to-Energy (WtE) facilities, one with co-generation of heat and power (CHP) and another with only power generation (Power), affected by diversion strategies of five waste fractions (fibres, plastic, metals, organics and glass), named "target fractions". The study assumed three possible responses to waste diversion in the WtE facilities: (i) biomass was added to maintain a constant thermal load, (ii) Refused-Derived-Fuel (RDF) was included to maintain a constant thermal load, or (iii) no reaction occurred resulting in a reduced waste throughput without full utilization of the facility capacity. Results demonstrated that marginal costs of diversion from WtE were up to eleven times larger than average costs and dependent on the response in the WtE plant. Marginal cost of diversion were between 39 and 287 € Mg(-1) target fraction when biomass was added in a CHP (from 34 to 303 € Mg(-1) target fraction in the only Power case), between -2 and 300 € Mg(-1) target fraction when RDF was added in a CHP (from -2 to 294 € Mg(-1) target fraction in the only Power case) and between 40 and 303 € Mg(-1) target fraction when no reaction happened in a CHP (from 35 to 296 € Mg(-1) target fraction in the only Power case). Although average costs at WtE facilities were highly influenced by energy selling prices, marginal costs were not (provided a response was initiated at the WtE to keep constant the utilized thermal capacity). Failing to systematically

Radiation effects on active camera electronics in the target chamber at the National Ignition Facility

NASA Astrophysics Data System (ADS)

Dayton, M.; Datte, P.; Carpenter, A.; Eckart, M.; Manuel, A.; Khater, H.; Hargrove, D.; Bell, P.

2017-08-01

The National Ignition Facility's (NIF) harsh radiation environment can cause electronics to malfunction during high-yield DT shots. Until now there has been little experience fielding electronic-based cameras in the target chamber under these conditions; hence, the performance of electronic components in NIF's radiation environment was unknown. It is possible to purchase radiation tolerant devices, however, they are usually qualified for radiation environments different to NIF, such as space flight or nuclear reactors. This paper presents the results from a series of online experiments that used two different prototype camera systems built from non-radiation hardened components and one commercially available camera that permanently failed at relatively low total integrated dose. The custom design built in Livermore endured a 5 × 1015 neutron shot without upset, while the other custom design upset at 2 × 1014 neutrons. These results agreed with offline testing done with a flash x-ray source and a 14 MeV neutron source, which suggested a methodology for developing and qualifying electronic systems for NIF. Further work will likely lead to the use of embedded electronic systems in the target chamber during high-yield shots.

Target identification in Fusobacterium nucleatum by subtractive genomics approach and enrichment analysis of host-pathogen protein-protein interactions.

PubMed

Kumar, Amit; Thotakura, Pragna Lakshmi; Tiwary, Basant Kumar; Krishna, Ramadas

2016-05-12

Fusobacterium nucleatum, a well studied bacterium in periodontal diseases, appendicitis, gingivitis, osteomyelitis and pregnancy complications has recently gained attention due to its association with colorectal cancer (CRC) progression. Treatment with berberine was shown to reverse F. nucleatum-induced CRC progression in mice by balancing the growth of opportunistic pathogens in tumor microenvironment. Intestinal microbiota imbalance and the infections caused by F. nucleatum might be regulated by therapeutic intervention. Hence, we aimed to predict drug target proteins in F. nucleatum, through subtractive genomics approach and host-pathogen protein-protein interactions (HP-PPIs). We also carried out enrichment analysis of host interacting partners to hypothesize the possible mechanisms involved in CRC progression due to F. nucleatum. In subtractive genomics approach, the essential, virulence and resistance related proteins were retrieved from RefSeq proteome of F. nucleatum by searching against Database of Essential Genes (DEG), Virulence Factor Database (VFDB) and Antibiotic Resistance Gene-ANNOTation (ARG-ANNOT) tool respectively. A subsequent hierarchical screening to identify non-human homologous, metabolic pathway-independent/pathway-specific and druggable proteins resulted in eight pathway-independent and 27 pathway-specific druggable targets. Co-aggregation of F. nucleatum with host induces proinflammatory gene expression thereby potentiates tumorigenesis. Hence, proteins from IBDsite, a database for inflammatory bowel disease (IBD) research and those involved in colorectal adenocarcinoma as interpreted from The Cancer Genome Atlas (TCGA) were retrieved to predict drug targets based on HP-PPIs with F. nucleatum proteome. Prediction of HP-PPIs exhibited 186 interactions contributed by 103 host and 76 bacterial proteins. Bacterial interacting partners were accounted as putative targets. And enrichment analysis of host interacting partners showed statistically

Structure-Based Analysis Reveals Cancer Missense Mutations Target Protein Interaction Interfaces.

PubMed

Engin, H Billur; Kreisberg, Jason F; Carter, Hannah

2016-01-01

Recently it has been shown that cancer mutations selectively target protein-protein interactions. We hypothesized that mutations affecting distinct protein interactions involving established cancer genes could contribute to tumor heterogeneity, and that novel mechanistic insights might be gained into tumorigenesis by investigating protein interactions under positive selection in cancer. To identify protein interactions under positive selection in cancer, we mapped over 1.2 million nonsynonymous somatic cancer mutations onto 4,896 experimentally determined protein structures and analyzed their spatial distribution. In total, 20% of mutations on the surface of known cancer genes perturbed protein-protein interactions (PPIs), and this enrichment for PPI interfaces was observed for both tumor suppressors (Odds Ratio 1.28, P-value < 10(-4)) and oncogenes (Odds Ratio 1.17, P-value < 10(-3)). To study this further, we constructed a bipartite network representing structurally resolved PPIs from all available human complexes in the Protein Data Bank (2,864 proteins, 3,072 PPIs). Analysis of frequently mutated cancer genes within this network revealed that tumor-suppressors, but not oncogenes, are significantly enriched with functional mutations in homo-oligomerization regions (Odds Ratio 3.68, P-Value < 10(-8)). We present two important examples, TP53 and beta-2-microglobulin, for which the patterns of somatic mutations at interfaces provide insights into specifically perturbed biological circuits. In patients with TP53 mutations, patient survival correlated with the specific interactions that were perturbed. Moreover, we investigated mutations at the interface of protein-nucleotide interactions and observed an unexpected number of missense mutations but not silent mutations occurring within DNA and RNA binding sites. Finally, we provide a resource of 3,072 PPI interfaces ranked according to their mutation rates. Analysis of this list highlights 282 novel candidate cancer

Ideology and gender: observers' system justification and targets' gender as interactive predictors of citizenship expectations.

PubMed

Chiaburu, Dan S; Harris, T Brad; Smith, Troy A

2014-01-01

We integrate system justification and social role theory to explain how observers' system justification and target employees' gender interact to predict observers' expectations of targets' sportsmanship citizenship behaviors. In contrast with social role theory predictions, observers did not expect greater levels of sportsmanship from women compared to men. Yet observers expected more sportsmanship from women (a) when observers were ideologically motivated by gender-specific beliefs (gender-specific system justification; Study 1) and (b) when system justification was cued experimentally (Study 2). A heretofore-unexamined aspect, observers' ideology, modifies their expectations of sportsmanship citizenship across target genders. This has implications for system justification, social role, and organizational citizenship theoretical perspectives.

Analysis of protein targets in pathogen-host interaction in infectious diseases: a case study on Plasmodium falciparum and Homo sapiens interaction network.

PubMed

Saha, Sovan; Sengupta, Kaustav; Chatterjee, Piyali; Basu, Subhadip; Nasipuri, Mita

2017-09-23

Infection and disease progression is the outcome of protein interactions between pathogen and host. Pathogen, the role player of Infection, is becoming a severe threat to life as because of its adaptability toward drugs and evolutionary dynamism in nature. Identifying protein targets by analyzing protein interactions between host and pathogen is the key point. Proteins with higher degree and possessing some topologically significant graph theoretical measures are found to be drug targets. On the other hand, exceptional nodes may be involved in infection mechanism because of some pathway process and biologically unknown factors. In this article, we attempt to investigate characteristics of host-pathogen protein interactions by presenting a comprehensive review of computational approaches applied on different infectious diseases. As an illustration, we have analyzed a case study on infectious disease malaria, with its causative agent Plasmodium falciparum acting as 'Bait' and host, Homo sapiens/human acting as 'Prey'. In this pathogen-host interaction network based on some interconnectivity and centrality properties, proteins are viewed as central, peripheral, hub and non-hub nodes and their significance on infection process. Besides, it is observed that because of sparseness of the pathogen and host interaction network, there may be some topologically unimportant but biologically significant proteins, which can also act as Bait/Prey. So, functional similarity or gene ontology mapping can help us in this case to identify these proteins. © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Nike Facility Diagnostics and Data Acquisition System

NASA Astrophysics Data System (ADS)

Chan, Yung; Aglitskiy, Yefim; Karasik, Max; Kehne, David; Obenschain, Steve; Oh, Jaechul; Serlin, Victor; Weaver, Jim

2013-10-01

The Nike laser-target facility is a 56-beam krypton fluoride system that can deliver 2 to 3 kJ of laser energy at 248 nm onto targets inside a two meter diameter vacuum chamber. Nike is used to study physics and technology issues related to laser direct-drive ICF fusion, including hydrodynamic and laser-plasma instabilities, material behavior at extreme pressures, and optical and x-ray diagnostics for laser-heated targets. A suite of laser and target diagnostics are fielded on the Nike facility, including high-speed, high-resolution x-ray and visible imaging cameras, spectrometers and photo-detectors. A centrally-controlled, distributed computerized data acquisition system provides robust data management and near real-time analysis feedback capability during target shots. Work supported by DOE/NNSA.

Image-Based Multi-Target Tracking through Multi-Bernoulli Filtering with Interactive Likelihoods.

PubMed

Hoak, Anthony; Medeiros, Henry; Povinelli, Richard J

2017-03-03

We develop an interactive likelihood (ILH) for sequential Monte Carlo (SMC) methods for image-based multiple target tracking applications. The purpose of the ILH is to improve tracking accuracy by reducing the need for data association. In addition, we integrate a recently developed deep neural network for pedestrian detection along with the ILH with a multi-Bernoulli filter. We evaluate the performance of the multi-Bernoulli filter with the ILH and the pedestrian detector in a number of publicly available datasets (2003 PETS INMOVE, Australian Rules Football League (AFL) and TUD-Stadtmitte) using standard, well-known multi-target tracking metrics (optimal sub-pattern assignment (OSPA) and classification of events, activities and relationships for multi-object trackers (CLEAR MOT)). In all datasets, the ILH term increases the tracking accuracy of the multi-Bernoulli filter.

Image-Based Multi-Target Tracking through Multi-Bernoulli Filtering with Interactive Likelihoods

PubMed Central

Hoak, Anthony; Medeiros, Henry; Povinelli, Richard J.

2017-01-01

We develop an interactive likelihood (ILH) for sequential Monte Carlo (SMC) methods for image-based multiple target tracking applications. The purpose of the ILH is to improve tracking accuracy by reducing the need for data association. In addition, we integrate a recently developed deep neural network for pedestrian detection along with the ILH with a multi-Bernoulli filter. We evaluate the performance of the multi-Bernoulli filter with the ILH and the pedestrian detector in a number of publicly available datasets (2003 PETS INMOVE, Australian Rules Football League (AFL) and TUD-Stadtmitte) using standard, well-known multi-target tracking metrics (optimal sub-pattern assignment (OSPA) and classification of events, activities and relationships for multi-object trackers (CLEAR MOT)). In all datasets, the ILH term increases the tracking accuracy of the multi-Bernoulli filter. PMID:28273796

Nanosized Drug Delivery Systems in Gastrointestinal Targeting: Interactions with Microbiota

PubMed Central

Karavolos, Michail; Holban, Alina

2016-01-01

The new age of nanotechnology has signaled a stream of entrepreneurial possibilities in various areas, form industry to medicine. Drug delivery has benefited the most by introducing nanostructured systems in the transport and controlled release of therapeutic molecules at targeted sites associated with a particular disease. As many nanosized particles reach the gastrointestinal tract by various means, their interactions with the molecular components of this highly active niche are intensively investigated. The well-characterized antimicrobial activities of numerous nanoparticles are currently being considered as a reliable and efficient alternative to the eminent world crisis in antimicrobial drug discovery. The interactions of nanosystems present in the gastrointestinal route with host microbiota is unavoidable; hence, a major research initiative is needed to explore the mechanisms and effects of these nanomaterials on microbiota and the impact that microbiota may have in the outcome of therapies entailing drug delivery nanosystems through the gastrointestinal route. These coordinated studies will provide novel techniques to replace or act synergistically with current technologies and help develop new treatments for major diseases via the discovery of unique antimicrobial molecules. PMID:27690060

Computational study of radiation doses at UNLV accelerator facility

NASA Astrophysics Data System (ADS)

Hodges, Matthew; Barzilov, Alexander; Chen, Yi-Tung; Lowe, Daniel

2017-09-01

A Varian K15 electron linear accelerator (linac) has been considered for installation at University of Nevada, Las Vegas (UNLV). Before experiments can be performed, it is necessary to evaluate the photon and neutron spectra as generated by the linac, as well as the resulting dose rates within the accelerator facility. A computational study using MCNPX was performed to characterize the source terms for the bremsstrahlung converter. The 15 MeV electron beam available in the linac is above the photoneutron threshold energy for several materials in the linac assembly, and as a result, neutrons must be accounted for. The angular and energy distributions for bremsstrahlung flux generated by the interaction of the 15 MeV electron beam with the linac target were determined. This source term was used in conjunction with the K15 collimators to determine the dose rates within the facility.

Flow Property Measurement Using Laser-Induced Fluorescence in the NASA Ames Interaction Heating Facility

NASA Technical Reports Server (NTRS)

Grinstead, Jay Henderson; Porter, Barry J.; Carballo, Julio Enrique

2011-01-01

The spectroscopic diagnostic technique of two photon absorption laser-induced fluorescence (TALIF) of atomic species has been applied to single-point measurements of velocity and static temperature in the NASA Ames Interaction Heating Facility (IHF) arc jet. Excitation spectra of atomic oxygen and nitrogen were recorded while scanning a tunable dye laser over the absorption feature. Thirty excitation spectra were acquired during 8 arc jet runs at two facility operating conditions; the number of scans per run varied between 2 and 6. Curve fits to the spectra were analyzed to recover their Doppler shifts and widths, from which the flow velocities and static temperatures, respectively, were determined. An increase in the number of independent flow property pairs from each as-measured scan was obtained by extracting multiple lower-resolution scans. The larger population sample size enabled the mean property values and their uncertainties for each run to be characterized with greater confidence. The average plus or minus 2 sigma uncertainties in the mean velocities and temperatures for all 8 runs were plus or minus 1.4% and plus or minus 11%, respectively.

The enemy within: Targeting host–parasite interaction for antileishmanial drug discovery

PubMed Central

Späth, Gerald F.; Rachidi, Najma; Prina, Eric

2017-01-01

The state of antileishmanial chemotherapy is strongly compromised by the emergence of drug-resistant Leishmania. The evolution of drug-resistant phenotypes has been linked to the parasites’ intrinsic genome instability, with frequent gene and chromosome amplifications causing fitness gains that are directly selected by environmental factors, including the presence of antileishmanial drugs. Thus, even though the unique eukaryotic biology of Leishmania and its dependence on parasite-specific virulence factors provide valid opportunities for chemotherapeutical intervention, all strategies that target the parasite in a direct fashion are likely prone to select for resistance. Here, we review the current state of antileishmanial chemotherapy and discuss the limitations of ongoing drug discovery efforts. We finally propose new strategies that target Leishmania viability indirectly via mechanisms of host–parasite interaction, including parasite-released ectokinases and host epigenetic regulation, which modulate host cell signaling and transcriptional regulation, respectively, to establish permissive conditions for intracellular Leishmania survival. PMID:28594938

Cryogenic target system for hydrogen layering

DOE PAGES

Parham, T.; Kozioziemski, B.; Atkinson, D.; ...

2015-11-24

Here, a cryogenic target positioning system was designed and installed on the National Ignition Facility (NIF) target chamber. This instrument incorporates the ability to fill, form, and characterize the NIF targets with hydrogen isotopes needed for ignition experiments inside the NIF target bay then transport and position them in the target chamber. This effort brought to fruition years of research in growing and metrologizing high-quality hydrogen fuel layers and landed it in an especially demanding operations environment in the NIF facility. D-T (deuterium-tritium) layers for NIF ignition experiments have extremely tight specifications and must be grown in a very highlymore » constrained environment: a NIF ignition target inside a cryogenic target positioner inside the NIF target bay. Exquisite control of temperature, pressure, contaminant level, and thermal uniformity are necessary throughout seed formation and layer growth to create an essentially-groove-free single crystal layer.« less

Chemical Synthesis of Hydrocarbon-Stapled Peptides for Protein Interaction Research and Therapeutic Targeting

PubMed Central

Bird, Gregory H.; Crannell, W. Christian; Walensky, Loren D.

2016-01-01

The peptide alpha-helix represents one of Nature’s most featured protein shapes and is employed in a diversity of protein architectures, spanning the very cytoskeletal infrastructure of the cell to the most intimate contact points between crucial signaling proteins. By installing an all-hydrocarbon crosslink into native sequences, we recapitulate the shape and biological activity of natural peptide alpha-helices, yielding a chemical toolbox to both interrogate the protein interactome and modulate interaction networks for potential therapeutic benefit. Here, we describe our latest approach to synthesizing Stabilized Alpha-Helices (SAH) corresponding to key protein interaction domains. We emphasize a stepwise approach to the production of crosslinking non-natural amino acids, their incorporation into peptide templates, and the application of ruthenium-catalyzed ring closing metathesis to generate hydrocarbon-stapled peptides. Through facile derivatization and functionalization steps, SAHs can be tailored for a broad range of applications in biochemical, structural, proteomic, cellular and in vivo studies. PMID:23801563

Plasma block acceleration based upon the interaction between double targets and an ultra-intense linearly polarized laser pulse

NASA Astrophysics Data System (ADS)

Xu, Yanxia; Wang, Jiaxiang; Hora, Heinrich; Qi, Xin; Xing, Yifan; Yang, Lei; Zhu, Wenjun

2018-04-01

A new scheme of plasma block acceleration based upon the interaction between double targets and an ultra-intense linearly polarized laser pulse with intensity I ˜ 1022 W/cm2 is investigated via two-dimensional particle-in-cell simulations. The targets are composed of a pre-target of low-density aluminium plasma and an overdense main-target of hydrogen plasma. Through intensive parameter optimization, we have observed highly efficient plasma block accelerations with a monochromatic proton beam peaked at GeVs. The underlying mechanism is attributed to the enhancement of the charge separation field due to the properly selected pre-target.

DETECTORS AND EXPERIMENTAL METHODS: Studies of a scintillator-bar detector for a neutron wall at an external target facility

NASA Astrophysics Data System (ADS)

Yu, Yu-Hong; Xu, Hua-Gen; Xu, Hu-Shan; Zhan, Wen-Long; Sun, Zhi-Yu; Guo, Zhong-Yan; Hu, Zheng-Guo; Wang, Jian-Song; Chen, Jun-Ling; Zheng, Chuan

2009-07-01

To achieve a better time resolution of a scintillator-bar detector for a neutron wall at the external target facility of HIRFL-CSR, we have carried out a detailed study of the photomultiplier, the wrapping material and the coupling media. The timing properties of a scintillator-bar detector have been studied in detail with cosmic rays using a high and low level signal coincidence. A time resolution of 80 ps has been achieved in the center of the scintillator-bar detector.

In-situ formation of solidified hydrogen thin-membrane targets using a pulse tube cryocooler

NASA Astrophysics Data System (ADS)

Astbury, S.; Bedacht, S.; Brummitt, P.; Carroll, D.; Clarke, R.; Crisp, S.; Hernandez-Gomez, C.; Holligan, P.; Hook, S.; Merchan, J. S.; Neely, D.; Ortner, A.; Rathbone, D.; Rice, P.; Schaumann, G.; Scott, G.; Spindloe, C.; Spurdle, S.; Tebartz, A.; Tomlinson, S.; Wagner, F.; Borghesi, M.; Roth, M.; Tolley, M. K.

2016-04-01

An account is given of the Central Laser Facility's work to produce a cryogenic hydrogen targetry system using a pulse tube cryocooler. Due to the increasing demand for low Z thin laser targets, CLF (in collaboration with TUD) have been developing a system which allows the production of solid hydrogen membranes by engineering a design which can achieve this remotely; enabling the gas injection, condensation and solidification of hydrogen without compromising the vacuum of the target chamber. A dynamic sealing mechanism was integrated which allows targets to be grown and then remotely exposed to open vacuum for laser interaction. Further research was conducted on the survivability of the cryogenic targets which concluded that a warm gas effect causes temperature spiking when exposing the solidified hydrogen to the outer vacuum. This effect was shown to be mitigated by improving the pumping capacity of the environment and reducing the minimum temperature obtainable on the target mount. This was achieved by developing a two-stage radiation shield encased with superinsulating blanketing; reducing the base temperature from 14 ± 0.5 K to 7.2 ± 0.2 K about the coldhead as well as improving temperature control stability following the installation of a high-performance temperature controller and sensor apparatus. The system was delivered experimentally and in July 2014 the first laser shots were taken upon hydrogen targets in the Vulcan TAP facility.

Method for detection of nuclear-plasma interactions in a 134Xe-doped exploding pusher at the National Ignition Facility

DOE PAGES

Bleuel, Daniel L.; Bernstein, Lee A.; Brand, Christopher A.; ...

2016-06-10

Angular momentum changes due to nuclear-plasma interactions on highly-excited nuclei in high energy density plasmas created at the National Ignition Facility can be measured through a change in isomer feeding following gamma emission. Here, we propose an experiment to detect these effects in 133Xe* in exploding pusher capsules.

Method for detection of nuclear-plasma interactions in a 134Xe-doped exploding pusher at the National Ignition Facility

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

Bleuel, Daniel L.; Bernstein, Lee A.; Brand, Christopher A.

Angular momentum changes due to nuclear-plasma interactions on highly-excited nuclei in high energy density plasmas created at the National Ignition Facility can be measured through a change in isomer feeding following gamma emission. Here, we propose an experiment to detect these effects in 133Xe* in exploding pusher capsules.

Facile Preparation of Doxorubicin-Loaded and Folic Acid-Conjugated Carbon Nanotubes@Poly(N-vinyl pyrrole) for Targeted Synergistic Chemo-Photothermal Cancer Treatment.

PubMed

Wang, Daquan; Ren, Yibo; Shao, Yongping; Yu, Demei; Meng, Lingjie

2017-11-15

We developed a bifunctional nanoplatform for targeted synergistic chemo-photothermal cancer treatment. The nanoplatform was constructed through a facile method in which poly(N-vinyl pyrrole) (PVPy) was coated on cut multiwalled carbon nanotubes (c-MWNTs); FA-PEG-SH was then linked by thiol-ene click reaction to improve the active targeting ability, water dispersibility, and biocompatibility and to extend the circulation time in blood. The PVPy shell not only enhanced the photothermal effect of c-MWNTs significantly but also provided a surface that could tailor targeting molecules and drugs. The resulting MWNT@PVPy-S-PEG-FA possessed high drug-loading ratio as well as pH-sensitive unloading capacity for a broad-spectrum anticancer agent, doxorubicin. Owing to its outstanding efficiency in photothermal conversion and ability in targeted drug delivery, the material could potentially be used as an efficient chemo-photothermal therapeutic nanoagent to treat cancer.

The Interactions between the Long Non-coding RNA NERDL and Its Target Gene Affect Wood Formation in Populus tomentosa

PubMed Central

Shi, Wan; Quan, Mingyang; Du, Qingzhang; Zhang, Deqiang

2017-01-01

Long non-coding RNAs (lncRNAs) are important regulatory factors for plant growth and development, but little is known about the allelic interactions of lncRNAs with mRNA in perennial plants. Here, we analyzed the interaction of the NERD (Needed for RDR2-independent DNA methylation) Populus tomentosa gene PtoNERD with its putative regulator, the lncRNA NERDL (NERD-related lncRNA), which partially overlaps with the promoter region of this gene. Expression analysis in eight tissues showed a positive correlation between NERDL and PtoNERD (r = 0.62), suggesting that the interaction of NERDL with its putative target might be involved in wood formation. We conducted association mapping in a natural population of P. tomentosa (435 unrelated individuals) to evaluate genetic variation and the interaction of the lncRNA NERDL with PtoNERD. Using additive and dominant models, we identified 30 SNPs (P < 0.01) associated with five tree growth and wood property traits. Each SNP explained 3.90–8.57% of phenotypic variance, suggesting that NERDL and its putative target play a common role in wood formation. Epistasis analysis uncovered nine SNP-SNP association pairs between NERDL and PtoNERD, with an information gain of -7.55 to 2.16%, reflecting the strong interactions between NERDL and its putative target. This analysis provides a powerful method for deciphering the genetic interactions of lncRNAs with mRNA and dissecting the complex genetic network of quantitative traits in trees. PMID:28674544

miRTar2GO: a novel rule-based model learning method for cell line specific microRNA target prediction that integrates Ago2 CLIP-Seq and validated microRNA-target interaction data.

PubMed

Ahadi, Alireza; Sablok, Gaurav; Hutvagner, Gyorgy

2017-04-07

MicroRNAs (miRNAs) are ∼19-22 nucleotides (nt) long regulatory RNAs that regulate gene expression by recognizing and binding to complementary sequences on mRNAs. The key step in revealing the function of a miRNA, is the identification of miRNA target genes. Recent biochemical advances including PAR-CLIP and HITS-CLIP allow for improved miRNA target predictions and are widely used to validate miRNA targets. Here, we present miRTar2GO, which is a model, trained on the common rules of miRNA-target interactions, Argonaute (Ago) CLIP-Seq data and experimentally validated miRNA target interactions. miRTar2GO is designed to predict miRNA target sites using more relaxed miRNA-target binding characteristics. More importantly, miRTar2GO allows for the prediction of cell-type specific miRNA targets. We have evaluated miRTar2GO against other widely used miRNA target prediction algorithms and demonstrated that miRTar2GO produced significantly higher F1 and G scores. Target predictions, binding specifications, results of the pathway analysis and gene ontology enrichment of miRNA targets are freely available at http://www.mirtar2go.org. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

Glucocorticoid Receptor Interacting Co-regulators: Putative Candidates for Future Drug Targeting Therapy.

PubMed

Di Silvestre, Alessia; Lucafo, Marianna; De Iudicibus, Sara; Ventura, Alessandro; Martelossi, Stefano; Stocco, Gabriele; Decorti, Giuliana

2017-01-01

Glucocorticoids (GCs) are largely used in different inflammatory, autoimmune and proliferative diseases. To date their mechanism of action is not completely clear and more studies are necessary, in particular to explain the great interindividual variability in clinical response. In this panorama the glucocorticoid receptor (GR) has an important role: in fact it regulates the pharmacological response thanks to the capability to interact with different molecules (DNA, RNA, ncRNA and proteins) that are known to influence its activity. In this review our aim is to highlight the knowledge about the role of protein-protein, RNAprotein interactions and epigenetic modifications on the GR and the consequent response to GCs. The characteristics of these interactions with the GR and their effects on the pharmacological activity of GCs will be examined. This information could contribute to the prediction of individual sensitivity to steroids through the identification of new markers of GC resistance. In addition this knowledge may be used in developing new strategies for targeted therapy. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Surface targeting of the dopamine transporter involves discrete epitopes in the distal C terminus but does not require canonical PDZ domain interactions.

PubMed

Bjerggaard, Christian; Fog, Jacob U; Hastrup, Hanne; Madsen, Kenneth; Loland, Claus J; Javitch, Jonathan A; Gether, Ulrik

2004-08-04

The human dopamine transporter (hDAT) contains a C-terminal type 2 PDZ (postsynaptic density 95/Discs large/zona occludens 1) domain-binding motif (LKV) known to interact with PDZ domain proteins such as PICK1 (protein interacting with C-kinase 1). As reported previously, we found that, after deletion of this motif, hDAT was retained in the endoplasmic reticulum (ER) of human embryonic kidney (HEK) 293 and Neuro2A cells, suggesting that PDZ domain interactions might be critical for hDAT targeting. Nonetheless, substitution of LKV with SLL, the type 1 PDZ-binding sequence from the beta2-adrenergic receptor, did not disrupt plasma membrane targeting. Moreover, the addition of an alanine to the hDAT C terminus (+Ala), resulting in an LKVA termination sequence, or substitution of LKV with alanines (3xAla_618-620) prevented neither plasma membrane targeting nor targeting into sprouting neurites of differentiated N2A cells. The inability of +Ala and 3xAla_618-620 to bind PDZ domains was confirmed by lack of colocalization with PICK1 in cotransfected HEK293 cells and by the inability of corresponding C-terminal fusion proteins to pull down purified PICK1. Thus, although residues in the hDAT C terminus are indispensable for proper targeting, PDZ domain interactions are not required. By progressive substitutions with beta2-adrenergic receptor sequence, and by triple-alanine substitutions in the hDAT C terminus, we examined the importance of epitopes preceding the LKV motif. Substitution of RHW(615-617) with alanines caused retention of the transporter in the ER despite preserved ability of this mutant to bind PICK1. We propose dual roles of the hDAT C terminus: a role independent of PDZ interactions for ER export and surface targeting, and a not fully clarified role involving PDZ interactions with proteins such as PICK1.

Interactive radiopharmaceutical facility between Yale Medical Center and Brookhaven National Laboratory. Progress report, October 1976-June 1979

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

Gottschalk, A.

1979-01-01

DOE Contract No. EY-76-S-02-4078 was started in October 1976 to set up an investigative radiochemical facility at the Yale Medical Center which would bridge the gap between current investigation with radionuclides at the Yale School of Medicine and the facilities in the Chemistry Department at the Brookhaven National Laboratory. To facilitate these goals, Dr. Mathew L. Thakur was recruited who joined the Yale University faculty in March of 1977. This report briefly summarizes our research accomplishments through the end of June 1979. These can be broadly classified into three categories: (1) research using indium-111 labelled cellular blood components; (2) developmentmore » of new radiopharmaceuticals; and (3) interaction with Dr. Alfred Wolf and colleagues in the Chemistry Department of Brookhaven National Laboratory.« less

Rational Design of Multifunctional Gold Nanoparticles via Host-Guest Interaction for Cancer-Targeted Therapy.

PubMed

Chen, Wei-Hai; Lei, Qi; Luo, Guo-Feng; Jia, Hui-Zhen; Hong, Sheng; Liu, Yu-Xin; Cheng, Yin-Jia; Zhang, Xian-Zheng

2015-08-12

A versatile gold nanoparticle-based multifunctional nanocomposite AuNP@CD-AD-DOX/RGD was constructed flexibly via host-guest interaction for targeted cancer chemotherapy. The pH-sensitive anticancer prodrug AD-Hyd-DOX and the cancer-targeted peptide AD-PEG8-GRGDS were modified on the surface of AuNP@CD simultaneously, which endowed the resultant nanocomposite with the capability to selectively eliminate cancer cells. In vitro studies indicated that the AuNP@CD-AD-DOX/RGD nanocomposite was preferentially uptaken by cancer cells via receptor-mediated endocytosis. Subsequently, anticancer drug DOX was released rapidly upon the intracellular trigger of the acid microenvirenment of endo/lysosomes, inducing apoptosis in cancer cells. As the ideal drug nanocarrier, the multifunctional gold nanoparticles with the active targeting and controllable intracellular release ability hold the great potential in cancer therapy.

Discriminative facility and its role in the perceived quality of interactional experiences.

PubMed

Cheng, C; Chiu, C Y; Hong, Y Y; Cheung, J S

2001-10-01

Discriminative facility refers to an individual's sensitivity to subtle cues about the psychological meaning of a situation. This research aimed at examining (a) the conceptual distinctiveness of discriminative facility, (b) the situation-appropriate aspect of this construct, and (c) the relationship between discriminative facility and interpersonal experiences. Discriminative facility was assessed by a new measure of situation-appropriate behaviors across a variety of novel stressful situations. Results from study 1 showed that discriminative facility had weak positive relationships with cognitive complexity and nonsignificant relationships with self-monitoring and social desirability, indicating that discriminative facility is a unique construct. Results from Study 2 revealed that higher levels of discriminative facility were associated with higher levels of perceived social support and a greater number of pleasant interpersonal events experienced, thus providing support for the theoretical proposition that discriminative facility is an aspect of social intelligence.

First PIC simulations modeling the interaction of ultra-intense lasers with sub-micron, liquid crystal targets

NASA Astrophysics Data System (ADS)

McMahon, Matthew; Poole, Patrick; Willis, Christopher; Andereck, David; Schumacher, Douglass

2014-10-01

We recently introduced liquid crystal films as on-demand, variable thickness (50-5000 nanometers), low cost targets for intense laser experiments. Here we present the first particle-in-cell (PIC) simulations of short pulse laser excitation of liquid crystal targets treating Scarlet (OSU) class lasers using the PIC code LSP. In order to accurately model the target evolution, a low starting temperature and field ionization model are employed. This is essential as large starting temperatures, often used to achieve large Debye lengths, lead to expansion of the target causing significant reduction of the target density before the laser pulse can interact. We also present an investigation of the modification of laser pulses by very thin targets. This work was supported by the DARPA PULSE program through a grant from ARMDEC, by the US Department of Energy under Contract No. DE-NA0001976, and allocations of computing time from the Ohio Supercomputing Center.

Trident Laser Facility

Science.gov Websites

-trillion watt Trident Laser enters from the bottom to interact with a one-micrometer thick foil target in tens of millions of volts. In this time-integrated image, one sees many colorful plasmas that result from the bottom to interact with a one-micrometer thick foil target in the center of the photo. In this

PIE preparation of the MEGAPIE target

NASA Astrophysics Data System (ADS)

Wohlmuther, Michael; Wagner, Werner

2012-12-01

The MEGAPIE target, after successfully operating for 4 months at a beam power of 0.77 MW, is now being prepared for post irradiation examination PIE. The lead-bismuth eutectic (LBE) target was irradiated from August until December 2006, and in this period received a beam charge of 2.8 A h of 575 MeV protons. After that, the target was stored in the target storage facility of PSI, waiting for its post irradiation examination. In the meantime several campaigns of tests have been conducted by PSI and ZWILAG, the interim storage facility of Swiss nuclear power plants. In these tests the feasibility of the conditioning of the target and the extraction of sample material for the PIE has been proven. After transport to the hot cell facility at ZWILAG in June 2009, the dismantling of the MEGAPIE target started. It finally was cut into 21 pieces. Ten of these pieces will be shipped to the Hot Laboratory of PSI ('PSI hotlab') to extract samples from the structural materials as well as from the LBE. Currently it is foreseen that the sample extraction will start in the first half of 2011. The remaining parts of the MEGAPIE target were conditioned as radioactive waste. The present paper will mainly focus on the dismantling and first visual inspection of the MEGAPIE target. In addition an outlook on the PIE phase of MEGAPIE is given.

Medical Isotope Production Analyses In KIPT Neutron Source Facility

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

Talamo, Alberto; Gohar, Yousry

Medical isotope production analyses in Kharkov Institute of Physics and Technology (KIPT) neutron source facility were performed to include the details of the irradiation cassette and the self-shielding effect. An updated detailed model of the facility was used for the analyses. The facility consists of an accelerator-driven system (ADS), which has a subcritical assembly using low-enriched uranium fuel elements with a beryllium-graphite reflector. The beryllium assemblies of the reflector have the same outer geometry as the fuel elements, which permits loading the subcritical assembly with different number of fuel elements without impacting the reflector performance. The subcritical assembly is drivenmore » by an external neutron source generated from the interaction of 100-kW electron beam with a tungsten target. The facility construction was completed at the end of 2015, and it is planned to start the operation during the year of 2016. It is the first ADS in the world, which has a coolant system for removing the generated fission power. Argonne National Laboratory has developed the design concept and performed extensive design analyses for the facility including its utilization for the production of different radioactive medical isotopes. 99Mo is the parent isotope of 99mTc, which is the most commonly used medical radioactive isotope. Detailed analyses were performed to define the optimal sample irradiation location and the generated activity, for several radioactive medical isotopes, as a function of the irradiation time.« less

Coupled Facility/Payload Vibration Modeling Improvements

NASA Technical Reports Server (NTRS)

Carnahan, Timothy M.; Kaiser, Michael

2015-01-01

A major phase of aerospace hardware verification is vibration testing. The standard approach for such testing is to use a shaker to induce loads into the payload. In preparation for vibration testing at NASA/GSFC there is an analysis to assess the responses of the payload. A new method of modeling the test is presented that takes into account dynamic interactions between the facility and the payload. This dynamic interaction has affected testing in the past, but been ignored or adjusted for during testing. By modeling the combination of the facility and test article (payload) it is possible to improve the prediction of hardware responses. Many aerospace test facilities work in similar way to those at NASA Goddard Space Flight Center. Lessons learned here should be applicable to other test facilities with similar setups.

Identification of Histone Deacetylase (HDAC) as a drug target against MRSA via interolog method of protein-protein interaction prediction.

PubMed

Uddin, Reaz; Tariq, Syeda Sumayya; Azam, Syed Sikander; Wadood, Abdul; Moin, Syed Tarique

2017-08-30

Patently, Protein-Protein Interactions (PPIs) lie at the core of significant biological functions and make the foundation of host-pathogen relationships. Hence, the current study is aimed to use computational biology techniques to predict host-pathogen Protein-Protein Interactions (HP-PPIs) between MRSA and Humans as potential drug targets ultimately proposing new possible inhibitors against them. As a matter of fact this study is based on the Interolog method which implies that homologous proteins retain their ability to interact. A distant homolog approach based on Interolog method was employed to speculate MRSA protein homologs in Humans using PSI-BLAST. In addition the protein interaction partners of these homologs as listed in Database of Interacting Proteins (DIP) were predicted to interact with MRSA as well. Moreover, a direct approach using BLAST was also applied so as to attain further confidence in the strategy. Consequently, the common HP-PPIs predicted by both approaches are suggested as potential drug targets (22%) whereas, the unique HP-PPIs estimated only through distant homolog approach are presented as novel drug targets (12%). Furthermore, the most repeated entry in our results was found to be MRSA Histone Deacetylase (HDAC) which was then modeled using SWISS-MODEL. Eventually, small molecules from ZINC, selected randomly, were docked against HDAC using Auto Dock and are suggested as potential binders (inhibitors) based on their energetic profiles. Thus the current study provides basis for further in-depth analysis of such data which not only include MRSA but other deadly pathogens as well. Copyright © 2017 Elsevier B.V. All rights reserved.

Requirements Doc for Refurb of JASPER Facility in B131HB

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

Knittel, Kenn M.

The Joint Actinide Shock Physics Experimental Research (JASPER) Program target fabrication facility is currently located in building 131 (B131) of the Lawrence Livermore National Laboratory (LLNL). A portion of this current facility has been committed to another program as part of a larger effort to consolidate LLNL capabilities into newer facilities. This facility assembles precision targets for scientific studies at the Nevada National Security Site (NNSS). B131 is also going through a modernization project to upgrade the infrastructure and abate asbestos. These activities will interrupt the continuous target fabrication efforts for the JASPER Program. Several options are explored to meetmore » the above conflicting requirements, with the final recommendation to prepare a new facility for JASPER target fabrication operations before modernization efforts begin in the current facility assigned to JASPER. This recommendation fits within all schedule constraints and minimizes the disruption to the JASPER Program. This option is not without risk, as it requires moving an aged, precision coordinate measuring machine, which is essential to the JASPER Program’s success. The selected option balances the risk to the machine with continuity of operations.« less

Simulation of Targets Feeding Pipe Rupture in Wendelstein 7-X Facility Using RELAP5 and COCOSYS Codes

NASA Astrophysics Data System (ADS)

Kaliatka, T.; Povilaitis, M.; Kaliatka, A.; Urbonavicius, E.

2012-10-01

Wendelstein nuclear fusion device W7-X is a stellarator type experimental device, developed by Max Planck Institute of plasma physics. Rupture of one of the 40 mm inner diameter coolant pipes providing water for the divertor targets during the "baking" regime of the facility operation is considered to be the most severe accident in terms of the plasma vessel pressurization. "Baking" regime is the regime of the facility operation during which plasma vessel structures are heated to the temperature acceptable for the plasma ignition in the vessel. This paper presents the model of W7-X cooling system (pumps, valves, pipes, hydro-accumulators, and heat exchangers), developed using thermal-hydraulic state-of-the-art RELAP5 Mod3.3 code, and model of plasma vessel, developed by employing the lumped-parameter code COCOSYS. Using both models the numerical simulation of processes in W7-X cooling system and plasma vessel has been performed. The results of simulation showed, that the automatic valve closure time 1 s is the most acceptable (no water hammer effect occurs) and selected area of the burst disk is sufficient to prevent pressure in the plasma vessel.

Target-specific NMR detection of protein-ligand interactions with antibody-relayed 15N-group selective STD.

PubMed

Hetényi, Anasztázia; Hegedűs, Zsófia; Fajka-Boja, Roberta; Monostori, Éva; Kövér, Katalin E; Martinek, Tamás A

2016-12-01

Fragment-based drug design has been successfully applied to challenging targets where the detection of the weak protein-ligand interactions is a key element. 1 H saturation transfer difference (STD) NMR spectroscopy is a powerful technique for this work but it requires pure homogeneous proteins as targets. Monoclonal antibody (mAb)-relayed 15 N-GS STD spectroscopy has been developed to resolve the problem of protein mixtures and impure proteins. A 15 N-labelled target-specific mAb is selectively irradiated and the saturation is relayed through the target to the ligand. Tests on the anti-Gal-1 mAb/Gal-1/lactose system showed that the approach is experimentally feasible in a reasonable time frame. This method allows detection and identification of binding molecules directly from a protein mixture in a multicomponent system.

Random walks on mutual microRNA-target gene interaction network improve the prediction of disease-associated microRNAs.

PubMed

Le, Duc-Hau; Verbeke, Lieven; Son, Le Hoang; Chu, Dinh-Toi; Pham, Van-Huy

2017-11-14

MicroRNAs (miRNAs) have been shown to play an important role in pathological initiation, progression and maintenance. Because identification in the laboratory of disease-related miRNAs is not straightforward, numerous network-based methods have been developed to predict novel miRNAs in silico. Homogeneous networks (in which every node is a miRNA) based on the targets shared between miRNAs have been widely used to predict their role in disease phenotypes. Although such homogeneous networks can predict potential disease-associated miRNAs, they do not consider the roles of the target genes of the miRNAs. Here, we introduce a novel method based on a heterogeneous network that not only considers miRNAs but also the corresponding target genes in the network model. Instead of constructing homogeneous miRNA networks, we built heterogeneous miRNA networks consisting of both miRNAs and their target genes, using databases of known miRNA-target gene interactions. In addition, as recent studies demonstrated reciprocal regulatory relations between miRNAs and their target genes, we considered these heterogeneous miRNA networks to be undirected, assuming mutual miRNA-target interactions. Next, we introduced a novel method (RWRMTN) operating on these mutual heterogeneous miRNA networks to rank candidate disease-related miRNAs using a random walk with restart (RWR) based algorithm. Using both known disease-associated miRNAs and their target genes as seed nodes, the method can identify additional miRNAs involved in the disease phenotype. Experiments indicated that RWRMTN outperformed two existing state-of-the-art methods: RWRMDA, a network-based method that also uses a RWR on homogeneous (rather than heterogeneous) miRNA networks, and RLSMDA, a machine learning-based method. Interestingly, we could relate this performance gain to the emergence of "disease modules" in the heterogeneous miRNA networks used as input for the algorithm. Moreover, we could demonstrate that RWRMTN is stable

Efficient Parvovirus Replication Requires CRL4Cdt2-Targeted Depletion of p21 to Prevent Its Inhibitory Interaction with PCNA

PubMed Central

Pintel, David J.

2014-01-01

Infection by the autonomous parvovirus minute virus of mice (MVM) induces a vigorous DNA damage response in host cells which it utilizes for its efficient replication. Although p53 remains activated, p21 protein levels remain low throughout the course of infection. We show here that efficient MVM replication required the targeting for degradation of p21 during this time by the CRL4Cdt2 E3-ubiquitin ligase which became re-localized to MVM replication centers. PCNA provides a molecular platform for substrate recognition by the CRL4Cdt2 E3-ubiquitin ligase and p21 targeting during MVM infection required its interaction both with Cdt2 and PCNA. PCNA is also an important co-factor for MVM replication which can be antagonized by p21 in vitro. Expression of a stable p21 mutant that retained interaction with PCNA inhibited MVM replication, while a stable p21 mutant which lacked this interaction did not. Thus, while interaction with PCNA was important for targeting p21 to the CRL4Cdt2 ligase re-localized to MVM replication centers, efficient viral replication required subsequent depletion of p21 to abrogate its inhibition of PCNA. PMID:24699724

Efficient parvovirus replication requires CRL4Cdt2-targeted depletion of p21 to prevent its inhibitory interaction with PCNA.

PubMed

Adeyemi, Richard O; Fuller, Matthew S; Pintel, David J

2014-04-01

Infection by the autonomous parvovirus minute virus of mice (MVM) induces a vigorous DNA damage response in host cells which it utilizes for its efficient replication. Although p53 remains activated, p21 protein levels remain low throughout the course of infection. We show here that efficient MVM replication required the targeting for degradation of p21 during this time by the CRL4Cdt2 E3-ubiquitin ligase which became re-localized to MVM replication centers. PCNA provides a molecular platform for substrate recognition by the CRL4Cdt2 E3-ubiquitin ligase and p21 targeting during MVM infection required its interaction both with Cdt2 and PCNA. PCNA is also an important co-factor for MVM replication which can be antagonized by p21 in vitro. Expression of a stable p21 mutant that retained interaction with PCNA inhibited MVM replication, while a stable p21 mutant which lacked this interaction did not. Thus, while interaction with PCNA was important for targeting p21 to the CRL4Cdt2 ligase re-localized to MVM replication centers, efficient viral replication required subsequent depletion of p21 to abrogate its inhibition of PCNA.

Direct Interaction between the WD40 Repeat Protein WDR-23 and SKN-1/Nrf Inhibits Binding to Target DNA

PubMed Central

Leung, Chi K.; Hasegawa, Koichi; Wang, Ying; Deonarine, Andrew; Tang, Lanlan; Miwa, Johji

2014-01-01

SKN-1/Nrf transcription factors activate cytoprotective genes in response to reactive small molecules and strongly influence stress resistance, longevity, and development. The molecular mechanisms of SKN-1/Nrf regulation are poorly defined. We previously identified the WD40 repeat protein WDR-23 as a repressor of Caenorhabditis elegans SKN-1 that functions with a ubiquitin ligase to presumably target the factor for degradation. However, SKN-1 activity and nuclear accumulation are not always correlated, suggesting that there could be additional regulatory mechanisms. Here, we integrate forward genetics and biochemistry to gain insights into how WDR-23 interacts with and regulates SKN-1. We provide evidence that WDR-23 preferentially regulates one of three SKN-1 variants through a direct interaction that is required for normal stress resistance and development. Homology modeling predicts that WDR-23 folds into a β-propeller, and we identify the top of this structure and four motifs at the termini of SKN-1c as essential for the interaction. Two of these SKN-1 motifs are highly conserved in human Nrf1 and Nrf2 and two directly interact with target DNA. Lastly, we demonstrate that WDR-23 can block the ability of SKN-1c to interact with DNA sequences of target promoters identifying a new mechanism of regulation that is independent of the ubiquitin proteasome system, which can become occupied with damaged proteins during stress. PMID:24912676

Interactive food and beverage marketing: targeting adolescents in the digital age.

PubMed

Montgomery, Kathryn C; Chester, Jeff

2009-09-01

Because of their avid use of new media and their increased spending power, adolescents have become primary targets of a new "Media and Marketing Ecosystem." Digital media resonate particularly well with many of the fundamental developmental tasks of adolescence by enabling instantaneous and constant contact with peers, providing opportunities for self-expression, identity exploration, and social interaction, and facilitating mobility and independence. Six key features of interactive media--ubiquitous connectivity, personalization, peer-to-peer networking, engagement, immersion, and content creation--are emblematic of the ways in which young people are both shaping and being shaped by this new digital culture. The advertising industry, in many instances led by food and beverage marketers, is purposefully exploiting the special relationship that teenagers have with new media, with online marketing campaigns that create unprecedented intimacies between adolescents and the brands and products that now literally surround them. Major food and beverage companies, including Coca-Cola, McDonald's, Burger King, and Kentucky Fried Chicken (KFC), have incorporated these elements into their interactive marketing strategies, posing particular risks to adolescents, who are not being addressed in the current U.S. policy and self-regulatory regimens. However, recent and emerging neuroscience and psychological research on adolescents suggests a need to revisit the traditional approach to regulation of advertising. Despite the growth of interactive marketing, academic research on the impact of digital advertising on children and youth remains underdeveloped. Additional research and policy initiatives are needed to address the growing health threat facing youth in the digital marketplace.

The national ignition facility and atomic data

NASA Astrophysics Data System (ADS)

Crandall, David H.

1998-07-01

The National Ignition Facility (NIF) is under construction, capping over 25 years of development of the inertial confinement fusion concept by providing the facility to obtain fusion ignition in the laboratory for the first time. The NIF is a 192 beam glass laser to provide energy controlled in space and time so that a millimeter-scale capsule containing deuterium and tritium can be compressed to fusion conditions. Light transport, conversion of light in frequency, interaction of light with matter in solid and plasma forms, and diagnostics of extreme material conditions on small scale all use atomic data in preparing for use of the NIF. The NIF will provide opportunity to make measurements of atomic data in extreme physical environments related to fusion energy, nuclear weapon detonation, and astrophysics. The first laser beams of NIF should be operational in 2001 and the full facility completed at the end of 2003. NIF is to provide 1.8 megajoule of blue light on fusion targets and is intended to achieve fusion ignition by about the end of 2007. Today's inertial fusion development activities use atomic data to design and predict fusion capsule performance and in non-fusion applications to analyze radiation transport and radiation effects on matter. Conditions investigated involve radiation temperature of hundreds of eV, pressures up to gigabars and time scales of femptoseconds.

Shock-induced perturbation evolution in planar laser targets

NASA Astrophysics Data System (ADS)

Aglitskiy, Y.; Karasik, M.; Velikovich, A. L.; Serlin, V.; Weaver, J. L.; Kessler, T. J.; Schmitt, A. J.; Obenschain, S. P.; Metzler, N.; Oh, J.

2013-10-01

Experimental studies of hydrodynamic perturbation evolution triggered by a laser-driven shock wave in a planar target done on the KrF Nike laser facility are reported. The targets were made of solid plastic and/or plastic foam with single mode sinusoidal perturbation on the front or back surface or plastic/foam interface. Two specific cases are discussed. When a planar solid plastic target rippled at the front side is irradiated with a 350 ps long laser pulse, ablative Richtmyer-Meshkov (RM) oscillation of its areal mass modulation amplitude is detected while the laser is on, followed by observed strong oscillations of the areal mass in the unsupported shock flow after the laser pulse ends. When the target is rippled at the rear side, the nature of the perturbation evolution after the shock breakout is determined by the strength of the laser-driven shock wave. At pressure below 1 Mbar shock interaction with rear-surface ripples produces planar collimated jets manifesting the development of a classical RM instability in a weakly compressible shocked fluid. At shock pressure ~ 8 Mbar sufficient for vaporizing the shocked target material we observed instead the strong areal mass oscillations characteristic of a rippled centered rarefaction wave. Work supported by US DOE, Defense Programs.

Overview: Development of the National Ignition Facility and the Transition to a User Facility for the Ignition Campaign and High Energy Density Scientific Research

DOE PAGES

Moses, E. I.; Lindl, J. D.; Spaeth, M. L.; ...

2017-03-23

The National Ignition Facility (NIF) at Lawrence Livermore National Laboratory has been operational since March 2009 and has been transitioning to a user facility supporting ignition science, high energy density stockpile science, national security applications, and fundamental science. The facility has achieved its design goal of 1.8 MJ and 500 TW of 3ω light on target, and has performed target experiments with 1.9 MJ at peak powers of 410 TW. The National Ignition Campaign (NIC), established by the U.S. National Nuclear Security Administration in 2005, was responsible for transitioning NIF from a construction project to a national user facility. Besidesmore » the operation and optimization of the use of the NIF laser, the NIC program was responsible for developing capabilities including target fabrication facilities; cryogenic layering capabilities; over 60 optical, X-ray, and nuclear diagnostic systems; experimental platforms; and a wide range of other NIF facility infrastructure. This study provides a summary of some of the key experimental results for NIF to date, an overview of the NIF facility capabilities, and the challenges that were met in achieving these capabilities. Finally, they are covered in more detail in the papers that follow.« less

Overview: Development of the National Ignition Facility and the Transition to a User Facility for the Ignition Campaign and High Energy Density Scientific Research

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

Moses, E. I.; Lindl, J. D.; Spaeth, M. L.

The National Ignition Facility (NIF) at Lawrence Livermore National Laboratory has been operational since March 2009 and has been transitioning to a user facility supporting ignition science, high energy density stockpile science, national security applications, and fundamental science. The facility has achieved its design goal of 1.8 MJ and 500 TW of 3ω light on target, and has performed target experiments with 1.9 MJ at peak powers of 410 TW. The National Ignition Campaign (NIC), established by the U.S. National Nuclear Security Administration in 2005, was responsible for transitioning NIF from a construction project to a national user facility. Besidesmore » the operation and optimization of the use of the NIF laser, the NIC program was responsible for developing capabilities including target fabrication facilities; cryogenic layering capabilities; over 60 optical, X-ray, and nuclear diagnostic systems; experimental platforms; and a wide range of other NIF facility infrastructure. This study provides a summary of some of the key experimental results for NIF to date, an overview of the NIF facility capabilities, and the challenges that were met in achieving these capabilities. Finally, they are covered in more detail in the papers that follow.« less

Interaction of cellular proteins with BCL-xL targeted to cytoplasmic inclusion bodies in adenovirus infected cells.

PubMed

Subramanian, T; Vijayalingam, S; Kuppuswamy, M; Chinnadurai, G

2015-09-01

Adenovirus-mediated apoptosis was suppressed when cellular anti-apoptosis proteins (BCL-2 and BCL-xL) were substituted for the viral E1B-19K. For unbiased proteomic analysis of proteins targeted by BCL-xL in adenovirus-infected cells and to visualize the interactions with target proteins, BCL-xL was targeted to cytosolic inclusion bodies utilizing the orthoreovirus µNS protein sequences. The chimeric protein was localized in non-canonical cytosolic factory-like sites and promoted survival of virus-infected cells. The BCL-xL-associated proteins were isolated from the cytosolic inclusion bodies in adenovirus-infected cells and analyzed by LC-MS. These proteins included BAX, BAK, BID, BIK and BIM as well as mitochondrial proteins such as prohibitin 2, ATP synthase and DNA-PKcs. Our studies suggested that in addition to the interaction with various pro-apoptotic proteins, the association with certain mitochondrial proteins such as DNA-PKcs and prohibitins might augment the survival function of BCL-xL in virus infected cells. Copyright © 2015 Elsevier Inc. All rights reserved.

Coupled Facility-Payload Vibration Modeling Improvements

NASA Technical Reports Server (NTRS)

Carnahan, Timothy M.; Kaiser, Michael A.

2015-01-01

A major phase of aerospace hardware verification is vibration testing. The standard approach for such testing is to use a shaker to induce loads into the payload. In preparation for vibration testing at National Aeronautics and Space Administration/Goddard Space Flight Center an analysis is performed to assess the responses of the payload. A new method of modeling the test is presented that takes into account dynamic interactions between the facility and the payload. This dynamic interaction has affected testing in the past, but been ignored or adjusted for during testing. By modeling the combined dynamics of the facility and test article (payload) it is possible to improve the prediction of hardware responses. Many aerospace test facilities work in similar way to those at NASA/Goddard Space Flight Center. Lessons learned here should be applicable to other test facilities with similar setups.

Interaction of Sr-90 with site candidate soil for demonstration disposal facility at Serpong

NASA Astrophysics Data System (ADS)

Setiawan, Budi; Mila, Oktri; Safni

2014-03-01

Interaction of radiostrontium (Sr-90) with site candidate soil for demonstration disposal facility to be constructed in the near future at Serpong has been done. This activity is to anticipate the interim storage facility at Serpong nuclear area becomes full off condition, and show to the public how radioactive waste can be well managed with the existing technology. To ensure that the location is save, a reliability study of site candidate soil becomes very importance to be conducted through some experiments consisted some affected parameters such as contact time, effect of ionic strength, and effect of Sr+ ion in solution. Radiostrontium was used as a tracer on the experiments and has role as radionuclide reference in low-level radioactive waste due to its long half-live and it's easy to associate with organism in nature. So, interaction of radiostrontium and soil samples from site becomes important to be studied. Experiment was performed in batch method, and soil sample-solution containing radionuclide was mixed in a 20 ml of PE vial. Ratio of solid: liquid was 10-2 g/ml. Objective of the experiment is to collect the specific characteristics data of radionuclide sorption onto soil from site candidate. Distribution coefficient value was used as indicator where the amount of initial and final activities of radiostrontium in solution was compared. Result showed that equilibrium condition was reached after contact time 10 days with Kd values ranged from 1600-2350 ml/g. Increased in ionic strength in solution made decreased of Kd value into soil sample due to competition of background salt and radiostrontium into soil samples, and increased in Sr ion in solution caused decreased of Kd value in soil sample due to limitation of sorption capacity in soil samples. Fast condition in saturated of metal ion into soil samples was reached due to a simple reaction was occurred.

Biosecurity and bird movement practices in upland game bird facilities in the United States.

PubMed

Slota, Katharine E; Hill, Ashley E; Keefe, Thomas J; Bowen, Richard A; Pabilonia, Kristy L

2011-06-01

Since 1996, the emergence of Asian-origin highly pathogenic avian influenza subtype H5N1 has spurred great concern for the global poultry industry. In the United States, there is concern over the potential of a foreign avian disease incursion into the country. Noncommercial poultry operations, such as upland game bird facilities in the United States, may serve as a potential source of avian disease introduction to other bird populations including the commercial poultry industry, backyard flocks, or wildlife. In order to evaluate how to prevent disease transmission from these facilities to other populations, we examined biosecurity practices and bird movement within the upland game bird industry in the United States. Persons that held a current permit to keep, breed, or release upland game birds were surveyed for information on biosecurity practices, flock and release environments, and bird movement parameters. Biosecurity practices vary greatly among permit holders. Many facilities allow for interaction between wild birds and pen-reared birds, and there is regular long-distance movement of live adult birds among facilities. Results suggest that upland game bird facilities should be targeted for biosecurity education and disease surveillance efforts.

SHiP: a new facility with a dedicated detector for studying tau neutrino properties

NASA Astrophysics Data System (ADS)

Komatsu, M.; SHiP Collaboration

2017-06-01

SHiP (Search for Hidden Particles) is a new general purpose fixed target facility at the CERN SPS accelerator, with the aim of search for New Physics which has small coupling with standard particles by searching for long lived beyond standard model particles with masses below a few GeV/c2. The SHiP facility is a high intensity beam bump, the 400GeV proton beam extracted from the SPS will be dumped on a heavy target with the aim of integrating 2 ×1020 pot in 5 years. A dedicated detector, based on the OPERA-like ECC (Emulsion Cloud Chamber), will provide tau and anti-tau neutrino detection capability to study ντ and ν‾τ cross-sections with a statistics a few 100 times larger than the DONUT experiment. Moreover, the structure functions F4 and F5 which is only accessible by tau neutrino interactions can be measured first time. SHiP is the unique chance to study tau and anti tau neutrino properties.

SINGLE EVENT EFFECTS TEST FACILITY AT OAK RIDGE NATIONAL LABORATORY

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

Riemer, Bernie; Gallmeier, Franz X; Dominik, Laura J

2015-01-01

Increasing use of microelectronics of ever diminishing feature size in avionics systems has led to a growing Single Event Effects (SEE) susceptibility arising from the highly ionizing interactions of cosmic rays and solar particles. Single event effects caused by atmospheric radiation have been recognized in recent years as a design issue for avionics equipment and systems. To ensure a system meets all its safety and reliability requirements, SEE induced upsets and potential system failures need to be considered, including testing of the components and systems in a neutron beam. Testing of ICs and systems for use in radiation environments requiresmore » the utilization of highly advanced laboratory facilities that can run evaluations on microcircuits for the effects of radiation. This paper provides a background of the atmospheric radiation phenomenon and the resulting single event effects, including single event upset (SEU) and latch up conditions. A study investigating requirements for future single event effect irradiation test facilities and developing options at the Spallation Neutron Source (SNS) is summarized. The relatively new SNS with its 1.0 GeV proton beam, typical operation of 5000 h per year, expertise in spallation neutron sources, user program infrastructure, and decades of useful life ahead is well suited for hosting a world-class SEE test facility in North America. Emphasis was put on testing of large avionics systems while still providing tunable high flux irradiation conditions for component tests. Makers of ground-based systems would also be served well by these facilities. Three options are described; the most capable, flexible, and highest-test-capacity option is a new stand-alone target station using about one kW of proton beam power on a gas-cooled tungsten target, with dual test enclosures. Less expensive options are also described.« less

Interactions between the R2R3-MYB Transcription Factor, AtMYB61, and Target DNA Binding Sites

PubMed Central

Prouse, Michael B.; Campbell, Malcolm M.

2013-01-01

Despite the prominent roles played by R2R3-MYB transcription factors in the regulation of plant gene expression, little is known about the details of how these proteins interact with their DNA targets. For example, while Arabidopsis thaliana R2R3-MYB protein AtMYB61 is known to alter transcript abundance of a specific set of target genes, little is known about the specific DNA sequences to which AtMYB61 binds. To address this gap in knowledge, DNA sequences bound by AtMYB61 were identified using cyclic amplification and selection of targets (CASTing). The DNA targets identified using this approach corresponded to AC elements, sequences enriched in adenosine and cytosine nucleotides. The preferred target sequence that bound with the greatest affinity to AtMYB61 recombinant protein was ACCTAC, the AC-I element. Mutational analyses based on the AC-I element showed that ACC nucleotides in the AC-I element served as the core recognition motif, critical for AtMYB61 binding. Molecular modelling predicted interactions between AtMYB61 amino acid residues and corresponding nucleotides in the DNA targets. The affinity between AtMYB61 and specific target DNA sequences did not correlate with AtMYB61-driven transcriptional activation with each of the target sequences. CASTing-selected motifs were found in the regulatory regions of genes previously shown to be regulated by AtMYB61. Taken together, these findings are consistent with the hypothesis that AtMYB61 regulates transcription from specific cis-acting AC elements in vivo. The results shed light on the specifics of DNA binding by an important family of plant-specific transcriptional regulators. PMID:23741471

Laser-plasma extreme ultraviolet and soft X-ray sources based on a double stream gas puff target: interaction of the radiation pulses with matter

NASA Astrophysics Data System (ADS)

Bartnik, A.

2015-06-01

In this work a review of investigations concerning interaction of intense extreme ultraviolet (EUV) and soft X-ray (SXR) pulses with matter is presented. The investigations were performed using laser-produced plasma (LPP) EUV/SXR sources based on a double stream gas puff target. The sources are equipped with dedicated collectors allowing for efficient focusing of the EUV/SXR radiation pulses. Intense radiation in a wide spectral range, as well as a quasi-monochromatic radiation can be produced. In the paper different kinds of LPP EUV/SXR sources developed in the Institute of Optoelectronics, Military University of Technology are described. Radiation intensities delivered by the sources are sufficient for different kinds of interaction experiments including EUV/SXR induced ablation, surface treatment, EUV fluorescence or photoionized plasma creation. A brief review of the main results concerning this kind of experiments performed by author of the paper are presented. However, since the LPP sources cannot compete with large scale X-ray sources like synchrotrons, free electron lasers or high energy density plasma sources, it was indicated that some investigations not requiring extreme irradiation parameters can be performed using the small scale installations. Some results, especially concerning low temperature photoionized plasmas are very unique and could be hardly obtained using the large facilities.

Targeting nursing homes under the Quality Improvement Organization program's 9th statement of work.

PubMed

Stevenson, David G; Mor, Vincent

2009-09-01

In the Quality Improvement Organization (QIO) program's latest Statement of Work, the Centers for Medicare and Medicaid Services (CMS) is targeting its nursing home activities toward facilities that perform poorly on two quality measures-pressure ulcers and restraint use. The designation of target facilities is a shift in strategy for CMS and a direct response to criticism that QIO program resources were not being targeted effectively to facilities or clinical areas that most needed improvement. Using administrative data, this article analyzes implications of using narrowly defined criteria to identify facilities that need improvement, particularly in light of considerable evidence showing that nursing home quality is multidimensional and may change over time. The analyses show that one in four facilities is targeted for improvement nationally but that approximately half of some states' facilities are targeted while other states have almost none targeted. The analyses also convey deeper limitations to using threshold values on individual measures to identify poorly performing homes. Target facilities can be among the top performers on a range of other quality measures, and their performance on targeted measures themselves may change over time. The implication of these features is that a very different group of facilities would have been chosen had the QIO program targeted other measures or examined performance at a different point in time. Ultimately, CMS has chosen a blunt instrument to identify poorly performing nursing homes, and supplemental strategies-such as soliciting input from state survey agencies and more closely aligning quality improvement and quality assurance efforts-should be considered to address potential limitations.

A facile method to screen inhibitors of protein-protein interactions including MDM2-p53 displayed on T7 phage.

PubMed

Ishi, Kazutomo; Sugawara, Fumio

2008-05-01

Protein-protein interactions are essential in many biological processes including cell cycle and apoptosis. It is currently of great medical interest to inhibit specific protein-protein interactions in order to treat a variety of disease states. Here, we describe a facile multiwell plate assay method using T7 phage display to screen for candidate inhibitors of protein-protein interactions. Because T7 phage display is an effective method for detecting protein-protein interactions, we aimed to utilize this technique to screen for small-molecule inhibitors that disrupt these types of interaction. We used the well-characterized interaction between p53 and MDM2 and an inhibitor of this interaction, nutlin 3, as a model system to establish a new screening method. Phage particles displaying p53 interacted with GST-MDM2 immobilized on 96-well plates, and the interaction was inhibited by nutlin 3. Multiwell plate assay was then performed using a natural product library, which identified dehydroaltenusin as a candidate inhibitor of the p53-MDM2 interaction. We discuss the potential applications of this novel T7 phage display methodology, which we propose to call 'reverse phage display'.

Improved prediction of drug-target interactions using regularized least squares integrating with kernel fusion technique.

PubMed

Hao, Ming; Wang, Yanli; Bryant, Stephen H

2016-02-25

Identification of drug-target interactions (DTI) is a central task in drug discovery processes. In this work, a simple but effective regularized least squares integrating with nonlinear kernel fusion (RLS-KF) algorithm is proposed to perform DTI predictions. Using benchmark DTI datasets, our proposed algorithm achieves the state-of-the-art results with area under precision-recall curve (AUPR) of 0.915, 0.925, 0.853 and 0.909 for enzymes, ion channels (IC), G protein-coupled receptors (GPCR) and nuclear receptors (NR) based on 10 fold cross-validation. The performance can further be improved by using a recalculated kernel matrix, especially for the small set of nuclear receptors with AUPR of 0.945. Importantly, most of the top ranked interaction predictions can be validated by experimental data reported in the literature, bioassay results in the PubChem BioAssay database, as well as other previous studies. Our analysis suggests that the proposed RLS-KF is helpful for studying DTI, drug repositioning as well as polypharmacology, and may help to accelerate drug discovery by identifying novel drug targets. Published by Elsevier B.V.

Difficult relationships--interactions between family members and staff in long-term care.

PubMed

Norris, S

2000-01-01

Staff of long-term care facilities and family members have a common responsibility to ensure the best course of treatment and everyday care for residents who often cannot speak for themselves. Understanding the difference between instrumental and preservative care, and who the proper agent is to provide care in each category will not only improve staff/family interactions, but residential care in general. The Resident Enrichment and Activity Program improves the family/staff relationship obliquely by involving family in social activities; the Family Involvement in Care program, and the Patterns in Caregiving program directly target the relationship and involve the facility's administration to effect policy change.

Novel neutron sources at the Radiological Research Accelerator Facility.

PubMed

Xu, Yanping; Garty, Guy; Marino, Stephen A; Massey, Thomas N; Randers-Pehrson, Gerhard; Johnson, Gary W; Brenner, David J

2012-03-16

Since the 1960s, the Radiological Research Accelerator Facility (RARAF) has been providing researchers in biology, chemistry and physics with advanced irradiation techniques, using charged particles, photons and neutrons.We are currently developing a unique facility at RARAF, to simulate neutron spectra from an improvised nuclear device (IND), based on calculations of the neutron spectrum at 1.5 km from the epicenter of the Hiroshima atom bomb. This is significantly different from a standard fission spectrum, because the spectrum changes as the neutrons are transported through air, and is dominated by neutron energies between 0.05 and 8 MeV. This facility will be based on a mixed proton/deuteron beam impinging on a thick beryllium target.A second, novel facility under development is our new neutron microbeam. The neutron microbeam will, for the first time, provide a kinematically collimated neutron beam, 10-20 micron in diameter. This facility is based on a Proton Microbeam, impinging on a thin lithium target near the threshold of the (7)Li(p,n)(7)Be reaction. This novel neutron microbeam will enable studies of neutron damage to small targets, such as single cells, individual organs within small animals or microelectronic components.

Novel neutron sources at the Radiological Research Accelerator Facility

NASA Astrophysics Data System (ADS)

Xu, Y.; Garty, G.; Marino, S. A.; Massey, T. N.; Randers-Pehrson, G.; Johnson, G. W.; Brenner, D. J.

2012-03-01

Since the 1960s, the Radiological Research Accelerator Facility (RARAF) has been providing researchers in biology, chemistry and physics with advanced irradiation techniques, using charged particles, photons and neutrons. We are currently developing a unique facility at RARAF, to simulate neutron spectra from an improvised nuclear device (IND), based on calculations of the neutron spectrum at 1.5 km from the epicenter of the Hiroshima atom bomb. This is significantly different from a standard fission spectrum, because the spectrum changes as the neutrons are transported through air, and is dominated by neutron energies between 0.05 and 8 MeV. This facility will be based on a mixed proton/deuteron beam impinging on a thick beryllium target. A second, novel facility under development is our new neutron microbeam. The neutron microbeam will, for the first time, provide a kinematically collimated neutron beam, 10-20 micron in diameter. This facility is based on a proton microbeam, impinging on a thin lithium target near the threshold of the 7Li(p,n)7Be reaction. This novel neutron microbeam will enable studies of neutron damage to small targets, such as single cells, individual organs within small animals or microelectronic components.

Large Dog Relinquishment to Two Municipal Facilities in New York City and Washington, D.C.: Identifying Targets for Intervention

PubMed Central

Weiss, Emily; Slater, Margaret; Garrison, Laurie; Drain, Natasha; Dolan, Emily; Scarlett, Janet M.; Zawistowski, Stephen L.

2014-01-01

Simple Summary While the overall trend in euthanasia has been decreasing nationally, large dogs are at a higher risk of euthanasia than other-sized dogs in most animal shelters in the United States. We hypothesized that one way to increase the lives saved with regard to large dogs in shelters is to keep them home in the first place when possible. Our research is the first to collect data in New York City and Washington, D.C., identifying the process leading to the owner relinquishment of large dogs. We found that targets for interventions to decrease large dog relinquishment are likely different in each community. Abstract While the overall trend in euthanasia has been decreasing nationally, large dogs are at a higher risk of euthanasia than other sized dogs in most animal shelters in the United States. We hypothesized one way to increase the lives saved with respect to these large dogs is to keep them home when possible. In order to develop solutions to decrease relinquishment, a survey was developed to learn more about the reasons owners relinquish large dogs. The survey was administered to owners relinquishing their dogs at two large municipal facilities, one in New York City and one in Washington, D.C. There were 157 responses between the two facilities. We found both significant similarities and differences between respondents and their dogs from the two cities. We identified opportunities to potentially support future relinquishers and found that targets for interventions are likely different in each community. PMID:26480315

Design and construction of a spectrometer facility and experiment for intermediate energy proton scattering on helium. [Wave functions, preliminary experimental techniques

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

Rolfe, R.M.

1976-12-01

The goal of the research was to investigate proton scattering on nuclei at intermediate energies and in particular to investigate proton scattering on helium. A theoretical investigation of the helium nucleus and the nature of the intermediate energy interaction, design and optimization of an energy-loss spectrometer facility for proton-nucleus scattering, and the unique superfluid helium target and experimental design are discussed.

Aberration hubs in protein interaction networks highlight actionable targets in cancer.

PubMed

Karimzadeh, Mehran; Jandaghi, Pouria; Papadakis, Andreas I; Trainor, Sebastian; Rung, Johan; Gonzàlez-Porta, Mar; Scelo, Ghislaine; Vasudev, Naveen S; Brazma, Alvis; Huang, Sidong; Banks, Rosamonde E; Lathrop, Mark; Najafabadi, Hamed S; Riazalhosseini, Yasser

2018-05-18

Despite efforts for extensive molecular characterization of cancer patients, such as the international cancer genome consortium (ICGC) and the cancer genome atlas (TCGA), the heterogeneous nature of cancer and our limited knowledge of the contextual function of proteins have complicated the identification of targetable genes. Here, we present Aberration Hub Analysis for Cancer (AbHAC) as a novel integrative approach to pinpoint aberration hubs, i.e. individual proteins that interact extensively with genes that show aberrant mutation or expression. Our analysis of the breast cancer data of the TCGA and the renal cancer data from the ICGC shows that aberration hubs are involved in relevant cancer pathways, including factors promoting cell cycle and DNA replication in basal-like breast tumors, and Src kinase and VEGF signaling in renal carcinoma. Moreover, our analysis uncovers novel functionally relevant and actionable targets, among which we have experimentally validated abnormal splicing of spleen tyrosine kinase as a key factor for cell proliferation in renal cancer. Thus, AbHAC provides an effective strategy to uncover novel disease factors that are only identifiable by examining mutational and expression data in the context of biological networks.

The South African isotope facility project

NASA Astrophysics Data System (ADS)

Bark, R. A.; Barnard, A. H.; Conradie, J. L.; de Villiers, J. G.; van Schalkwyk, P. A.

2018-05-01

The South African Isotope Facility (SAIF) is a project in which iThemba LABS plans to build a radioactive-ion beam (RIB) facility. The project is divided into the Accelerator Centre of Exotic Isotopes (ACE Isotopes) and the Accelerator Centre for Exotic Beams (ACE Beams). For ACE Isotopes, a high-current, 70 MeV cyclotron will be acquired to take radionuclide production off the existing Separated Sector Cyclotron (SSC). A freed up SSC will then be available for an increased tempo of nuclear physics research and to serve as a driver accelerator for the ACE Beams project, in which protons will be used for the direct fission of Uranium, producing beams of fission fragments. The ACE Beams project has begun with "LeRIB" - a Low Energy RIB facility, now under construction. In a collaboration with INFN Legnaro, the target/ion-source "front-end" will be a copy of the front-end developed for the SPES project. A variety of targets may be inserted into the SPES front-end; a uranium-carbide target has been designed to produce up to 2 × 1013 fission/s using a 70 MeV proton beam of 150 µA intensity.

A network model of genomic hormone interactions underlying dementia and its translational validation through serendipitous off-target effect

PubMed Central

2013-01-01

Background While the majority of studies have focused on the association between sex hormones and dementia, emerging evidence supports the role of other hormone signals in increasing dementia risk. However, due to the lack of an integrated view on mechanistic interactions of hormone signaling pathways associated with dementia, molecular mechanisms through which hormones contribute to the increased risk of dementia has remained unclear and capacity of translating hormone signals to potential therapeutic and diagnostic applications in relation to dementia has been undervalued. Methods Using an integrative knowledge- and data-driven approach, a global hormone interaction network in the context of dementia was constructed, which was further filtered down to a model of convergent hormone signaling pathways. This model was evaluated for its biological and clinical relevance through pathway recovery test, evidence-based analysis, and biomarker-guided analysis. Translational validation of the model was performed using the proposed novel mechanism discovery approach based on ‘serendipitous off-target effects’. Results Our results reveal the existence of a well-connected hormone interaction network underlying dementia. Seven hormone signaling pathways converge at the core of the hormone interaction network, which are shown to be mechanistically linked to the risk of dementia. Amongst these pathways, estrogen signaling pathway takes the major part in the model and insulin signaling pathway is analyzed for its association to learning and memory functions. Validation of the model through serendipitous off-target effects suggests that hormone signaling pathways substantially contribute to the pathogenesis of dementia. Conclusions The integrated network model of hormone interactions underlying dementia may serve as an initial translational platform for identifying potential therapeutic targets and candidate biomarkers for dementia-spectrum disorders such as Alzheimer�

A Global Survey of Deep Underground Facilities; Examples of Geotechnical and Engineering Capabilities, Achievements, Challenges (Mines, Shafts, Tunnels, Boreholes, Sites and Underground Facilities for Nuclear Waste and Physics R&D): A Guide to Interactive Global Map Layers, Table Database, References and Notes

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

Tynan, Mark C.; Russell, Glenn P.; Perry, Frank V.

These associated tables, references, notes, and report present a synthesis of some notable geotechnical and engineering information used to create four interactive layer maps for selected: 1) deep mines and shafts; 2) existing, considered or planned radioactive waste management deep underground studies or disposal facilities 3) deep large diameter boreholes, and 4) physics underground laboratories and facilities from around the world. These data are intended to facilitate user access to basic information and references regarding “deep underground” facilities, history, activities, and plans. In general, the interactive maps and database provide each facility’s approximate site location, geology, and engineered features (e.g.:more » access, geometry, depth, diameter, year of operations, groundwater, lithology, host unit name and age, basin; operator, management organization, geographic data, nearby cultural features, other). Although the survey is not comprehensive, it is representative of many of the significant existing and historical underground facilities discussed in the literature addressing radioactive waste management and deep mined geologic disposal safety systems. The global survey is intended to support and to inform: 1) interested parties and decision makers; 2) radioactive waste disposal and siting option evaluations, and 3) safety case development applicable to any mined geologic disposal facility as a demonstration of historical and current engineering and geotechnical capabilities available for use in deep underground facility siting, planning, construction, operations and monitoring.« less

Biomimicking Platelet-Monocyte Interactions as a Novel Targeting Strategy for Heart Healing.

PubMed

Cheng, Bill; Toh, Elsie K W; Chen, Kun-Hung; Chang, Yuan-Chih; Hu, Che-Ming J; Wu, Han-Chung; Chau, Lee-Young; Chen, Peilin; Hsieh, Patrick C H

2016-10-01

In patients who survive myocardial infarction, many go on to develop congestive heart failure (CHF). Despite ongoing efforts to develop new approaches for postinfarction therapy, there are still no effective therapeutic options available to CHF patients. Currently, the delivery of cardioprotective drugs relies entirely on passive uptake via the enhanced permeability and retention (EPR) effect which occurs in proximity to the infarction site. However, in ischemic disease, unlike in cancer, the EPR effect only exists for a short duration postinfarction and thus insufficient for meaningful cardioprotection. Splenic monocytes are recruited to the heart in large numbers postinfarction, and are known to interact with platelets during circulation. Therefore, the strategy is to exploit this interaction by developing platelet-like proteoliposomes (PLPs), biomimicking platelet interactions with circulating monocytes. PLPs show strong binding affinity for monocytes but not for endothelial cells in vitro, mimicking normal platelet activity. Furthermore, intravital multiphoton imaging shows that comparing to plain liposomes, PLPs do not aggregate on uninjured endothelium but do accumulate at the injury site 72 h postinfarction. Importantly, PLPs enhance the targeting of anti-inflammatory drug, cobalt protoporphyrin, to the heart in an EPR-independent manner, which result in better therapeutic outcome. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Implementing Target Value Design.

PubMed

Alves, Thais da C L; Lichtig, Will; Rybkowski, Zofia K

2017-04-01

An alternative to the traditional way of designing projects is the process of target value design (TVD), which takes different departure points to start the design process. The TVD process starts with the client defining an allowable cost that needs to be met by the design and construction teams. An expected cost in the TVD process is defined through multiple interactions between multiple stakeholders who define wishes and others who define ways of achieving these wishes. Finally, a target cost is defined based on the expected profit the design and construction teams are expecting to make. TVD follows a series of continuous improvement efforts aimed at reaching the desired goals for the project and its associated target value cost. The process takes advantage of rapid cycles of suggestions, analyses, and implementation that starts with the definition of value for the client. In the traditional design process, the goal is to identify user preferences and find solutions that meet the needs of the client's expressed preferences. In the lean design process, the goal is to educate users about their values and advocate for a better facility over the long run; this way owners can help contractors and designers to identify better solutions. This article aims to inform the healthcare community about tools and techniques commonly used during the TVD process and how they can be used to educate and support project participants in developing better solutions to meet their needs now as well as in the future.

Wind turbine wake interactions at field scale: An LES study of the SWiFT facility

NASA Astrophysics Data System (ADS)

Yang, Xiaolei; Boomsma, Aaron; Barone, Matthew; Sotiropoulos, Fotis

2014-06-01

The University of Minnesota Virtual Wind Simulator (VWiS) code is employed to simulate turbine/atmosphere interactions in the Scaled Wind Farm Technology (SWiFT) facility developed by Sandia National Laboratories in Lubbock, TX, USA. The facility presently consists of three turbines and the simulations consider the case of wind blowing from South such that two turbines are in the free stream and the third turbine in the direct wake of one upstream turbine with separation of 5 rotor diameters. Large-eddy simulation (LES) on two successively finer grids is carried out to examine the sensitivity of the computed solutions to grid refinement. It is found that the details of the break-up of the tip vortices into small-scale turbulence structures can only be resolved on the finer grid. It is also shown that the power coefficient CP of the downwind turbine predicted on the coarse grid is somewhat higher than that obtained on the fine mesh. On the other hand, the rms (root-mean-square) of the CP fluctuations are nearly the same on both grids, although more small-scale turbulence structures are resolved upwind of the downwind turbine on the finer grid.

Program for studying fundamental interactions at the PIK reactor facilities

NASA Astrophysics Data System (ADS)

Serebrov, A. P.; Vassiljev, A. V.; Varlamov, V. E.; Geltenbort, P.; Gridnev, K. A.; Dmitriev, S. P.; Dovator, N. A.; Egorov, A. I.; Ezhov, V. F.; Zherebtsov, O. M.; Zinoviev, V. G.; Ivochkin, V. G.; Ivanov, S. N.; Ivanov, S. A.; Kolomensky, E. A.; Konoplev, K. A.; Krasnoschekova, I. A.; Lasakov, M. S.; Lyamkin, V. A.; Martemyanov, V. P.; Murashkin, A. N.; Neustroev, P. V.; Onegin, M. S.; Petelin, A. L.; Pirozhkov, A. N.; Polyushkin, A. O.; Prudnikov, D. V.; Ryabov, V. L.; Samoylov, R. M.; Sbitnev, S. V.; Fomin, A. K.; Fomichev, A. V.; Zimmer, O.; Cherniy, A. V.; Shoka, I. V.

2016-05-01

A research program aimed at studying fundamental interactions by means of ultracold and polarized cold neutrons at the GEK-4-4' channel of the PIK reactor is presented. The apparatus to be used includes a source of cold neutrons in the heavy-water reflector of the reactor, a source of ultracold neutrons based on superfluid helium and installed in a cold-neutron beam extracted from the GEK-4 channel, and a number of experimental facilities in neutron beams. An experiment devoted to searches for the neutron electric dipole moment and an experiment aimed at a measurement the neutron lifetime with the aid of a large gravitational trap are planned to be performed in a beam of ultracold neutrons. An experiment devoted to measuring neutron-decay asymmetries with the aid of a superconducting solenoid is planned in a beam of cold polarized neutrons from the GEK-4' channel. The second ultracold-neutron source and an experiment aimed at measuring the neutron lifetime with the aid of a magnetic trap are planned in the neutron-guide system of the GEK-3 channel. In the realms of neutrino physics, an experiment intended for sterile-neutrino searches is designed. The state of affairs around the preparation of the experimental equipment for this program is discussed.

Target weight achievement and ultrafiltration rate thresholds: potential patient implications.

PubMed

Flythe, Jennifer E; Assimon, Magdalene M; Overman, Robert A

2017-06-02

Higher ultrafiltration (UF) rates and extracellular hypo- and hypervolemia are associated with adverse outcomes among maintenance hemodialysis patients. The Centers for Medicare and Medicaid Services recently considered UF rate and target weight achievement measures for ESRD Quality Incentive Program inclusion. The dual measures were intended to promote balance between too aggressive and too conservative fluid removal. The National Quality Forum endorsed the UF rate measure but not the target weight measure. We examined the proposed target weight measure and quantified weight gains if UF rate thresholds were applied without treatment time (TT) extension or interdialytic weight gain (IDWG) reduction. Data were taken from the 2012 database of a large dialysis organization. Analyses considered 152,196 United States hemodialysis patients. We described monthly patient and dialysis facility target weight achievement patterns and examined differences in patient characteristics across target weight achievement status and differences in facilities across target weight measure scores. We computed the cumulative, theoretical 1-month fluid-related weight gain that would occur if UF rates were capped at 13 mL/h/kg without concurrent TT extension or IDWG reduction. Target weight achievement patterns were stable over the year. Patients who did not achieve target weight (post-dialysis weight ≥ 1 kg above or below target weight) tended to be younger, black and dialyze via catheter, and had shorter dialysis vintage, greater body weight, higher UF rate and more missed treatments compared with patients who achieved target weight. Facilities had, on average, 27.1 ± 9.7% of patients with average post-dialysis weight ≥ 1 kg above or below the prescribed target weight. In adjusted analyses, facilities located in the midwest and south and facilities with higher proportions of black and Hispanic patients and higher proportions of patients with shorter TTs were more likely to

The National Ignition Facility (NIF) as a User Facility

NASA Astrophysics Data System (ADS)

Keane, Christopher; NIF Team

2013-10-01

The National Ignition Facility (NIF) has made significant progress towards operation as a user facility. Through June 2013, NIF conducted over 1200 experiments in support of ICF, HED science, and development of facility capabilities. The NIF laser has met or achieved all specifications and a wide variety of diagnostic and target fabrication capabilities are in place. A NIF User Group and associated Executive Board have been formed. Two User Group meetings have been conducted since formation of the User Group. NIF experiments in fundamental science have provided important new results. NIF ramp compression experiments have been conducted using diamond and iron, with EOS results obtained at pressures up to approximately 50 Mbar and 8 Mbar, respectively. Initial experiments in supernova hydrodynamics, the fundamental physics of the Rayleigh-Taylor instability, and equation of state in the Gbar pressure regime have also been conducted. This presentation will discuss the fundamental science program at NIF, including the proposal solicitation and scientific review processes and other aspects of user facility operation. This work was performed under the auspices of the Lawrence Livermore National Security, LLC, (LLNS) under Contract No. DE-AC52-07NA27344.

High-efficiency-release targets for use at ISOL facilities: computational design

NASA Astrophysics Data System (ADS)

Liu, Y.; Alton, G. D.

1999-12-01

This report describes efforts made at the Oak Ridge National Laboratory to design high-efficiency-release targets that simultaneously incorporate the short diffusion lengths, high permeabilities, controllable temperatures, and heat-removal properties required for the generation of useful radioactive ion beam (RIB) intensities for nuclear physics and astrophysics research using the isotope separation on-line (ISOL) technique. Short diffusion lengths are achieved either by using thin fibrous target materials or by coating thin layers of selected target material onto low-density carbon fibers such as reticulated-vitreous-carbon fiber (RVCF) or carbon-bonded-carbon fiber (CBCF) to form highly permeable composite target matrices. Computational studies that simulate the generation and removal of primary beam deposited heat from target materials have been conducted to optimize the design of target/heat-sink systems for generating RIBs. The results derived from diffusion release-rate simulation studies for selected targets and thermal analyses of temperature distributions within a prototype target/heat-sink system subjected to primary ion beam irradiation are presented in this report.

Genome-wide identification of translationally inhibited and degraded miR-155 targets using RNA-interacting protein-IP

PubMed Central

Meier, Jan; Hovestadt, Volker; Zapatka, Marc; Pscherer, Armin; Lichter, Peter; Seiffert, Martina

2013-01-01

MicroRNAs (miRNAs) are single-stranded, small, non-coding RNAs, which fine-tune protein expression by degrading and/or translationally inhibiting mRNAs. Manipulation of miRNA expression in animal models frequently results in severe phenotypes indicating their relevance in controlling cellular functions, most likely by interacting with multiple targets. To better understand the effect of miRNA activities, genome-wide analysis of their targets are required. MicroRNA profiling as well as transcriptome analysis upon enforced miRNA expression were frequently used to investigate their relevance. However, these approaches often fail to identify relevant miRNAs targets. Therefore, we tested the precision of RNA-interacting protein immunoprecipitation (RIP) using AGO2-specific antibodies, a core component of the “RNA-induced silencing complex” (RISC), followed by RNA sequencing (Seq) in a defined cellular system, the HEK293T cells with stable, ectopic expression of miR-155. Thereby, we identified 100 AGO2-associated mRNAs in miR-155-expressing cells, of which 67 were in silico predicted miR-155 target genes. An integrated analysis of the corresponding expression profiles indicated that these targets were either regulated by mRNA decay or by translational repression. Of the identified miR-155 targets, 17 were related to cell cycle control, suggesting their involvement in the observed increase in cell proliferation of HEK293T cells upon miR-155 expression. Additional, secondary changes within the gene expression profile were detected and might contribute to this phenotype as well. Interestingly, by analyzing RIP-Seq data of HEK-293T cells and two B-cell lines we identified a recurrent disproportional enrichment of several miRNAs, including miR-155 and miRNAs of the miR-17-92 cluster, in the AGO2-associated precipitates, suggesting discrepancies in miRNA expression and activity. PMID:23673373

TARGET: Rapid Capture of Process Knowledge

NASA Technical Reports Server (NTRS)

Ortiz, C. J.; Ly, H. V.; Saito, T.; Loftin, R. B.

1993-01-01

TARGET (Task Analysis/Rule Generation Tool) represents a new breed of tool that blends graphical process flow modeling capabilities with the function of a top-down reporting facility. Since NASA personnel frequently perform tasks that are primarily procedural in nature, TARGET models mission or task procedures and generates hierarchical reports as part of the process capture and analysis effort. Historically, capturing knowledge has proven to be one of the greatest barriers to the development of intelligent systems. Current practice generally requires lengthy interactions between the expert whose knowledge is to be captured and the knowledge engineer whose responsibility is to acquire and represent the expert's knowledge in a useful form. Although much research has been devoted to the development of methodologies and computer software to aid in the capture and representation of some types of knowledge, procedural knowledge has received relatively little attention. In essence, TARGET is one of the first tools of its kind, commercial or institutional, that is designed to support this type of knowledge capture undertaking. This paper will describe the design and development of TARGET for the acquisition and representation of procedural knowledge. The strategies employed by TARGET to support use by knowledge engineers, subject matter experts, programmers and managers will be discussed. This discussion includes the method by which the tool employs its graphical user interface to generate a task hierarchy report. Next, the approach to generate production rules for incorporation in and development of a CLIPS based expert system will be elaborated. TARGET also permits experts to visually describe procedural tasks as a common medium for knowledge refinement by the expert community and knowledge engineer making knowledge consensus possible. The paper briefly touches on the verification and validation issues facing the CLIPS rule generation aspects of TARGET. A description of

Target diagnostics for commissioning the AWE HELEN Laser Facility 100 TW chirped pulse amplification beam

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

Eagleton, R. T.; Clark, E. L.; Davies, H. M.

2006-10-15

The capability of the HELEN laser at the Atomic Weapons Establishment Aldermaston has been enhanced by the addition of a short-pulse laser beam to augment the twin opposing nanosecond time scale beams. The short-pulse beam utilizes the chirped pulse amplification (CPA) technique and is capable of delivering up to 60 J on target in a 500 fs pulse, around 100 TW, at the fundamental laser wavelength of 1.054 {mu}m. During the commissioning phase a number of diagnostic systems have been fielded, these include: x-ray pinhole imaging of the laser heated spot, charged particle time of flight, thermoluminescent dosimeter array, calibratedmore » radiochromic film, and CR39 nuclear track detector. These diagnostic systems have been used to verify the performance of the CPA beam to achieve a focused intensity of around 10{sup 19} W cm{sup -2} and to underwrite the facility radiological safety system.« less

The application of an MPM-MFM method for simulating weapon-target interaction.

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

Ma, X.; Zou, Q.; Zhang, D. Z.

2005-01-01

During the past two decades, Los Alamos National Laboratory (LANL) has developed computational algorithms and software for analysis of multiphase flow suitable for high-speed projectile penetration of metallic and nonmetallic materials, using a material point method (MPM)-multiphase flow method (MFM). Recently, ACTA has teamed with LANL to advance a computational algorithm for simulating complex weapon-target interaction for penetrating and exploding munitions, such as tank rounds and artillery shells, as well as non-exploding kinetic energy penetrators. This paper will outline the mathematical basis for the MPM-MFM method as implemented in LANL's CartaBlanca code. CartaBlanca, written entirely in Java using object-oriented design,more » is used to solve complex problems involving (a) failure and penetration of solids, (b) heat transfer, (c) phase change, (d) chemical reactions, and (e) multiphase flow. We will present its application to the penetration of a steel target by a tungsten cylinder and compare results with time-resolved experimental data published by Anderson, et. al., Int. J. Impact Engng., Vol. 16, No. 1, pp. 1-18, 1995.« less

Novel neutron sources at the Radiological Research Accelerator Facility

PubMed Central

Xu, Yanping; Garty, Guy; Marino, Stephen A.; Massey, Thomas N.; Randers-Pehrson, Gerhard; Johnson, Gary W.; Brenner, David J.

2012-01-01

Since the 1960s, the Radiological Research Accelerator Facility (RARAF) has been providing researchers in biology, chemistry and physics with advanced irradiation techniques, using charged particles, photons and neutrons. We are currently developing a unique facility at RARAF, to simulate neutron spectra from an improvised nuclear device (IND), based on calculations of the neutron spectrum at 1.5 km from the epicenter of the Hiroshima atom bomb. This is significantly different from a standard fission spectrum, because the spectrum changes as the neutrons are transported through air, and is dominated by neutron energies between 0.05 and 8 MeV. This facility will be based on a mixed proton/deuteron beam impinging on a thick beryllium target. A second, novel facility under development is our new neutron microbeam. The neutron microbeam will, for the first time, provide a kinematically collimated neutron beam, 10–20 micron in diameter. This facility is based on a Proton Microbeam, impinging on a thin lithium target near the threshold of the 7Li(p,n)7Be reaction. This novel neutron microbeam will enable studies of neutron damage to small targets, such as single cells, individual organs within small animals or microelectronic components. PMID:22545061

Novel neutron sources at the Radiological Research Accelerator Facility

DOE PAGES

Xu, Yanping; Garty, G.; Marino, S. A.; ...

2012-03-16

Since the 1960s, the Radiological Research Accelerator Facility (RARAF) has been providing researchers in biology, chemistry and physics with advanced irradiation techniques, using charged particles, photons and neutrons. We are currently developing a unique facility at RARAF, to simulate neutron spectra from an improvised nuclear device (IND), based on calculations of the neutron spectrum at 1.5 km from the epicenter of the Hiroshima atom bomb. This is significantly different from a standard fission spectrum, because the spectrum changes as the neutrons are transported through air, and is dominated by neutron energies between 0.05 and 8 MeV. This facility will bemore » based on a mixed proton/deuteron beam impinging on a thick beryllium target. A second, novel facility under development is our new neutron microbeam. The neutron microbeam will, for the first time, provide a kinematically collimated neutron beam, 10-20 micron in diameter. This facility is based on a proton microbeam, impinging on a thin lithium target near the threshold of the Li-7(p,n)Be-7 reaction. Lastly, this novel neutron microbeam will enable studies of neutron damage to small targets, such as single cells, individual organs within small animals or microelectronic components.« less

Interactive Querying Techniques for an Office Filing Facility.

ERIC Educational Resources Information Center

Morrissey, J. M.; And Others

1986-01-01

Proposes a "Model of Querying" for users of office filing facilities and discusses its motivation, aspects, attributes, and advantages. A review of current information systems and attempts to combine information retrieval, artificial intelligence, and database management techniques leads to conclusion that no resultant system is adequate…

Solid hydrogen target for laser driven proton acceleration

NASA Astrophysics Data System (ADS)

Perin, J. P.; Garcia, S.; Chatain, D.; Margarone, D.

2015-05-01

The development of very high power lasers opens up new horizons in various fields, such as laser plasma acceleration in Physics and innovative approaches for proton therapy in Medicine. Laser driven proton acceleration is commonly based on the so-called Target Normal Sheath Acceleration (TNSA) mechanisms: a high power laser is focused onto a solid target (thin metallic or plastic foil) and interact with matter at very high intensity, thus generating a plasma; as a consequence "hot" electrons are produced and move into the forward direction through the target. Protons are generated at the target rear side, electrons try to escape from the target and an ultra-strong quasi-electrostatic field (~1TV/m) is generated. Such a field can accelerate protons with a wide energy spectrum (1-200 MeV) in a few tens of micrometers. The proton beam characteristics depend on the laser parameters and on the target geometry and nature. This technique has been validated experimentally in several high power laser facilities by accelerating protons coming from hydrogenated contaminant (mainly water) at the rear of metallic target, however, several research groups are investigating the possibility to perform experiments by using "pure" hydrogen targets. In this context, the low temperature laboratory at CEA-Grenoble has developed a cryostat able to continuously produce a thin hydrogen ribbon (from 40 to 100 microns thick). A new extrusion concept, without any moving part has been carried out, using only the thermodynamic properties of the fluid. First results and perspectives are presented in this paper.

Modeling Laser-Plasma Interactions at Direct-Drive Ignition-Relevant Plasma Conditions at the National Ignition Facility

NASA Astrophysics Data System (ADS)

Solodov, A. A.; Rosenberg, M. J.; Myatt, J. F.; Epstein, R.; Seka, W.; Hohenberger, M.; Short, R. W.; Shaw, J. G.; Regan, S. P.; Froula, D. H.; Radha, P. B.; Bates, J. W.; Schmitt, A. J.; Michel, P.; Moody, J. D.; Ralph, J. E.; Turnbull, D. P.; Barrios, M. A.

2016-10-01

Laser-plasma interaction instabilities, such as two-plasmon decay (TPD) and stimulated Raman scattering (SRS), can be detrimental for direct-drive inertial confinement fusion because of target preheat by generated high-energy electrons. The radiation-hydrodynamics code DRACO has been used to design planar-target experiments that generate plasma and interaction conditions relevant to direct-drive-ignition designs (IL 1015 W / cm 2 , Te > 3 KeV density gradient scale lengths of Ln 600 μm) . The hot-electron temperature of 40to50keV and the fraction of laser energy converted to hot electrons of 0.5to were inferred based on comparing the simulated and experimentally observed x-ray emission when the laser intensity at the quarter-critical surface increased from 6 to 15 ×1014 W / cm 2 . The measured SRS energy was sufficient to explain the observed total energy in hot electrons. Implications for ignition-scale direct-drive experiments and hot-electron preheat mitigation using mid- Z ablators will be discussed. This material is based upon work supported by the Department of Energy National Nuclear Security Administration under Award Number DE-NA0001944.

Recent progress on the National Ignition Facility advanced radiographic capability

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

Wegner, P.; Bowers, M.; Chen, H.

2016-01-08

The National Ignition Facility (NIF) is a megajoule (million-joule)-class laser and experimental facility built for Stockpile Stewardship and High Energy Density (HED) science research [1]. Up to several times a day, 192 laser pulses from NIF's 192 laser beamlines converge on a millimeter-scale target located at the center of the facility's 10-meter diameter target chamber. The carefully synchronized pulses, typically a few nanoseconds (billionths of a second) in duration and co-times to better than 20 picoseconds (trillionths of a second), a deliver a combined energy of up to 1.8 megajoules and a peak power of 500 terawatts (trillion watts). Furthermore,more » this drives temperatures inside the target to tens of millions of degrees and pressures to many billion times greater than Earth's atmosphere.« less

The RIB production target for the SPES project

NASA Astrophysics Data System (ADS)

Monetti, Alberto; Andrighetto, Alberto; Petrovich, Carlo; Manzolaro, Mattia; Corradetti, Stefano; Scarpa, Daniele; Rossetto, Francesco; Martinez Dominguez, Fernando; Vasquez, Jesus; Rossignoli, Massimo; Calderolla, Michele; Silingardi, Roberto; Mozzi, Aldo; Borgna, Francesca; Vivian, Gianluca; Boratto, Enrico; Ballan, Michele; Prete, Gianfranco; Meneghetti, Giovanni

2015-10-01

Facilities making use of the Isotope Separator On-Line (ISOL) method for the production of Radioactive Ion Beams (RIB) attract interest because they can be used for nuclear structure and reaction studies, astrophysics research and interdisciplinary applications. The ISOL technique is based on the fast release of the nuclear reaction products from the chosen target material together with their ionization into short-lived nuclei beams. Within this context, the SPES (Selective Production of Exotic Species) facility is now under construction in Italy at INFN-LNL (Istituto Nazionale di Fisica Nucleare — Laboratori Nazionali di Legnaro). The SPES facility will produce RIBs mainly from n-rich isotopes obtained by a 40 MeV cyclotron proton beam (200 μA) directly impinging on a uranium carbide multi-foil fission target. The aim of this work is to describe and update, from a comprehensive point of view, the most important results obtained by the analysis of the on-line behavior of the SPES production target assembly. In particular an improved target configuration has been studied by comparing different codes and physics models: the thermal analyses and the isotope production are re-evaluated. Then some consequent radioprotection aspects, which are essential for the installation and operation of the facility, are presented.

High power neutron production targets

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

Wender, S.

1996-06-01

The author describes issues of concern in the design of targets and associated systems for high power neutron production facilities. The facilities include uses for neutron scattering, accelerator driven transmutation, accelerator production of tritium, short pulse spallation sources, and long pulse spallation sources. Each of these applications requires a source with different design needs and consequently different implementation in practise.

Tyrosine dephosphorylation enhances the therapeutic target activity of epidermal growth factor receptor (EGFR) by disrupting its interaction with estrogen receptor (ER).

PubMed

Ma, Shao; Yin, Ning; Qi, Xiaomei; Pfister, Sandra L; Zhang, Mei-Jie; Ma, Rong; Chen, Guan

2015-05-30

Protein-protein interactions can increase or decrease its therapeutic target activity and the determining factors involved, however, are largely unknown. Here, we report that tyrosine-dephosphorylation of epidermal growth factor receptor (EGFR) increases its therapeutic target activity by disrupting its interaction with estrogen receptor (ER). Protein tyrosine phosphatase H1 (PTPH1) dephosphorylates the tyrosine kinase EGFR, disrupts its interaction with the nuclear receptor ER, and increases breast cancer sensitivity to small molecule tyrosine kinase inhibitors (TKIs). These effects require PTPH1 catalytic activity and its interaction with EGFR, suggesting that the phosphatase may increase the sensitivity by dephosphorylating EGFR leading to its dissociation with ER. Consistent with this notion, a nuclear-localization defective ER has a higher EGFR-binding activity and confers the resistance to TKI-induced growth inhibition. Additional analysis show that PTPH1 stabilizes EGFR, stimulates the membranous EGFR accumulation, and enhances the growth-inhibitory activity of a combination therapy of TKIs with an anti-estrogen. Since EGFR and ER both are substrates for PTPH1 in vitro and in intact cells, these results indicate that an inhibitory EGFR-ER protein complex can be switched off through a competitive enzyme-substrate binding. Our results would have important implications for the treatment of breast cancer with targeted therapeutics.

Emergency department access targets and the older patient: a retrospective cohort study of emergency department presentations by people living in residential aged care facilities.

PubMed

Street, Maryann; Marriott, Jonathon R; Livingston, Patricia M

2012-11-01

There is limited research on the effect of emergency access targets on health outcomes for older patients from Residential Aged Care Facilities. The aims were to: (1) identify length of stay for Residential Aged Care patients relative to access targets; and (2) examine hospital admission rates, readmission rates, inpatient costs and mortality. Retrospective cohort study of all emergency presentations for Residential Aged Care patients in 2009 at one Australian metropolitan health service. The 4637 emergency presentations by 3184 Residential Aged Care patients in 2009 represented 3.4% of all emergency presentations. Mean length of stay was 7.9 hours (SD=4.5 hours); 84% of Residential Aged Care patients remained in the Emergency Department longer than four hours. Admitted patients were 3.6 times more likely to spend more than eight hours in the Emergency Department compared with those not admitted (p<0.001). Patients in the urgent triage category were 9.5 times more likely to spend more than eight hours in the Emergency Department compared to patients triaged as non-urgent (p<0.001). Inpatient costs were associated with length of admission and median cost per day was $AUD 1175. Few Residential Aged Care patients were discharged within the four hours access target. This has implications for health care outcomes and costs associated with providing emergency care for patients living in Residential Aged Care Facilities. Copyright © 2012 College of Emergency Nursing Australasia Ltd. Published by Elsevier Ltd. All rights reserved.

Interactive Game for Teaching Laser Amplification Used at the National Ignition Facility

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

Lin, E

The purpose of this project was to create an interactive game to expose high school students to concepts in laser amplification by demonstrating the National Ignition Facility's main amplifier at Lawrence Livermore National Laboratory. To succeed, the game had to be able to communicate effectively the basic concepts of laser amplification as accurately as possible and to be capable of exposing as many students as possible. Since concepts need to be communicated in a way that students understand, the Science Content Standards for California Public Schools were used to make assumptions about high school students knowledge of light. Effectively communicatingmore » a new concept necessitates the omission on terminology and symbolism. Therefore, creating a powerful experience was ideal for communicating this material. Various methods of reinforcing this experience ranging from color choice to abstractions kept the student focused on the game to maximize concept retention. The program was created in Java to allow the creation of a Java Applet that can be embedded onto a webpage, which is a perfect medium for mass exposure. Because a game requires interaction, the game animations had to be easily manipulated to enable the program to respond to user input. Image sprites, as opposed to image folders, were used in these animations to minimize the number of Hypertext Transfer Protocol connections, and thus, significantly reduce the transfer time of necessary animation files. These image sprites were loaded and cropped into a list of animation frames. Since the caching of large transition animations caused the Java Virtual Machine to run out of memory, large animations were implemented as animated Graphics Interchange Format images since transitions require no interaction, and thus, no frame manipulation was needed. This reduced the animation's memory footprint. The first version of this game was completed during this project. Future work for the project could include the

Manifestation of anharmonic resonance in the interaction of intense ultrashort laser pulses with microstructured targets

NASA Astrophysics Data System (ADS)

Dalui, Malay; Kundu, M.; Madhu Trivikram, T.; Ray, Krishanu; Krishnamurthy, M.

2016-10-01

Identification of the basic processes responsible for an efficient heating of intense laser produced plasmas is one of the important features of high intensity laser matter interaction studies. Collisionless absorption due to the anharmonicity in the self-consistent electrostatic potential of the plasma, known as anharmonic resonance (AHR), has been proposed to be a basic mechanism but a clear experimental demonstration is needed. Here, we show that microstructured targets enhance X-ray emission and the polarization dependence ascribes the enhancement to anharmonic resonance heating. It is found that p-polarized pulses of 5 ×1017 W/cm2 intensity bring in a 16-fold enhancement in the X-ray emission in the energy range 20-350 keV compared to s-polarized pulses with microstructured targets. This ratio is 2 for the case of polished targets under otherwise identical conditions. Particle-in-cell simulations clearly show that AHR is the key absorption mechanism responsible for this effect.

Design and construction of a time-of-flight wall detector at External Target Facility of HIRFL-CSR

NASA Astrophysics Data System (ADS)

Sun, Y.; Sun, Z. Y.; Yu, Y. H.; Yan, D.; Tang, S. W.; Sun, Y. Z.; Wang, S. T.; Zhang, X. H.; Yue, K.; Fang, F.; Chen, J. L.; Zhang, Y. J.; Hu, B. T.

2018-06-01

A Time-Of-Flight Wall (TOFW) detector has been designed and constructed at the External Target Facility (ETF) of HIRFL-CSR. The detector covers a sensitive area of 1.2 × 1.2 m2 and consists of 30 modules. Each module is composed of a long plastic scintillator bar with two photo-multiplier tubes coupled at both ends for readout. The design and manufacture details are described and the test results are reported. The performance of the TOFW detector has been tested and measured with cosmic rays and a 310 MeV/u 40Ar beam. The results show that the time resolutions of all the TOFW modules are better than 128 ps, satisfying the requirements of the experiments which will be carried out at the ETF.

Dendrimers in drug delivery and targeting: Drug-dendrimer interactions and toxicity issues

PubMed Central

Madaan, Kanika; Kumar, Sandeep; Poonia, Neelam; Lather, Viney; Pandita, Deepti

2014-01-01

Dendrimers are the emerging polymeric architectures that are known for their defined structures, versatility in drug delivery and high functionality whose properties resemble with biomolecules. These nanostructured macromolecules have shown their potential abilities in entrapping and/or conjugating the high molecular weight hydrophilic/hydrophobic entities by host-guest interactions and covalent bonding (prodrug approach) respectively. Moreover, high ratio of surface groups to molecular volume has made them a promising synthetic vector for gene delivery. Owing to these properties dendrimers have fascinated the researchers in the development of new drug carriers and they have been implicated in many therapeutic and biomedical applications. Despite of their extensive applications, their use in biological systems is limited due to toxicity issues associated with them. Considering this, the present review has focused on the different strategies of their synthesis, drug delivery and targeting, gene delivery and other biomedical applications, interactions involved in formation of drug-dendrimer complex along with characterization techniques employed for their evaluation, toxicity problems and associated approaches to alleviate their inherent toxicity. PMID:25035633

Early Career. Harnessing nanotechnology for fusion plasma-material interface research in an in-situ particle-surface interaction facility

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

Allain, Jean Paul

2014-08-08

This project consisted of fundamental and applied research of advanced in-situ particle-beam interactions with surfaces/interfaces to discover novel materials able to tolerate intense conditions at the plasma-material interface (PMI) in future fusion burning plasma devices. The project established a novel facility that is capable of not only characterizing new fusion nanomaterials but, more importantly probing and manipulating materials at the nanoscale while performing subsequent single-effect in-situ testing of their performance under simulated environments in fusion PMI.

Open-source chemogenomic data-driven algorithms for predicting drug-target interactions.

PubMed

Hao, Ming; Bryant, Stephen H; Wang, Yanli

2018-02-06

While novel technologies such as high-throughput screening have advanced together with significant investment by pharmaceutical companies during the past decades, the success rate for drug development has not yet been improved prompting researchers looking for new strategies of drug discovery. Drug repositioning is a potential approach to solve this dilemma. However, experimental identification and validation of potential drug targets encoded by the human genome is both costly and time-consuming. Therefore, effective computational approaches have been proposed to facilitate drug repositioning, which have proved to be successful in drug discovery. Doubtlessly, the availability of open-accessible data from basic chemical biology research and the success of human genome sequencing are crucial to develop effective in silico drug repositioning methods allowing the identification of potential targets for existing drugs. In this work, we review several chemogenomic data-driven computational algorithms with source codes publicly accessible for predicting drug-target interactions (DTIs). We organize these algorithms by model properties and model evolutionary relationships. We re-implemented five representative algorithms in R programming language, and compared these algorithms by means of mean percentile ranking, a new recall-based evaluation metric in the DTI prediction research field. We anticipate that this review will be objective and helpful to researchers who would like to further improve existing algorithms or need to choose appropriate algorithms to infer potential DTIs in the projects. The source codes for DTI predictions are available at: https://github.com/minghao2016/chemogenomicAlg4DTIpred. Published by Oxford University Press 2018. This work is written by US Government employees and is in the public domain in the US.

Structure-function analysis of RBP-J-interacting and tubulin-associated (RITA) reveals regions critical for repression of Notch target genes.

PubMed

Tabaja, Nassif; Yuan, Zhenyu; Oswald, Franz; Kovall, Rhett A

2017-06-23

The Notch pathway is a cell-to-cell signaling mechanism that is essential for tissue development and maintenance, and aberrant Notch signaling has been implicated in various cancers, congenital defects, and cardiovascular diseases. Notch signaling activates the expression of target genes, which are regulated by the transcription factor CSL (CBF1/RBP-J, Su(H), Lag-1). CSL interacts with both transcriptional corepressor and coactivator proteins, functioning as both a repressor and activator, respectively. Although Notch activation complexes are relatively well understood at the structural level, less is known about how CSL interacts with corepressors. Recently, a new RBP-J (mammalian CSL ortholog)-interacting protein termed RITA has been identified and shown to export RBP-J out of the nucleus, thereby leading to the down-regulation of Notch target gene expression. However, the molecular details of RBP-J/RITA interactions are unclear. Here, using a combination of biochemical/cellular, structural, and biophysical techniques, we demonstrate that endogenous RBP-J and RITA proteins interact in cells, map the binding regions necessary for RBP-J·RITA complex formation, and determine the X-ray structure of the RBP-J·RITA complex bound to DNA. To validate the structure and glean more insights into function, we tested structure-based RBP-J and RITA mutants with biochemical/cellular assays and isothermal titration calorimetry. Whereas our structural and biophysical studies demonstrate that RITA binds RBP-J similarly to the RAM (RBP-J-associated molecule) domain of Notch, our biochemical and cellular assays suggest that RITA interacts with additional regions in RBP-J. Taken together, these results provide molecular insights into the mechanism of RITA-mediated regulation of Notch signaling, contributing to our understanding of how CSL functions as a transcriptional repressor of Notch target genes. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Traffic impacts of bicycle facilities : final report.

DOT National Transportation Integrated Search

2017-06-01

Engineers need information about interactions between vehicles and bicyclists to design efficient, safe transportation systems. This study involved a review of design guidelines for bicycle facilities, observation of bicycle-vehicle interactions at n...

Moonlighting Proteins and Protein–Protein Interactions as Neurotherapeutic Targets in the G Protein-Coupled Receptor Field

PubMed Central

Fuxe, Kjell; Borroto-Escuela, Dasiel O; Romero-Fernandez, Wilber; Palkovits, Miklós; Tarakanov, Alexander O; Ciruela, Francisco; Agnati, Luigi F

2014-01-01

There is serious interest in understanding the dynamics of the receptor–receptor and receptor–protein interactions in space and time and their integration in GPCR heteroreceptor complexes of the CNS. Moonlighting proteins are special multifunctional proteins because they perform multiple autonomous, often unrelated, functions without partitioning into different protein domains. Moonlighting through receptor oligomerization can be operationally defined as an allosteric receptor–receptor interaction, which leads to novel functions of at least one receptor protomer. GPCR-mediated signaling is a more complicated process than previously described as every GPCR and GPCR heteroreceptor complex requires a set of G protein interacting proteins, which interacts with the receptor in an orchestrated spatio-temporal fashion. GPCR heteroreceptor complexes with allosteric receptor–receptor interactions operating through the receptor interface have become major integrative centers at the molecular level and their receptor protomers act as moonlighting proteins. The GPCR heteroreceptor complexes in the CNS have become exciting new targets for neurotherapeutics in Parkinson's disease, schizophrenia, drug addiction, and anxiety and depression opening a new field in neuropsychopharmacology. PMID:24105074

Mapping interactions between the RNA chaperone FinO and its RNA targets

PubMed Central

Arthur, David C.; Tsutakawa, Susan; Tainer, John A.; Frost, Laura S.; Glover, J. N. Mark

2011-01-01

Bacterial conjugation is regulated by two-component repression comprising the antisense RNA FinP, and its protein co-factor FinO. FinO mediates base-pairing of FinP to the 5′-untranslated region (UTR) of traJ mRNA, which leads to translational inhibition of the transcriptional activator TraJ and subsequent down regulation of conjugation genes. Yet, little is known about how FinO binds to its RNA targets or how this interaction facilitates FinP and traJ mRNA pairing. Here, we use solution methods to determine how FinO binds specifically to its minimal high affinity target, FinP stem–loop II (SLII), and its complement SLIIc from traJ mRNA. Ribonuclease footprinting reveals that FinO contacts the base of the stem and the 3′ single-stranded tails of these RNAs. The phosphorylation or oxidation of the 3′-nucleotide blocks FinO binding, suggesting FinO binds the 3′-hydroxyl of its RNA targets. The collective results allow the generation of an energy-minimized model of the FinO–SLII complex, consistent with small-angle X-ray scattering data. The repression complex model was constrained using previously reported cross-linking data and newly developed footprinting results. Together, these data lead us to propose a model of how FinO mediates FinP/traJ mRNA pairing to down regulate bacterial conjugation. PMID:21278162

Single Event Effects Test Facility Options at the Oak Ridge National Laboratory

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

Riemer, Bernie; Gallmeier, Franz X; Dominik, Laura J

2015-01-01

Increasing use of microelectronics of ever diminishing feature size in avionics systems has led to a growing Single Event Effects (SEE) susceptibility arising from the highly ionizing interactions of cosmic rays and solar particles. Single event effects caused by atmospheric radiation have been recognized in recent years as a design issue for avionics equipment and systems. To ensure a system meets all its safety and reliability requirements, SEE induced upsets and potential system failures need to be considered, including testing of the components and systems in a neutron beam. Testing of integrated circuits (ICs) and systems for use in radiationmore » environments requires the utilization of highly advanced laboratory facilities that can run evaluations on microcircuits for the effects of radiation. This paper provides a background of the atmospheric radiation phenomenon and the resulting single event effects, including single event upset (SEU) and latch up conditions. A study investigating requirements for future single event effect irradiation test facilities and developing options at the Spallation Neutron Source (SNS) is summarized. The relatively new SNS with its 1.0 GeV proton beam, typical operation of 5000 h per year, expertise in spallation neutron sources, user program infrastructure, and decades of useful life ahead is well suited for hosting a world-class SEE test facility in North America. Emphasis was put on testing of large avionics systems while still providing tunable high flux irradiation conditions for component tests. Makers of ground-based systems would also be served well by these facilities. Three options are described; the most capable, flexible, and highest-test-capacity option is a new stand-alone target station using about one kW of proton beam power on a gas-cooled tungsten target, with dual test enclosures. Less expensive options are also described.« less

Pulsed-coil magnet systems for applying uniform 10-30 T fields to centimeter-scale targets on Sandia's Z facility

NASA Astrophysics Data System (ADS)

Rovang, D. C.; Lamppa, D. C.; Cuneo, M. E.; Owen, A. C.; McKenney, J.; Johnson, D. W.; Radovich, S.; Kaye, R. J.; McBride, R. D.; Alexander, C. S.; Awe, T. J.; Slutz, S. A.; Sefkow, A. B.; Haill, T. A.; Jones, P. A.; Argo, J. W.; Dalton, D. G.; Robertson, G. K.; Waisman, E. M.; Sinars, D. B.; Meissner, J.; Milhous, M.; Nguyen, D. N.; Mielke, C. H.

2014-12-01

Sandia has successfully integrated the capability to apply uniform, high magnetic fields (10-30 T) to high energy density experiments on the Z facility. This system uses an 8-mF, 15-kV capacitor bank to drive large-bore (5 cm diameter), high-inductance (1-3 mH) multi-turn, multi-layer electromagnets that slowly magnetize the conductive targets used on Z over several milliseconds (time to peak field of 2-7 ms). This system was commissioned in February 2013 and has been used successfully to magnetize more than 30 experiments up to 10 T that have produced exciting and surprising physics results. These experiments used split-magnet topologies to maintain diagnostic lines of sight to the target. We describe the design, integration, and operation of the pulsed coil system into the challenging and harsh environment of the Z Machine. We also describe our plans and designs for achieving fields up to 20 T with a reduced-gap split-magnet configuration, and up to 30 T with a solid magnet configuration in pursuit of the Magnetized Liner Inertial Fusion concept.

Pulsed-coil magnet systems for applying 10-30 Tesla Fields to cm-scale targets on Sandia's Z facility

DOE PAGES

Rovang, Dean C.; Lamppa, Derek C.; Cuneo, Michael Edward; ...

2014-12-04

We have successfully integrated the capability to apply uniform, high magnetic fields (10–30 T) to high energy density experiments on the Z facility. This system uses an 8-mF, 15-kV capacitor bank to drive large-bore (5 cm diameter), high-inductance (1–3 mH) multi-turn, multi-layer electromagnets that slowly magnetize the conductive targets used on Z over several milliseconds (time to peak field of 2–7 ms). This system was commissioned in February 2013 and has been used successfully to magnetize more than 30 experiments up to 10 T that have produced exciting and surprising physics results. These experiments used split-magnet topologies to maintain diagnosticmore » lines of sight to the target. We then describe the design, integration, and operation of the pulsed coil system into the challenging and harsh environment of the Z Machine. We also describe our plans and designs for achieving fields up to 20 T with a reduced-gap split-magnet configuration, and up to 30 T with a solid magnet configuration in pursuit of the Magnetized Liner Inertial Fusion concept.« less

In vitro Selection and Interaction Studies of a DNA Aptamer Targeting Protein A

PubMed Central

Stoltenburg, Regina; Schubert, Thomas; Strehlitz, Beate

2015-01-01

A new DNA aptamer targeting Protein A is presented. The aptamer was selected by use of the FluMag-SELEX procedure. The SELEX technology (Systematic Evolution of Ligands by EXponential enrichment) is widely applied as an in vitro selection and amplification method to generate target-specific aptamers and exists in various modified variants. FluMag-SELEX is one of them and is characterized by the use of magnetic beads for target immobilization and fluorescently labeled oligonucleotides for monitoring the aptamer selection progress. Structural investigations and sequence truncation experiments of the selected aptamer for Protein A led to the conclusion, that a stem-loop structure at its 5’-end including the 5’-primer binding site is essential for aptamer-target binding. Extensive interaction analyses between aptamer and Protein A were performed by methods like surface plasmon resonance, MicroScale Thermophoresis and bead-based binding assays using fluorescence measurements. The binding of the aptamer to its target was thus investigated in assays with immobilization of one of the binding partners each, and with both binding partners in solution. Affinity constants were determined in the low micromolar to submicromolar range, increasing to the nanomolar range under the assumption of avidity. Protein A provides more than one binding site for the aptamer, which may overlap with the known binding sites for immunoglobulins. The aptamer binds specifically to both native and recombinant Protein A, but not to other immunoglobulin-binding proteins like Protein G and L. Cross specificity to other proteins was not found. The application of the aptamer is directed to Protein A detection or affinity purification. Moreover, whole cells of Staphylococcus aureus, presenting Protein A on the cell surface, could also be bound by the aptamer. PMID:26221730

In vitro Selection and Interaction Studies of a DNA Aptamer Targeting Protein A.

PubMed

Stoltenburg, Regina; Schubert, Thomas; Strehlitz, Beate

2015-01-01

A new DNA aptamer targeting Protein A is presented. The aptamer was selected by use of the FluMag-SELEX procedure. The SELEX technology (Systematic Evolution of Ligands by EXponential enrichment) is widely applied as an in vitro selection and amplification method to generate target-specific aptamers and exists in various modified variants. FluMag-SELEX is one of them and is characterized by the use of magnetic beads for target immobilization and fluorescently labeled oligonucleotides for monitoring the aptamer selection progress. Structural investigations and sequence truncation experiments of the selected aptamer for Protein A led to the conclusion, that a stem-loop structure at its 5'-end including the 5'-primer binding site is essential for aptamer-target binding. Extensive interaction analyses between aptamer and Protein A were performed by methods like surface plasmon resonance, MicroScale Thermophoresis and bead-based binding assays using fluorescence measurements. The binding of the aptamer to its target was thus investigated in assays with immobilization of one of the binding partners each, and with both binding partners in solution. Affinity constants were determined in the low micromolar to submicromolar range, increasing to the nanomolar range under the assumption of avidity. Protein A provides more than one binding site for the aptamer, which may overlap with the known binding sites for immunoglobulins. The aptamer binds specifically to both native and recombinant Protein A, but not to other immunoglobulin-binding proteins like Protein G and L. Cross specificity to other proteins was not found. The application of the aptamer is directed to Protein A detection or affinity purification. Moreover, whole cells of Staphylococcus aureus, presenting Protein A on the cell surface, could also be bound by the aptamer.

Targeting protein-protein interaction between MLL1 and reciprocal proteins for leukemia therapy.

PubMed

Wang, Zhi-Hui; Li, Dong-Dong; Chen, Wei-Lin; You, Qi-Dong; Guo, Xiao-Ke

2018-01-15

The mixed lineage leukemia protein-1 (MLL1), as a lysine methyltransferase, predominantly regulates the methylation of histone H3 lysine 4 (H3K4) and functions in hematopoietic stem cell (HSC) self-renewal. MLL1 gene fuses with partner genes that results in the generation of MLL1 fusion proteins (MLL1-FPs), which are frequently detected in acute leukemia. In the progress of leukemogenesis, a great deal of proteins cooperate with MLL1 to form multiprotein complexes serving for the dysregulation of H3K4 methylation, the overexpression of homeobox (HOX) cluster genes, and the consequent generation of leukemia. Hence, disrupting the interactions between MLL1 and the reciprocal proteins has been considered to be a new treatment strategy for leukemia. Here, we reviewed potential protein-protein interactions (PPIs) between MLL1 and its reciprocal proteins, and summarized the inhibitors to target MLL1 PPIs. The druggability of MLL1 PPIs for leukemia were also discussed. Copyright © 2017. Published by Elsevier Ltd.

The Fundamental Neutron Physics Facilities at NIST.

PubMed

Nico, J S; Arif, M; Dewey, M S; Gentile, T R; Gilliam, D M; Huffman, P R; Jacobson, D L; Thompson, A K

2005-01-01

The program in fundamental neutron physics at the National Institute of Standards and Technology (NIST) began nearly two decades ago. The Neutron Interactions and Dosimetry Group currently maintains four neutron beam lines dedicated to studies of fundamental neutron interactions. The neutrons are provided by the NIST Center for Neutron Research, a national user facility for studies that include condensed matter physics, materials science, nuclear chemistry, and biological science. The beam lines for fundamental physics experiments include a high-intensity polychromatic beam, a 0.496 nm monochromatic beam, a 0.89 nm monochromatic beam, and a neutron interferometer and optics facility. This paper discusses some of the parameters of the beam lines along with brief presentations of some of the experiments performed at the facilities.

The Fundamental Neutron Physics Facilities at NIST

PubMed Central

Nico, J. S.; Arif, M.; Dewey, M. S.; Gentile, T. R.; Gilliam, D. M.; Huffman, P. R.; Jacobson, D. L.; Thompson, A. K.

2005-01-01

The program in fundamental neutron physics at the National Institute of Standards and Technology (NIST) began nearly two decades ago. The Neutron Interactions and Dosimetry Group currently maintains four neutron beam lines dedicated to studies of fundamental neutron interactions. The neutrons are provided by the NIST Center for Neutron Research, a national user facility for studies that include condensed matter physics, materials science, nuclear chemistry, and biological science. The beam lines for fundamental physics experiments include a high-intensity polychromatic beam, a 0.496 nm monochromatic beam, a 0.89 nm monochromatic beam, and a neutron interferometer and optics facility. This paper discusses some of the parameters of the beam lines along with brief presentations of some of the experiments performed at the facilities. PMID:27308110

Overview of the ISOL facility for the RISP

NASA Astrophysics Data System (ADS)

Woo, H. J.; Kang, B. H.; Tshoo, K.; Seo, C. S.; Hwang, W.; Park, Y.-H.; Yoon, J. W.; Yoo, S. H.; Kim, Y. K.; Jang, D. Y.

2015-02-01

The key feature of the Isotope Separation On-Line (ISOL) facility is its ability to provide high-intensity and high-quality beams of neutron-rich isotopes with masses in the range of 80-160 by means of a 70-MeV proton beam directly impinging on uranium-carbide thin-disc targets to perform forefront research in nuclear structure, nuclear astrophysics, reaction dynamics and interdisciplinary fields like medical, biological and material sciences. The technical design of the 10-kW and the 35-kW direct fission targets with in-target fission rates of up to 1014 fissions/s has been finished, and for the development of the ISOL fission-target chemistry an initial effort has been made to produce porous lanthanum-carbide (LaCx) discs as a benchmark for the final production of porous UCx discs. For the production of various beams, three classes of ion sources are under development at RISP (Rare Isotope Science Project), the surface ion source, the plasma ion source (FEBIAD), the laser ion source, and the engineering design of the FEBIAD is in progress for prototype fabrication. The engineering design of the ISOL target/ion source front-end system is also in progress, and a prototype will be used for an off-line test facility in front of the pre-separator. The technical designs of other basic elements at the ISOL facility, such as the RF-cooler, the high-resolution mass separator, and the A/q separator, have been finished, and the results, along with the future plans, are introduced.

Changes in the level of perforin and its transcript during effector and target cell interactions.

PubMed

Kim, K K; Blakely, A; Zhou, Z; Davis, J; Clark, W; Kwon, B S

1993-05-01

Perforin is a cytoplasmic granule protein expressed in cytotoxic lymphocytes, and is capable of lysing target cells. This protein is induced as cytotoxic T cells are activated, and the mRNA expression is modulated by various stimulators. These observations suggest possible changes in the level of perforin transcripts and protein when killer lymphocytes meet specific target cells leading to target cell death. To address this question, we examined three murine T-cell clones and primary human NK cells in perforin expression. When the cytotoxic lymphocytes were exposed to sensitive targets, perforin mRNA disappeared within 5 to 30 min and appeared within an hour thereafter. Among the murine T cell clones, L3 and OE4 showed two phases of mRNA decrease while human NK cells and the third murine T cell clone, AB.1, showed only one phase of mRNA loss during a 240 min period. The data indicate that when cytotoxic lymphocytes receive signals from a sensitive target, the cells rapidly degrade previously accumulated perforin mRNA and synthesize new transcripts. Interestingly, heat shock protein 70 mRNA was induced as the perforin mRNA levels recovered, while P55 Il-2 receptor mRNA was downregulated within 5 min after exposure to targets. The perforin protein level also rapidly decreased immediately after the interaction with the target, followed by a recovery, and then another decrease as seen in primary human NK cells, OE4 and L3 cells. However, in the AB.1 clone, no change in perforin content was detectable, despite the loss of perforin mRNA.(ABSTRACT TRUNCATED AT 250 WORDS)

Electromagnetic radiations from laser interaction with gas-filled Hohlraum

NASA Astrophysics Data System (ADS)

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

2018-01-01

The emission of intensive electromagnetic pulse (EMP) due to laser-target interactions at the ShenGuang-III laser facility has been evaluated by probes. EMP signals measured using the small discone antennas demonstrated two variation trends including a bilateral oscillation wave and a unilateral oscillation wave. The new trend of unilateral oscillation could be attributed to the hohlraum structure and low-Z gas in the hohlraum. The EMP waveform showed multiple peaks when the gas-filled hohlraum was shot by the high-power laser. Comparing the EMP signals with the verification of stimulated Raman scattering energy and hard x-ray energy spectrum, we found that the intensity of EMP signals decreased with the increase of the hohlraum size. The current results are expected to offer preliminary information to study physical processes on laser injecting gas-filled hohlraums in the National Ignition Facility implementation.

Controllability analysis of the directed human protein interaction network identifies disease genes and drug targets

PubMed Central

Vinayagam, Arunachalam; Gibson, Travis E.; Lee, Ho-Joon; Yilmazel, Bahar; Roesel, Charles; Hu, Yanhui; Kwon, Young; Sharma, Amitabh; Liu, Yang-Yu; Perrimon, Norbert; Barabási, Albert-László

2016-01-01

The protein–protein interaction (PPI) network is crucial for cellular information processing and decision-making. With suitable inputs, PPI networks drive the cells to diverse functional outcomes such as cell proliferation or cell death. Here, we characterize the structural controllability of a large directed human PPI network comprising 6,339 proteins and 34,813 interactions. This network allows us to classify proteins as “indispensable,” “neutral,” or “dispensable,” which correlates to increasing, no effect, or decreasing the number of driver nodes in the network upon removal of that protein. We find that 21% of the proteins in the PPI network are indispensable. Interestingly, these indispensable proteins are the primary targets of disease-causing mutations, human viruses, and drugs, suggesting that altering a network’s control property is critical for the transition between healthy and disease states. Furthermore, analyzing copy number alterations data from 1,547 cancer patients reveals that 56 genes that are frequently amplified or deleted in nine different cancers are indispensable. Among the 56 genes, 46 of them have not been previously associated with cancer. This suggests that controllability analysis is very useful in identifying novel disease genes and potential drug targets. PMID:27091990

Ingroup categorization and response conflict: Interactive effects of target race, flanker compatibility, and infrequency on N2 amplitude.

PubMed

Dickter, Cheryl L; Bartholow, Bruce D

2010-05-01

Three largely independent lines of research have investigated experimental manipulations that influence the amplitude of the N2 component of the event-related brain potential (ERP), one linking heightened N2 amplitude to response conflict, another showing that N2 is sensitive to stimulus infrequency, and the third showing larger N2 amplitude during categorization of racial ingroup relative to racial outgroup targets. The purpose of this research was to investigate potential interactions between these three features on the amplitude of the N2. ERPs were recorded while participants completed a modified flanker task using pictures of ingroup and outgroup faces. Results showed a 3-way interaction, indicating that the N2 was largest for ingroup targets on high-conflict trials but only when such trials were relatively infrequent. Implications of these findings for theories of both conflict monitoring and person perception are discussed.

Quercetin targets the interaction of calcineurin with LxVP-type motifs in immunosuppression

PubMed Central

Zhao, Yane; Zhang, Jin; Shi, Xiaoyu; Li, Jing; Wang, Rui; Song, Ruiwen; Wei, Qun; Cai, Huaibin; Luo, Jing

2016-01-01

Calcineurin (CN) is a unique calcium/calmodulin (CaM)-activated serine/threonine phosphatase. To perform its diverse biological functions, CN communicates with many substrates and other proteins. In the physiological activation of T cells, CN acts through transcriptional factors belonging to the NFAT family and other transcriptional effectors. The classic immunosuppressive drug cyclosporin A (CsA) can bind to cyclophilin (CyP) and compete with CN for the NFAT LxVP motif. CsA has debilitating side effects, including nephrotoxicity, hypertension and tremor. It is desirable to develop alternative immunosuppressive agents. To this end, we first tested the interactions between CN and the LxVP-type substrates, including endogenous regulators of calcineurin (RCAN1) and NFAT. Interestingly, we found that quercetin, the primary dietary flavonol, can inhibit the activity of CN and significantly disrupt the associations between CN and its LxVP-type substrates. We then validated the inhibitory effects of quercetin on the CN-NFAT interactions in cell-based assays. Further, quercetin also shows dose-dependent suppression of cytokine gene expression in mouse spleen cells. These data raise the possibility that the interactions of CN with its LxVP-type substrates are potential targets for immunosuppressive agents. PMID:27109380

NMR investigations of the dual targeting peptide of Thr-tRNA synthetase and its interaction with the mitochondrial Tom20 receptor in Arabidopsis thaliana.

PubMed

Ye, Weihua; Spånning, Erika; Unnerståle, Sofia; Gotthold, David; Glaser, Elzbieta; Mäler, Lena

2012-10-01

Most mitochondrial proteins are synthesized in the cytosol as precursor proteins containing an N-terminal targeting peptide and are imported into mitochondria through the import machineries, the translocase of the outer mitochondrial membrane (TOM) and the translocase of the inner mitochondrial membrane (TIM). The N-terminal targeting peptide of precursor proteins destined for the mitochondrial matrix is recognized by the Tom20 receptor and plays an important role in the import process. Protein import is usually organelle specific, but several plant proteins are dually targeted into mitochondria and chloroplasts using an ambiguous dual targeting peptide. We present NMR studies of the dual targeting peptide of Thr-tRNA synthetase and its interaction with Tom20 in Arabidopsis thaliana. Our findings show that the targeting peptide is mostly unstructured in buffer, with a propensity to form α-helical structure in one region, S6-F27, and a very weak β-strand propensity for Q34-Q38. The α-helical structured region has an amphiphilic character and a φχχφφ motif, both of which have previously been shown to be important for mitochondrial import. Using NMR we have mapped out two regions in the peptide that are important for Tom20 recognition: one of them, F9-V28, overlaps with the amphiphilic region, and the other comprises residues L30-Q39. Our results show that the targeting peptide may interact with Tom20 in several ways. Furthermore, our results indicate a weak, dynamic interaction. The results provide for the first time molecular details on the interaction of the Tom20 receptor with a dual targeting peptide. © 2012 The Authors Journal compilation © 2012 FEBS.

Multiplicity distributions of shower particles and target fragments in 84 Kr 36-emulsion interactions at 1 GeV per nucleon

NASA Astrophysics Data System (ADS)

Singh, M. K.; Soma, A. K.; Pathak, Ramji; Singh, V.

2014-03-01

This article focuses on multiplicity distributions of shower particles and target fragments for interaction of 84 Kr 36 with NIKFI BR-2 nuclear emulsion target at kinetic energy of 1 GeV per nucleon. Experimental multiplicity distributions of shower particles, grey particles, black particles and heavily ionization particles are well described by multi-component Erlang distribution of multi-source thermal model. We have observed a linear correlation in multiplicities for the above mentioned particles or fragments. Further experimental studies have shown a saturation phenomenon in shower particle multiplicity with the increase of target fragment multiplicity.

Identification of polycystic ovary syndrome potential drug targets based on pathobiological similarity in the protein-protein interaction network

PubMed Central

Li, Wan; Wei, Wenqing; Li, Yiran; Xie, Ruiqiang; Guo, Shanshan; Wang, Yahui; Jiang, Jing; Chen, Binbin; Lv, Junjie; Zhang, Nana; Chen, Lina; He, Weiming

2016-01-01

Polycystic ovary syndrome (PCOS) is one of the most common endocrinological disorders in reproductive aged women. PCOS and Type 2 Diabetes (T2D) are closely linked in multiple levels and possess high pathobiological similarity. Here, we put forward a new computational approach based on the pathobiological similarity to identify PCOS potential drug target modules (PPDT-Modules) and PCOS potential drug targets in the protein-protein interaction network (PPIN). From the systems level and biological background, 1 PPDT-Module and 22 PCOS potential drug targets were identified, 21 of which were verified by literatures to be associated with the pathogenesis of PCOS. 42 drugs targeting to 13 PCOS potential drug targets were investigated experimentally or clinically for PCOS. Evaluated by independent datasets, the whole PPDT-Module and 22 PCOS potential drug targets could not only reveal the drug response, but also distinguish the statuses between normal and disease. Our identified PPDT-Module and PCOS potential drug targets would shed light on the treatment of PCOS. And our approach would provide valuable insights to research on the pathogenesis and drug response of other diseases. PMID:27191267

An electric propulsion long term test facility

NASA Technical Reports Server (NTRS)

Trump, G.; James, E.; Vetrone, R.; Bechtel, R.

1979-01-01

An existing test facility was modified to provide for extended testing of multiple electric propulsion thruster subsystems. A program to document thruster subsystem characteristics as a function of time is currently in progress. The facility is capable of simultaneously operating three 2.7-kW, 30-cm mercury ion thrusters and their power processing units. Each thruster is installed via a separate air lock so that it can be extended into the 7m x 10m main chamber without violating vacuum integrity. The thrusters exhaust into a 3m x 5m frozen mercury target. An array of cryopanels collect sputtered target material. Power processor units are tested in an adjacent 1.5m x 2m vacuum chamber or accompanying forced convection enclosure. The thruster subsystems and the test facility are designed for automatic unattended operation with thruster operation computer controlled. Test data are recorded by a central data collection system scanning 200 channels of data a second every two minutes. Results of the Systems Demonstration Test, a short shakedown test of 500 hours, and facility performance during the first year of testing are presented.

Progress in long scale length laser plasma interactions

NASA Astrophysics Data System (ADS)

Glenzer, S. H.; Arnold, P.; Bardsley, G.; Berger, R. L.; Bonanno, G.; Borger, T.; Bower, D. E.; Bowers, M.; Bryant, R.; Buckman, S.; Burkhart, S. C.; Campbell, K.; Chrisp, M. P.; Cohen, B. I.; Constantin, C.; Cooper, F.; Cox, J.; Dewald, E.; Divol, L.; Dixit, S.; Duncan, J.; Eder, D.; Edwards, J.; Erbert, G.; Felker, B.; Fornes, J.; Frieders, G.; Froula, D. H.; Gardner, S. D.; Gates, C.; Gonzalez, M.; Grace, S.; Gregori, G.; Greenwood, A.; Griffith, R.; Hall, T.; Hammel, B. A.; Haynam, C.; Heestand, G.; Henesian, M.; Hermes, G.; Hinkel, D.; Holder, J.; Holdner, F.; Holtmeier, G.; Hsing, W.; Huber, S.; James, T.; Johnson, S.; Jones, O. S.; Kalantar, D.; Kamperschroer, J. H.; Kauffman, R.; Kelleher, T.; Knight, J.; Kirkwood, R. K.; Kruer, W. L.; Labiak, W.; Landen, O. L.; Langdon, A. B.; Langer, S.; Latray, D.; Lee, A.; Lee, F. D.; Lund, D.; MacGowan, B.; Marshall, S.; McBride, J.; McCarville, T.; McGrew, L.; Mackinnon, A. J.; Mahavandi, S.; Manes, K.; Marshall, C.; Menapace, J.; Mertens, E.; Meezan, N.; Miller, G.; Montelongo, S.; Moody, J. D.; Moses, E.; Munro, D.; Murray, J.; Neumann, J.; Newton, M.; Ng, E.; Niemann, C.; Nikitin, A.; Opsahl, P.; Padilla, E.; Parham, T.; Parrish, G.; Petty, C.; Polk, M.; Powell, C.; Reinbachs, I.; Rekow, V.; Rinnert, R.; Riordan, B.; Rhodes, M.; Roberts, V.; Robey, H.; Ross, G.; Sailors, S.; Saunders, R.; Schmitt, M.; Schneider, M. B.; Shiromizu, S.; Spaeth, M.; Stephens, A.; Still, B.; Suter, L. J.; Tietbohl, G.; Tobin, M.; Tuck, J.; Van Wonterghem, B. M.; Vidal, R.; Voloshin, D.; Wallace, R.; Wegner, P.; Whitman, P.; Williams, E. A.; Williams, K.; Winward, K.; Work, K.; Young, B.; Young, P. E.; Zapata, P.; Bahr, R. E.; Seka, W.; Fernandez, J.; Montgomery, D.; Rose, H.

2004-12-01

The first experiments on the National Ignition Facility (NIF) have employed the first four beams to measure propagation and laser backscattering losses in large ignition-size plasmas. Gas-filled targets between 2 and 7 mm length have been heated from one side by overlapping the focal spots of the four beams from one quad operated at 351 nm (3ω) with a total intensity of 2 × 1015 W cm-2. The targets were filled with 1 atm of CO2 producing up to 7 mm long homogeneously heated plasmas with densities of ne = 6 × 1020 cm-3 and temperatures of Te = 2 keV. The high energy in an NIF quad of beams of 16 kJ, illuminating the target from one direction, creates unique conditions for the study of laser-plasma interactions at scale lengths not previously accessible. The propagation through the large-scale plasma was measured with a gated x-ray imager that was filtered for 3.5 keV x-rays. These data indicate that the beams interact with the full length of this ignition-scale plasma during the last ~1 ns of the experiment. During that time, the full aperture measurements of the stimulated Brillouin scattering and stimulated Raman scattering show scattering into the four focusing lenses of 3% for the smallest length (~2 mm), increasing to 10-12% for ~7 mm. These results demonstrate the NIF experimental capabilities and further provide a benchmark for three-dimensional modelling of the laser-plasma interactions at ignition-size scale lengths.

Alkaloids from psychotria target sirtuins: in silico and in vitro interaction studies.

PubMed

Sacconnay, Lionel; Ryckewaert, Lucie; Dos Santos Passos, Carolina; Guerra, Maria Cristina; Kato, Lucilia; Alves de Oliveira, Cecilia Maria; Henriques, Amélia; Carrupt, Pierre-Alain; Simões-Pires, Claudia; Nurisso, Alessandra

2015-04-01

Epigenetic enzymes such as histone deacetylases play a crucial role in the development of ageing-related diseases. Among the 18 histone deacetylase isoforms found in humans, class III histone deacetylases, also known as sirtuins, seem to be promising targets for treating neurodegenerative conditions. Recently, Psychotria alkaloids, mainly monoterpene indoles, have been reported for their inhibitory properties against central nervous system cholinesterase and monoamine oxidase proteins. Given the multifunctional profile of these alkaloids in the central nervous system, and the fact that the indole scaffold has been previously associated with sirtuin inhibition, we hypothesized that these indole derivatives could also interact with sirtuins. In the present study, alkaloids previously isolated from Psychotria spp. were evaluated for their potential interaction with human sirtuin 1 and sirtuin 2 by molecular docking and molecular dynamics simulation approaches. The in silico results allowed for the selection of five potentially active compounds, namely, prunifoleine, 14-oxoprunifoleine, E-vallesiachotamine, Z-vallesiachotamine, and vallesiachotamine lactone. The sirtuin inhibition of these compounds was confirmed in vitro in a dose-response manner, with preliminary information on their pharmacokinetics properties. Georg Thieme Verlag KG Stuttgart · New York.

The emergence of care facilities in Thailand for older German-speaking people: structural backgrounds and facility operators as transnational actors.

PubMed

Bender, Désirée; Hollstein, Tina; Schweppe, Cornelia

2017-12-01

This paper presents findings from an ethnographic study of old age care facilities for German-speaking people in Thailand. It analyses the conditions and processes behind the development and specific designs of such facilities. It first looks at the intertwinement, at the socio-structural level, of different transborder developments in which the facilities' emergence is embedded. Second, it analyses the processes that accompany the emergence, development and organisation of these facilities at the local level. In this regard, it points out the central role of the facility operators as transnational actors who mediate between different frames of reference and groups of actors involved in these facilities. It concludes that the processes of mediation and intertwining are an important and distinctive feature of the emergence of these facilities, necessitated by the fact that, although the facilities are located in Thailand, their 'markets' are in the German-speaking countries of their target groups.

Scattering by truncated targets with and without boundary interactions

NASA Astrophysics Data System (ADS)

Marston, Philip L.; Baik, Kyungmin; Espana, Aubrey; Osterhoudt, Curtis F.; Morse, Scot F.; Hefner, Brian T.; Blonigen, Florian J.

2005-04-01

Ray methods have been applied to the scattering of various truncated targets having wavenumber-radius products as small as 10 [F. J. Blonigen and P. L. Marston, J. Acoust. Soc. Am. 107, 689-698 (2000); S. F. Morse and P. L. Marston, ibid. 112, 1318-1326 (2002); B. T. Hefner and P. L. Marston, ARLO 2, 55-60 (2001)]. Recent work emphasizes the exploration of scattering enhancements for other situations including plastic cylinders having curved ends, truncated plastic cones, partially exposed cylinders, and objects in simulated conditions for burial in a seabed. Enhanced scattering is often associated with a locally flat outgoing wavefront. For plastic targets it has been helpful to examine the time dependence of the backscattered envelope as a function of target tilt for targets illuminated by short tone bursts. For partially exposed objects it is helpful to examine the backscattering as a function of the target exposure. For simulated buried targets, it has been helpful to excite target resonances. [Work supported by the Office of Naval Research.

Analysis of 440 GeV proton beam-matter interaction experiments at the High Radiation Materials test facility at CERN

NASA Astrophysics Data System (ADS)

Burkart, F.; Schmidt, R.; Raginel, V.; Wollmann, D.; Tahir, N. A.; Shutov, A.; Piriz, A. R.

2015-08-01

In a previous paper [Schmidt et al., Phys. Plasmas 21, 080701 (2014)], we presented the first results on beam-matter interaction experiments that were carried out at the High Radiation Materials test facility at CERN. In these experiments, extended cylindrical targets of solid copper were irradiated with beam of 440 GeV protons delivered by the Super Proton Synchrotron (SPS). The beam comprised of a large number of high intensity proton bunches, each bunch having a length of 0.5 ns with a 50 ns gap between two neighboring bunches, while the length of this entire bunch train was about 7 μs. These experiments established the existence of the hydrodynamic tunneling phenomenon the first time. Detailed numerical simulations of these experiments were also carried out which were reported in detail in another paper [Tahir et al., Phys. Rev. E 90, 063112 (2014)]. Excellent agreement was found between the experimental measurements and the simulation results that validate our previous simulations done using the Large Hadron Collider (LHC) beam of 7 TeV protons [Tahir et al., Phys. Rev. Spec. Top.--Accel. Beams 15, 051003 (2012)]. According to these simulations, the range of the full LHC proton beam and the hadronic shower can be increased by more than an order of magnitude due to the hydrodynamic tunneling, compared to that of a single proton. This effect is of considerable importance for the design of machine protection system for hadron accelerators such as SPS, LHC, and Future Circular Collider. Recently, using metal cutting technology, the targets used in these experiments have been dissected into finer pieces for visual and microscopic inspection in order to establish the precise penetration depth of the protons and the corresponding hadronic shower. This, we believe will be helpful in studying the very important phenomenon of hydrodynamic tunneling in a more quantitative manner. The details of this experimental work together with a comparison with the numerical

Cognitive enhancers (Nootropics). Part 3: drugs interacting with targets other than receptors or enzymes. Disease-modifying drugs. Update 2014.

PubMed

Froestl, Wolfgang; Pfeifer, Andrea; Muhs, Andreas

2014-01-01

Scientists working in the field of Alzheimer's disease and, in particular, cognitive enhancers, are very productive. The review "Drugs interacting with Targets other than Receptors or Enzymes. Disease-modifying Drugs" was accepted in October 2012. In the last 20 months, new targets for the potential treatment of Alzheimer's disease were identified. Enormous progress was realized in the pharmacological characterization of natural products with cognitive enhancing properties. This review covers the evolution of research in this field through May 2014.

Comparison and analysis of the results of direct-driven targets implosion

NASA Astrophysics Data System (ADS)

Demchenko, N. N.; Dolgoleva, G. V.; Gus'kov, S. Yu; Kuchugov, P. A.; Rozanov, V. B.; Stepanov, R. V.; Zmitrenko, N. V.; Yakhin, R. A.

2017-10-01

The article presents calculation results, which were received for the implosion of the typical cryogenic thermonuclear direct-drive targets that are intended for use at the OMEGA facility, NIF and Russian laser facility. The compression and burning characteristics, which were obtained using various numerical codes of different scientific groups, are compared. The data indicate good agreement between the numerical results. Various sources of target irradiation inhomogeneity and their influence on the implosion parameters are considered. The nominal scales of these disturbances for various facilities are close to each other. The main negative effect on the efficiency of compression and burning is due to the accidental offset of the target from the center of the chamber.

Quantitative Properties of the Macro Supply and Demand Structure for Care Facilities for Elderly in Japan.

PubMed

Nishino, Tatsuya

2017-12-01

As the Asian country with the most aged population, Japan, has been modifying its social welfare system. In 2000, the Japanese social care vision turned towards meeting the elderly's care needs in their own homes with proper formal care services. This study aims to understand the quantitative properties of the macro supply and demand structure for facilities for the elderly who require support or long-term care throughout Japan and present them as index values. Additionally, this study compares the targets for establishing long-term care facilities set by Japan's Ministry of Health, Labor and Welfare for 2025. In 2014, approximately 90% of all the people who were certified as requiring support and long-term care and those receiving preventive long-term care or long-term care services, were 75 years or older. The target increases in the number of established facilities by 2025 (for the 75-years-or-older population) were calculated to be 3.3% for nursing homes; 2.71% for long-term-care health facilities; 1.7% for group living facilities; and, 1.84% for community-based multi-care facilities. It was revealed that the establishment targets for 2025 also increase over current projections with the expected increase of the absolute number of users of group living facilities and community-based multi-care facilities. On the other hand, the establishment target for nursing homes remains almost the same as the current projection, whereas that for long-term-care health facilities decreases. These changes of facility ratios reveal that the Japanese social care system is shifting to realize 'Ageing in Place'. When considering households' tendencies, the target ratios for established facilities are expected to be applied to the other countries in Asia.

Quantitative Properties of the Macro Supply and Demand Structure for Care Facilities for Elderly in Japan

PubMed Central

Nishino, Tatsuya

2017-01-01

As the Asian country with the most aged population, Japan, has been modifying its social welfare system. In 2000, the Japanese social care vision turned towards meeting the elderly’s care needs in their own homes with proper formal care services. This study aims to understand the quantitative properties of the macro supply and demand structure for facilities for the elderly who require support or long-term care throughout Japan and present them as index values. Additionally, this study compares the targets for establishing long-term care facilities set by Japan’s Ministry of Health, Labor and Welfare for 2025. In 2014, approximately 90% of all the people who were certified as requiring support and long-term care and those receiving preventive long-term care or long-term care services, were 75 years or older. The target increases in the number of established facilities by 2025 (for the 75-years-or-older population) were calculated to be 3.3% for nursing homes; 2.71% for long-term-care health facilities; 1.7% for group living facilities; and, 1.84% for community-based multi-care facilities. It was revealed that the establishment targets for 2025 also increase over current projections with the expected increase of the absolute number of users of group living facilities and community-based multi-care facilities. On the other hand, the establishment target for nursing homes remains almost the same as the current projection, whereas that for long-term-care health facilities decreases. These changes of facility ratios reveal that the Japanese social care system is shifting to realize ‘Ageing in Place’. When considering households’ tendencies, the target ratios for established facilities are expected to be applied to the other countries in Asia. PMID:29194405

In-Depth Study of the Interaction, Sensitivity, and Gating Modulation by PUFAs on K+ Channels; Interaction and New Targets

PubMed Central

Moreno, Cristina; de la Cruz, Alicia; Valenzuela, Carmen

2016-01-01

Voltage gated potassium channels (KV) are membrane proteins that allow selective flow of K+ ions in a voltage-dependent manner. These channels play an important role in several excitable cells as neurons, cardiomyocytes, and vascular smooth muscle. Over the last 20 years, it has been shown that omega-3 polyunsaturated fatty acids (PUFAs) enhance or decrease the activity of several cardiac KV channels. PUFAs-dependent modulation of potassium ion channels has been reported to be cardioprotective. However, the precise cellular mechanism underlying the cardiovascular benefits remained unclear in part because new PUFAs targets and signaling pathways continue being discovered. In this review, we will focus on recent data available concerning the following aspects of the KV channel modulation by PUFAs: (i) the exact residues involved in PUFAs-KV channels interaction; (ii) the structural PUFAs determinants important for their effects on KV channels; (iii) the mechanism of the gating modulation of KV channels and, finally, (iv) the PUFAs modulation of a few new targets present in smooth muscle cells (SMC), KCa1.1, K2P, and KATP channels, involved in vascular relaxation. PMID:27933000

Natural products used as a chemical library for protein-protein interaction targeted drug discovery.

PubMed

Jin, Xuemei; Lee, Kyungro; Kim, Nam Hee; Kim, Hyun Sil; Yook, Jong In; Choi, Jiwon; No, Kyoung Tai

2018-01-01

Protein-protein interactions (PPIs), which are essential for cellular processes, have been recognized as attractive therapeutic targets. Therefore, the construction of a PPI-focused chemical library is an inevitable necessity for future drug discovery. Natural products have been used as traditional medicines to treat human diseases for millennia; in addition, their molecular scaffolds have been used in diverse approved drugs and drug candidates. The recent discovery of the ability of natural products to inhibit PPIs led us to use natural products as a chemical library for PPI-targeted drug discovery. In this study, we collected natural products (NPDB) from non-commercial and in-house databases to analyze their similarities to small-molecule PPI inhibitors (iPPIs) and FDA-approved drugs by using eight molecular descriptors. Then, we evaluated the distribution of NPDB and iPPIs in the chemical space, represented by the molecular fingerprint and molecular scaffolds, to identify the promising scaffolds, which could interfere with PPIs. To investigate the ability of natural products to inhibit PPI targets, molecular docking was used. Then, we predicted a set of high-potency natural products by using the iPPI-likeness score based on a docking score-weighted model. These selected natural products showed high binding affinities to the PPI target, namely XIAP, which were validated in an in vitro experiment. In addition, the natural products with novel scaffolds might provide a promising starting point for further medicinal chemistry developments. Overall, our study shows the potency of natural products in targeting PPIs, which might help in the design of a PPI-focused chemical library for future drug discovery. Copyright © 2017 Elsevier Inc. All rights reserved.

Computational design of high efficiency release targets for use at ISOL facilities

NASA Astrophysics Data System (ADS)

Liu, Y.; Alton, G. D.; Middleton, J. W.

1999-06-01

This report describes efforts made at the Oak Ridge National Laboratory to design high-efficiency-release targets that simultaneously incorporate the short diffusion lengths, high permeabilities, controllable temperatures, and heat removal properties required for the generation of useful radioactive ion beam (RIB) intensities for nuclear physics and astrophysics research using the isotope separation on-line (ISOL) technique. Short diffusion lengths are achieved either by using thin fibrous target materials or by coating thin layers of selected target material onto low-density carbon fibers such as reticulated vitreous carbon fiber (RVCF) or carbon-bonded-carbon-fiber (CBCF) to form highly permeable composite target matrices. Computational studies which simulate the generation and removal of primary beam deposited heat from target materials have been conducted to optimize the design of target/heat-sink systems for generating RIBs. The results derived from diffusion release-rate simulation studies for selected targets and thermal analyses of temperature distributions within a prototype target/heat-sink system subjected to primary ion beam irradiation will be presented in this report.

Strong electromagnetic pulses generated in laser-matter interactions with 10TW-class fs laser

NASA Astrophysics Data System (ADS)

Rączka, Piotr; Rosiński, Marcin; Zaraś-Szydłowska, Agnieszka; Wołowski, Jerzy; Badziak, Jan

2018-01-01

The results of an experiment on the generation of electromagnetic pulses (EMP) in the interaction of 10TW fs pulses with thick (mm scale) and thin foil (μm scale) targets are described. Such pulses, with frequencies in the GHz range, may pose a threat to safe and reliable operation of high-power, high-intensity laser facilities. The main point of the experiment is to investigate the fine temporal structure of such pulses using an oscilloscope capable of measurements at very high sampling rate. It is found that the amazing reproducibility of such pulses is confirmed at this high sampling rate. Furthermore, the differences between the EMP signals generated from thick and thin foil targets are clearly seen, which indicates that besides electric polarization of the target and the target neutralization current there may be other factors essential for the EMP emission.

National Ignition Facility: Experimental plan

NASA Astrophysics Data System (ADS)

1994-05-01

As part of the Conceptual Design Report (CDR) for the National Ignition Facility (NIF), scientists from Lawrence Livermore National Laboratory (LLNL), Los Alamos National Laboratory (LANL), Sandia National Laboratory (SNL), the University of Rochester's Laboratory for Laser Energetics (UR/LLE), and EG&G formed an NIF Target Diagnostics Working Group. The purpose of the Target Diagnostics Working Group is to prepare conceptual designs of target diagnostics for inclusion in the facility CDR and to determine how these specifications impact the CDR. To accomplish this, a subgroup has directed its efforts at constructing an approximate experimental plan for the ignition campaign of the NIF CDR. The results of this effort are contained in this document, the Experimental Plan for achieving fusion ignition in the NIF. This group initially concentrated on the flow-down requirements of the experimental campaign leading to ignition, which will dominate the initial efforts of the NIF. It is envisaged, however, that before ignition, there will be parallel campaigns supporting weapons physics, weapons effects, and other research. This plan was developed by analyzing the sequence of activities required to finally fire the laser at the level of power and precision necessary to achieve the conditions of an ignition hohlraum target, and to then use our experience in activating and running Nova experiments to estimate the rate of completing these activities.

OPTIMIZATION OF EXPERIMENTAL DESIGNS BY INCORPORATING NIF FACILITY IMPACTS

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

Eder, D C; Whitman, P K; Koniges, A E

2005-08-31

For experimental campaigns on the National Ignition Facility (NIF) to be successful, they must obtain useful data without causing unacceptable impact on the facility. Of particular concern is excessive damage to optics and diagnostic components. There are 192 fused silica main debris shields (MDS) exposed to the potentially hostile target chamber environment on each shot. Damage in these optics results either from the interaction of laser light with contamination and pre-existing imperfections on the optic surface or from the impact of shrapnel fragments. Mitigation of this second damage source is possible by identifying shrapnel sources and shielding optics from them.more » It was recently demonstrated that the addition of 1.1-mm thick borosilicate disposable debris shields (DDS) block the majority of debris and shrapnel fragments from reaching the relatively expensive MDS's. However, DDS's cannot stop large, faster moving fragments. We have experimentally demonstrated one shrapnel mitigation technique showing that it is possible to direct fast moving fragments by changing the source orientation, in this case a Ta pinhole array. Another mitigation method is to change the source material to one that produces smaller fragments. Simulations and validating experiments are necessary to determine which fragments can penetrate or break 1-3 mm thick DDS's. Three-dimensional modeling of complex target-diagnostic configurations is necessary to predict the size, velocity, and spatial distribution of shrapnel fragments. The tools we are developing will be used to set the allowed level of debris and shrapnel generation for all NIF experimental campaigns.« less

Topological robustness analysis of protein interaction networks reveals key targets for overcoming chemotherapy resistance in glioma

NASA Astrophysics Data System (ADS)

Azevedo, Hátylas; Moreira-Filho, Carlos Alberto

2015-11-01

Biological networks display high robustness against random failures but are vulnerable to targeted attacks on central nodes. Thus, network topology analysis represents a powerful tool for investigating network susceptibility against targeted node removal. Here, we built protein interaction networks associated with chemoresistance to temozolomide, an alkylating agent used in glioma therapy, and analyzed their modular structure and robustness against intentional attack. These networks showed functional modules related to DNA repair, immunity, apoptosis, cell stress, proliferation and migration. Subsequently, network vulnerability was assessed by means of centrality-based attacks based on the removal of node fractions in descending orders of degree, betweenness, or the product of degree and betweenness. This analysis revealed that removing nodes with high degree and high betweenness was more effective in altering networks’ robustness parameters, suggesting that their corresponding proteins may be particularly relevant to target temozolomide resistance. In silico data was used for validation and confirmed that central nodes are more relevant for altering proliferation rates in temozolomide-resistant glioma cell lines and for predicting survival in glioma patients. Altogether, these results demonstrate how the analysis of network vulnerability to topological attack facilitates target prioritization for overcoming cancer chemoresistance.

National direct-drive program on OMEGA and the National Ignition Facility

NASA Astrophysics Data System (ADS)

Goncharov, V. N.; Regan, S. P.; Campbell, E. M.; Sangster, T. C.; Radha, P. B.; Myatt, J. F.; Froula, D. H.; Betti, R.; Boehly, T. R.; Delettrez, J. A.; Edgell, D. H.; Epstein, R.; Forrest, C. J.; Glebov, V. Yu; Harding, D. R.; Hu, S. X.; Igumenshchev, I. V.; Marshall, F. J.; McCrory, R. L.; Michel, D. T.; Seka, W.; Shvydky, A.; Stoeckl, C.; Theobald, W.; Gatu-Johnson, M.

2017-01-01

A major advantage of the laser direct-drive (DD) approach to ignition is the increased fraction of laser drive energy coupled to the hot spot and relaxed hot-spot requirements for the peak pressure and convergence ratios relative to the indirect-drive approach at equivalent laser energy. With the goal of a successful ignition demonstration using DD, the recently established national strategy has several elements and involves multiple national and international institutions. These elements include the experimental demonstration on OMEGA cryogenic implosions of hot-spot conditions relevant for ignition at MJ-scale energies available at the National Ignition Facility (NIF) and developing an understanding of laser-plasma interactions and laser coupling using DD experiments on the NIF. DD designs require reaching central stagnation pressures in excess of 100 Gbar. The current experiments on OMEGA have achieved inferred peak pressures of 56 Gbar (Regan et al 2016 Phys. Rev. Lett. 117 025001). Extensive analysis of the cryogenic target experiments and two- and three-dimensional simulations suggest that power balance, target offset, and target quality are the main limiting factors in target performance. In addition, cross-beam energy transfer (CBET) has been identified as the main mechanism reducing laser coupling. Reaching the goal of demonstrating hydrodynamic equivalence on OMEGA includes improving laser power balance, target position, and target quality at shot time. CBET must also be significantly reduced and several strategies have been identified to address this issue.

Nuclear Reactions Studies in Laser-Plasmas at the forthcoming ELI-NP facilities

NASA Astrophysics Data System (ADS)

Lanzalone, G.; Muoio, A.; Altana, C.; Frassetto, M.; Malferrari, L.; Mascali, D.; Odorici, F.; Tudisco, S.; Gizzi, L. A.; Labate, L.; Puglia, S. M. R.; Trifirò, A.

2018-05-01

This work aim to prepare a program of studies on nuclear physics and astrophysics, which will be conducted at the new ELI-NP Laser facility, which actually is under construction in Bucharest, Romania. For the arguments treated, such activity has required also a multidisciplinary approach and knowledge in the fields of nuclear physics, astrophysics, laser and plasma physics join with also some competences on solid state physics related to the radiation detection. A part of this work has concerned to the experimental test, which have been performed in several laboratories and in order to study and increase the level of knowledge on the different parts of the project. In particular have been performed studies on the laser matter interaction at the ILIL laboratory of Pisa Italy and at the LENS laboratory in Catania, where (by using different experimental set-ups) has been investigated some key points concerning the production of the plasma stream. Test has been performed on several target configurations in terms of: composition, structure and size. All the work has been devoted to optimize the conditions of target in order to have the best performance on the production yields and on energies distribution of the inner plasma ions. A parallel activity has been performed in order to study the two main detectors, which will constitute the full detections system, which will be installed at the ELI-NP facility.

The Oncogene PDRG1 Is an Interaction Target of Methionine Adenosyltransferases

PubMed Central

Garrido, Francisco; Reytor, Edel; Portillo, Francisco; Pajares, María A.

2016-01-01

Methionine adenosyltransferases MAT I and MAT III (encoded by Mat1a) catalyze S-adenosylmethionine synthesis in normal liver. Major hepatic diseases concur with reduced levels of this essential methyl donor, which are primarily due to an expression switch from Mat1a towards Mat2a. Additional changes in the association state and even in subcellular localization of these isoenzymes are also detected. All these alterations result in a reduced content of the moderate (MAT I) and high Vmax (MAT III) isoenzymes, whereas the low Vmax (MAT II) isoenzyme increases and nuclear accumulation of MAT I is observed. These changes derive in a reduced availability of cytoplasmic S-adenosylmethionine, together with an effort to meet its needs in the nucleus of damaged cells, rendering enhanced levels of certain epigenetic modifications. In this context, the putative role of protein-protein interactions in the control of S-adenosylmethionine synthesis has been scarcely studied. Using yeast two hybrid and a rat liver library we identified PDRG1 as an interaction target for MATα1 (catalytic subunit of MAT I and MAT III), further confirmation being obtained by immunoprecipitation and pull-down assays. Nuclear MATα interacts physically and functionally with the PDRG1 oncogene, resulting in reduced DNA methylation levels. Increased Pdrg1 expression is detected in acute liver injury and hepatoma cells, together with decreased Mat1a expression and nuclear accumulation of MATα1. Silencing of Pdrg1 expression in hepatoma cells alters their steady-state expression profile on microarrays, downregulating genes associated with tumor progression according to GO pathway analysis. Altogether, the results unveil the role of PDRG1 in the control of the nuclear methylation status through methionine adenosyltransferase binding and its putative collaboration in the progression of hepatic diseases. PMID:27548429

SuperTarget and Matador: resources for exploring drug-target relationships.

PubMed

Günther, Stefan; Kuhn, Michael; Dunkel, Mathias; Campillos, Monica; Senger, Christian; Petsalaki, Evangelia; Ahmed, Jessica; Urdiales, Eduardo Garcia; Gewiess, Andreas; Jensen, Lars Juhl; Schneider, Reinhard; Skoblo, Roman; Russell, Robert B; Bourne, Philip E; Bork, Peer; Preissner, Robert

2008-01-01

The molecular basis of drug action is often not well understood. This is partly because the very abundant and diverse information generated in the past decades on drugs is hidden in millions of medical articles or textbooks. Therefore, we developed a one-stop data warehouse, SuperTarget that integrates drug-related information about medical indication areas, adverse drug effects, drug metabolization, pathways and Gene Ontology terms of the target proteins. An easy-to-use query interface enables the user to pose complex queries, for example to find drugs that target a certain pathway, interacting drugs that are metabolized by the same cytochrome P450 or drugs that target the same protein but are metabolized by different enzymes. Furthermore, we provide tools for 2D drug screening and sequence comparison of the targets. The database contains more than 2500 target proteins, which are annotated with about 7300 relations to 1500 drugs; the vast majority of entries have pointers to the respective literature source. A subset of these drugs has been annotated with additional binding information and indirect interactions and is available as a separate resource called Matador. SuperTarget and Matador are available at http://insilico.charite.de/supertarget and http://matador.embl.de.

miRNet - dissecting miRNA-target interactions and functional associations through network-based visual analysis

PubMed Central

Fan, Yannan; Siklenka, Keith; Arora, Simran K.; Ribeiro, Paula; Kimmins, Sarah; Xia, Jianguo

2016-01-01

MicroRNAs (miRNAs) can regulate nearly all biological processes and their dysregulation is implicated in various complex diseases and pathological conditions. Recent years have seen a growing number of functional studies of miRNAs using high-throughput experimental technologies, which have produced a large amount of high-quality data regarding miRNA target genes and their interactions with small molecules, long non-coding RNAs, epigenetic modifiers, disease associations, etc. These rich sets of information have enabled the creation of comprehensive networks linking miRNAs with various biologically important entities to shed light on their collective functions and regulatory mechanisms. Here, we introduce miRNet, an easy-to-use web-based tool that offers statistical, visual and network-based approaches to help researchers understand miRNAs functions and regulatory mechanisms. The key features of miRNet include: (i) a comprehensive knowledge base integrating high-quality miRNA-target interaction data from 11 databases; (ii) support for differential expression analysis of data from microarray, RNA-seq and quantitative PCR; (iii) implementation of a flexible interface for data filtering, refinement and customization during network creation; (iv) a powerful fully featured network visualization system coupled with enrichment analysis. miRNet offers a comprehensive tool suite to enable statistical analysis and functional interpretation of various data generated from current miRNA studies. miRNet is freely available at http://www.mirnet.ca. PMID:27105848

Glucose-conjugated chitosan nanoparticles for targeted drug delivery and their specific interaction with tumor cells

NASA Astrophysics Data System (ADS)

Li, Jing; Ma, Fang-Kui; Dang, Qi-Feng; Liang, Xing-Guo; Chen, Xi-Guang

2014-12-01

A novel targeted drug delivery system, glucose-conjugated chitosan nanoparticles (GCNPs), was developed for specific recognition and interaction with glucose transporters (Gluts) over-expressed by tumor cells. GC was synthesized by using succinic acid as a linker between glucosamine and chitosan (CS), and successful synthesis was confirmed by NMR and elemental analysis. GCNPs were prepared by ionic crosslinking method, and characterized in terms of morphology, size, and zeta potential. The optimally prepared nanoparticles showed spherical shapes with an average particle size of (187.9 ± 3.8) nm and a zeta potential of (- 15.43 ± 0.31) mV. The GCNPs showed negligible cytotoxicity to mouse embryo fibroblast and 4T1 cells. Doxorubicin (DOX) could be efficiently entrapped into GCNPs, with a loading capacity and encapsulation efficiency of 20.11% and 64.81%, respectively. DOX-loaded nanoparticles exhibited sustained-release behavior in phosphate buffered saline (pH 7.4). In vitro cellular uptake studies showed that the GCNPs had better endocytosis ability than CSNPs, and the antitumor activity of DOX/GCNPs was 4-5 times effectiveness in 4T1 cell killing than that of DOX/CSNPs. All the results demonstrate that nanoparticles decorated with glucose have specific interactions with cancer cells via the recognition between glucose and Gluts. Therefore, Gluts-targeted GCNPs may be promising delivery agents in cancer therapies.

Simple model of the indirect compression of targets under conditions close to the national ignition facility at an energy of 1.5 MJ

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

Rozanov, V. B., E-mail: rozanov@sci.lebedev.ru; Vergunova, G. A., E-mail: verg@sci.lebedev.ru

2015-11-15

The possibility of the analysis and interpretation of the reported experiments with the megajoule National Ignition Facility (NIF) laser on the compression of capsules in indirect-irradiation targets by means of the one-dimensional RADIAN program in the spherical geometry has been studied. The problem of the energy balance in a target and the determination of the laser energy that should be used in the spherical model of the target has been considered. The results of action of pulses differing in energy and time profile (“low-foot” and “high-foot” regimes) have been analyzed. The parameters of the compression of targets with a high-densitymore » carbon ablator have been obtained. The results of the simulations are in satisfactory agreement with the measurements and correspond to the range of the observed parameters. The set of compared results can be expanded, in particular, for a more detailed determination of the parameters of a target near the maximum compression of the capsule. The physical foundation of the possibility of using the one-dimensional description is the necessity of the closeness of the last stage of the compression of the capsule to a one-dimensional process. The one-dimensional simulation of the compression of the capsule can be useful in establishing the boundary behind which two-dimensional and three-dimensional simulation should be used.« less

Developing targets for radiation transport experiments at the Omega laser facility

DOE PAGES

Capelli, Deanna; Charsley-Groffman, C. A.; Randolph, Randall Blaine; ...

2017-07-13

Targets have been developed to measure supersonic radiation transport in aerogel foams using absorption spectroscopy. The target consists of an aerogel foam uniformly doped with either titanium or scandium inserted into an undoped aerogel foam package. This creates a localized doped foam region to provide spatial resolution for the measurement. Development and characterization of the foams is a key challenge in addition to machining and assembling the two foams so they mate without gaps. The foam package is inserted into a beryllium sleeve and mounted on a gold hohlraum. The target is mounted to a holder created using additive manufacturingmore » and mounted on a stalk. As a result, the manufacturing of the components, along with assembly and metrology of the target are described here.« less

Developing targets for radiation transport experiments at the Omega laser facility

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

Capelli, Deanna; Charsley-Groffman, C. A.; Randolph, Randall Blaine

Targets have been developed to measure supersonic radiation transport in aerogel foams using absorption spectroscopy. The target consists of an aerogel foam uniformly doped with either titanium or scandium inserted into an undoped aerogel foam package. This creates a localized doped foam region to provide spatial resolution for the measurement. Development and characterization of the foams is a key challenge in addition to machining and assembling the two foams so they mate without gaps. The foam package is inserted into a beryllium sleeve and mounted on a gold hohlraum. The target is mounted to a holder created using additive manufacturingmore » and mounted on a stalk. As a result, the manufacturing of the components, along with assembly and metrology of the target are described here.« less

[Segment analysis of the target market of physiotherapeutic services].

PubMed

Babaskin, D V

2010-01-01

The objective of the present study was to demonstrate the possibilities to analyse selected segments of the target market of physiotherapeutic services provided by medical and preventive-facilities of two major types. The main features of a target segment, such as provision of therapeutic massage, are illustrated in terms of two characteristics, namely attractiveness to the users and the ability of a given medical facility to satisfy their requirements. Based on the analysis of portfolio of the available target segments the most promising ones (winner segments) were selected for further marketing studies. This choice does not exclude the possibility of involvement of other segments of medical services in marketing activities.

A new strategy to identify hepatitis B virus entry inhibitors by AlphaScreen technology targeting the envelope-receptor interaction.

PubMed

Saso, Wakana; Tsukuda, Senko; Ohashi, Hirofumi; Fukano, Kento; Morishita, Ryo; Matsunaga, Satoko; Ohki, Mio; Ryo, Akihide; Park, Sam-Yong; Suzuki, Ryosuke; Aizaki, Hideki; Muramatsu, Masamichi; Sureau, Camille; Wakita, Takaji; Matano, Tetsuro; Watashi, Koichi

2018-06-22

Current anti-hepatitis B virus (HBV) agents have limited effect in curing HBV infection, and thus novel anti-HBV agents with different modes of action are in demand. In this study, we applied AlphaScreen assay to high-throughput screening of small molecules inhibiting the interaction between HBV large surface antigen (LHBs) and the HBV entry receptor, sodium taurocholate cotransporting polypeptide (NTCP). From the chemical screening, we identified that rapamycin, an immunosuppressant, strongly inhibited the LHBs-NTCP interaction. Rapamycin inhibited hepatocyte infection with HBV without significant cytotoxicity. This activity was due to impaired attachment of the LHBs preS1 domain to cell surface. Pretreatment of target cells with rapamycin remarkably reduced their susceptibility to preS1 attachment, while rapamycin pretreatment to preS1 did not affect its attachment activity, suggesting that rapamycin targets the host side. In support of this, a surface plasmon resonance analysis showed a direct interaction of rapamycin with NTCP. Consistently, rapamycin also prevented hepatitis D virus infection, whose entry into cells is also mediated by NTCP. We also identified two rapamycin derivatives, everolimus and temsirolimus, which possessed higher anti-HBV potencies than rapamycin. Thus, this is the first report for application of AlphaScreen technology that monitors a viral envelope-receptor interaction to identify viral entry inhibitors. Copyright © 2018 Elsevier Inc. All rights reserved.

Design and Synthesis of Irreversible Analogues of Bardoxolone Methyl for the Identification of Pharmacologically Relevant Targets and Interaction Sites.

PubMed

Wong, Michael H L; Bryan, Holly K; Copple, Ian M; Jenkins, Rosalind E; Chiu, Pak Him; Bibby, Jaclyn; Berry, Neil G; Kitteringham, Neil R; Goldring, Christopher E; O'Neill, Paul M; Park, B Kevin

2016-03-24

Semisynthetic triterpenoids such as bardoxolone methyl (methyl-2-cyano 3,12-dioxooleano-1,9-dien-28-oate; CDDO-Me) (4) are potent inducers of antioxidant and anti-inflammatory signaling pathways, including those regulated by the transcription factor Nrf2. However, the reversible nature of the interaction between triterpenoids and thiols has hindered attempts to identify pharmacologically relevant targets and characterize the sites of interaction. Here, we report a shortened synthesis and SAR profiling of 4, enabling the design of analogues that react irreversibly with model thiols, as well as the model protein glutathione S-transferase P1, in vitro. We show that one of these analogues, CDDO-epoxide (13), is comparable to 4 in terms of cytotoxicity and potency toward Nrf2 in rat hepatoma cells and stably modifies specific cysteine residues (namely, Cys-257, -273, -288, -434, -489, and -613) within Keap1, the major repressor of Nrf2, both in vitro and in living cells. Supported by molecular modeling, these data demonstrate the value of 13 for identifying site(s) of interaction with pharmacologically relevant targets and informing the continuing development of triterpenoids as novel drug candidates.

No Interactions of Stacked Bt Maize with the Non-target Aphid Rhopalosiphum padi and the Spider Mite Tetranychus urticae.

PubMed

Shu, Yinghua; Romeis, Jörg; Meissle, Michael

2018-01-01

In the agroecosystem, genetically engineered plants producing insecticidal Cry proteins from Bacillus thuringiensis (Bt) interact with non-target herbivores and other elements of the food web. Stacked Bt crops expose herbivores to multiple Cry proteins simultaneously. In this study, the direct interactions between SmartStax ® Bt maize producing six different Cry proteins and two herbivores with different feeding modes were investigated. Feeding on leaves of Bt maize had no effects on development time, fecundity, or longevity of the aphid Rhopalosiphum padi (Hemiptera: Aphididae), and no effects on the egg hatching time, development time, sex ratio, fecundity, and survival of the spider mite Tetranychus urticae (Acari: Tetranychidae). The results thus confirm the lack of effects on those species reported previously for some of the individual Cry proteins. In the Bt maize leaves, herbivore infestation did not result in a consistent change of Cry protein concentrations. However, occasional statistical differences between infested and non-infested leaves were observed for some Cry proteins and experimental repetitions. Overall, the study provides evidence that the Cry proteins in stacked Bt maize do not interact with two common non-target herbivores.

Polarized internal target apparatus

DOEpatents

Holt, Roy J.

1986-01-01

A polarized internal target apparatus with a polarized gas target of improved polarization and density achieved by mixing target gas atoms with a small amount of alkali metal gas atoms, and passing a high intensity polarized light source into the mixture to cause the alkali metal gas atoms to become polarized which interact in spin exchange collisions with target gas atoms yielding polarized target gas atoms.

Specular Reflectivity and Hot-Electron Generation in High-Contrast Relativistic Laser-Plasma Interactions

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

Kemp, Gregory Elijah

2013-01-01

Ultra-intense laser (> 1018 W/cm2) interactions with matter are capable of producing relativistic electrons which have a variety of applications in state-of-the-art scientific and medical research conducted at universities and national laboratories across the world. Control of various aspects of these hot-electron distributions is highly desired to optimize a particular outcome. Hot-electron generation in low-contrast interactions, where significant amounts of under-dense pre-plasma are present, can be plagued by highly non-linear relativistic laser-plasma instabilities and quasi-static magnetic field generation, often resulting in less than desirable and predictable electron source characteristics. High-contrast interactions offer more controlled interactions but often at the costmore » of overall lower coupling and increased sensitivity to initial target conditions. An experiment studying the differences in hot-electron generation between high and low-contrast pulse interactions with solid density targets was performed on the Titan laser platform at the Jupiter Laser Facility at Lawrence Livermore National Laboratory in Livermore, CA. To date, these hot-electrons generated in the laboratory are not directly observable at the source of the interaction. Instead, indirect studies are performed using state-of-the-art simulations, constrained by the various experimental measurements. These measurements, more-often-than-not, rely on secondary processes generated by the transport of these electrons through the solid density materials which can susceptible to a variety instabilities and target material/geometry effects. Although often neglected in these types of studies, the specularly reflected light can provide invaluable insight as it is directly influenced by the interaction. In this thesis, I address the use of (personally obtained) experimental specular reflectivity measurements to indirectly study hot-electron generation in the context of high

75 FR 54627 - Best Management Practices for Unused Pharmaceuticals at Health Care Facilities

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-08

... at Health Care Facilities AGENCY: Environmental Protection Agency (EPA). ACTION: Notice. SUMMARY: EPA... Unused Pharmaceuticals at Health Care Facilities. The guidance is targeted at hospitals, medical clinics... drafted a guidance document for health care facilities, which describes: Techniques for reducing or...

Targeting YAP/TAZ-TEAD protein-protein interactions using fragment-based and computational modeling approaches

PubMed Central

Verma, Chandra

2017-01-01

The Hippo signaling pathway, which is implicated in the regulation of organ size, has emerged as a potential target for the development of cancer therapeutics. YAP, TAZ (transcription co-activators) and TEAD (transcription factor) are the downstream transcriptional machinery and effectors of the pathway. Formation of the YAP/TAZ-TEAD complex leads to transcription of growth-promoting genes. Conversely, disrupting the interactions of the complex decreases cell proliferation. Herein, we screened a 1000-member fragment library using Thermal Shift Assay and identified a hit fragment. We confirmed its binding at the YAP/TAZ-TEAD interface by X-ray crystallography, and showed that it occupies the same hydrophobic pocket as a conserved phenylalanine of YAP/TAZ. This hit fragment serves as a scaffold for the development of compounds that have the potential to disrupt YAP/TAZ-TEAD interactions. Structure-activity relationship studies and computational modeling were also carried out to identify more potent compounds that may bind at this validated druggable binding site. PMID:28570566

Targeting protein-protein interactions with trimeric ligands: high affinity inhibitors of the MAGUK protein family.

PubMed

Nissen, Klaus B; Haugaard-Kedström, Linda M; Wilbek, Theis S; Nielsen, Line S; Åberg, Emma; Kristensen, Anders S; Bach, Anders; Jemth, Per; Strømgaard, Kristian

2015-01-01

PDZ domains in general, and those of PSD-95 in particular, are emerging as promising drug targets for diseases such as ischemic stroke. We have previously shown that dimeric ligands that simultaneously target PDZ1 and PDZ2 of PSD-95 are highly potent inhibitors of PSD-95. However, PSD-95 and the related MAGUK proteins contain three consecutive PDZ domains, hence we envisioned that targeting all three PDZ domains simultaneously would lead to more potent and potentially more specific interactions with the MAGUK proteins. Here we describe the design, synthesis and characterization of a series of trimeric ligands targeting all three PDZ domains of PSD-95 and the related MAGUK proteins, PSD-93, SAP-97 and SAP-102. Using our dimeric ligands targeting the PDZ1-2 tandem as starting point, we designed novel trimeric ligands by introducing a PDZ3-binding peptide moiety via a cysteine-derivatized NPEG linker. The trimeric ligands generally displayed increased affinities compared to the dimeric ligands in fluorescence polarization binding experiments and optimized trimeric ligands showed low nanomolar inhibition towards the four MAGUK proteins, thus being the most potent inhibitors described. Kinetic experiments using stopped-flow spectrometry showed that the increase in affinity is caused by a decrease in the dissociation rate of the trimeric ligand as compared to the dimeric ligands, likely reflecting the lower probability of simultaneous dissociation of all three PDZ ligands. Thus, we have provided novel inhibitors of the MAGUK proteins with exceptionally high affinity, which can be used to further elucidate the therapeutic potential of these proteins.

Experimental equipment for an advanced ISOL facility[Isotope Separation On-Line Facility

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

Baktash, C.; Lee, I.Y.; Rehm, K.E.

This report summarizes the proceedings and recommendations of the Workshop on the Experimental Equipment for an Advanced ISOL Facility which was held at Lawrence Berkeley National Laboratory on July 22--25, 1998. The purpose of this workshop was to discuss the performance requirements, manpower and cost estimates, as well as a schedule of the experimental equipment needed to fully exploit the new physics which can be studied at an advanced ISOL facility. An overview of the new physics opportunities that would be provided by such a facility has been presented in the White Paper that was issued following the Columbus Meeting.more » The reactions and experimental techniques discussed in the Columbus White Paper served as a guideline for the formulation of the detector needs at the Berkeley Workshop. As outlined a new ISOL facility with intense, high-quality beams of radioactive nuclei would provide exciting new research opportunities in the areas of: the nature of nucleonic matter; the origin of the elements; and tests of the Standard Model. After an introductory section, the following equipment is discussed: gamma-ray detectors; recoil separators; magnetic spectrographs; particle detectors; targets; and apparatus using non-accelerated beams.« less

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

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

Bauer, G.S.; Atchison, F.

1995-10-01

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

Interactive Television: The Influence of User Control and Interactive Structure.

ERIC Educational Resources Information Center

Gagnon, Diana; And Others

A series of studies underway at the Audience Research Facility at MIT (the Massachusetts Institute of Technology) are examining the influence of interactive video on learning and entertainment television viewing. The first study compared the learning of spatial content from interactive (user controlled video games) versus observational…

USGS aerial resolution targets.

USGS Publications Warehouse

Salamonowicz, P.H.

1982-01-01

It is necessary to measure the achievable resolution of any airborne sensor that is to be used for metric purposes. Laboratory calibration facilities may be inadequate or inappropriate for determining the resolution of non-photographic sensors such as optical-mechanical scanners, television imaging tubes, and linear arrays. However, large target arrays imaged in the field can be used in testing such systems. The USGS has constructed an array of resolution targets in order to permit field testing of a variety of airborne sensing systems. The target array permits any interested organization with an airborne sensing system to accurately determine the operational resolution of its system. -from Author

The National Ignition Facility and Industry

NASA Astrophysics Data System (ADS)

Harri, J. G.; Paisner, J. A.; Lowdermilk, W. H.; Boyes, J. D.; Kumpan, S. A.; Sorem, M. S.

1994-09-01

The mission of the National Ignition Facility is to achieve ignition and gain in inertial confinement fusion targets in the laboratory. The facility will be used for defense applications such as weapons physics and weapons effects testing, and for civilian applications such as fusion energy development and fundamental studies of matter at high temperatures and densities. The National Ignition Facility construction project will require the best of our construction industries and its success will depend on the best products offered by hundreds of the nation's high technology companies. Three-fourths of the construction costs will be invested in industry. This article reviews the design, cost and schedule, and required industrial involvement associated with the construction project.

Automatic target alignment of the Helios laser system

NASA Astrophysics Data System (ADS)

Liberman, I.; Viswanathan, V. K.; Klein, M.; Seery, B. D.

1980-05-01

An automatic target-alignment technique for the Helios laser facility is reported and verified experimentally. The desired alignment condition is completely described by an autocollimation test. A computer program examines the autocollimated return pattern from the surrogate target and correctly describes any changes required in mirror orientation to yield optimum target alignment with either aberrated or misaligned beams. Automated on-line target alignment is thus shown to be feasible.

Targeted studies on the interaction of nicotine and morin molecules with amyloid β-protein.

PubMed

Boopathi, Subramaniam; Kolandaivel, Ponmalai

2014-03-01

Alzheimer's disease (AD) is a neurodegenerative disorder that occurs due to progressive deposition of amyloid β-protein (Aβ) in the brain. Stable conformations of solvated Aβ₁₋₄₂ protein were predicted by molecular dynamics (MD) simulation using the OPLSAA force field. The seven residue peptide (Lys-Leu-Val-Phe-Phe-Ala-Glu) Aβ₁₆₋₂₂ associated with AD was studied and reported in this paper. Since effective therapeutic agents have not yet been studied in detail, attention has focused on the use of natural products as effective anti-aggregation compounds, targeting the Aβ₁₋₄₂ protein directly. Experimental and theoretical investigation suggests that some compounds extracted from natural products might be useful, but detailed insights into the mechanism by which they might act remains elusive. The molecules nicotine and morin are found in cigarettes and beverages. Here, we report the results of interaction studies of these compounds at each hydrophobic residue of Aβ₁₆₋₂₂ peptide using the hybrid ONIOM (B3LYP/6-31G**:UFF) method. It was found that interaction with nicotine produced higher deformation in the Aβ₁₆₋₂₂ peptide than interaction with morin. MD simulation studies revealed that interaction of the nicotine molecule with the β-sheet of Aβ₁₆₋₂₂ peptide transforms the β-sheet to an α-helical structure, which helps prohibit the aggregation of Aβ-protein.

Target materials for exotic ISOL beams

NASA Astrophysics Data System (ADS)

Gottberg, A.

2016-06-01

The demand for intensity, purity, reliability and availability of short-lived isotopes far from stability is steadily high, and considerably exceeding the supply. In many cases the ISOL (Isotope Separation On-Line) method can provide beams of high intensity and purity. Limitations in terms of accessible chemical species and minimum half-life are driven mainly by chemical reactions and physical processes inside of the thick target. A wide range of materials are in use, ranging from thin metallic foils and liquids to refractory ceramics, while poly-phasic mixed uranium carbides have become the reference target material for most ISOL facilities world-wide. Target material research and development is often complex and especially important post-irradiation analyses are hindered by the high intrinsic radiotoxicity of these materials. However, recent achievements have proven that these investigations are possible if the effort of different facilities is combined, leading to the development of new material matrices that can supply new beams of unprecedented intensity and beam current stability.

Polarized internal target apparatus

DOEpatents

Holt, R.J.

1984-10-10

A polarized internal target apparatus with a polarized gas target of improved polarization and density (achieved by mixing target gas atoms with a small amount of alkali metal gas atoms, and passing a high intensity polarized light source into the mixture to cause the alkali metal gas atoms to become polarized which interact in spin exchange collisions with target gas atoms yielding polarized target gas atoms) is described.

Analysis of 440 GeV proton beam–matter interaction experiments at the High Radiation Materials test facility at CERN

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

Burkart, F.; Schmidt, R.; Wollmann, D.

2015-08-07

In a previous paper [Schmidt et al., Phys. Plasmas 21, 080701 (2014)], we presented the first results on beam–matter interaction experiments that were carried out at the High Radiation Materials test facility at CERN. In these experiments, extended cylindrical targets of solid copper were irradiated with beam of 440 GeV protons delivered by the Super Proton Synchrotron (SPS). The beam comprised of a large number of high intensity proton bunches, each bunch having a length of 0.5 ns with a 50 ns gap between two neighboring bunches, while the length of this entire bunch train was about 7 μs. These experiments established the existencemore » of the hydrodynamic tunneling phenomenon the first time. Detailed numerical simulations of these experiments were also carried out which were reported in detail in another paper [Tahir et al., Phys. Rev. E 90, 063112 (2014)]. Excellent agreement was found between the experimental measurements and the simulation results that validate our previous simulations done using the Large Hadron Collider (LHC) beam of 7 TeV protons [Tahir et al., Phys. Rev. Spec. Top.--Accel. Beams 15, 051003 (2012)]. According to these simulations, the range of the full LHC proton beam and the hadronic shower can be increased by more than an order of magnitude due to the hydrodynamic tunneling, compared to that of a single proton. This effect is of considerable importance for the design of machine protection system for hadron accelerators such as SPS, LHC, and Future Circular Collider. Recently, using metal cutting technology, the targets used in these experiments have been dissected into finer pieces for visual and microscopic inspection in order to establish the precise penetration depth of the protons and the corresponding hadronic shower. This, we believe will be helpful in studying the very important phenomenon of hydrodynamic tunneling in a more quantitative manner. The details of this experimental work together with a comparison with the

Use of information technology for medication management in residential care facilities: correlates of facility characteristics.

PubMed

Bhuyan, Soumitra S; Chandak, Aastha; Powell, M Paige; Kim, Jungyoon; Shiyanbola, Olayinka; Zhu, He; Shiyanbola, Oyewale

2015-06-01

The effectiveness of information technology in resolving medication problems has been well documented. Long-term care settings such as residential care facilities (RCFs) may see the benefits of using such technologies in addressing the problem of medication errors among their resident population, who are usually older and have numerous chronic conditions. The aim of this study was two-fold: to examine the extent of use of Electronic Medication Management (EMM) in RCFs and to analyze the organizational factors associated with the use of EMM functionalities in RCFs. Data on RCFs were obtained from the 2010 National Survey of Residential Care Facilities. The association between facility, director and staff, and resident characteristics of RCFs and adoption of four EMM functionalities was assessed through multivariate logistic regression. The four EMM functionalities included were maintaining lists of medications, ordering for prescriptions, maintaining active medication allergy lists, and warning of drug interactions or contraindications. About 12% of the RCFs adopted all four EMM functionalities. Additionally, maintaining lists of medications had the highest adoption rate (34.5%), followed by maintaining active medication allergy lists (31.6%), ordering for prescriptions (19.7%), and warning of drug interactions or contraindications (17.9%). Facility size and ownership status were significantly associated with adoption of all four EMM functionalities. Medicaid certification status, facility director's age, education and license status, and the use of personal care aides in the RCF were significantly associated with the adoption of some of the EMM functionalities. EMM is expected to improve the quality of care and patient safety in long-term care facilities including RCFs. The extent of adoption of the four EMM functionalities is relatively low in RCFs. Some RCFs may strategize to use these functionalities to cater to the increasing demands from the market and also to

Recent progress in the development of protein-protein interaction inhibitors targeting androgen receptor-coactivator binding in prostate cancer.

PubMed

Biron, Eric; Bédard, François

2016-07-01

The androgen receptor (AR) is a key regulator for the growth, differentiation and survival of prostate cancer cells. Identified as a primary target for the treatment of prostate cancer, many therapeutic strategies have been developed to attenuate AR signaling in prostate cancer cells. While frontline androgen-deprivation therapies targeting either the production or action of androgens usually yield favorable responses in prostate cancer patients, a significant number acquire treatment resistance. Known as the castration-resistant prostate cancer (CRPC), the treatment options are limited for this advanced stage. It has been shown that AR signaling is restored in CRPC due to many aberrant mechanisms such as AR mutations, amplification or expression of constitutively active splice-variants. Coregulator recruitment is a crucial regulatory step in AR signaling and the direct blockade of coactivator binding to AR offers the opportunity to develop therapeutic agents that would remain effective in prostate cancer cells resistant to conventional endocrine therapies. Structural analyses of the AR have identified key surfaces involved in protein-protein interaction with coregulators that have been recently used to design and develop promising AR-coactivator binding inhibitors. In this review we will discuss the design and development of small-molecule inhibitors targeting the AR-coactivator interactions for the treatment of prostate cancer. Copyright © 2015 Elsevier Ltd. All rights reserved.

The interactions of p53 with tau and Aß as potential therapeutic targets for Alzheimer's disease.

PubMed

Jazvinšćak Jembrek, Maja; Slade, Neda; Hof, Patrick R; Šimić, Goran

2018-05-04

Alzheimer's disease (AD), the most common progressive neurodegenerative disorder, is characterized by severe cognitive decline and personality changes as a result of synaptic and neuronal loss. The defining clinicopathological hallmarks of the disease are deposits of amyloid precursor protein (APP)-derived amyloid-β peptides (Aβ) in the brain parenchyma, and intracellular aggregates of truncated and hyperphosphorylated tau protein in neurofibrillary tangles (NFT). At the cellular and molecular levels, many intertwined pathological mechanisms that relate Aβ and tau pathology with a transcription factor p53 have been revealed. p53 is activated in response to various stressors that threaten genomic stability. Depending on damage severity, it promotes neuronal death or survival, predominantly via transcription-dependent mechanisms that affect expression of apoptosis-related target genes. Levels of p53 are enhanced in the AD brain and maintain sustained tau hyperphosphorylation, whereas intracellular Aβ directly contributes to p53 pool and promotes downstream p53 effects. The review summarizes the role of p53 in neuronal function, discusses the interactions of p53, tau, and Aβ in the normal brain and during the progression of AD pathology, and considers the impact of the most prominent hereditary risk factors of AD on p53/tau/Aβ interactions. A better understanding of this intricate interplay would provide deeper insight into AD pathology and might offer some novel therapeutic targets for the improvement of treatment options. In this regard, drugs and natural compounds targeting the p53 pathway are of growing interest in neuroprotection as they may represent promising therapeutic approaches in the prevention of oxidative stress-dependent pathological processes underlying AD. Copyright © 2018 Elsevier Ltd. All rights reserved.

Biotechnology Protein Expression and Purification Facility

NASA Technical Reports Server (NTRS)

2003-01-01

The purpose of the Project Scientist Core Facility is to provide purified proteins, both recombinant and natural, to the Biotechnology Science Team Project Scientists and the NRA-Structural Biology Test Investigators. Having a core facility for this purpose obviates the need for each scientist to develop the necessary expertise and equipment for molecular biology, protein expression, and protein purification. Because of this, they are able to focus their energies as well as their funding on the crystallization and structure determination of their target proteins.

A diamond active target for the PADME experiment

NASA Astrophysics Data System (ADS)

Chiodini, G.

2017-02-01

The PADME (Positron Annihilation into Dark Mediator Experiment) collaboration searches for dark photons produced in the annihilation e++e-→γ+A' of accelerated positrons with atomic electrons of a fixed target at the Beam Test Facility of Laboratori Nazionali di Frascati. The apparatus can detect dark photons decaying into visible A'→e+e- and invisible A'→χχ channels, where χ's are particles of a secluded sector weakly interacting and therefore undetected. In order to improve the missing mass resolution and to measure the beam flux, PADME has an active target able to reconstruct the beam spot position and the bunch multiplicity. In this work the active target is described, which is made of a detector grade polycrystalline synthetic diamond with strip electrodes on both surfaces. The electrodes segmentation allows to measure the beam profile along X and Y and evaluate the average beam position bunch per bunch. The results of beam tests for the first two diamond detector prototypes are shown. One of them holds innovative graphitic electrodes built with a custom process developed in the laboratory, and the other one with commercially available traditional Cr-Au electrodes. The front-end electronics used in the test beam is discussed and the performance observed is presented. Finally, the final design of the target to be realized at the beginning of 2017 to be ready for data taking in 2018 is illustrated.

T Cell Post-Transcriptional miRNA-mRNA Interaction Networks Identify Targets Associated with Susceptibility/Resistance to Collagen-induced Arthritis