WorldWideScience

Sample records for multiple rgr targets

  1. NIMH Repository and Genomics Resources (RGR)

    Data.gov (United States)

    U.S. Department of Health & Human Services — The NIMH Repository and Genomics Resource (RGR) stores biosamples, genetic, pedigree and clinical data collected in designated NIMH-funded human subject studies. The...

  2. Design of Human – Machine Interface and Altering of Pelvic Obliquity with RGR Trainer

    OpenAIRE

    Pietrusinski, Maciej; Unluhisarcikli, Ozer; Mavroidis, Constantinos; Cajigas, Iahn; Bonato, Paolo

    2011-01-01

    The Robotic Gait Rehabilitation (RGR) Trainer targets secondary gait deviations in stroke survivors undergoing rehabilitation. Using an impedance control strategy and a linear electromagnetic actuator, the device generates a force field to control pelvic obliquity through a Human-Machine Interface (i.e. a lower body exoskeleton). Herein we describe the design of the RGR Trainer Human-Machine Interface (HMI) and we demonstrate the system’s ability to alter the pattern of movement of the pelvis...

  3. Design of Human-Machine Interface and altering of pelvic obliquity with RGR Trainer.

    Science.gov (United States)

    Pietrusinski, Maciej; Unluhisarcikli, Ozer; Mavroidis, Constantinos; Cajigas, Iahn; Bonato, Paolo

    2011-01-01

    The Robotic Gait Rehabilitation (RGR) Trainer targets secondary gait deviations in stroke survivors undergoing rehabilitation. Using an impedance control strategy and a linear electromagnetic actuator, the device generates a force field to control pelvic obliquity through a Human-Machine Interface (i.e. a lower body exoskeleton). Herein we describe the design of the RGR Trainer Human-Machine Interface (HMI) and we demonstrate the system's ability to alter the pattern of movement of the pelvis during gait in a healthy subject. Results are shown for experiments during which we induced hip-hiking - in healthy subjects. Our findings indicate that the RGR Trainer has the ability of affecting pelvic obliquity during gait. Furthermore, we provide preliminary evidence of short-term retention of the modified pelvic obliquity pattern induced by the RGR Trainer. © 2011 IEEE

  4. Design of Human – Machine Interface and Altering of Pelvic Obliquity with RGR Trainer

    Science.gov (United States)

    Pietrusinski, Maciej; Unluhisarcikli, Ozer; Mavroidis, Constantinos; Cajigas, Iahn; Bonato, Paolo

    2012-01-01

    The Robotic Gait Rehabilitation (RGR) Trainer targets secondary gait deviations in stroke survivors undergoing rehabilitation. Using an impedance control strategy and a linear electromagnetic actuator, the device generates a force field to control pelvic obliquity through a Human-Machine Interface (i.e. a lower body exoskeleton). Herein we describe the design of the RGR Trainer Human-Machine Interface (HMI) and we demonstrate the system’s ability to alter the pattern of movement of the pelvis during gait in a healthy subject. Results are shown for experiments during which we induced hip-hiking – in healthy subjects. Our findings indicate that the RGR Trainer has the ability of affecting pelvic obliquity during gait. Furthermore, we provide preliminary evidence of short-term retention of the modified pelvic obliquity pattern induced by the RGR Trainer. PMID:22275693

  5. Targeted therapy of multiple myeloma.

    Science.gov (United States)

    Dolloff, Nathan G; Talamo, Giampaolo

    2013-01-01

    Multiple myeloma (MM) is a plasma cell malignancy and the second most common hematologic cancer. MM is characterized by the accumulation of malignant plasma cells within the bone marrow, and presents clinically with a broad range of symptoms, including hypercalcemia, renal insufficiency, anemia, and lytic bone lesions. MM is a heterogeneous disease associated with genomic instability, where patients may express multiple genetic abnormalities that affect several oncogenic pathways. Commonly detected genetic aberrations are translocations involving immunoglobulin heavy chain (IgH) switch regions (chromosome 14q32) and oncogenes such as c-maf [t(14:16)], cyclin D1 [t(11:14)], and FGFR3/MMSET [t(4:14)]. Advances in the basic understanding of MM and the development of novel agents, such as the immunomodulatory drugs (IMiDs) thalidomide and lenalidomide and the proteasome inhibitor bortezomib, have increased therapeutic response rates and prolonged patient survival. Despite these advances MM remains incurable in the majority of patients, and it is therefore critical to identify additional therapeutic strategies and targets for its treatment. In this chapter, we review the underlying genetic components of MM and discuss the results of recent clinical trials that demonstrate the effectiveness of targeted agents in the management of MM. In addition, we discuss experimental therapies that are currently in clinical development along with their molecular rationale in the treatment of MM.

  6. Resources transfer and centralization in Brazilian electrical sector: the reversion global reserve (RGR) and the guarantee global reserve (GGR)

    International Nuclear Information System (INIS)

    Souza Amaral Filho, J.B. de.

    1991-01-01

    This dissertation makes the analysis of resources transfer and centralization in Brazilian electrical sector, through reversion global reserve (RGR) and guarantee global reserve (GGR). RGR and GGR are funds. RGR finances sectorial investments in electric power and GGR aims the supply of deficient concessionaires. Governmental investments and the results of this application are showing. (M.V.M.). 55 refs, 2 figs, 61 tabs

  7. Multiple Target Laser Designator (MTLD)

    Science.gov (United States)

    2007-03-01

    Optimized Liquid Crystal Scanning Element Optimize the Nonimaging Predictive Algorithm for Target Ranging, Tracking, and Position Estimation...commercial potential. 3.0 PROGRESS THIS QUARTER 3.1 Optimization of Nonimaging Holographic Antenna for Target Tracking and Position Estimation (Task 6) In

  8. Protein search for multiple targets on DNA

    Energy Technology Data Exchange (ETDEWEB)

    Lange, Martin [Johannes Gutenberg University, Mainz 55122 (Germany); Department of Chemistry, Rice University, Houston, Texas 77005 (United States); Kochugaeva, Maria [Department of Chemistry, Rice University, Houston, Texas 77005 (United States); Kolomeisky, Anatoly B., E-mail: tolya@rice.edu [Department of Chemistry, Rice University, Houston, Texas 77005 (United States); Center for Theoretical Biological Physics, Rice University, Houston, Texas 77005 (United States)

    2015-09-14

    Protein-DNA interactions are crucial for all biological processes. One of the most important fundamental aspects of these interactions is the process of protein searching and recognizing specific binding sites on DNA. A large number of experimental and theoretical investigations have been devoted to uncovering the molecular description of these phenomena, but many aspects of the mechanisms of protein search for the targets on DNA remain not well understood. One of the most intriguing problems is the role of multiple targets in protein search dynamics. Using a recently developed theoretical framework we analyze this question in detail. Our method is based on a discrete-state stochastic approach that takes into account most relevant physical-chemical processes and leads to fully analytical description of all dynamic properties. Specifically, systems with two and three targets have been explicitly investigated. It is found that multiple targets in most cases accelerate the search in comparison with a single target situation. However, the acceleration is not always proportional to the number of targets. Surprisingly, there are even situations when it takes longer to find one of the multiple targets in comparison with the single target. It depends on the spatial position of the targets, distances between them, average scanning lengths of protein molecules on DNA, and the total DNA lengths. Physical-chemical explanations of observed results are presented. Our predictions are compared with experimental observations as well as with results from a continuum theory for the protein search. Extensive Monte Carlo computer simulations fully support our theoretical calculations.

  9. Cooperative target convergence using multiple agents

    International Nuclear Information System (INIS)

    Kwok, K.S.; Driessen, B.J.

    1997-01-01

    This work considers the problem of causing multiple (100''s) autonomous mobile robots to converge to a target and provides a follow-the-leader approach to the problem. Each robot has only a limited-range sensor for sending the target and also larger but also limited-range robot-to-robot communication capability. Because of the small amount of information available to the robots, a practical approach to improve convergence to the target is to have a robot follow the robot with the best quality of information. Specifically, each robot emits a signal that informs in-range robots what its status is. A robot has a status value of 0 if it is itself in range of the target. A robot has a status of 1 if it is not in range of the target but is in communication range of a robot that is in range of the target. A robot has a status of 2 if it is not in range of the target but is within range of another robot that has status 1, and so on. Of all the mobile robots that any given robot is in range of, it follows the one with the best status. The emergent behavior is the ant-like trails of robots following each other toward the target. If the robot is not in range of another robot that is either in range of the target or following another robot, the robot will assign-1 to its quality-of-information, and will execute an exhaustive search. The exhaustive search will continue until it encounters either the target or another robot with a nonnegative quality-of-information. The quality of information approach was extended to the case where each robot only has two-bit signals informing it of distance to in-range robots

  10. Cooperative target convergence using multiple agents

    Energy Technology Data Exchange (ETDEWEB)

    Kwok, K.S.; Driessen, B.J.

    1997-10-01

    This work considers the problem of causing multiple (100`s) autonomous mobile robots to converge to a target and provides a follow-the-leader approach to the problem. Each robot has only a limited-range sensor for sending the target and also larger but also limited-range robot-to-robot communication capability. Because of the small amount of information available to the robots, a practical approach to improve convergence to the target is to have a robot follow the robot with the best quality of information. Specifically, each robot emits a signal that informs in-range robots what its status is. A robot has a status value of 0 if it is itself in range of the target. A robot has a status of 1 if it is not in range of the target but is in communication range of a robot that is in range of the target. A robot has a status of 2 if it is not in range of the target but is within range of another robot that has status 1, and so on. Of all the mobile robots that any given robot is in range of, it follows the one with the best status. The emergent behavior is the ant-like trails of robots following each other toward the target. If the robot is not in range of another robot that is either in range of the target or following another robot, the robot will assign-1 to its quality-of-information, and will execute an exhaustive search. The exhaustive search will continue until it encounters either the target or another robot with a nonnegative quality-of-information. The quality of information approach was extended to the case where each robot only has two-bit signals informing it of distance to in-range robots.

  11. Resources transfer and centralization in Brazilian electrical sector: the reversion global reserve (RGR) and the guarantee global reserve (GGR); Centralizacao e transferencia de recursos no setor eletrico brasileiro: a reserva global de reversao (RGR) e a reserva global de garantia (RGG)

    Energy Technology Data Exchange (ETDEWEB)

    Souza Amaral Filho, J.B. de

    1991-12-31

    This dissertation makes the analysis of resources transfer and centralization in Brazilian electrical sector, through reversion global reserve (RGR) and guarantee global reserve (GGR). RGR and GGR are funds. RGR finances sectorial investments in electric power and GGR aims the supply of deficient concessionaires. Governmental investments and the results of this application are showing. (M.V.M.). 55 refs, 2 figs, 61 tabs.

  12. Resources transfer and centralization in Brazilian electrical sector: the reversion global reserve (RGR) and the guarantee global reserve (GGR); Centralizacao e transferencia de recursos no setor eletrico brasileiro: a reserva global de reversao (RGR) e a reserva global de garantia (RGG)

    Energy Technology Data Exchange (ETDEWEB)

    Souza Amaral Filho, J.B. de

    1992-12-31

    This dissertation makes the analysis of resources transfer and centralization in Brazilian electrical sector, through reversion global reserve (RGR) and guarantee global reserve (GGR). RGR and GGR are funds. RGR finances sectorial investments in electric power and GGR aims the supply of deficient concessionaires. Governmental investments and the results of this application are showing. (M.V.M.). 55 refs, 2 figs, 61 tabs.

  13. Targeting the Pim kinases in multiple myeloma.

    LENUS (Irish Health Repository)

    Keane, N A

    2015-07-17

    Multiple myeloma (MM) is a plasma cell malignancy that remains incurable. Novel treatment strategies to improve survival are urgently required. The Pims are a small family of serine\\/threonine kinases with increased expression across the hematological malignancies. Pim-2 shows highest expression in MM and constitutes a promising therapeutic target. It is upregulated by the bone marrow microenvironment to mediate proliferation and promote MM survival. Pim-2 also has a key role in the bone destruction typically seen in MM. Additional putative roles of the Pim kinases in MM include trafficking of malignant cells, promoting oncogenic signaling in the hypoxic bone marrow microenvironment and mediating resistance to therapy. A number of Pim inhibitors are now under development with lead compounds entering the clinic. The ATP-competitive Pim inhibitor LGH447 has recently been reported to have single agent activity in MM. It is anticipated that Pim inhibition will be of clinical benefit in combination with standard treatments and\\/or with novel drugs targeting other survival pathways in MM.

  14. A triple axes multiple target holder assembly

    International Nuclear Information System (INIS)

    Tribedi, L.C.; Narvekar, S.D.; Pillay, R.G.; Tandon, P.N.

    1993-01-01

    We have designed and fabricated a rotatable target holder assembly capable of accommodating 27 targets. The target foils are mounted along two concentric circles on a ss wheel. On the outer circle 18 targets can be mounted each 20deg apart, and on the inner circle the remaining targets are positioned each 40deg apart. The self supporting or carbon backed targets are mounted on thin frames and are placed concentrically at the targets are mounted on thin frames and are placed concentrically at the target position on the wheel. Three degrees of freedom are provided to the target holder assembly. (author). 1 fig

  15. Quantum partial search for uneven distribution of multiple target items

    Science.gov (United States)

    Zhang, Kun; Korepin, Vladimir

    2018-06-01

    Quantum partial search algorithm is an approximate search. It aims to find a target block (which has the target items). It runs a little faster than full Grover search. In this paper, we consider quantum partial search algorithm for multiple target items unevenly distributed in a database (target blocks have different number of target items). The algorithm we describe can locate one of the target blocks. Efficiency of the algorithm is measured by number of queries to the oracle. We optimize the algorithm in order to improve efficiency. By perturbation method, we find that the algorithm runs the fastest when target items are evenly distributed in database.

  16. Effects of multiple scattering and target structure on photon emission

    International Nuclear Information System (INIS)

    Blankenbecler, R.

    1996-05-01

    The Landau-Pomeranchuk-Migdal effect is the suppression of Bethe-Heitler radiation caused by multiple scattering in the target medium. The quantum treatment given by S.D. Drell and the author for homogeneous targets of finite thickness will be reviewed. It will then be extended to structured targets. In brief, it is shown that radiators composed of separated plates or of a medium with a spatially varying radiation length can exhibit unexpected structure, even coherence maxima and minima, in their photon spectra. Finally, a functional integral method for performing the averaging implicit in multiple scattering will be briefly discussed and the leading corrections to previous results evaluated

  17. Adaptive Waveform Design for Cognitive Radar in Multiple Targets Situations

    Directory of Open Access Journals (Sweden)

    Xiaowen Zhang

    2018-02-01

    Full Text Available In this paper, the problem of cognitive radar (CR waveform optimization design for target detection and estimation in multiple extended targets situations is investigated. This problem is analyzed in signal-dependent interference, as well as additive channel noise for extended targets with unknown target impulse response (TIR. To address this problem, an improved algorithm is employed for target detection by maximizing the detection probability of the received echo on the promise of ensuring the TIR estimation precision. In this algorithm, an additional weight vector is introduced to achieve a trade-off among different targets. Both the estimate of TIR and transmit waveform can be updated at each step based on the previous step. Under the same constraint on waveform energy and bandwidth, the information theoretical approach is also considered. In addition, the relationship between the waveforms that are designed based on the two criteria is discussed. Unlike most existing works that only consider single target with temporally correlated characteristics, waveform design for multiple extended targets is considered in this method. Simulation results demonstrate that compared with linear frequency modulated (LFM signal, waveforms designed based on maximum detection probability and maximum mutual information (MI criteria can make radar echoes contain more multiple-target information and improve radar performance as a result.

  18. Memory for found targets interferes with subsequent performance in multiple-target visual search.

    Science.gov (United States)

    Cain, Matthew S; Mitroff, Stephen R

    2013-10-01

    Multiple-target visual searches--when more than 1 target can appear in a given search display--are commonplace in radiology, airport security screening, and the military. Whereas 1 target is often found accurately, additional targets are more likely to be missed in multiple-target searches. To better understand this decrement in 2nd-target detection, here we examined 2 potential forms of interference that can arise from finding a 1st target: interference from the perceptual salience of the 1st target (a now highly relevant distractor in a known location) and interference from a newly created memory representation for the 1st target. Here, we found that removing found targets from the display or making them salient and easily segregated color singletons improved subsequent search accuracy. However, replacing found targets with random distractor items did not improve subsequent search accuracy. Removing and highlighting found targets likely reduced both a target's visual salience and its memory load, whereas replacing a target removed its visual salience but not its representation in memory. Collectively, the current experiments suggest that the working memory load of a found target has a larger effect on subsequent search accuracy than does its perceptual salience. PsycINFO Database Record (c) 2013 APA, all rights reserved.

  19. Immunogenic Targets for Specific Immunotherapy in Multiple Myeloma

    Directory of Open Access Journals (Sweden)

    Lu Zhang

    2012-01-01

    Full Text Available Multiple myeloma remains an incurable disease although the prognosis has been improved by novel therapeutics and agents recently. Relapse occurs in the majority of patients and becomes fatal finally. Immunotherapy might be a powerful intervention to maintain a long-lasting control of minimal residual disease or to even eradicate disseminated tumor cells. Several tumor-associated antigens have been identified in patients with multiple myeloma. These antigens are expressed in a tumor-specific or tumor-restricted pattern, are able to elicit immune response, and thus could serve as targets for immunotherapy. This review discusses immunogenic antigens with therapeutic potential for multiple myeloma.

  20. Functional Response (FR) and Relative Growth Rate (RGR) Do Not Show the Known Invasiveness of Lemna minuta (Kunth)

    Science.gov (United States)

    Boets, Pieter; Goethals, Peter L. M.

    2016-01-01

    Growing travel and trade threatens biodiversity as it increases the rate of biological invasions globally, either by accidental or intentional introduction. Therefore, avoiding these impacts by forecasting invasions and impeding further spread is of utmost importance. In this study, three forecasting approaches were tested and combined to predict the invasive behaviour of the alien macrophyte Lemna minuta in comparison with the native Lemna minor: the functional response (FR) and relative growth rate (RGR), supplemented with a combined biomass-based nutrient removal (BBNR). Based on the idea that widespread invasive species are more successful competitors than local, native species, a higher FR and RGR were expected for the invasive compared to the native species. Five different nutrient concentrations were tested, ranging from low (4 mgN.L-1 and 1 mgP.L-1) to high (70 mgN.L-1 and 21 mgP.L-1). After four days, a significant amount of nutrients was removed by both Lemna spp., though significant differences among L. minor and L. minuta were only observed at lower nutrient concentrations (lower than 17 mgN.L-1 and 6 mgP.L-1) with higher nutrient removal exerted by L. minor. The derived FR did not show a clear dominance of the invasive L. minuta, contradicting field observations. Similarly, the RGR ranged from 0.4 to 0.6 d-1, but did not show a biomass-based dominance of L. minuta (0.5 ± 0.1 d-1 versus 0.63 ± 0.09 d-1 for L. minor). BBNR showed similar results as the FR. Contrary to our expectations, all three approaches resulted in higher values for L. minor. Consequently, based on our results FR is sensitive to differences, though contradicted the expectations, while RGR and BBNR do not provide sufficient power to differentiate between a native and an invasive alien macrophyte and should be supplemented with additional ecosystem-based experiments to determine the invasion impact. PMID:27861603

  1. A mathematical analysis of multiple-target SELEX.

    Science.gov (United States)

    Seo, Yeon-Jung; Chen, Shiliang; Nilsen-Hamilton, Marit; Levine, Howard A

    2010-10-01

    SELEX (Systematic Evolution of Ligands by Exponential Enrichment) is a procedure by which a mixture of nucleic acids can be fractionated with the goal of identifying those with specific biochemical activities. One combines the mixture with a specific target molecule and then separates the target-NA complex from the resulting reactions. The target-NA complex is separated from the unbound NA by mechanical means (such as by filtration), the NA is eluted from the complex, amplified by PCR (polymerase chain reaction), and the process repeated. After several rounds, one should be left with the nucleic acids that best bind to the target. The problem was first formulated mathematically in Irvine et al. (J. Mol. Biol. 222:739-761, 1991). In Levine and Nilsen-Hamilton (Comput. Biol. Chem. 31:11-25, 2007), a mathematical analysis of the process was given. In Vant-Hull et al. (J. Mol. Biol. 278:579-597, 1998), multiple target SELEX was considered. It was assumed that each target has a single nucleic acid binding site that permits occupation by no more than one nucleic acid. Here, we revisit Vant-Hull et al. (J. Mol. Biol. 278:579-597, 1998) using the same assumptions. The iteration scheme is shown to be convergent and a simplified algorithm is given. Our interest here is in the behavior of the multiple target SELEX process as a discrete "time" dynamical system. Our goal is to characterize the limiting states and their dependence on the initial distribution of nucleic acid and target fraction components. (In multiple target SELEX, we vary the target component fractions, but not their concentrations, as fixed and the initial pool of nucleic acids as a variable starting condition). Given N nucleic acids and a target consisting of M subtarget component species, there is an M × N matrix of affinities, the (i,j) entry corresponding to the affinity of the jth nucleic acid for the ith subtarget. We give a structure condition on this matrix that is equivalent to the following

  2. A compound chimeric antigen receptor strategy for targeting multiple myeloma.

    Science.gov (United States)

    Chen, K H; Wada, M; Pinz, K G; Liu, H; Shuai, X; Chen, X; Yan, L E; Petrov, J C; Salman, H; Senzel, L; Leung, E L H; Jiang, X; Ma, Y

    2018-02-01

    Current clinical outcomes using chimeric-antigen receptors (CARs) against multiple myeloma show promise in the eradication of bulk disease. However, these anti-BCMA (CD269) CARs observe relapse as a common phenomenon after treatment due to the reemergence of either antigen-positive or -negative cells. Hence, the development of improvements in CAR design to target antigen loss and increase effector cell persistency represents a critical need. Here, we report on the anti-tumor activity of a CAR T-cell possessing two complete and independent CAR receptors against the multiple myeloma antigens BCMA and CS1. We determined that the resulting compound CAR (cCAR) T-cell possesses consistent, potent and directed cytotoxicity against each target antigen population. Using multiple mouse models of myeloma and mixed cell populations, we are further able to show superior in vivo survival by directed cytotoxicity against multiple populations compared to a single-expressing CAR T-cell. These findings indicate that compound targeting of BCMA and CS1 on myeloma cells can potentially be an effective strategy for augmenting the response against myeloma bulk disease and for initiation of broader coverage CAR therapy.

  3. Multiple operating system rotation environment moving target defense

    Science.gov (United States)

    Evans, Nathaniel; Thompson, Michael

    2016-03-22

    Systems and methods for providing a multiple operating system rotation environment ("MORE") moving target defense ("MTD") computing system are described. The MORE-MTD system provides enhanced computer system security through a rotation of multiple operating systems. The MORE-MTD system increases attacker uncertainty, increases the cost of attacking the system, reduces the likelihood of an attacker locating a vulnerability, and reduces the exposure time of any located vulnerability. The MORE-MTD environment is effectuated by rotation of the operating systems at a given interval. The rotating operating systems create a consistently changing attack surface for remote attackers.

  4. A multiple sampling ionization chamber for the External Target Facility

    International Nuclear Information System (INIS)

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

    2015-01-01

    A multiple sampling ionization chamber used as a particle identification device for high energy heavy ions has been developed for the External Target Facility. The performance of this detector was tested with a 239 Pu α source and RI beams. A Z resolution (FWHM) of 0.4–0.6 was achieved for nuclear fragments of 18 O at 400 AMeV

  5. Cooperative multi-robot observation of multiple moving targets

    International Nuclear Information System (INIS)

    Parker, L.E.; Emmons, B.A.

    1997-01-01

    An important issue that arises in the automation of many security, surveillance, and reconnaissance tasks is that of monitoring, or observing, the movements of targets navigating in a bounded area of interest. A key research issue in these problems is that of sensor placement--determining where sensors should be located to maintain the targets in view. In complex applications of this type, the use of multiple sensors dynamically moving over time is required. In this paper, the authors investigate the sue of a cooperative team of autonomous sensor-based robots for multi-robot observation of multiple moving targets. They focus primarily on developing the distributed control strategies that allow the robot team to attempt to maximize the collective tie during which each object is being observed by at least one robot in the area of interest. The initial efforts in this problem address the aspects of distributed control in homogeneous robot teams with equivalent sensing and movement capabilities working in an uncluttered, bounded area. This paper first formalizes the problem, discusses related work, and then shows that this problem is NP-hard. They then present a distributed approximate approach to solving this problem that combines low-level multi-robot control with higher-level control

  6. Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma

    DEFF Research Database (Denmark)

    Lokhorst, Henk M; Plesner, Torben; Laubach, Jacob P

    2015-01-01

    BACKGROUND: Multiple myeloma cells uniformly overexpress CD38. We studied daratumumab, a CD38-targeting, human IgG1κ monoclonal antibody, in a phase 1-2 trial involving patients with relapsed myeloma or relapsed myeloma that was refractory to two or more prior lines of therapy. METHODS: In part 1...... interval [CI], 4.2 to 8.1), and 65% (95% CI, 28 to 86) of the patients who had a response did not have progression at 12 months. CONCLUSIONS: Daratumumab monotherapy had a favorable safety profile and encouraging efficacy in patients with heavily pretreated and refractory myeloma. (Funded by Janssen...

  7. A global calibration method for multiple vision sensors based on multiple targets

    International Nuclear Information System (INIS)

    Liu, Zhen; Zhang, Guangjun; Wei, Zhenzhong; Sun, Junhua

    2011-01-01

    The global calibration of multiple vision sensors (MVS) has been widely studied in the last two decades. In this paper, we present a global calibration method for MVS with non-overlapping fields of view (FOVs) using multiple targets (MT). MT is constructed by fixing several targets, called sub-targets, together. The mutual coordinate transformations between sub-targets need not be known. The main procedures of the proposed method are as follows: one vision sensor is selected from MVS to establish the global coordinate frame (GCF). MT is placed in front of the vision sensors for several (at least four) times. Using the constraint that the relative positions of all sub-targets are invariant, the transformation matrix from the coordinate frame of each vision sensor to GCF can be solved. Both synthetic and real experiments are carried out and good result is obtained. The proposed method has been applied to several real measurement systems and shown to be both flexible and accurate. It can serve as an attractive alternative to existing global calibration methods

  8. Targeting multiple heterogeneous hardware platforms with OpenCL

    Science.gov (United States)

    Fox, Paul A.; Kozacik, Stephen T.; Humphrey, John R.; Paolini, Aaron; Kuller, Aryeh; Kelmelis, Eric J.

    2014-06-01

    The OpenCL API allows for the abstract expression of parallel, heterogeneous computing, but hardware implementations have substantial implementation differences. The abstractions provided by the OpenCL API are often insufficiently high-level to conceal differences in hardware architecture. Additionally, implementations often do not take advantage of potential performance gains from certain features due to hardware limitations and other factors. These factors make it challenging to produce code that is portable in practice, resulting in much OpenCL code being duplicated for each hardware platform being targeted. This duplication of effort offsets the principal advantage of OpenCL: portability. The use of certain coding practices can mitigate this problem, allowing a common code base to be adapted to perform well across a wide range of hardware platforms. To this end, we explore some general practices for producing performant code that are effective across platforms. Additionally, we explore some ways of modularizing code to enable optional optimizations that take advantage of hardware-specific characteristics. The minimum requirement for portability implies avoiding the use of OpenCL features that are optional, not widely implemented, poorly implemented, or missing in major implementations. Exposing multiple levels of parallelism allows hardware to take advantage of the types of parallelism it supports, from the task level down to explicit vector operations. Static optimizations and branch elimination in device code help the platform compiler to effectively optimize programs. Modularization of some code is important to allow operations to be chosen for performance on target hardware. Optional subroutines exploiting explicit memory locality allow for different memory hierarchies to be exploited for maximum performance. The C preprocessor and JIT compilation using the OpenCL runtime can be used to enable some of these techniques, as well as to factor in hardware

  9. Aliskiren targets multiple systems to alleviate cancer cachexia.

    Science.gov (United States)

    Wang, Chaoyi; Guo, Dunwei; Wang, Qiang; You, Song; Qiao, Zhongpeng; Liu, Yong; Dai, Hang; Tang, Hua

    2016-11-01

    To examine the effects of aliskiren, a small-molecule renin inhibitor, on cancer cachexia and to explore the underlying mechanisms. A cancer cachexia model was established by subcutaneously injecting C26 mouse colon carcinoma cells into isogenic BALB/c mice. Aliskiren was administered intragastrically [10 mg/kg body weight (BW)] on day 5 (as a preventive strategy, AP group) or on day 12 (as a therapeutic strategy, AT group) after C26 injection. Mice that received no C26 injection (healthy controls, HC group) or only C26 injection but not aliskiren (cancer, CA group) were used as controls. BW, tumor growth, whole body functions, and survival were monitored daily in half of the mice in each group, whereas serum, tumors, and gastrocnemius muscles were harvested from the other mice after sacrifice on day 20 for further analysis. Aliskiren significantly alleviated multiple cachexia‑associated symptoms, including BW loss, tumor burden, muscle wasting, muscular dysfunction, and shortened survival. On the molecular level, aliskiren antagonized cachexia‑induced activation of the renin‑angiotensin system (RAS), systematic and muscular inflammation, oxidative stress, and autophagy‑lysosome as well as ubiquitin‑proteasome stimulation. In addition, early administration of aliskiren before cachexia development (AP group) resulted in more robust effects in alleviating cachexia or targeting underlying mechanisms than administration after cachexia development (AT group). Aliskiren exhibited potent anti‑cachexia activities. These activities were achieved through the targeting of at least four mechanisms underlying cachexia development: RAS activation, increase in systematic inflammation, upregulation of oxidative stress, and stimulation of autophagy-lysosome pathway (ALP) and ubiquitin-proteasome pathway (UPP).

  10. Optimizing megakaryocyte polyploidization by targeting multiple pathways of cytokinesis.

    Science.gov (United States)

    Avanzi, Mauro P; Chen, Amanda; He, Wu; Mitchell, W Beau

    2012-11-01

    Large-scale in vitro production of platelets (PLTs) from cord blood stem cells is one goal of stem cell research. One step toward this goal will be to produce polyploid megakaryocytes capable of releasing high numbers of PLTs. Megakaryocyte polyploidization requires distinct cytoskeletal and cellular mechanisms, including actin polymerization, myosin activation, microtubule formation, and increased DNA production. In this study we variably combined inhibition of these principal mechanisms of cytokinesis with the goal of driving polyploidization in megakaryocytes. Megakaryocytes were derived from umbilical cord blood and cultured with reagents that inhibit distinct mechanisms of cytokinesis: Rho-Rock inhibitor (RRI), Src inhibitor (SI), nicotinamide (NIC), aurora B inhibitor (ABI), and myosin light chain kinase inhibitor (MLCKI). Combinations of reagents were used to determine their interactions and to maximize megakaryocyte ploidy. Treatment with RRI, NIC, SI, and ABI, but not with MLCKI, increased the final ploidy and RRI was the most effective single reagent. RRI and MLCKI, both inhibitors of MLC activation, resulted in opposite ploidy outcomes. Combinations of reagents also increased ploidy and the use of NIC, SI, and ABI was as effective as RRI alone. Addition of MLCKI to NIC, SI, and ABI reached the highest level of polyploidization. Megakaryocyte polyploidization results from modulation of a combination of distinct cytokinesis pathways. Reagents targeting distinct cytoskeletal pathways produced additive effects in final megakaryocyte ploidy. The RRI, however, showed no additive effect but produced a high final ploidy due to overlapping inhibition of multiple cytokinesis pathways. © 2012 American Association of Blood Banks.

  11. Global Calibration of Multiple Cameras Based on Sphere Targets

    Directory of Open Access Journals (Sweden)

    Junhua Sun

    2016-01-01

    Full Text Available Global calibration methods for multi-camera system are critical to the accuracy of vision measurement. Proposed in this paper is such a method based on several groups of sphere targets and a precision auxiliary camera. Each camera to be calibrated observes a group of spheres (at least three, while the auxiliary camera observes all the spheres. The global calibration can be achieved after each camera reconstructs the sphere centers in its field of view. In the process of reconstructing a sphere center, a parameter equation is used to describe the sphere projection model. Theoretical analysis and computer simulation are carried out to analyze the factors that affect the calibration accuracy. Simulation results show that the parameter equation can largely improve the reconstruction accuracy. In the experiments, a two-camera system calibrated by our method is used to measure a distance about 578 mm, and the root mean squared error is within 0.14 mm. Furthermore, the experiments indicate that the method has simple operation and good flexibility, especially for the onsite multiple cameras without common field of view.

  12. The meninges: new therapeutic targets for multiple sclerosis.

    Science.gov (United States)

    Russi, Abigail E; Brown, Melissa A

    2015-02-01

    The central nervous system (CNS) largely comprises nonregenerating cells, including neurons and myelin-producing oligodendrocytes, which are particularly vulnerable to immune cell-mediated damage. To protect the CNS, mechanisms exist that normally restrict the transit of peripheral immune cells into the brain and spinal cord, conferring an "immune-specialized" status. Thus, there has been a long-standing debate as to how these restrictions are overcome in several inflammatory diseases of the CNS, including multiple sclerosis (MS). In this review, we highlight the role of the meninges, tissues that surround and protect the CNS and enclose the cerebral spinal fluid, in promoting chronic inflammation that leads to neuronal damage. Although the meninges have traditionally been considered structures that provide physical protection for the brain and spinal cord, new data have established these tissues as sites of active immunity. It has been hypothesized that the meninges are important players in normal immunosurveillance of the CNS but also serve as initial sites of anti-myelin immune responses. The resulting robust meningeal inflammation elicits loss of localized blood-brain barrier (BBB) integrity and facilitates a large-scale influx of immune cells into the CNS parenchyma. We propose that targeting the cells and molecules mediating these inflammatory responses within the meninges offers promising therapies for MS that are free from the constraints imposed by the BBB. Importantly, such therapies may avoid the systemic immunosuppression often associated with the existing treatments. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Multiple target sound quality balance for hybrid electric powertrain noise

    Science.gov (United States)

    Mosquera-Sánchez, J. A.; Sarrazin, M.; Janssens, K.; de Oliveira, L. P. R.; Desmet, W.

    2018-01-01

    The integration of the electric motor to the powertrain in hybrid electric vehicles (HEVs) presents acoustic stimuli that elicit new perceptions. The large number of spectral components, as well as the wider bandwidth of this sort of noises, pose new challenges to current noise, vibration and harshness (NVH) approaches. This paper presents a framework for enhancing the sound quality (SQ) of the hybrid electric powertrain noise perceived inside the passenger compartment. Compared with current active sound quality control (ASQC) schemes, where the SQ improvement is just an effect of the control actions, the proposed technique features an optimization stage, which enables the NVH specialist to actively implement the amplitude balance of the tones that better fits into the auditory expectations. Since Loudness, Roughness, Sharpness and Tonality are the most relevant SQ metrics for interior HEV noise, they are used as performance metrics in the concurrent optimization analysis, which, eventually, drives the control design method. Thus, multichannel active sound profiling systems that feature cross-channel compensation schemes are guided by the multi-objective optimization stage, by means of optimal sets of amplitude gain factors that can be implemented at each single sensor location, while minimizing cross-channel effects that can either degrade the original SQ condition, or even hinder the implementation of independent SQ targets. The proposed framework is verified experimentally, with realistic stationary hybrid electric powertrain noise, showing SQ enhancement for multiple locations within a scaled vehicle mock-up. The results show total success rates in excess of 90%, which indicate that the proposed method is promising, not only for the improvement of the SQ of HEV noise, but also for a variety of periodic disturbances with similar features.

  14. Multiple Model Particle Filtering For Multi-Target Tracking

    National Research Council Canada - National Science Library

    Hero, Alfred; Kreucher, Chris; Kastella, Keith

    2004-01-01

    .... The details of this method have been presented elsewhere 1. One feature of real targets is that they are poorly described by a single kinematic model Target behavior may change dramatically i.e...

  15. Realization of quantum gates with multiple control qubits or multiple target qubits in a cavity

    Science.gov (United States)

    Waseem, Muhammad; Irfan, Muhammad; Qamar, Shahid

    2015-06-01

    We propose a scheme to realize a three-qubit controlled phase gate and a multi-qubit controlled NOT gate of one qubit simultaneously controlling n-target qubits with a four-level quantum system in a cavity. The implementation time for multi-qubit controlled NOT gate is independent of the number of qubit. Three-qubit phase gate is generalized to n-qubit phase gate with multiple control qubits. The number of steps reduces linearly as compared to conventional gate decomposition method. Our scheme can be applied to various types of physical systems such as superconducting qubits coupled to a resonator and trapped atoms in a cavity. Our scheme does not require adjustment of level spacing during the gate implementation. We also show the implementation of Deutsch-Joza algorithm. Finally, we discuss the imperfections due to cavity decay and the possibility of physical implementation of our scheme.

  16. MODELING OF TARGETED DRUG DELIVERY PART II. MULTIPLE DRUG ADMINISTRATION

    Directory of Open Access Journals (Sweden)

    A. V. Zaborovskiy

    2017-01-01

    Full Text Available In oncology practice, despite significant advances in early cancer detection, surgery, radiotherapy, laser therapy, targeted therapy, etc., chemotherapy is unlikely to lose its relevance in the near future. In this context, the development of new antitumor agents is one of the most important problems of cancer research. In spite of the importance of searching for new compounds with antitumor activity, the possibilities of the “old” agents have not been fully exhausted. Targeted delivery of antitumor agents can give them a “second life”. When developing new targeted drugs and their further introduction into clinical practice, the change in their pharmacodynamics and pharmacokinetics plays a special role. The paper describes a pharmacokinetic model of the targeted drug delivery. The conditions under which it is meaningful to search for a delivery vehicle for the active substance were described. Primary screening of antitumor agents was undertaken to modify them for the targeted delivery based on underlying assumptions of the model.

  17. Analyzing the multiple-target-multiple-agent scenario using optimal assignment algorithms

    Science.gov (United States)

    Kwok, Kwan S.; Driessen, Brian J.; Phillips, Cynthia A.; Tovey, Craig A.

    1997-09-01

    This work considers the problem of maximum utilization of a set of mobile robots with limited sensor-range capabilities and limited travel distances. The robots are initially in random positions. A set of robots properly guards or covers a region if every point within the region is within the effective sensor range of at least one vehicle. We wish to move the vehicles into surveillance positions so as to guard or cover a region, while minimizing the maximum distance traveled by any vehicle. This problem can be formulated as an assignment problem, in which we must optimally decide which robot to assign to which slot of a desired matrix of grid points. The cost function is the maximum distance traveled by any robot. Assignment problems can be solved very efficiently. Solution times for one hundred robots took only seconds on a silicon graphics crimson workstation. The initial positions of all the robots can be sampled by a central base station and their newly assigned positions communicated back to the robots. Alternatively, the robots can establish their own coordinate system with the origin fixed at one of the robots and orientation determined by the compass bearing of another robot relative to this robot. This paper presents example solutions to the multiple-target-multiple-agent scenario using a matching algorithm. Two separate cases with one hundred agents in each were analyzed using this method. We have found these mobile robot problems to be a very interesting application of network optimization methods, and we expect this to be a fruitful area for future research.

  18. Analyzing the multiple-target-multiple-agent scenario using optimal assignment algorithms

    International Nuclear Information System (INIS)

    Kwok, K.S.; Driessen, B.J.; Phillips, C.A.; Tovey, C.A.

    1997-01-01

    This work considers the problem of maximum utilization of a set of mobile robots with limited sensor-range capabilities and limited travel distances. The robots are initially in random positions. A set of robots properly guards or covers a region if every point within the region is within the effective sensor range of at least one vehicle. The authors wish to move the vehicles into surveillance positions so as to guard or cover a region, while minimizing the maximum distance traveled by any vehicle. This problem can be formulated as an assignment problem, in which they must optimally decide which robot to assign to which slot of a desired matrix of grid points. The cost function is the maximum distance traveled by any robot. Assignment problems can be solved very efficiently. Solutions times for one hundred robots took only seconds on a Silicon Graphics Crimson workstation. The initial positions of all the robots can be sampled by a central base station and their newly assigned positions communicated back to the robots. Alternatively, the robots can establish their own coordinate system with the origin fixed at one of the robots and orientation determined by the compass bearing of another robot relative to this robot. This paper presents example solutions to the multiple-target-multiple-agent scenario using a matching algorithm. Two separate cases with one hundred agents in each were analyzed using this method. They have found these mobile robot problems to be a very interesting application of network optimization methods, and they expect this to be a fruitful area for future research

  19. Tracking a convoy of multiple targets using acoustic sensor data

    Science.gov (United States)

    Damarla, T. R.

    2003-08-01

    In this paper we present an algorithm to track a convoy of several targets in a scene using acoustic sensor array data. The tracking algorithm is based on template of the direction of arrival (DOA) angles for the leading target. Often the first target is the closest target to the sensor array and hence the loudest with good signal to noise ratio. Several steps were used to generate a template of the DOA angle for the leading target, namely, (a) the angle at the present instant should be close to the angle at the previous instant and (b) the angle at the present instant should be within error bounds of the predicted value based on the previous values. Once the template of the DOA angles of the leading target is developed, it is used to predict the DOA angle tracks of the remaining targets. In order to generate the tracks for the remaining targets, a track is established if the angles correspond to the initial track values of the first target. Second the time delay between the first track and the remaining tracks are estimated at the highest correlation points between the first track and the remaining tracks. As the vehicles move at different speeds the tracks either compress or expand depending on whether a target is moving fast or slow compared to the first target. The expansion and compression ratios are estimated and used to estimate the predicted DOA angle values of the remaining targets. Based on these predicted DOA angles of the remaining targets the DOA angles obtained from the MVDR or Incoherent MUSIC will be appropriately assigned to proper tracks. Several other rules were developed to avoid mixing the tracks. The algorithm is tested on data collected at Aberdeen Proving Ground with a convoy of 3, 4 and 5 vehicles. Some of the vehicles are tracked and some are wheeled vehicles. The tracking algorithm results are found to be good. The results will be presented at the conference and in the paper.

  20. Random Scenario Generation for a Multiple Target Tracking Environment Evaluation

    DEFF Research Database (Denmark)

    Hussain, Dil Muhammad Akbar

    2006-01-01

    , which were normally crossing targets, was to test the efficiency of the track splitting algorithm for different situations. However this approach only gives a measure of performance for a specific, possibly unrealistic, scenario and it was felt appropriate to develop procedures that would enable a more...... general performance assessment. Therefore, a random target motion scenario is adopted. Its implementation in particular for testing the track splitting algorithm using Kalman filters is used and a couple of tracking performance parameters are computed to investigate such random scenarios....

  1. Five kepler target stars that show multiple transiting exoplanet candidates

    DEFF Research Database (Denmark)

    Steffen..[], Jason H.; Batalha, N. M.; Broucki, W J.

    2010-01-01

    We present and discuss five candidate exoplanetary systems identified with the Kepler spacecraft. These five systems show transits from multiple exoplanet candidates. Should these objects prove to be planetary in nature, then these five systems open new opportunities for the field of exoplanets a...

  2. Interleukin-6, a new target for therapy in multiple myeloma?

    NARCIS (Netherlands)

    van Oers, M. H.; van Zaanen, H. C.; Lokhorst, H. M.

    1993-01-01

    During the past few years much insight has been gained into the immunobiology of multiple myeloma. It has become evident that the growth of myeloma cells is regulated by cytokines, notably interleukin-6. In this paper a brief review is given of the evidence derived from in vitro as well as in vivo

  3. Autonomous Shepherding Behaviors of Multiple Target Steering Robots.

    Science.gov (United States)

    Lee, Wonki; Kim, DaeEun

    2017-11-25

    This paper presents a distributed coordination methodology for multi-robot systems, based on nearest-neighbor interactions. Among many interesting tasks that may be performed using swarm robots, we propose a biologically-inspired control law for a shepherding task, whereby a group of external agents drives another group of agents to a desired location. First, we generated sheep-like robots that act like a flock. We assume that each agent is capable of measuring the relative location and velocity to each of its neighbors within a limited sensing area. Then, we designed a control strategy for shepherd-like robots that have information regarding where to go and a steering ability to control the flock, according to the robots' position relative to the flock. We define several independent behavior rules; each agent calculates to what extent it will move by summarizing each rule. The flocking sheep agents detect the steering agents and try to avoid them; this tendency leads to movement of the flock. Each steering agent only needs to focus on guiding the nearest flocking agent to the desired location. Without centralized coordination, multiple steering agents produce an arc formation to control the flock effectively. In addition, we propose a new rule for collecting behavior, whereby a scattered flock or multiple flocks are consolidated. From simulation results with multiple robots, we show that each robot performs actions for the shepherding behavior, and only a few steering agents are needed to control the whole flock. The results are displayed in maps that trace the paths of the flock and steering robots. Performance is evaluated via time cost and path accuracy to demonstrate the effectiveness of this approach.

  4. Autonomous Shepherding Behaviors of Multiple Target Steering Robots

    Directory of Open Access Journals (Sweden)

    Wonki Lee

    2017-11-01

    Full Text Available This paper presents a distributed coordination methodology for multi-robot systems, based on nearest-neighbor interactions. Among many interesting tasks that may be performed using swarm robots, we propose a biologically-inspired control law for a shepherding task, whereby a group of external agents drives another group of agents to a desired location. First, we generated sheep-like robots that act like a flock. We assume that each agent is capable of measuring the relative location and velocity to each of its neighbors within a limited sensing area. Then, we designed a control strategy for shepherd-like robots that have information regarding where to go and a steering ability to control the flock, according to the robots’ position relative to the flock. We define several independent behavior rules; each agent calculates to what extent it will move by summarizing each rule. The flocking sheep agents detect the steering agents and try to avoid them; this tendency leads to movement of the flock. Each steering agent only needs to focus on guiding the nearest flocking agent to the desired location. Without centralized coordination, multiple steering agents produce an arc formation to control the flock effectively. In addition, we propose a new rule for collecting behavior, whereby a scattered flock or multiple flocks are consolidated. From simulation results with multiple robots, we show that each robot performs actions for the shepherding behavior, and only a few steering agents are needed to control the whole flock. The results are displayed in maps that trace the paths of the flock and steering robots. Performance is evaluated via time cost and path accuracy to demonstrate the effectiveness of this approach.

  5. Rational polypharmacology: systematically identifying and engaging multiple drug targets to promote axon growth

    Science.gov (United States)

    Al-Ali, Hassan; Lee, Do-Hun; Danzi, Matt C.; Nassif, Houssam; Gautam, Prson; Wennerberg, Krister; Zuercher, Bill; Drewry, David H.; Lee, Jae K.; Lemmon, Vance P.; Bixby, John L.

    2016-01-01

    Mammalian Central Nervous System (CNS) neurons regrow their axons poorly following injury, resulting in irreversible functional losses. Identifying therapeutics that encourage CNS axon repair has been difficult, in part because multiple etiologies underlie this regenerative failure. This suggests a particular need for drugs that engage multiple molecular targets. Although multi-target drugs are generally more effective than highly selective alternatives, we lack systematic methods for discovering such drugs. Target-based screening is an efficient technique for identifying potent modulators of individual targets. In contrast, phenotypic screening can identify drugs with multiple targets; however, these targets remain unknown. To address this gap, we combined the two drug discovery approaches using machine learning and information theory. We screened compounds in a phenotypic assay with primary CNS neurons and also in a panel of kinase enzyme assays. We used learning algorithms to relate the compounds’ kinase inhibition profiles to their influence on neurite outgrowth. This allowed us to identify kinases that may serve as targets for promoting neurite outgrowth, as well as others whose targeting should be avoided. We found that compounds that inhibit multiple targets (polypharmacology) promote robust neurite outgrowth in vitro. One compound with exemplary polypharmacology, was found to promote axon growth in a rodent spinal cord injury model. A more general applicability of our approach is suggested by its ability to deconvolve known targets for a breast cancer cell line, as well as targets recently shown to mediate drug resistance. PMID:26056718

  6. Five Kepler target stars that show multiple transiting exoplanet candidates

    Energy Technology Data Exchange (ETDEWEB)

    Steffen, Jason H.; /Fermilab; Batalha, Natalie M.; /San Jose State U.; Borucki, William J.; /NASA, Ames; Buchhave, Lars A.; /Harvard-Smithsonian Ctr. Astrophys. /Bohr Inst.; Caldwell, Douglas A.; /NASA, Ames /SETI Inst., Mtn. View; Cochran, William D.; /Texas U.; Endl, Michael; /Texas U.; Fabrycky, Daniel C.; /Harvard-Smithsonian Ctr. Astrophys.; Fressin, Francois; /Harvard-Smithsonian Ctr. Astrophys.; Ford, Eric B.; /Florida U.; Fortney, Jonathan J.; /UC, Santa Cruz, Phys. Dept. /NASA, Ames

    2010-06-01

    We present and discuss five candidate exoplanetary systems identified with the Kepler spacecraft. These five systems show transits from multiple exoplanet candidates. Should these objects prove to be planetary in nature, then these five systems open new opportunities for the field of exoplanets and provide new insights into the formation and dynamical evolution of planetary systems. We discuss the methods used to identify multiple transiting objects from the Kepler photometry as well as the false-positive rejection methods that have been applied to these data. One system shows transits from three distinct objects while the remaining four systems show transits from two objects. Three systems have planet candidates that are near mean motion commensurabilities - two near 2:1 and one just outside 5:2. We discuss the implications that multitransiting systems have on the distribution of orbital inclinations in planetary systems, and hence their dynamical histories; as well as their likely masses and chemical compositions. A Monte Carlo study indicates that, with additional data, most of these systems should exhibit detectable transit timing variations (TTV) due to gravitational interactions - though none are apparent in these data. We also discuss new challenges that arise in TTV analyses due to the presence of more than two planets in a system.

  7. Gray Matter Is Targeted in First-Attack Multiple Sclerosis

    Energy Technology Data Exchange (ETDEWEB)

    Schutzer, Steven E.; Angel, Thomas E.; Liu, Tao; Schepmoes, Athena A.; Xie, Fang; Bergquist, Jonas P.; Vecsei, Lazlo' ; Zadori, Denes; Camp, David G.; Holland, Bart K.; Smith, Richard D.; Coyle, Patricia K.

    2013-09-10

    The cause of multiple sclerosis (MS), its driving pathogenesis at the earliest stages, and what factors allow the first clinical attack to manifest remain unknown. Some imaging studies suggest gray rather than white matter may be involved early, and some postulate this may be predictive of developing MS. Other imaging studies are in conflict. To determine if there was objective molecular evidence of gray matter involvement in early MS we used high-resolution mass spectrometry to identify proteins in the cerebrospinal fluid (CSF) of first-attack MS patients (two independent groups) compared to established relapsing remitting (RR) MS and controls. We found that the CSF proteins in first-attack patients were differentially enriched for gray matter components (axon, neuron, synapse). Myelin components did not distinguish these groups. The results support that gray matter dysfunction is involved early in MS, and also may be integral for the initial clinical presentation.

  8. Circadian phase resetting via single and multiple control targets.

    Directory of Open Access Journals (Sweden)

    Neda Bagheri

    2008-07-01

    Full Text Available Circadian entrainment is necessary for rhythmic physiological functions to be appropriately timed over the 24-hour day. Disruption of circadian rhythms has been associated with sleep and neuro-behavioral impairments as well as cancer. To date, light is widely accepted to be the most powerful circadian synchronizer, motivating its use as a key control input for phase resetting. Through sensitivity analysis, we identify additional control targets whose individual and simultaneous manipulation (via a model predictive control algorithm out-perform the open-loop light-based phase recovery dynamics by nearly 3-fold. We further demonstrate the robustness of phase resetting by synchronizing short- and long-period mutant phenotypes to the 24-hour environment; the control algorithm is robust in the presence of model mismatch. These studies prove the efficacy and immediate application of model predictive control in experimental studies and medicine. In particular, maintaining proper circadian regulation may significantly decrease the chance of acquiring chronic illness.

  9. Quinolinic Acid: An Endogenous Neurotoxin with Multiple Targets

    Directory of Open Access Journals (Sweden)

    Rafael Lugo-Huitrón

    2013-01-01

    Full Text Available Quinolinic acid (QUIN, a neuroactive metabolite of the kynurenine pathway, is normally presented in nanomolar concentrations in human brain and cerebrospinal fluid (CSF and is often implicated in the pathogenesis of a variety of human neurological diseases. QUIN is an agonist of N-methyl-D-aspartate (NMDA receptor, and it has a high in vivo potency as an excitotoxin. In fact, although QUIN has an uptake system, its neuronal degradation enzyme is rapidly saturated, and the rest of extracellular QUIN can continue stimulating the NMDA receptor. However, its toxicity cannot be fully explained by its activation of NMDA receptors it is likely that additional mechanisms may also be involved. In this review we describe some of the most relevant targets of QUIN neurotoxicity which involves presynaptic receptors, energetic dysfunction, oxidative stress, transcription factors, cytoskeletal disruption, behavior alterations, and cell death.

  10. Romidepsin targets multiple survival signaling pathways in malignant T cells

    International Nuclear Information System (INIS)

    Valdez, B C; Brammer, J E; Li, Y; Murray, D; Liu, Y; Hosing, C; Nieto, Y; Champlin, R E; Andersson, B S

    2015-01-01

    Romidepsin is a cyclic molecule that inhibits histone deacetylases. It is Food and Drug Administration-approved for treatment of cutaneous and peripheral T-cell lymphoma, but its precise mechanism of action against malignant T cells is unknown. To better understand the biological effects of romidepsin in these cells, we exposed PEER and SUPT1 T-cell lines, and a primary sample from T-cell lymphoma patient (Patient J) to romidepsin. We then examined the consequences in some key oncogenic signaling pathways. Romidepsin displayed IC 50 values of 10.8, 7.9 and 7.0 nm in PEER, SUPT1 and Patient J cells, respectively. Strong inhibition of histone deacetylases and demethylases, increased production of reactive oxygen species and decreased mitochondrial membrane potential were observed, which may contribute to the observed DNA-damage response and apoptosis. The stress-activated protein kinase/c-Jun N-terminal kinase signaling pathway and unfolded protein response in the endoplasmic reticulum were activated, whereas the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) and β-catenin pro-survival pathways were inhibited. The decreased level of β-catenin correlated with the upregulation of its inhibitor SFRP1 through romidepsin-mediated hypomethylation of its gene promoter. Our results provide new insights into how romidepsin invokes malignant T-cell killing, show evidence of its associated DNA hypomethylating activity and offer a rationale for the development of romidepsin-containing combination therapies

  11. Extending Data Worth Analyses to Select Multiple Observations Targeting Multiple Forecasts

    DEFF Research Database (Denmark)

    Vilhelmsen, Troels Norvin; Ferre, Ty Paul

    2017-01-01

    . In the present study, we extend previous data worth analyses to include: simultaneous selection of multiple new measurements and consideration of multiple forecasts of interest. We show how the suggested approach can be used to optimize data collection. This can be used in a manner that suggests specific...... measurement sets or that produces probability maps indicating areas likely to be informative for specific forecasts. Moreover, we provide examples documenting that sequential measurement election approaches often lead to suboptimal designs and that estimates of data covariance should be included when...

  12. Lesional-targeting of neuroprotection to the inflammatory penumbra in experimental multiple sclerosis

    NARCIS (Netherlands)

    Al-Izki, S.; Pryce, G.; Hankey, D.J.R.; Lidster, K.; von Kutzleben, S.M.; Browne, L.; Clutterbuck, L.; Posada, C.; Chan, A.W.E.; Amor, S.; Perkins, V.; Gerritsen, W.H.; Ummenthum, K.; Peferoen-Baert, R.; van der Valk, P.; Montoya, A.; Joel, S.P.; Garthwaite, J.; Giovannoni, G.; Selwood, D.L.; Baker, D.

    2014-01-01

    Progressive multiple sclerosis is associated with metabolic failure of the axon and excitotoxicity that leads to chronic neurodegeneration. Global sodium-channel blockade causes side effects that can limit its use for neuroprotection in multiple sclerosis. Through selective targeting of drugs to

  13. Multiple scattering in electron fluid and energy loss in multi-ionic targets

    Energy Technology Data Exchange (ETDEWEB)

    Deutsch, C., E-mail: claude.deutsch@u-psud.fr [LPGP, UParis-Sud, 91405-Orsay (France); Tahir, N.A. [GSI, 1Planck Str., 64291-Darmstadt (Germany); Barriga-Carrasco, M. [ETSII, UCastilla-la-Mancha, 13071 Ciudad-Real (Spain); Ceban, V. [LPGP, UParis-Sud, 91405-Orsay (France); Fromy, P. [CRI, UParis-Sud, 91405-Orsay (France); Gilles, D. [CEA/Saclay/DSM/IRFU/SAP, 91191-Gif-s-Yvette (France); Leger, D. [Laboratoire Monthouy, UValenciennes-Hainaut Cambresis (France); Maynard, G. [LPGP, UParis-Sud, 91405-Orsay (France); Tashev, B. [Department of Physics, KazNu, Tole Bi82, Almaty (Kazakhstan); Volpe, L. [Department of Physics, UMilano-Bicocca, Milano 20126 (Italy)

    2014-01-01

    Extensions of the standard stopping model (SSM) for ion projectiles interacting with dense targets of timely concern for ICF and WDM are reviewed. They include multiple scattering on partially degenerate electrons, low velocity ion slowing down in demixing H–He mixtures within Jovian planets core or multiionic target such as Kapton.

  14. Multiple scattering in electron fluid and energy loss in multi-ionic targets

    International Nuclear Information System (INIS)

    Deutsch, C.; Tahir, N.A.; Barriga-Carrasco, M.; Ceban, V.; Fromy, P.; Gilles, D.; Leger, D.; Maynard, G.; Tashev, B.; Volpe, L.

    2014-01-01

    Extensions of the standard stopping model (SSM) for ion projectiles interacting with dense targets of timely concern for ICF and WDM are reviewed. They include multiple scattering on partially degenerate electrons, low velocity ion slowing down in demixing H–He mixtures within Jovian planets core or multiionic target such as Kapton

  15. Identification of Multiple Cryptococcal Fungicidal Drug Targets by Combined Gene Dosing and Drug Affinity Responsive Target Stability Screening

    Directory of Open Access Journals (Sweden)

    Yoon-Dong Park

    2016-08-01

    Full Text Available Cryptococcus neoformans is a pathogenic fungus that is responsible for up to half a million cases of meningitis globally, especially in immunocompromised individuals. Common fungistatic drugs, such as fluconazole, are less toxic for patients but have low efficacy for initial therapy of the disease. Effective therapy against the disease is provided by the fungicidal drug amphotericin B; however, due to its high toxicity and the difficulty in administering its intravenous formulation, it is imperative to find new therapies targeting the fungus. The antiparasitic drug bithionol has been recently identified as having potent fungicidal activity. In this study, we used a combined gene dosing and drug affinity responsive target stability (GD-DARTS screen as well as protein modeling to identify a common drug binding site of bithionol within multiple NAD-dependent dehydrogenase drug targets. This combination genetic and proteomic method thus provides a powerful method for identifying novel fungicidal drug targets for further development.

  16. Irradiation uniformity of spherical targets by multiple uv beams from OMEGA

    International Nuclear Information System (INIS)

    Beich, W.; Dunn, M.; Hutchison, R.

    1984-01-01

    Direct-drive laser fusion demands extremely high levels of irradiation uniformity to ensure uniform compression of spherical targets. The assessment of illumination uniformity of targets irradiated by multiple beams from the OMEGA facility is made with the aid of multiple beams spherical superposition codes, which take into account ray tracing and absorption and a detailed knowledge of the intensity distribution of each beam in the target plane. In this report, recent estimates of the irradiation uniformity achieved with 6 and 12 uv beams of OMEGA will be compared with previous measurements in the IR, and predictions will be made for the uv illumination uniformity achievable with 24 beams of OMEGA

  17. Extending Data Worth Analyses to Select Multiple Observations Targeting Multiple Forecasts.

    Science.gov (United States)

    Vilhelmsen, Troels N; Ferré, Ty P A

    2017-09-15

    Hydrological models are often set up to provide specific forecasts of interest. Owing to the inherent uncertainty in data used to derive model structure and used to constrain parameter variations, the model forecasts will be uncertain. Additional data collection is often performed to minimize this forecast uncertainty. Given our common financial restrictions, it is critical that we identify data with maximal information content with respect to forecast of interest. In practice, this often devolves to qualitative decisions based on expert opinion. However, there is no assurance that this will lead to optimal design, especially for complex hydrogeological problems. Specifically, these complexities include considerations of multiple forecasts, shared information among potential observations, information content of existing data, and the assumptions and simplifications underlying model construction. In the present study, we extend previous data worth analyses to include: simultaneous selection of multiple new measurements and consideration of multiple forecasts of interest. We show how the suggested approach can be used to optimize data collection. This can be used in a manner that suggests specific measurement sets or that produces probability maps indicating areas likely to be informative for specific forecasts. Moreover, we provide examples documenting that sequential measurement election approaches often lead to suboptimal designs and that estimates of data covariance should be included when selecting future measurement sets. © 2017, National Ground Water Association.

  18. Exploring the potential of a structural alphabet-based tool for mining multiple target conformations and target flexibility insight.

    Science.gov (United States)

    Regad, Leslie; Chéron, Jean-Baptiste; Triki, Dhoha; Senac, Caroline; Flatters, Delphine; Camproux, Anne-Claude

    2017-01-01

    Protein flexibility is often implied in binding with different partners and is essential for protein function. The growing number of macromolecular structures in the Protein Data Bank entries and their redundancy has become a major source of structural knowledge of the protein universe. The analysis of structural variability through available redundant structures of a target, called multiple target conformations (MTC), obtained using experimental or modeling methods and under different biological conditions or different sources is one way to explore protein flexibility. This analysis is essential to improve the understanding of various mechanisms associated with protein target function and flexibility. In this study, we explored structural variability of three biological targets by analyzing different MTC sets associated with these targets. To facilitate the study of these MTC sets, we have developed an efficient tool, SA-conf, dedicated to capturing and linking the amino acid and local structure variability and analyzing the target structural variability space. The advantage of SA-conf is that it could be applied to divers sets composed of MTCs available in the PDB obtained using NMR and crystallography or homology models. This tool could also be applied to analyze MTC sets obtained by dynamics approaches. Our results showed that SA-conf tool is effective to quantify the structural variability of a MTC set and to localize the structural variable positions and regions of the target. By selecting adapted MTC subsets and comparing their variability detected by SA-conf, we highlighted different sources of target flexibility such as induced by binding partner, by mutation and intrinsic flexibility. Our results support the interest to mine available structures associated with a target using to offer valuable insight into target flexibility and interaction mechanisms. The SA-conf executable script, with a set of pre-compiled binaries are available at http://www.mti.univ-paris-diderot.fr/recherche/plateformes/logiciels.

  19. Exploring the potential of a structural alphabet-based tool for mining multiple target conformations and target flexibility insight.

    Directory of Open Access Journals (Sweden)

    Leslie Regad

    Full Text Available Protein flexibility is often implied in binding with different partners and is essential for protein function. The growing number of macromolecular structures in the Protein Data Bank entries and their redundancy has become a major source of structural knowledge of the protein universe. The analysis of structural variability through available redundant structures of a target, called multiple target conformations (MTC, obtained using experimental or modeling methods and under different biological conditions or different sources is one way to explore protein flexibility. This analysis is essential to improve the understanding of various mechanisms associated with protein target function and flexibility. In this study, we explored structural variability of three biological targets by analyzing different MTC sets associated with these targets. To facilitate the study of these MTC sets, we have developed an efficient tool, SA-conf, dedicated to capturing and linking the amino acid and local structure variability and analyzing the target structural variability space. The advantage of SA-conf is that it could be applied to divers sets composed of MTCs available in the PDB obtained using NMR and crystallography or homology models. This tool could also be applied to analyze MTC sets obtained by dynamics approaches. Our results showed that SA-conf tool is effective to quantify the structural variability of a MTC set and to localize the structural variable positions and regions of the target. By selecting adapted MTC subsets and comparing their variability detected by SA-conf, we highlighted different sources of target flexibility such as induced by binding partner, by mutation and intrinsic flexibility. Our results support the interest to mine available structures associated with a target using to offer valuable insight into target flexibility and interaction mechanisms. The SA-conf executable script, with a set of pre-compiled binaries are available at

  20. A Convenient Cas9-based Conditional Knockout Strategy for Simultaneously Targeting Multiple Genes in Mouse.

    Science.gov (United States)

    Chen, Jiang; Du, Yinan; He, Xueyan; Huang, Xingxu; Shi, Yun S

    2017-03-31

    The most powerful way to probe protein function is to characterize the consequence of its deletion. Compared to conventional gene knockout (KO), conditional knockout (cKO) provides an advanced gene targeting strategy with which gene deletion can be performed in a spatially and temporally restricted manner. However, for most species that are amphiploid, the widely used Cre-flox conditional KO (cKO) system would need targeting loci in both alleles to be loxP flanked, which in practice, requires time and labor consuming breeding. This is considerably significant when one is dealing with multiple genes. CRISPR/Cas9 genome modulation system is advantaged in its capability in targeting multiple sites simultaneously. Here we propose a strategy that could achieve conditional KO of multiple genes in mouse with Cre recombinase dependent Cas9 expression. By transgenic construction of loxP-stop-loxP (LSL) controlled Cas9 (LSL-Cas9) together with sgRNAs targeting EGFP, we showed that the fluorescence molecule could be eliminated in a Cre-dependent manner. We further verified the efficacy of this novel strategy to target multiple sites by deleting c-Maf and MafB simultaneously in macrophages specifically. Compared to the traditional Cre-flox cKO strategy, this sgRNAs-LSL-Cas9 cKO system is simpler and faster, and would make conditional manipulation of multiple genes feasible.

  1. Multiple-Targeted Graphene-based Nanocarrier for Intracellular Imaging of mRNAs

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Ying; Li, Zhaohui; Liu, Misha; Hu, Dehong; Lin, Yuehe; Li, Jinghong

    2017-08-29

    Simultaneous detection and imaging of multiple intracellular messenger RNA (mRNAs) hold great significant for early cancer diagnostics and preventive medicine development. Herein, we propose a multiple-targeted graphene oxide (GO) nanocarrier that can simultaneously detect and image different type mRNAs in living cells. First of all, in vitro detection of multiple targets have been realized successfully based on the multiple-targeted GO nanocarrier with linear relationship ranging from 3 nM to 200 nM, as well as sensitive detection limit of 1.84 nM for manganese superoxide dismutase (Mn-SOD) mRNA and 2.45 nM for β-actin mRNA. Additionally, this nanosensing platform composed of fluorescent labeled single strand DNA probes and GO nanocarrier can identify Mn-SOD mRNA and endogenous mRNA of β-actin in living cancer cells, showing rapid response, high specificity, nuclease stability, and good biocompatibility during the cell imaging. Thirdly, changes of the expression levels of mRNA in living cells before or after the drug treatment can be monitored successfully. By using multiple ssDNA as probes and GO nanocarrier as the cellular delivery cargo, the proposed simultaneous multiple-targeted sensing platform will be of great potential as a powerful tool for intracellular trafficking process from basic research to clinical diagnosis.

  2. Through-Wall Multiple Targets Vital Signs Tracking Based on VMD Algorithm

    Directory of Open Access Journals (Sweden)

    Jiaming Yan

    2016-08-01

    Full Text Available Targets located at the same distance are easily neglected in most through-wall multiple targets detecting applications which use the single-input single-output (SISO ultra-wideband (UWB radar system. In this paper, a novel multiple targets vital signs tracking algorithm for through-wall detection using SISO UWB radar has been proposed. Taking advantage of the high-resolution decomposition of the Variational Mode Decomposition (VMD based algorithm, the respiration signals of different targets can be decomposed into different sub-signals, and then, we can track the time-varying respiration signals accurately when human targets located in the same distance. Intensive evaluation has been conducted to show the effectiveness of our scheme with a 0.15 m thick concrete brick wall. Constant, piecewise-constant and time-varying vital signs could be separated and tracked successfully with the proposed VMD based algorithm for two targets, even up to three targets. For the multiple targets’ vital signs tracking issues like urban search and rescue missions, our algorithm has superior capability in most detection applications.

  3. Dynamic studies of multiple configurations of CERN's Antiproton Decelerator Target core under proton beam impact

    CERN Document Server

    AUTHOR|(CDS)2248381

    Antiprotons, like many other exotic particles, are produced by impacting high energy proton beams onto fixed targets. At the European Organization for Nuclear Research (CERN), this is done in the Antiproton Decelerator (AD) Facility. The engineering challenges related to the design of an optimal configuration of the AD-Target system derive from the extremely high energy depositions reached in the very thin target core as a consequence of each proton beam impact. A new target design is foreseen for operation after 2021, triggering multiple R&D activities since 2013 for this purpose. The goal of the present Master Thesis is to complement these activities with analytical and numerical calculations, delving into the phenomena associated to the dynamic response of the target core. In this context, two main studies have been carried out. First, the experimental data observed in targets subjected to low intensity proton pulses was cross-checked with analytical and computational methods for modal analysis, applie...

  4. Category-based attentional guidance can operate in parallel for multiple target objects.

    Science.gov (United States)

    Jenkins, Michael; Grubert, Anna; Eimer, Martin

    2018-04-30

    The question whether the control of attention during visual search is always feature-based or can also be based on the category of objects remains unresolved. Here, we employed the N2pc component as an on-line marker for target selection processes to compare the efficiency of feature-based and category-based attentional guidance. Two successive displays containing pairs of real-world objects (line drawings of kitchen or clothing items) were separated by a 10 ms SOA. In Experiment 1, target objects were defined by their category. In Experiment 2, one specific visual object served as target (exemplar-based search). On different trials, targets appeared either in one or in both displays, and participants had to report the number of targets (one or two). Target N2pc components were larger and emerged earlier during exemplar-based search than during category-based search, demonstrating the superior efficiency of feature-based attentional guidance. On trials where target objects appeared in both displays, both targets elicited N2pc components that overlapped in time, suggesting that attention was allocated in parallel to these target objects. Critically, this was the case not only in the exemplar-based task, but also when targets were defined by their category. These results demonstrate that attention can be guided by object categories, and that this type of category-based attentional control can operate concurrently for multiple target objects. Copyright © 2018 Elsevier B.V. All rights reserved.

  5. Clinical efficacy and management of monoclonal antibodies targeting CD38 and SLAMF7 in multiple myeloma

    DEFF Research Database (Denmark)

    van de Donk, Niels W C J; Moreau, Philippe; Plesner, Torben

    2016-01-01

    Immunotherapeutic strategies are emerging as promising therapeutic approaches in multiple myeloma (MM), with several monoclonal antibodies in advanced stages of clinical development. Of these agents, CD38-targeting antibodies have marked single agent activity in extensively pretreated MM...... of therapeutic antibodies with immunofixation and serum protein electrophoresis assays may lead to underestimation of complete response. Strategies to mitigate interference, based on shifting the therapeutic antibody band, are in development. Furthermore, daratumumab, and probably also other CD38-targeting...

  6. Getting satisfied with "satisfaction of search": How to measure errors during multiple-target visual search.

    Science.gov (United States)

    Biggs, Adam T

    2017-07-01

    Visual search studies are common in cognitive psychology, and the results generally focus upon accuracy, response times, or both. Most research has focused upon search scenarios where no more than 1 target will be present for any single trial. However, if multiple targets can be present on a single trial, it introduces an additional source of error because the found target can interfere with subsequent search performance. These errors have been studied thoroughly in radiology for decades, although their emphasis in cognitive psychology studies has been more recent. One particular issue with multiple-target search is that these subsequent search errors (i.e., specific errors which occur following a found target) are measured differently by different studies. There is currently no guidance as to which measurement method is best or what impact different measurement methods could have upon various results and conclusions. The current investigation provides two efforts to address these issues. First, the existing literature is reviewed to clarify the appropriate scenarios where subsequent search errors could be observed. Second, several different measurement methods are used with several existing datasets to contrast and compare how each method would have affected the results and conclusions of those studies. The evidence is then used to provide appropriate guidelines for measuring multiple-target search errors in future studies.

  7. Detection and localization of multiple short range targets using FMCW radar signal

    KAUST Repository

    Jardak, Seifallah

    2016-07-26

    In this paper, a 24 GHz frequency-modulated continuous wave radar is used to detect and localize both stationary and moving targets. Depending on the application, the implemented software offers different modes of operation. For example, it can simply output raw data samples for advanced offline processing or directly carry out a two dimensional fast Fourier transform to estimate the location and velocity of multiple targets. To suppress clutter and detect only moving targets, two methods based on the background reduction and the slow time processing techniques are implemented. A trade-off between the two methods is presented based on their performance and the required processing time. © 2016 IEEE.

  8. Multiple-target method for sputtering amorphous films for bubble-domain devices

    International Nuclear Information System (INIS)

    Burilla, C.T.; Bekebrede, W.R.; Smith, A.B.

    1976-01-01

    Previously, sputtered amorphous metal alloys for bubble applications have ordinarily been prepared by standard sputtering techniques using a single target electrode. The deposition of these alloys is reported using a multiple target rf technique in which a separate target is used for each element contained in the alloy. One of the main advantages of this multiple-target approach is that the film composition can be easily changed by simply varying the voltages applied to the elemental targets. In the apparatus, the centers of the targets are positioned on a 15 cm-radius circle. The platform holding the film substrate is on a 15 cm-long arm which can rotate about the center, thus bringing the sample successively under each target. The platform rotation rate is adjustable from 0 to 190 rpm. That this latter speed is sufficient to homogenize the alloys produced is demonstrated by measurements made of the uniaxial anisotropy constant in Gd 0 . 12 Co 0 . 59 Cu 0 . 29 films. The anisotropy is 6.0 x 10 5 ergs/cm 3 and independent of rotation rate above approximately 25 rpm, but it drops rapidly for slower rotation rates, reaching 1.8 x 10 5 ergs/cm 3 for 7 rpm. The film quality is equal to that of films made by conventional methods. Coercivities of a few oersteds in samples with stripe widths of 1 to 2 μm and magnetizations of 800 to 2800 G were observed

  9. Multiple-targeted graphene-based nanocarrier for intracellular imaging of mRNAs

    International Nuclear Information System (INIS)

    Wang, Ying; Li, Zhaohui; Liu, Misha; Xu, Jinjin; Hu, Dehong; Lin, Yuehe; Li, Jinghong

    2017-01-01

    Simultaneous detection and imaging of multiple intracellular messenger RNA (mRNAs) hold great significant for early cancer diagnostics and preventive medicine development. Herein, we propose a multiple-targeted graphene oxide (GO) nanocarrier that can simultaneously detect and image different type mRNAs in living cells. First of all, in vitro detection of multiple targets have been realized successfully based on the multiple-targeted GO nanocarrier with linear relationship ranging from 3 nM to 200 nM, as well as sensitive detection limit of 1.84 nM for manganese superoxide dismutase (Mn-SOD) mRNA and 2.45 nM for β-actin mRNA. Additionally, this nanosensing platform composed of fluorescent labelled single strand DNA probes and GO nanocarrier can identify Mn-SOD mRNA and endogenous mRNA of β-actin in living cancer cells, showing rapid response, high specificity, nuclease stability, and good biocompatibility during the cell imaging. Thirdly, changes of the expression levels of mRNA in living cells before or after the drug treatment can be monitored successfully. By using multiple ssDNA as probes and GO nanocarrier as the cellular delivery cargo, the proposed simultaneous multiple-targeted sensing platform will be of great potential as a powerful tool for intracellular trafficking process from basic research to clinical diagnosis. - Graphical abstract: Schematic illustration of simultaneously multiple mRNAs monitoring inside single living breast cancer cell based on GO nanocarrier. In particular, the fluorescent signals could be monitored when Mn-SOD probe (red) and β-actin probe (green) hybridizes with their mRNA targets inside the living cells. Random probe (orange) was regarded as control probe for the sensing strategy. - Highlights: • A multiple-targeted GO nanocarrier was used for mRNAs imaging and expression changes after drug treatment can be monitored successfully. • Sensitive detection limit of 1.84 nM for manganese superoxide dismutase (Mn-SOD) m

  10. Multiple Maneuvering Target Tracking by Improved Particle Filter Based on Multiscan JPDA

    Directory of Open Access Journals (Sweden)

    Jing Liu

    2012-01-01

    Full Text Available The multiple maneuvering target tracking algorithm based on a particle filter is addressed. The equivalent-noise approach is adopted, which uses a simple dynamic model consisting of target state and equivalent noise which accounts for the combined effects of the process noise and maneuvers. The equivalent-noise approach converts the problem of maneuvering target tracking to that of state estimation in the presence of nonstationary process noise with unknown statistics. A novel method for identifying the nonstationary process noise is proposed in the particle filter framework. Furthermore, a particle filter based multiscan Joint Probability Data Association (JPDA filter is proposed to deal with the data association problem in a multiple maneuvering target tracking. In the proposed multiscan JPDA algorithm, the distributions of interest are the marginal filtering distributions for each of the targets, and these distributions are approximated with particles. The multiscan JPDA algorithm examines the joint association events in a multiscan sliding window and calculates the marginal posterior probability based on the multiscan joint association events. The proposed algorithm is illustrated via an example involving the tracking of two highly maneuvering, at times closely spaced and crossed, targets, based on resolved measurements.

  11. Locations of serial reach targets are coded in multiple reference frames.

    Science.gov (United States)

    Thompson, Aidan A; Henriques, Denise Y P

    2010-12-01

    an egocentric frame anchored to the eye. However, the amount of change in this distance was smaller than predicted by a pure eye-fixed representation, suggesting that relative positions of the targets or allocentric coding was also used in sequential reach planning. The spatial coding and updating of sequential reach target locations seems to rely on a combined weighting of multiple reference frames, with one of them centered on the eye. Copyright © 2010 Elsevier Ltd. All rights reserved.

  12. A Single Unexpected Change in Target- but Not Distractor Motion Impairs Multiple Object Tracking

    Directory of Open Access Journals (Sweden)

    Hauke S. Meyerhoff

    2013-02-01

    Full Text Available Recent research addresses the question whether motion information of multiple objects contributes to maintaining a selection of objects across a period of motion. Here, we investigate whether target and/or distractor motion information is used during attentive tracking. We asked participants to track four objects and changed either the motion direction of targets, the motion direction of distractors, neither, or both during a brief flash in the middle of a tracking interval. We observed that a single direction change of targets is sufficient to impair tracking performance. In contrast, changing the motion direction of distractors had no effect on performance. This indicates that target- but not distractor motion information is evaluated during tracking.

  13. Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening

    Science.gov (United States)

    Machutta, Carl A.; Kollmann, Christopher S.; Lind, Kenneth E.; Bai, Xiaopeng; Chan, Pan F.; Huang, Jianzhong; Ballell, Lluis; Belyanskaya, Svetlana; Besra, Gurdyal S.; Barros-Aguirre, David; Bates, Robert H.; Centrella, Paolo A.; Chang, Sandy S.; Chai, Jing; Choudhry, Anthony E.; Coffin, Aaron; Davie, Christopher P.; Deng, Hongfeng; Deng, Jianghe; Ding, Yun; Dodson, Jason W.; Fosbenner, David T.; Gao, Enoch N.; Graham, Taylor L.; Graybill, Todd L.; Ingraham, Karen; Johnson, Walter P.; King, Bryan W.; Kwiatkowski, Christopher R.; Lelièvre, Joël; Li, Yue; Liu, Xiaorong; Lu, Quinn; Lehr, Ruth; Mendoza-Losana, Alfonso; Martin, John; McCloskey, Lynn; McCormick, Patti; O'Keefe, Heather P.; O'Keeffe, Thomas; Pao, Christina; Phelps, Christopher B.; Qi, Hongwei; Rafferty, Keith; Scavello, Genaro S.; Steiginga, Matt S.; Sundersingh, Flora S.; Sweitzer, Sharon M.; Szewczuk, Lawrence M.; Taylor, Amy; Toh, May Fern; Wang, Juan; Wang, Minghui; Wilkins, Devan J.; Xia, Bing; Yao, Gang; Zhang, Jean; Zhou, Jingye; Donahue, Christine P.; Messer, Jeffrey A.; Holmes, David; Arico-Muendel, Christopher C.; Pope, Andrew J.; Gross, Jeffrey W.; Evindar, Ghotas

    2017-07-01

    The identification and prioritization of chemically tractable therapeutic targets is a significant challenge in the discovery of new medicines. We have developed a novel method that rapidly screens multiple proteins in parallel using DNA-encoded library technology (ELT). Initial efforts were focused on the efficient discovery of antibacterial leads against 119 targets from Acinetobacter baumannii and Staphylococcus aureus. The success of this effort led to the hypothesis that the relative number of ELT binders alone could be used to assess the ligandability of large sets of proteins. This concept was further explored by screening 42 targets from Mycobacterium tuberculosis. Active chemical series for six targets from our initial effort as well as three chemotypes for DHFR from M. tuberculosis are reported. The findings demonstrate that parallel ELT selections can be used to assess ligandability and highlight opportunities for successful lead and tool discovery.

  14. Tracking and Recognition of Multiple Human Targets Moving in a Wireless Pyroelectric Infrared Sensor Network

    Directory of Open Access Journals (Sweden)

    Ji Xiong

    2014-04-01

    Full Text Available With characteristics of low-cost and easy deployment, the distributed wireless pyroelectric infrared sensor network has attracted extensive interest, which aims to make it an alternate infrared video sensor in thermal biometric applications for tracking and identifying human targets. In these applications, effectively processing signals collected from sensors and extracting the features of different human targets has become crucial. This paper proposes the application of empirical mode decomposition and the Hilbert-Huang transform to extract features of moving human targets both in the time domain and the frequency domain. Moreover, the support vector machine is selected as the classifier. The experimental results demonstrate that by using this method the identification rates of multiple moving human targets are around 90%.

  15. First passage times for multiple particles with reversible target-binding kinetics

    Science.gov (United States)

    Grebenkov, Denis S.

    2017-10-01

    We investigate the first passage problem for multiple particles that diffuse towards a target, partially adsorb there, and then desorb after a finite exponentially distributed residence time. We search for the first time when m particles undergoing such reversible target-binding kinetics are found simultaneously on the target that may trigger an irreversible chemical reaction or a biophysical event. Even if the particles are independent, the finite residence time on the target yields an intricate temporal coupling between particles. We compute analytically the mean first passage time (MFPT) for two independent particles by mapping the original problem to higher-dimensional surface-mediated diffusion and solving the coupled partial differential equations. The respective effects of the adsorption and desorption rates on the MFPT are revealed and discussed.

  16. NEWTONIAN IMPERIALIST COMPETITVE APPROACH TO OPTIMIZING OBSERVATION OF MULTIPLE TARGET POINTS IN MULTISENSOR SURVEILLANCE SYSTEMS

    Directory of Open Access Journals (Sweden)

    A. Afghan-Toloee

    2013-09-01

    Full Text Available The problem of specifying the minimum number of sensors to deploy in a certain area to face multiple targets has been generally studied in the literatures. In this paper, we are arguing the multi-sensors deployment problem (MDP. The Multi-sensor placement problem can be clarified as minimizing the cost required to cover the multi target points in the area. We propose a more feasible method for the multi-sensor placement problem. Our method makes provision the high coverage of grid based placements while minimizing the cost as discovered in perimeter placement techniques. The NICA algorithm as improved ICA (Imperialist Competitive Algorithm is used to decrease the performance time to explore an enough solution compared to other meta-heuristic schemes such as GA, PSO and ICA. A three dimensional area is used for clarify the multiple target and placement points, making provision x, y, and z computations in the observation algorithm. A structure of model for the multi-sensor placement problem is proposed: The problem is constructed as an optimization problem with the objective to minimize the cost while covering all multiple target points upon a given probability of observation tolerance.

  17. Multi-target detection and positioning in crowds using multiple camera surveillance

    Science.gov (United States)

    Huang, Jiahu; Zhu, Qiuyu; Xing, Yufeng

    2018-04-01

    In this study, we propose a pixel correspondence algorithm for positioning in crowds based on constraints on the distance between lines of sight, grayscale differences, and height in a world coordinates system. First, a Gaussian mixture model is used to obtain the background and foreground from multi-camera videos. Second, the hair and skin regions are extracted as regions of interest. Finally, the correspondences between each pixel in the region of interest are found under multiple constraints and the targets are positioned by pixel clustering. The algorithm can provide appropriate redundancy information for each target, which decreases the risk of losing targets due to a large viewing angle and wide baseline. To address the correspondence problem for multiple pixels, we construct a pixel-based correspondence model based on a similar permutation matrix, which converts the correspondence problem into a linear programming problem where a similar permutation matrix is found by minimizing an objective function. The correct pixel correspondences can be obtained by determining the optimal solution of this linear programming problem and the three-dimensional position of the targets can also be obtained by pixel clustering. Finally, we verified the algorithm with multiple cameras in experiments, which showed that the algorithm has high accuracy and robustness.

  18. Detection-Discrimination Method for Multiple Repeater False Targets Based on Radar Polarization Echoes

    Directory of Open Access Journals (Sweden)

    Z. W. ZONG

    2014-04-01

    Full Text Available Multiple repeat false targets (RFTs, created by the digital radio frequency memory (DRFM system of jammer, are widely used in practical to effectively exhaust the limited tracking and discrimination resource of defence radar. In this paper, common characteristic of radar polarization echoes of multiple RFTs is used for target recognition. Based on the echoes from two receiving polarization channels, the instantaneous polarization radio (IPR is defined and its variance is derived by employing Taylor series expansion. A detection-discrimination method is designed based on probability grids. By using the data from microwave anechoic chamber, the detection threshold of the method is confirmed. Theoretical analysis and simulations indicate that the method is valid and feasible. Furthermore, the estimation performance of IPRs of RFTs due to the influence of signal noise ratio (SNR is also covered.

  19. Exploitation of Microdoppler and Multiple Scattering Phenomena for Radar Target Recognition

    Science.gov (United States)

    2006-08-24

    progress on the reserach grant "Exploitation of MicroDoppler and Multiple Scattering Phenomena for Radar Target Recognition" during the period 1...paper describes a methodology of modeling A number of ray-based EM techniques have been interferometric synthetic aperture radar (IFSAR) images...modes including the single present an IFSAR simulation methodology to simulate the antenna transmit mode, the ping-pong mode or the repeat interferogram

  20. One Novel Multiple-Target Plasmid Reference Molecule Targeting Eight Genetically Modified Canola Events for Genetically Modified Canola Detection.

    Science.gov (United States)

    Li, Zhuqing; Li, Xiang; Wang, Canhua; Song, Guiwen; Pi, Liqun; Zheng, Lan; Zhang, Dabing; Yang, Litao

    2017-09-27

    Multiple-target plasmid DNA reference materials have been generated and utilized as good substitutes of matrix-based reference materials in the analysis of genetically modified organisms (GMOs). Herein, we report the construction of one multiple-target plasmid reference molecule, pCAN, which harbors eight GM canola event-specific sequences (RF1, RF2, MS1, MS8, Topas 19/2, Oxy235, RT73, and T45) and a partial sequence of the canola endogenous reference gene PEP. The applicability of this plasmid reference material in qualitative and quantitative PCR assays of the eight GM canola events was evaluated, including the analysis of specificity, limit of detection (LOD), limit of quantification (LOQ), and performance of pCAN in the analysis of various canola samples, etc. The LODs are 15 copies for RF2, MS1, and RT73 assays using pCAN as the calibrator and 10 genome copies for the other events. The LOQ in each event-specific real-time PCR assay is 20 copies. In quantitative real-time PCR analysis, the PCR efficiencies of all event-specific and PEP assays are between 91% and 97%, and the squared regression coefficients (R 2 ) are all higher than 0.99. The quantification bias values varied from 0.47% to 20.68% with relative standard deviation (RSD) from 1.06% to 24.61% in the quantification of simulated samples. Furthermore, 10 practical canola samples sampled from imported shipments in the port of Shanghai, China, were analyzed employing pCAN as the calibrator, and the results were comparable with those assays using commercial certified materials as the calibrator. Concluding from these results, we believe that this newly developed pCAN plasmid is one good candidate for being a plasmid DNA reference material in the detection and quantification of the eight GM canola events in routine analysis.

  1. Simple and Efficient Targeting of Multiple Genes Through CRISPR-Cas9 in Physcomitrella patens

    Directory of Open Access Journals (Sweden)

    Mauricio Lopez-Obando

    2016-11-01

    Full Text Available Powerful genome editing technologies are needed for efficient gene function analysis. The CRISPR-Cas9 system has been adapted as an efficient gene-knock-out technology in a variety of species. However, in a number of situations, knocking out or modifying a single gene is not sufficient; this is particularly true for genes belonging to a common family, or for genes showing redundant functions. Like many plants, the model organism Physcomitrella patens has experienced multiple events of polyploidization during evolution that has resulted in a number of families of duplicated genes. Here, we report a robust CRISPR-Cas9 system, based on the codelivery of a CAS9 expressing cassette, multiple sgRNA vectors, and a cassette for transient transformation selection, for gene knock-out in multiple gene families. We demonstrate that CRISPR-Cas9-mediated targeting of five different genes allows the selection of a quintuple mutant, and all possible subcombinations of mutants, in one experiment, with no mutations detected in potential off-target sequences. Furthermore, we confirmed the observation that the presence of repeats in the vicinity of the cutting region favors deletion due to the alternative end joining pathway, for which induced frameshift mutations can be potentially predicted. Because the number of multiple gene families in Physcomitrella is substantial, this tool opens new perspectives to study the role of expanded gene families in the colonization of land by plants.

  2. EBF factors drive expression of multiple classes of target genes governing neuronal development.

    Science.gov (United States)

    Green, Yangsook S; Vetter, Monica L

    2011-04-30

    Early B cell factor (EBF) family members are transcription factors known to have important roles in several aspects of vertebrate neurogenesis, including commitment, migration and differentiation. Knowledge of how EBF family members contribute to neurogenesis is limited by a lack of detailed understanding of genes that are transcriptionally regulated by these factors. We performed a microarray screen in Xenopus animal caps to search for targets of EBF transcriptional activity, and identified candidate targets with multiple roles, including transcription factors of several classes. We determined that, among the most upregulated candidate genes with expected neuronal functions, most require EBF activity for some or all of their expression, and most have overlapping expression with ebf genes. We also found that the candidate target genes that had the most strongly overlapping expression patterns with ebf genes were predicted to be direct transcriptional targets of EBF transcriptional activity. The identification of candidate targets that are transcription factor genes, including nscl-1, emx1 and aml1, improves our understanding of how EBF proteins participate in the hierarchy of transcription control during neuronal development, and suggests novel mechanisms by which EBF activity promotes migration and differentiation. Other candidate targets, including pcdh8 and kcnk5, expand our knowledge of the types of terminal differentiated neuronal functions that EBF proteins regulate.

  3. EBF factors drive expression of multiple classes of target genes governing neuronal development

    Directory of Open Access Journals (Sweden)

    Vetter Monica L

    2011-04-01

    Full Text Available Abstract Background Early B cell factor (EBF family members are transcription factors known to have important roles in several aspects of vertebrate neurogenesis, including commitment, migration and differentiation. Knowledge of how EBF family members contribute to neurogenesis is limited by a lack of detailed understanding of genes that are transcriptionally regulated by these factors. Results We performed a microarray screen in Xenopus animal caps to search for targets of EBF transcriptional activity, and identified candidate targets with multiple roles, including transcription factors of several classes. We determined that, among the most upregulated candidate genes with expected neuronal functions, most require EBF activity for some or all of their expression, and most have overlapping expression with ebf genes. We also found that the candidate target genes that had the most strongly overlapping expression patterns with ebf genes were predicted to be direct transcriptional targets of EBF transcriptional activity. Conclusions The identification of candidate targets that are transcription factor genes, including nscl-1, emx1 and aml1, improves our understanding of how EBF proteins participate in the hierarchy of transcription control during neuronal development, and suggests novel mechanisms by which EBF activity promotes migration and differentiation. Other candidate targets, including pcdh8 and kcnk5, expand our knowledge of the types of terminal differentiated neuronal functions that EBF proteins regulate.

  4. Targeting accuracy of single-isocenter intensity-modulated radiosurgery for multiple lesions

    Energy Technology Data Exchange (ETDEWEB)

    Calvo-Ortega, J.F., E-mail: jfcdrr@yahoo.es; Pozo, M.; Moragues, S.; Casals, J.

    2017-07-01

    To investigate the targeting accuracy of intensity-modulated SRS (IMRS) plans designed to simultaneously treat multiple brain metastases with a single isocenter. A home-made acrylic phantom able to support a film (EBT3) in its coronal plane was used. The phantom was CT scanned and three coplanar small targets (a central and two peripheral) were outlined in the Eclipse system. Peripheral targets were 6 cm apart from the central one. A reference IMRS plan was designed to simultaneously treat the three targets, but only a single isocenter located at the center of the central target was used. After positioning the phantom on the linac using the room lasers, a CBCT scan was acquired and the reference plan were mapped on it, by placing the planned isocenter at the intersection of the landmarks used in the film showing the linac isocenter. The mapped plan was then recalculated and delivered. The film dose distribution was derived using a cloud computing application ( (www.radiochromic.com)) that uses a triple-channel dosimetry algorithm. Comparison of dose distributions using the gamma index (5%/1 mm) were performed over a 5 × 5 cm{sup 2} region centered over each target. 2D shifts required to get the best gamma passing rates on the peripheral target regions were compared with the reported ones for the central target. The experiment was repeated ten times in different sessions. Average 2D shifts required to achieve optimal gamma passing rates (99%, 97%, 99%) were 0.7 mm (SD: 0.3 mm), 0.8 mm (SD: 0.4 mm) and 0.8 mm (SD: 0.3 mm), for the central and the two peripheral targets, respectively. No statistical differences (p > 0.05) were found for targeting accuracy between the central and the two peripheral targets. The study revealed a targeting accuracy within 1 mm for off-isocenter targets within 6 cm of the linac isocenter, when a single-isocenter IMRS plan is designed.

  5. Low power multiple shell fusion targets for use with electron and ion beams

    International Nuclear Information System (INIS)

    Lindl, J.D.; Bangerter, R.O.

    1975-01-01

    Use of double shell targets with a separate low Z, low density ablator at large radius for the outer shell, reduces the focusing and power requirements while maintaining reasonable aspect ratios. A high Z, high density pusher shell is placed at a much smaller radius in order to obtain an aspect ratio small enough to protect against fluid instability. Velocity multiplication between these shells further lowers the power requirements. Careful tuning of the power profile and intershell density results in a low entropy implosion which allows breakeven at low powers. Ion beams appear to be a promising power source and breakeven at 10-20 Terrawatts with 10 MeV alpha particles appears feasible. Predicted performance of targets with various energy sources is shown and comparison is made with single shell targets

  6. The pituitary tumor transforming gene 1 (PTTG-1: An immunological target for multiple myeloma

    Directory of Open Access Journals (Sweden)

    Gagliano Nicoletta

    2008-04-01

    Full Text Available Abstract Background Multiple Myeloma is a cancer of B plasma cells, which produce non-specific antibodies and proliferate uncontrolled. Due to the potential relapse and non-specificity of current treatments, immunotherapy promises to be more specific and may induce long-term immunity in patients. The pituitary tumor transforming gene 1 (PTTG-1 has been shown to be a novel oncogene, expressed in the testis, thymus, colon, lung and placenta (undetectable in most other tissues. Furthermore, it is over expressed in many tumors such as the pituitary adenoma, breast, gastrointestinal cancers, leukemia, lymphoma, and lung cancer and it seems to be associated with tumorigenesis, angiogenesis and cancer progression. The purpose was to investigate the presence/rate of expression of PTTG-1 in multiple myeloma patients. Methods We analyzed the PTTG-1 expression at the transcriptional and the protein level, by PCR, immunocytochemical methods, Dot-blot and ELISA performed on patient's sera in 19 multiple myeloma patients, 6 different multiple myeloma cell lines and in normal human tissue. Results We did not find PTTG-1 presence in the normal human tissue panel, but PTTG-1 mRNA was detectable in 12 of the 19 patients, giving evidence of a 63% rate of expression (data confirmed by ELISA. Four of the 6 investigated cell lines (66.6% were positive for PTTG-1. Investigations of protein expression gave evidence of 26.3% cytoplasmic expression and 16% surface expression in the plasma cells of multiple myeloma patients. Protein presence was also confirmed by Dot-blot in both cell lines and patients. Conclusion We established PTTG-1's presence at both the transcriptional and protein levels. These data suggest that PTTG-1 is aberrantly expressed in multiple myeloma plasma cells, is highly immunogenic and is a suitable target for immunotherapy of multiple myeloma.

  7. Exploiting off-targeting in guide-RNAs for CRISPR systems for simultaneous editing of multiple genes

    DEFF Research Database (Denmark)

    Ferreira, Raphael; Gatto, Francesco; Nielsen, Jens

    2017-01-01

    Bioinformatics tools to design guide-RNAs (gRNAs) in Clustered Regularly Interspaced Short Palindromic Repeats systems mostly focused on minimizing off-targeting to enhance efficacy of genome editing. However, there are circumstances in which off-targeting might be desirable to target multiple ge...

  8. Method for Multiple Targets Tracking in Cognitive Radar Based on Compressed Sensing

    Directory of Open Access Journals (Sweden)

    Yang Jun

    2016-02-01

    Full Text Available A multiple targets cognitive radar tracking method based on Compressed Sensing (CS is proposed. In this method, the theory of CS is introduced to the case of cognitive radar tracking process in multiple targets scenario. The echo signal is sparsely expressed. The designs of sparse matrix and measurement matrix are accomplished by expressing the echo signal sparsely, and subsequently, the restruction of measurement signal under the down-sampling condition is realized. On the receiving end, after considering that the problems that traditional particle filter suffers from degeneracy, and require a large number of particles, the particle swarm optimization particle filter is used to track the targets. On the transmitting end, the Posterior Cramér-Rao Bounds (PCRB of the tracking accuracy is deduced, and the radar waveform parameters are further cognitively designed using PCRB. Simulation results show that the proposed method can not only reduce the data quantity, but also provide a better tracking performance compared with traditional method.

  9. Two-dimensional multiplicity fluctuation analysis of target residues in nuclear collisions

    International Nuclear Information System (INIS)

    Dong-Hai, Zhang; Yao-Jie, Niu; Li-Chun, Wang; Wen-Jun, Yan; Li-Juan, Gao; Ming-Xing, Li; Li-Ping, Wu; Hui-Ling, Li; Jun-Sheng, Li

    2010-01-01

    Multiplicity fluctuation of the target residues emitted in the interactions in a wide range of projectile energies from 500 A MeV to 60 A GeV is investigated in the framework of two-dimensional scaled factorial moment methodology. The evidence of non-statistical multiplicity fluctuation is found in 16 O–AgBr collisions at 60 A GeV, but not in 56 Fe–AgBr collisions at 500 A MeV, 84 Kr–AgBr collisions at 1.7 A GeV, 16 O–AgBr collisions at 3.7 A GeV and 197 Au–AgBr collisions at 10.7 A GeV. (nuclear physics)

  10. Multiplicities of charged kaons from deep-inelastic muon scattering off an isoscalar target

    CERN Document Server

    Adolph, C.

    2017-04-10

    Precise measurements of charged-kaon multiplicities in deep inelastic scattering were performed. The results are presented in three-dimensional bins of the Bjorken scaling variable x, the relative virtual-photon energy y, and the fraction z of the virtual-photon energy carried by the produced hadron. The data were obtained by the COMPASS Collaboration by scattering 160 GeV muons off an isoscalar 6 LiD target. They cover the kinematic domain 1 (GeV/c)2 5 GeV/c^2 in the invariant mass of the hadronic system. The results from the sum of the z-integrated K+ and K- multiplicities at high x point to a value of the non-strange quark fragmentation function larger than obtained by the earlier DSS fit.

  11. Multiplicities of charged kaons from deep-inelastic muon scattering off an isoscalar target

    Directory of Open Access Journals (Sweden)

    C. Adolph

    2017-04-01

    Full Text Available Precise measurements of charged-kaon multiplicities in deep inelastic scattering were performed. The results are presented in three-dimensional bins of the Bjorken scaling variable x, the relative virtual-photon energy y, and the fraction z of the virtual-photon energy carried by the produced hadron. The data were obtained by the COMPASS Collaboration by scattering 160 GeV muons off an isoscalar 6LiD target. They cover the kinematic domain 1(GeV/c25 GeV/c2 in the invariant mass of the hadronic system. The results from the sum of the z-integrated K+ and K− multiplicities at high x point to a value of the non-strange quark fragmentation function larger than obtained by the earlier DSS fit.

  12. A Targeted "Capture" and "Removal" Scavenger toward Multiple Pollutants for Water Remediation based on Molecular Recognition.

    Science.gov (United States)

    Wang, Jie; Shen, Haijing; Hu, Xiaoxia; Li, Yan; Li, Zhihao; Xu, Jinfan; Song, Xiufeng; Zeng, Haibo; Yuan, Quan

    2016-03-01

    For the water remediation techniques based on adsorption, the long-standing contradictories between selectivity and multiple adsorbability, as well as between affinity and recyclability, have put it on weak defense amid more and more severe environment crisis. Here, a pollutant-targeting hydrogel scavenger is reported for water remediation with both high selectivity and multiple adsorbability for several pollutants, and with strong affinity and good recyclability through rationally integrating the advantages of multiple functional materials. In the scavenger, aptamers fold into binding pockets to accommodate the molecular structure of pollutants to afford perfect selectivity, and Janus nanoparticles with antibacterial function as well as anisotropic surfaces to immobilize multiple aptamers allow for simultaneously handling different kinds of pollutants. The scavenger exhibits high efficiencies in removing pollutants from water and it can be easily recycled for many times without significant loss of loading capacities. Moreover, the residual concentrations of each contaminant are well below the drinking water standards. Thermodynamic behavior of the adsorption process is investigated and the rate-controlling process is determined. Furthermore, a point of use device is constructed and it displays high efficiency in removing pollutants from environmental water. The scavenger exhibits great promise to be applied in the next generation of water purification systems.

  13. Analysis of multiple-foil XRL targets using x-ray spectroscopy

    International Nuclear Information System (INIS)

    Wang, J.; Boehly, T.; Yaakobi, B.; Epstein, R.; Meyerhofer, D.; Richardson, M.C.; Russotto, M.; Soures, J.M.

    1989-01-01

    The multiple-foil collisional excitation x-ray laser targets proposed by LLE have been studied spectroscopically. Using spatially resolved 3d-2p x-ray spectra, the authors compare the temperatures and densities obtained in single- and double-foil geometries. They use the ratio of the dipole transitions to the electric quadrupole transitions in the Neon-like species as a density diagnostic. A non-LTE average-ion atomic physics model is used to describe the ionization process and a relativistic atomic physics code is used for calculation of the level energies, populations, and gain calculations. They support their claims that the double-vfoils provide higher densities and in some cases concave density profiles. The XUV spectra in the range of 20-300 A show the effect of target geometry and incident laser intensity on the lasing lines and the ionization balance

  14. One For All? Hitting multiple Alzheimer’s Disease targets with one drug

    Directory of Open Access Journals (Sweden)

    Rebecca Ellen Hughes

    2016-04-01

    Full Text Available Alzheimer’s disease is a complex and multifactorial disease for which the mechanism is still not fully understood. As new insights into disease progression are discovered, new drugs must be designed to target those aspects of the disease that cause neuronal damage rather than just the symptoms currently addressed by single target drugs. It is becoming possible to target several aspects of the disease pathology at once using multi-target drugs. Intended as a introduction for non-experts, this review describes the key multi-target drug design approaches, namely structure-based, in silico, and data-mining, to evaluate what is preventing compounds progressing through the clinic to the market. Repurposing current drugs using their off-target effects reduces the cost of development, time to launch and also the uncertainty associated with safety and pharmacokinetics. The most promising drugs currently being investigated for repurposing to Alzheimer’s Disease are rasagiline, originally developed for the treatment of Parkinson’s Disease, and liraglutide, an antidiabetic. Rational drug design can combine pharmacophores of multiple drugs, systematically change functional groups, and rank them by virtual screening. Hits confirmed experimentally are rationally modified to generate an effective multi-potent lead compound. Examples from this approach are ASS234 with properties similar to rasagiline, and donecopride, a hybrid of an acetylcholinesterase inhibitor and a 5-HT4 receptor agonist with pro-cognitive effects. Exploiting these interdisciplinary approaches, public-private collaborative lead factories promise faster delivery of new drugs to the clinic.

  15. Interpolating between random walks and optimal transportation routes: Flow with multiple sources and targets

    Science.gov (United States)

    Guex, Guillaume

    2016-05-01

    In recent articles about graphs, different models proposed a formalism to find a type of path between two nodes, the source and the target, at crossroads between the shortest-path and the random-walk path. These models include a freely adjustable parameter, allowing to tune the behavior of the path toward randomized movements or direct routes. This article presents a natural generalization of these models, namely a model with multiple sources and targets. In this context, source nodes can be viewed as locations with a supply of a certain good (e.g. people, money, information) and target nodes as locations with a demand of the same good. An algorithm is constructed to display the flow of goods in the network between sources and targets. With again a freely adjustable parameter, this flow can be tuned to follow routes of minimum cost, thus displaying the flow in the context of the optimal transportation problem or, by contrast, a random flow, known to be similar to the electrical current flow if the random-walk is reversible. Moreover, a source-targetcoupling can be retrieved from this flow, offering an optimal assignment to the transportation problem. This algorithm is described in the first part of this article and then illustrated with case studies.

  16. SAR Target Recognition Based on Multi-feature Multiple Representation Classifier Fusion

    Directory of Open Access Journals (Sweden)

    Zhang Xinzheng

    2017-10-01

    Full Text Available In this paper, we present a Synthetic Aperture Radar (SAR image target recognition algorithm based on multi-feature multiple representation learning classifier fusion. First, it extracts three features from the SAR images, namely principal component analysis, wavelet transform, and Two-Dimensional Slice Zernike Moments (2DSZM features. Second, we harness the sparse representation classifier and the cooperative representation classifier with the above-mentioned features to get six predictive labels. Finally, we adopt classifier fusion to obtain the final recognition decision. We researched three different classifier fusion algorithms in our experiments, and the results demonstrate thatusing Bayesian decision fusion gives thebest recognition performance. The method based on multi-feature multiple representation learning classifier fusion integrates the discrimination of multi-features and combines the sparse and cooperative representation classification performance to gain complementary advantages and to improve recognition accuracy. The experiments are based on the Moving and Stationary Target Acquisition and Recognition (MSTAR database,and they demonstrate the effectiveness of the proposed approach.

  17. Multiple targets of salicylic acid and its derivatives in plants and animals

    Directory of Open Access Journals (Sweden)

    Daniel F. Klessig

    2016-05-01

    Full Text Available Salicylic acid (SA is a critical plant hormone that is involved in many processes, including seed germination, root initiation, stomatal closure, floral induction, thermogenesis, and response to abiotic and biotic stresses. Its central role in plant immunity, although extensively studied, is still only partially understood. Classical biochemical approaches and, more recently, genome-wide high-throughput screens have identified more than two dozen plant SA-binding proteins (SABPs, as well as multiple candidates that have yet to be characterized. Some of these proteins bind SA with high affinity, while the affinity others exhibit is low. Given that SA levels vary greatly even within a particular plant species depending on subcellular location, tissue type, developmental stage, and with respect to both time and location after an environmental stimulus such as infection, the presence of SABPs exhibiting a wide range of affinities for SA may provide great flexibility and multiple mechanisms through which SA can act. SA and its derivatives, both natural and synthetic, also have multiple targets in animals/humans. Interestingly, many of these proteins, like their plant counterparts, are associated with immunity or disease development. Two recently identified SABPs, High Mobility Group Box protein (HMGB and Glyceraldehyde 3-Phosphate Dehydrogenase (GAPDH, are critical proteins that not only serve key structural or metabolic functions, but also play prominent roles in disease responses in both kingdoms.

  18. Multiple cyber attacks against a target with observation errors and dependent outcomes: Characterization and optimization

    International Nuclear Information System (INIS)

    Hu, Xiaoxiao; Xu, Maochao; Xu, Shouhuai; Zhao, Peng

    2017-01-01

    In this paper we investigate a cybersecurity model: An attacker can launch multiple attacks against a target with a termination strategy that says that the attacker will stop after observing a number of successful attacks or when the attacker is out of attack resources. However, the attacker's observation of the attack outcomes (i.e., random variables indicating whether the target is compromised or not) has an observation error that is specified by both a false-negative and a false-positive probability. The novelty of the model we study is the accommodation of the dependence between the attack outcomes, because the dependence was assumed away in the literature. In this model, we characterize the monotonicity and bounds of the compromise probability (i.e., the probability that the target is compromised). In addition to extensively showing the impact of dependence on quantities such as compromise probability and attack cost, we give methods for finding the optimal strategy that leads to maximum compromise probability or minimum attack cost. This study highlights that the dependence between random variables cannot be assumed away, because the results will be misleading. - Highlights: • A novel cybersecurity model is proposed to accommodate the dependence among attack outcomes. • The monotonicity and bounds of the compromise probability are studied. • The dependence effect on the compromise probability and attack cost is discussed via simulation. • The optimal strategy that leads to maximum compromise probability or minimum attack cost is presented.

  19. Targeting MUC1-C suppresses polycomb repressive complex 1 in multiple myeloma.

    Science.gov (United States)

    Tagde, Ashujit; Markert, Tahireh; Rajabi, Hasan; Hiraki, Masayuki; Alam, Maroof; Bouillez, Audrey; Avigan, David; Anderson, Kenneth; Kufe, Donald

    2017-09-19

    The polycomb repressive complex 1 (PRC1) includes the BMI1, RING1 and RING2 proteins. BMI1 is required for survival of multiple myeloma (MM) cells. The MUC1-C oncoprotein is aberrantly expressed by MM cells, activates MYC and is also necessary for MM cell survival. The present studies show that targeting MUC1-C with (i) stable and inducible silencing and CRISPR/Cas9 editing and (ii) the pharmacologic inhibitor GO-203, which blocks MUC1-C function, downregulates BMI1, RING1 and RING2 expression. The results demonstrate that MUC1-C drives BMI1 transcription by a MYC-dependent mechanism. MUC1-C thus promotes MYC occupancy on the BMI1 promoter and thereby activates BMI1 expression. We also show that the MUC1-C→MYC pathway induces RING2 expression. Moreover, in contrast to BMI1 and RING2, we found that MUC1-C drives RING1 by an NF-κB p65-dependent mechanism. Targeting MUC1-C and thereby the suppression of these key PRC1 proteins was associated with downregulation of the PRC1 E3 ligase activity as evidenced by decreases in ubiquitylation of histone H2A. Targeting MUC1-C also resulted in activation of the PRC1-repressed tumor suppressor genes, PTEN, CDNK2A and BIM . These findings identify a heretofore unrecognized role for MUC1-C in the epigenetic regulation of MM cells.

  20. Sensitivity studies of the neutron multiplicity spectrum in the spallation of Pb targets

    International Nuclear Information System (INIS)

    Sinha, A.; Garg, S.B.; Srinivasan, M.

    1986-01-01

    The number of neutrons produced per incident proton in the spallation of Pb targets is of direct relevance to the design of accelerator breeders. The nuclear cascade initiated by high-energy protons in spallation targets is usually described by an intranuclear cascade evaporation (INCE) model. Even though this model describes various average nuclear properties of spallation targets fairly well, differential quantities such as energy spectra, angular spectra etc., are not reproduced within the limits of experimental uncertainty. One of the reasons for this is the uncertainty in the magnitude of the parameters involved in the model, notably the level density parameter Bsub(O) whose magnitude is quoted by different workers to be in the range of 8-20 MeV. The accuracy of Bsub(O) could be improved if we could experimentally determine a quantity which is much more sensitive to Bsub(O) than the average neutron yield. In this paper we discuss one such quantity, namely the neutron multiplicity spectrum (MS). We compute the MS due to the spallation of Pb targets of different sizes at proton energies of 1.5, 1.0 and 0.59 GeV using the Monte Carlo code HETC. It is noticed that for the 1.5 GeV proton case the probability P(ν) for leakage of ν neutrons for ν in the range of 60-65, changes by about 70% when Bsub(O) is varied from 8 to 20 MeV. The corresponding change in the average neutron yield is <20%. It is therefore suggested that an accurate measurement of the MS can serve as a useful tool to narrow down the range of uncertainty in the Bsub(O) parameter. (author)

  1. P2-21: Searching for Multiple Targets Using the iPad

    Directory of Open Access Journals (Sweden)

    Ian Thornton

    2012-10-01

    Full Text Available Search for multiple targets is constrained by both retrospective (i.e., where you've been and prospective (i.e., where you're planning to go components of performance. Previous studies using the Multi-Item Localisation (MILO task have demonstrated that participants accurately remember and discount locations they have already visited and that they plan future actions up to 2 or 3 items ahead (Thornton & Horowitz, 2004 Perception & Psychophysics 66 38–50. A prominent feature of the MILO serial-reaction time (SRT function is a highly elevated, that is slowed, response, to T1 compared to T2 and all the other items. This “prospective gap” is typically between 600 ms and 1000 ms. Here we present three experiments that use the MILO iPad app to explore this “prospective gap”. In Experiment 1, we “shuffled” the position of future targets each time a response was made. This blocks planning and thus slows all responses to the level of first target, effectively eliminating the gap. In Experiment 2, participants responded to eight identical targets, removing the need to plan a specific sequence of actions. In this situation, absolute response time is greatly reduced and the T1–T2 gap shrinks to around 350 ms. In Experiment 3, participants repeated their search through the same array 10 times. Under these circumstances, the gap systematically reduced from 1300 ms on trial 1 to 300 ms on trial 10. Together, these results suggest that the previously observed prospective gap is a combination of set-up time for registering a new visual layout, response preparation, and sequence planning.

  2. Simultaneous detection of multiple DNA targets by integrating dual-color graphene quantum dot nanoprobes and carbon nanotubes.

    Science.gov (United States)

    Qian, Zhaosheng; Shan, Xiaoyue; Chai, Lujing; Chen, Jianrong; Feng, Hui

    2014-12-01

    Simultaneous detection of multiple DNA targets was achieved based on a biocompatible graphene quantum dots (GQDs) and carbon nanotubes (CNTs) platform through spontaneous assembly between dual-color GQD-based probes and CNTs and subsequently self-recognition between DNA probes and targets. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  3. New and emerging immune-targeted drugs for the treatment of multiple sclerosis.

    Science.gov (United States)

    Palmer, Alan M

    2014-07-01

    Multiple sclerosis (MS) is a neurodegenerative disease with a major inflammatory component that constitutes the most common progressive and disabling neurological condition in young adults. Injectable immunomodulatory medicines such as interferon drugs and glatiramer acetate have dominated the MS market for over the past two decades but this situation is set to change. This is because of: (i) patent expirations, (ii) the introduction of natalizumab, which targets the interaction between leukocytes and the blood-CNS barrier, (iii) the launch of three oral immunomodulatory drugs (fingolimod, dimethyl fumarate and teriflunomide), with another (laquinimod) under regulatory review and (iv) a number of immunomodulatory monoclonal antibodies (alemtuzumab, daclizumab and ocrelizumab) about to enter the market. Current and emerging medicines are reviewed and their impact on people with MS considered. © 2013 The British Pharmacological Society.

  4. A novel sampling method for multiple multiscale targets from scattering amplitudes at a fixed frequency

    Science.gov (United States)

    Liu, Xiaodong

    2017-08-01

    A sampling method by using scattering amplitude is proposed for shape and location reconstruction in inverse acoustic scattering problems. Only matrix multiplication is involved in the computation, thus the novel sampling method is very easy and simple to implement. With the help of the factorization of the far field operator, we establish an inf-criterion for characterization of underlying scatterers. This result is then used to give a lower bound of the proposed indicator functional for sampling points inside the scatterers. While for the sampling points outside the scatterers, we show that the indicator functional decays like the bessel functions as the sampling point goes away from the boundary of the scatterers. We also show that the proposed indicator functional continuously depends on the scattering amplitude, this further implies that the novel sampling method is extremely stable with respect to errors in the data. Different to the classical sampling method such as the linear sampling method or the factorization method, from the numerical point of view, the novel indicator takes its maximum near the boundary of the underlying target and decays like the bessel functions as the sampling points go away from the boundary. The numerical simulations also show that the proposed sampling method can deal with multiple multiscale case, even the different components are close to each other.

  5. M402, a novel heparan sulfate mimetic, targets multiple pathways implicated in tumor progression and metastasis.

    Directory of Open Access Journals (Sweden)

    He Zhou

    Full Text Available Heparan sulfate proteoglycans (HSPGs play a key role in shaping the tumor microenvironment by presenting growth factors, cytokines, and other soluble factors that are critical for host cell recruitment and activation, as well as promoting tumor progression, metastasis, and survival. M402 is a rationally engineered, non-cytotoxic heparan sulfate (HS mimetic, designed to inhibit multiple factors implicated in tumor-host cell interactions, including VEGF, FGF2, SDF-1α, P-selectin, and heparanase. A single s.c. dose of M402 effectively inhibited seeding of B16F10 murine melanoma cells to the lung in an experimental metastasis model. Fluorescent-labeled M402 demonstrated selective accumulation in the primary tumor. Immunohistological analyses of the primary tumor revealed a decrease in microvessel density in M402 treated animals, suggesting anti-angiogenesis to be one of the mechanisms involved in-vivo. M402 treatment also normalized circulating levels of myeloid derived suppressor cells in tumor bearing mice. Chronic administration of M402, alone or in combination with cisplatin or docetaxel, inhibited spontaneous metastasis and prolonged survival in an orthotopic 4T1 murine mammary carcinoma model. These data demonstrate that modulating HSPG biology represents a novel approach to target multiple factors involved in tumor progression and metastasis.

  6. B-cell activating factor in the pathophysiology of multiple myeloma: a target for therapy?

    International Nuclear Information System (INIS)

    Hengeveld, P J; Kersten, M J

    2015-01-01

    Multiple myeloma (MM) is a currently incurable malignancy of plasma cells. Malignant myeloma cells (MMCs) are heavily dependent upon the bone marrow (BM) microenvironment for their survival. One component of this tumor microenvironment, B-Cell Activating Factor (BAFF), has been implicated as a key player in this interaction. This review discusses the role of BAFF in the pathophysiology of MM, and the potential of BAFF-inhibitory therapy for the treatment of MM. Multiple studies have shown that BAFF functions as a survival factor for MMCs. Furthermore, MMCs express several BAFF-binding receptors. Of these, only Transmembrane Activator and CAML Interactor (TACI) correlates with the MMC's capability to ligate BAFF. Additionally, the level of expression of TACI correlates with the level of the MMC's BM dependency. Ligation of BAFF receptors on MMCs causes activation of the Nuclear Factor of κ-B (NF-κB) pathway, a crucial pathway for the pathogenesis of many B-cell malignancies. Serum BAFF levels are significantly elevated in MM patients when compared to healthy controls, and correlate inversely with overall survival. BAFF signaling is thus an interesting target for the treatment of MM. Several BAFF-inhibitory drugs are currently under evaluation for the treatment of MM. These include BAFF-monoclonal antibodies (tabalumab) and antibody-drug conjugates (GSK2857916)

  7. Nucleotide excision repair is a potential therapeutic target in multiple myeloma

    Science.gov (United States)

    Szalat, R; Samur, M K; Fulciniti, M; Lopez, M; Nanjappa, P; Cleynen, A; Wen, K; Kumar, S; Perini, T; Calkins, A S; Reznichenko, E; Chauhan, D; Tai, Y-T; Shammas, M A; Anderson, K C; Fermand, J-P; Arnulf, B; Avet-Loiseau, H; Lazaro, J-B; Munshi, N C

    2018-01-01

    Despite the development of novel drugs, alkylating agents remain an important component of therapy in multiple myeloma (MM). DNA repair processes contribute towards sensitivity to alkylating agents and therefore we here evaluate the role of nucleotide excision repair (NER), which is involved in the removal of bulky adducts and DNA crosslinks in MM. We first evaluated NER activity using a novel functional assay and observed a heterogeneous NER efficiency in MM cell lines and patient samples. Using next-generation sequencing data, we identified that expression of the canonical NER gene, excision repair cross-complementation group 3 (ERCC3), significantly impacted the outcome in newly diagnosed MM patients treated with alkylating agents. Next, using small RNA interference, stable knockdown and overexpression, and small-molecule inhibitors targeting xeroderma pigmentosum complementation group B (XPB), the DNA helicase encoded by ERCC3, we demonstrate that NER inhibition significantly increases sensitivity and overcomes resistance to alkylating agents in MM. Moreover, inhibiting XPB leads to the dual inhibition of NER and transcription and is particularly efficient in myeloma cells. Altogether, we show that NER impacts alkylating agents sensitivity in myeloma cells and identify ERCC3 as a potential therapeutic target in MM. PMID:28588253

  8. Hairpin RNA Targeting Multiple Viral Genes Confers Strong Resistance to Rice Black-Streaked Dwarf Virus

    Directory of Open Access Journals (Sweden)

    Fangquan Wang

    2016-05-01

    Full Text Available Rice black-streaked dwarf virus (RBSDV belongs to the genus Fijivirus in the family of Reoviridae and causes severe yield loss in rice-producing areas in Asia. RNA silencing, as a natural defence mechanism against plant viruses, has been successfully exploited for engineering virus resistance in plants, including rice. In this study, we generated transgenic rice lines harbouring a hairpin RNA (hpRNA construct targeting four RBSDV genes, S1, S2, S6 and S10, encoding the RNA-dependent RNA polymerase, the putative core protein, the RNA silencing suppressor and the outer capsid protein, respectively. Both field nursery and artificial inoculation assays of three generations of the transgenic lines showed that they had strong resistance to RBSDV infection. The RBSDV resistance in the segregating transgenic populations correlated perfectly with the presence of the hpRNA transgene. Furthermore, the hpRNA transgene was expressed in the highly resistant transgenic lines, giving rise to abundant levels of 21–24 nt small interfering RNA (siRNA. By small RNA deep sequencing, the RBSDV-resistant transgenic lines detected siRNAs from all four viral gene sequences in the hpRNA transgene, indicating that the whole chimeric fusion sequence can be efficiently processed by Dicer into siRNAs. Taken together, our results suggest that long hpRNA targeting multiple viral genes can be used to generate stable and durable virus resistance in rice, as well as other plant species.

  9. Hairpin RNA Targeting Multiple Viral Genes Confers Strong Resistance to Rice Black-Streaked Dwarf Virus.

    Science.gov (United States)

    Wang, Fangquan; Li, Wenqi; Zhu, Jinyan; Fan, Fangjun; Wang, Jun; Zhong, Weigong; Wang, Ming-Bo; Liu, Qing; Zhu, Qian-Hao; Zhou, Tong; Lan, Ying; Zhou, Yijun; Yang, Jie

    2016-05-11

    Rice black-streaked dwarf virus (RBSDV) belongs to the genus Fijivirus in the family of Reoviridae and causes severe yield loss in rice-producing areas in Asia. RNA silencing, as a natural defence mechanism against plant viruses, has been successfully exploited for engineering virus resistance in plants, including rice. In this study, we generated transgenic rice lines harbouring a hairpin RNA (hpRNA) construct targeting four RBSDV genes, S1, S2, S6 and S10, encoding the RNA-dependent RNA polymerase, the putative core protein, the RNA silencing suppressor and the outer capsid protein, respectively. Both field nursery and artificial inoculation assays of three generations of the transgenic lines showed that they had strong resistance to RBSDV infection. The RBSDV resistance in the segregating transgenic populations correlated perfectly with the presence of the hpRNA transgene. Furthermore, the hpRNA transgene was expressed in the highly resistant transgenic lines, giving rise to abundant levels of 21-24 nt small interfering RNA (siRNA). By small RNA deep sequencing, the RBSDV-resistant transgenic lines detected siRNAs from all four viral gene sequences in the hpRNA transgene, indicating that the whole chimeric fusion sequence can be efficiently processed by Dicer into siRNAs. Taken together, our results suggest that long hpRNA targeting multiple viral genes can be used to generate stable and durable virus resistance in rice, as well as other plant species.

  10. Endocytosis of Cytotoxic Granules Is Essential for Multiple Killing of Target Cells by T Lymphocytes.

    Science.gov (United States)

    Chang, Hsin-Fang; Bzeih, Hawraa; Schirra, Claudia; Chitirala, Praneeth; Halimani, Mahantappa; Cordat, Emmanuelle; Krause, Elmar; Rettig, Jens; Pattu, Varsha

    2016-09-15

    CTLs are serial killers that kill multiple target cells via exocytosis of cytotoxic granules (CGs). CG exocytosis is tightly regulated and has been investigated in great detail; however, whether CG proteins are endocytosed following exocytosis and contribute to serial killing remains unknown. By using primary CTLs derived from a knock-in mouse of the CG membrane protein Synaptobrevin2, we show that CGs are endocytosed in a clathrin- and dynamin-dependent manner. Following acidification, endocytosed CGs are recycled through early and late, but not recycling endosomes. CGs are refilled with granzyme B at the late endosome stage and polarize to subsequent synapses formed between the CTL and new target cells. Importantly, inhibiting CG endocytosis in CTLs results in a significant reduction of their cytotoxic activity. Thus, our data demonstrate that continuous endocytosis of CG membrane proteins is a prerequisite for efficient serial killing of CTLs and identify key events in this process. Copyright © 2016 by The American Association of Immunologists, Inc.

  11. Monoclonal IgG in MGUS and multiple myeloma targets infectious pathogens

    Science.gov (United States)

    Bosseboeuf, Adrien; Feron, Delphine; Tallet, Anne; Rossi, Cédric; Charlier, Cathy; Garderet, Laurent; Caillot, Denis; Moreau, Philippe; Cardó-Vila, Marina; Pasqualini, Renata; Nelson, Alfreda Destea; Wilson, Bridget S.; Perreault, Hélène; Piver, Eric; Weigel, Pierre; Harb, Jean; Bigot-Corbel, Edith; Hermouet, Sylvie

    2017-01-01

    Subsets of mature B cell neoplasms are linked to infection with intracellular pathogens such as Epstein-Barr virus (EBV), hepatitis C virus (HCV), or Helicobacter pylori. However, the association between infection and the immunoglobulin-secreting (Ig-secreting) B proliferative disorders remains largely unresolved. We investigated whether the monoclonal IgG (mc IgG) produced by patients diagnosed with monoclonal gammopathy of undetermined significance (MGUS) or multiple myeloma (MM) targets infectious pathogens. Antigen specificity of purified mc IgG from a large patient cohort (n = 244) was determined using a multiplex infectious-antigen array (MIAA), which screens for reactivity to purified antigens or lysates from 9 pathogens. Purified mc IgG from 23.4% of patients (57 of 244) specifically recognized 1 pathogen in the MIAA. EBV was the most frequent target (15.6%), with 36 of 38 mc IgGs recognizing EBV nuclear antigen-1 (EBNA-1). MM patients with EBNA-1–specific mc IgG (14.0%) showed substantially greater bone marrow plasma cell infiltration and higher β2-microglobulin and inflammation/infection–linked cytokine levels compared with other smoldering myeloma/MM patients. Five other pathogens were the targets of mc IgG: herpes virus simplex-1 (2.9%), varicella zoster virus (1.6%), cytomegalovirus (0.8%), hepatitis C virus (1.2%), and H. pylori (1.2%). We conclude that a dysregulated immune response to infection may underlie disease onset and/or progression of MGUS and MM for subsets of patients. PMID:28978808

  12. Damage to Preheated Tungsten Targets after Multiple Plasma Impacts Simulating ITER ELMs

    Energy Technology Data Exchange (ETDEWEB)

    Garkusha, I.E.; Bandura, A.N.; Byrka, O.V.; Chebotarev, V.V.; Makhlay, V.A.; Tereshin, V.I. [Kharkov Inst. of Physics and Technology, Inst. of Plasma Physics of National Science Center, Akademicheskaya street, 1, 61108 Kharkov (Ukraine); Landman, I.; Pestchanyi, S. [FZK-Forschungszentrum Karlsruhe, Association Euratom-FZK, Technik und Umwelt, Postfach 3640, D-7602 1 Karlsruhe (Germany)

    2007-07-01

    Full text of publication follows: The energy loads onto ITER divertor surfaces associated with the Type I ELMs are expected to be up to 1 MJ/m{sup 2} during 0.1-0.5 ms, with the number of pulses about 103 per discharge. Tungsten is a candidate material for major part of the surface, but its brittleness can result in substantial macroscopic erosion after the repetitive heat loads. To minimize the brittle destruction, tungsten may be preheated above the ductile-to-brittle transition temperature. In this work the behavior of preheated tungsten targets under repetitive ELM-like plasma pulses is studied in simulation experiments with the quasi-stationary plasma accelerator QSPA Kh-50. The targets have been exposed up to 450 pulses of the duration 0.25 ms and the heat loads either 0.45 MJ/m{sup 2} or 0.75 MJ/m{sup 2}, which is respectively below and above the melting threshold. During the exposures the targets were permanently kept preheated at 650 deg. C by a heater at target backside. In the course of exposures the irradiated surfaces were examined after regular numbers of pulses using the SEM and the optical microscopy. The profilometry, XRD, microhardness and weight loss measurements have been performed, as well as comparisons of surface damages after the heat loads both below and above the melting threshold. It is obtained that macro-cracks do not develop on the preheated surface. After the impacts with surface melting, a fine mesh of intergranular microcracks has appeared. The width of fine intergranular cracks grows with pulse number, achieving 1-1.5 microns after 100 pulses, and after 210 pulses the crack width increases up to 20 microns, which is comparable with grain sizes. Threshold changes in surface morphology resulting in corrugation structures and pits on the surface as well as importance of surface tension in resulted 'micro-brush' structures are discussed. Further evolution of the surface pattern is caused by loss of separated grains on exposed

  13. Detecting and Georegistering Moving Ground Targets in Airborne QuickSAR via Keystoning and Multiple-Phase Center Interferometry

    Directory of Open Access Journals (Sweden)

    R. P. Perry

    2008-03-01

    Full Text Available SAR images experience significant range walk and, without some form of motion compensation, can be quite blurred. The MITRE-developed Keystone formatting simultaneously and automatically compensates for range walk due to the radial velocity component of each moving target, independent of the number of targets or the value of each target's radial velocity with respect to the ground. Target radial motion also causes moving targets in synthetic aperture radar images to appear at locations offset from their true instantaneous locations on the ground. In a multichannel radar, the interferometric phase values associated with all nonmoving points on the ground appear as a continuum of phase differences while the moving targets appear as interferometric phase discontinuities. By multiple threshold comparisons and grouping of pixels within the intensity and the phase images, we show that it is possible to reliably detect and accurately georegister moving targets within short-duration SAR (QuickSAR images.

  14. Multi-Target Angle Tracking Algorithm for Bistatic Multiple-Input Multiple-Output (MIMO Radar Based on the Elements of the Covariance Matrix

    Directory of Open Access Journals (Sweden)

    Zhengyan Zhang

    2018-03-01

    Full Text Available In this paper, we consider the problem of tracking the direction of arrivals (DOA and the direction of departure (DOD of multiple targets for bistatic multiple-input multiple-output (MIMO radar. A high-precision tracking algorithm for target angle is proposed. First, the linear relationship between the covariance matrix difference and the angle difference of the adjacent moment was obtained through three approximate relations. Then, the proposed algorithm obtained the relationship between the elements in the covariance matrix difference. On this basis, the performance of the algorithm was improved by averaging the covariance matrix element. Finally, the least square method was used to estimate the DOD and DOA. The algorithm realized the automatic correlation of the angle and provided better performance when compared with the adaptive asymmetric joint diagonalization (AAJD algorithm. The simulation results demonstrated the effectiveness of the proposed algorithm. The algorithm provides the technical support for the practical application of MIMO radar.

  15. Multi-Target Angle Tracking Algorithm for Bistatic Multiple-Input Multiple-Output (MIMO) Radar Based on the Elements of the Covariance Matrix.

    Science.gov (United States)

    Zhang, Zhengyan; Zhang, Jianyun; Zhou, Qingsong; Li, Xiaobo

    2018-03-07

    In this paper, we consider the problem of tracking the direction of arrivals (DOA) and the direction of departure (DOD) of multiple targets for bistatic multiple-input multiple-output (MIMO) radar. A high-precision tracking algorithm for target angle is proposed. First, the linear relationship between the covariance matrix difference and the angle difference of the adjacent moment was obtained through three approximate relations. Then, the proposed algorithm obtained the relationship between the elements in the covariance matrix difference. On this basis, the performance of the algorithm was improved by averaging the covariance matrix element. Finally, the least square method was used to estimate the DOD and DOA. The algorithm realized the automatic correlation of the angle and provided better performance when compared with the adaptive asymmetric joint diagonalization (AAJD) algorithm. The simulation results demonstrated the effectiveness of the proposed algorithm. The algorithm provides the technical support for the practical application of MIMO radar.

  16. Targeting p110gamma in gastrointestinal cancers: attack on multiple fronts

    Directory of Open Access Journals (Sweden)

    Marco eFalasca

    2014-10-01

    Full Text Available Phosphoinositide 3-kinases (PI3Ks regulate several cellular functions that are critical for cancer progression and development, including cell survival, proliferation and migration. Three classes of PI3Ks exist with the class I PI3K encompassing four isoforms of the catalytic subunit known as p110α, p110β, p110γ and p110δ. Although for many years attention has been mainly focused on p110α recent evidence supports the conclusion that p110β, p110γ and p110δ can also have a role in cancer. Amongst these, accumulating evidence now supports the conclusion that p110γ is involved in several cellular processes associated with cancer development and progression and indeed this specific isoform has emerged as a novel important player in cancer progression. Studies from our laboratory have identified a specific overexpression of p110γ in human pancreatic ductal adenocarcinoma (PDAC and in hepatocellular carcinoma (HCC tissues compared to their normal counterparts. Our data have further established that selective inhibition of this PI3K isoform is able to block PDAC and HCC cell proliferation, strongly suggesting that pharmacological inhibition of this enzyme can directly affect these tumors growth. Furthermore increasing evidence suggests that p110γ plays also a key role in the interactions between cancer cells and tumor microenvironment and in particular in tumor-associated immune response. It has also been reported that p110γ can regulate invasion of myeloid cells into tumors and tumor angiogenesis. Finally p110γ has also been directly involved in regulation of cancer cell migration. Taken together these data indicate that p110γ plays multiple roles in regulation of several processes that are critical for tumor progression and metastasis. This review will discuss the role of p110γ in gastrointestinal tumor development and progression and how targeting this enzyme might represent a way to target very aggressive tumors such as pancreatic and

  17. Dual-target cost in visual search for multiple unfamiliar faces.

    Science.gov (United States)

    Mestry, Natalie; Menneer, Tamaryn; Cave, Kyle R; Godwin, Hayward J; Donnelly, Nick

    2017-08-01

    The efficiency of visual search for one (single-target) and either of two (dual-target) unfamiliar faces was explored to understand the manifestations of capacity and guidance limitations in face search. The visual similarity of distractor faces to target faces was manipulated using morphing (Experiments 1 and 2) and multidimensional scaling (Experiment 3). A dual-target cost was found in all experiments, evidenced by slower and less accurate search in dual- than single-target conditions. The dual-target cost was unequal across the targets, with performance being maintained on one target and reduced on the other, which we label "preferred" and "non-preferred" respectively. We calculated the capacity for each target face and show reduced capacity for representing the non-preferred target face. However, results show that the capacity for the non-preferred target can be increased when the dual-target condition is conducted after participants complete the single-target conditions. Analyses of eye movements revealed evidence for weak guidance of fixations in single-target search, and when searching for the preferred target in dual-target search. Overall, the experiments show dual-target search for faces is capacity- and guidance-limited, leading to superior search for 1 face over the other in dual-target search. However, learning faces individually may improve capacity with the second face. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  18. Group Targets Tracking Using Multiple Models GGIW-CPHD Based on Best-Fitting Gaussian Approximation and Strong Tracking Filter

    Directory of Open Access Journals (Sweden)

    Yun Wang

    2016-01-01

    Full Text Available Gamma Gaussian inverse Wishart cardinalized probability hypothesis density (GGIW-CPHD algorithm was always used to track group targets in the presence of cluttered measurements and missing detections. A multiple models GGIW-CPHD algorithm based on best-fitting Gaussian approximation method (BFG and strong tracking filter (STF is proposed aiming at the defect that the tracking error of GGIW-CPHD algorithm will increase when the group targets are maneuvering. The best-fitting Gaussian approximation method is proposed to implement the fusion of multiple models using the strong tracking filter to correct the predicted covariance matrix of the GGIW component. The corresponding likelihood functions are deduced to update the probability of multiple tracking models. From the simulation results we can see that the proposed tracking algorithm MM-GGIW-CPHD can effectively deal with the combination/spawning of groups and the tracking error of group targets in the maneuvering stage is decreased.

  19. Benznidazole biotransformation and multiple targets in Trypanosoma cruzi revealed by metabolomics.

    Directory of Open Access Journals (Sweden)

    Andrea Trochine

    2014-05-01

    Full Text Available The first line treatment for Chagas disease, a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi, involves administration of benznidazole (Bzn. Bzn is a 2-nitroimidazole pro-drug which requires nitroreduction to become active, although its mode of action is not fully understood. In the present work we used a non-targeted MS-based metabolomics approach to study the metabolic response of T. cruzi to Bzn.Parasites treated with Bzn were minimally altered compared to untreated trypanosomes, although the redox active thiols trypanothione, homotrypanothione and cysteine were significantly diminished in abundance post-treatment. In addition, multiple Bzn-derived metabolites were detected after treatment. These metabolites included reduction products, fragments and covalent adducts of reduced Bzn linked to each of the major low molecular weight thiols: trypanothione, glutathione, γ-glutamylcysteine, glutathionylspermidine, cysteine and ovothiol A. Bzn products known to be generated in vitro by the unusual trypanosomal nitroreductase, TcNTRI, were found within the parasites, but low molecular weight adducts of glyoxal, a proposed toxic end-product of NTRI Bzn metabolism, were not detected.Our data is indicative of a major role of the thiol binding capacity of Bzn reduction products in the mechanism of Bzn toxicity against T. cruzi.

  20. A low-complexity interacting multiple model filter for maneuvering target tracking

    KAUST Repository

    Khalid, Syed Safwan

    2017-01-22

    In this work, we address the target tracking problem for a coordinate-decoupled Markovian jump-mean-acceleration based maneuvering mobility model. A novel low-complexity alternative to the conventional interacting multiple model (IMM) filter is proposed for this class of mobility models. The proposed tracking algorithm utilizes a bank of interacting filters where the interactions are limited to the mixing of the mean estimates, and it exploits a fixed off-line computed Kalman gain matrix for the entire filter bank. Consequently, the proposed filter does not require matrix inversions during on-line operation which significantly reduces its complexity. Simulation results show that the performance of the low-complexity proposed scheme remains comparable to that of the traditional (highly-complex) IMM filter. Furthermore, we derive analytical expressions that iteratively evaluate the transient and steady-state performance of the proposed scheme, and establish the conditions that ensure the stability of the proposed filter. The analytical findings are in close accordance with the simulated results.

  1. GSK3-mediated MAF phosphorylation in multiple myeloma as a potential therapeutic target

    International Nuclear Information System (INIS)

    Herath, N I; Rocques, N; Garancher, A; Eychène, A; Pouponnot, C

    2014-01-01

    Multiple myeloma (MM) is an incurable haematological malignancy characterised by the proliferation of mature antibody-secreting plasma B cells in the bone marrow. MM can arise from initiating translocations, of which the musculoaponeurotic fibrosarcoma (MAF) family is implicated in ∼5%. MMs bearing Maf translocations are of poor prognosis. These translocations are associated with elevated Maf expression, including c-MAF, MAFB and MAFA, and with t(14;16) and t(14;20) translocations, involving c-MAF and MAFB, respectively. c-MAF is also overexpressed in MM through MEK/ERK activation, bringing the number of MMs driven by the deregulation of a Maf gene close to 50%. Here we demonstrate that MAFB and c-MAF are phosphorylated by the Ser/Thr kinase GSK3 in human MM cell lines. We show that LiCl-induced GSK3 inhibition targets these phosphorylations and specifically decreases proliferation and colony formation of Maf-expressing MM cell lines. Interestingly, bortezomib induced stabilisation of Maf phosphorylation, an observation that could explain, at least partially, the low efficacy of bortezomib for patients carrying Maf translocations. Thus, GSK3 inhibition could represent a new therapeutic approach for these patients

  2. A low-complexity interacting multiple model filter for maneuvering target tracking

    KAUST Repository

    Khalid, Syed Safwan; Abrar, Shafayat

    2017-01-01

    In this work, we address the target tracking problem for a coordinate-decoupled Markovian jump-mean-acceleration based maneuvering mobility model. A novel low-complexity alternative to the conventional interacting multiple model (IMM) filter is proposed for this class of mobility models. The proposed tracking algorithm utilizes a bank of interacting filters where the interactions are limited to the mixing of the mean estimates, and it exploits a fixed off-line computed Kalman gain matrix for the entire filter bank. Consequently, the proposed filter does not require matrix inversions during on-line operation which significantly reduces its complexity. Simulation results show that the performance of the low-complexity proposed scheme remains comparable to that of the traditional (highly-complex) IMM filter. Furthermore, we derive analytical expressions that iteratively evaluate the transient and steady-state performance of the proposed scheme, and establish the conditions that ensure the stability of the proposed filter. The analytical findings are in close accordance with the simulated results.

  3. Visualizing multiple inter-organelle contact sites using the organelle-targeted split-GFP system.

    Science.gov (United States)

    Kakimoto, Yuriko; Tashiro, Shinya; Kojima, Rieko; Morozumi, Yuki; Endo, Toshiya; Tamura, Yasushi

    2018-04-18

    Functional integrity of eukaryotic organelles relies on direct physical contacts between distinct organelles. However, the entity of organelle-tethering factors is not well understood due to lack of means to analyze inter-organelle interactions in living cells. Here we evaluate the split-GFP system for visualizing organelle contact sites in vivo and show its advantages and disadvantages. We observed punctate GFP signals from the split-GFP fragments targeted to any pairs of organelles among the ER, mitochondria, peroxisomes, vacuole and lipid droplets in yeast cells, which suggests that these organelles form contact sites with multiple organelles simultaneously although it is difficult to rule out the possibilities that these organelle contacts sites are artificially formed by the irreversible associations of the split-GFP probes. Importantly, split-GFP signals in the overlapped regions of the ER and mitochondria were mainly co-localized with ERMES, an authentic ER-mitochondria tethering structure, suggesting that split-GFP assembly depends on the preexisting inter-organelle contact sites. We also confirmed that the split-GFP system can be applied to detection of the ER-mitochondria contact sites in HeLa cells. We thus propose that the split-GFP system is a potential tool to observe and analyze inter-organelle contact sites in living yeast and mammalian cells.

  4. An individual differences approach to multiple-target visual search errors: How search errors relate to different characteristics of attention.

    Science.gov (United States)

    Adamo, Stephen H; Cain, Matthew S; Mitroff, Stephen R

    2017-12-01

    A persistent problem in visual search is that searchers are more likely to miss a target if they have already found another in the same display. This phenomenon, the Subsequent Search Miss (SSM) effect, has remained despite being a known issue for decades. Increasingly, evidence supports a resource depletion account of SSM errors-a previously detected target consumes attentional resources leaving fewer resources available for the processing of a second target. However, "attention" is broadly defined and is composed of many different characteristics, leaving considerable uncertainty about how attention affects second-target detection. The goal of the current study was to identify which attentional characteristics (i.e., selection, limited capacity, modulation, and vigilance) related to second-target misses. The current study compared second-target misses to an attentional blink task and a vigilance task, which both have established measures that were used to operationally define each of four attentional characteristics. Second-target misses in the multiple-target search were correlated with (1) a measure of the time it took for the second target to recovery from the blink in the attentional blink task (i.e., modulation), and (2) target sensitivity (d') in the vigilance task (i.e., vigilance). Participants with longer recovery and poorer vigilance had more second-target misses in the multiple-target visual search task. The results add further support to a resource depletion account of SSM errors and highlight that worse modulation and poor vigilance reflect a deficit in attentional resources that can account for SSM errors. Copyright © 2016 Elsevier Ltd. All rights reserved.

  5. Targeting a heterologous protein to multiple plant organelles via rationally designed 5? mRNA tags

    NARCIS (Netherlands)

    Voges, M.J.; Silver, P.A.; Way, J.C.; Mattozzi, M.D.

    2013-01-01

    Background Plant bioengineers require simple genetic devices for predictable localization of heterologous proteins to multiple subcellular compartments. Results We designed novel hybrid signal sequences for multiple-compartment localization and characterize their function when fused to GFP in

  6. Time-resolved x-ray line emission studies of thermal transport in multiple beam uv-irradiated targets

    International Nuclear Information System (INIS)

    Jaanimagi, P.A.; Henke, B.L.; Delettrez, J.; Richardson, M.C.

    1984-01-01

    Thermal transport in spherical targets irradiated with multiple, nanosecond duration laser beams, has been a topic of much discussion recently. Different inferences on the level of thermal flux inhibition have been drawn from plasma velocity and x-ray spectroscopic diagnostics. We present new measurements of thermal transport on spherical targets made through time-resolved x-ray spectroscopic measurements of the progress of the ablation surface through thin layers of material on the surface of the target. These measurements, made with 6 and 12 uv (351 nm) nanosecond beams from OMEGA, will be compared to previous thermal transport measurements. Transparencies of the conference presentation are given

  7. Sphingosine 1-Phosphate Receptor 1 as a Useful Target for Treatment of Multiple Sclerosis

    Directory of Open Access Journals (Sweden)

    Kunitomo Adachi

    2012-05-01

    Full Text Available Sphingosine 1-phosphate (S1P, a lysophospholipid mediator, is generated from sphingosine by sphingosine kinases and binds five known cell surface receptors. S1P receptor 1 (S1P1 plays an essential role in lymphocyte egress from secondary lymphoid organs (SLO, as evinced by the inability of lymphocytes to exit from the SLO in mice lacking lymphocytic S1P1. Fingolimod hydrochloride (FTY720 is a first-in-class, orally active, S1P receptor modulator with a structure closely related to sphingosine. FTY720 was first synthesized by chemical modification of a natural product, myriocin. FTY720 is effectively converted to an active metabolite, FTY720 phosphate (FTY720-P by sphingosine kinases. FTY720-P shows high affinity to 4 of the S1P receptors (S1P1, S1P3, S1P4, and S1P5. In particular, FTY720-P strongly induces internalization and degradation of S1P1, inhibits S1P responsiveness of lymphocytes in the SLO, and acts as a functional antagonist at lymphocytic S1P1. Consequently, FTY720 inhibits S1P1-dependent lymphocyte egress from the SLO to decrease circulation of lymphocytes including autoreactive Th17 cells and is highly effective in experimental autoimmune encephalomyelitis (EAE, an animal model of multiple sclerosis (MS. Because FTY720 shows a superior efficacy in relapsing remitting MS patients compared to intramuscular interferon-β-1a (Avonex®, S1P1 is presumed to be a useful target for the therapy of MS.

  8. Aspirin acetylates multiple cellular proteins in HCT-116 colon cancer cells: Identification of novel targets.

    Science.gov (United States)

    Marimuthu, Srinivasan; Chivukula, Raghavender S V; Alfonso, Lloyd F; Moridani, Majid; Hagen, Fred K; Bhat, G Jayarama

    2011-11-01

    Epidemiological and clinical observations provide consistent evidence that regular intake of aspirin may effectively inhibit the occurrence of epithelial tumors; however, the molecular mechanisms are not completely understood. In the present study, we determined the ability of aspirin to acetylate and post-translationally modify cellular proteins in HCT-116 human colon cancer cells to understand the potential mechanisms by which it may exerts anti-cancer effects. Using anti-acetyl lysine antibodies, here we demonstrate that aspirin causes the acetylation of multiple proteins whose molecular weight ranged from 20 to 200 kDa. The identity of these proteins was determined, using immuno-affinity purification, mass spectrometry and immuno-blotting. A total of 33 cellular proteins were potential targets of aspirin-mediated acetylation, while 16 were identified as common to both the control and aspirin-treated samples. These include enzymes of glycolytic pathway, cytoskeleton proteins, histones, ribosomal and mitochondrial proteins. The glycolytic enzymes which were identified include aldolase, glyceraldehyde-3-phosphate dehydrogenase, enolase, pyruvate kinase M2, and lactate dehydrogenase A and B chains. Immunoblotting experiment showed that aspirin also acetylated glucose-6-phosphate dehydrogenase and transketolase, both enzymes of pentose phosphate pathway involved in ribonucleotide biosynthesis. In vitro assays of these enzymes revealed that aspirin did not affect pyruvate kinase and lactate dehydrogenase activity; however, it decreased glucose 6 phosphate dehydrogenase activity. Similar results were also observed in HT-29 human colon cancer cells. Selective inhibition of glucose-6-phosphate dehydrogenase may represent an important mechanism by which aspirin may exert its anti-cancer effects through inhibition of ribonucleotide synthesis.

  9. Assisting People with Multiple Disabilities by Improving Their Computer Pointing Efficiency with an Automatic Target Acquisition Program

    Science.gov (United States)

    Shih, Ching-Hsiang; Shih, Ching-Tien; Peng, Chin-Ling

    2011-01-01

    This study evaluated whether two people with multiple disabilities would be able to improve their pointing performance through an Automatic Target Acquisition Program (ATAP) and a newly developed mouse driver (i.e. a new mouse driver replaces standard mouse driver, and is able to monitor mouse movement and intercept click action). Initially, both…

  10. Estimating Single and Multiple Target Locations Using K-Means Clustering with Radio Tomographic Imaging in Wireless Sensor Networks

    Science.gov (United States)

    2015-03-26

    clustering is an algorithm that has been used in data mining applications such as machine learning applications , pattern recognition, hyper-spectral imagery...42 3.7.2 Application of K-means Clustering . . . . . . . . . . . . . . . . . 42 3.8 Experiment Design...Tomographic Imaging WLAN Wireless Local Area Networks WSN Wireless Sensor Network xx ESTIMATING SINGLE AND MULTIPLE TARGET LOCATIONS USING K-MEANS CLUSTERING

  11. Treatment planning with intensity modulated particle therapy for multiple targets in stage IV non-small cell lung cancer

    Science.gov (United States)

    Anderle, Kristjan; Stroom, Joep; Vieira, Sandra; Pimentel, Nuno; Greco, Carlo; Durante, Marco; Graeff, Christian

    2018-01-01

    Intensity modulated particle therapy (IMPT) can produce highly conformal plans, but is limited in advanced lung cancer patients with multiple lesions due to motion and planning complexity. A 4D IMPT optimization including all motion states was expanded to include multiple targets, where each target (isocenter) is designated to specific field(s). Furthermore, to achieve stereotactic treatment planning objectives, target and OAR weights plus objective doses were automatically iteratively adapted. Finally, 4D doses were calculated for different motion scenarios. The results from our algorithm were compared to clinical stereotactic body radiation treatment (SBRT) plans. The study included eight patients with 24 lesions in total. Intended dose regimen for SBRT was 24 Gy in one fraction, but lower fractionated doses had to be delivered in three cases due to OAR constraints or failed plan quality assurance. The resulting IMPT treatment plans had no significant difference in target coverage compared to SBRT treatment plans. Average maximum point dose and dose to specific volume in OARs were on average 65% and 22% smaller with IMPT. IMPT could also deliver 24 Gy in one fraction in a patient where SBRT was limited due to the OAR vicinity. The developed algorithm shows the potential of IMPT in treatment of multiple moving targets in a complex geometry.

  12. Bi-objective optimization of a multiple-target active debris removal mission

    Science.gov (United States)

    Bérend, Nicolas; Olive, Xavier

    2016-05-01

    The increasing number of space debris in Low-Earth Orbit (LEO) raises the question of future Active Debris Removal (ADR) operations. Typical ADR scenarios rely on an Orbital Transfer Vehicle (OTV) using one of the two following disposal strategies: the first one consists in attaching a deorbiting kit, such as a solid rocket booster, to the debris after rendezvous; with the second one, the OTV captures the debris and moves it to a low-perigee disposal orbit. For multiple-target ADR scenarios, the design of such a mission is very complex, as it involves two optimization levels: one for the space debris sequence, and a second one for the "elementary" orbit transfer strategy from a released debris to the next one in the sequence. This problem can be seen as a Time-Dependant Traveling Salesman Problem (TDTSP) with two objective functions to minimize: the total mission duration and the total propellant consumption. In order to efficiently solve this problem, ONERA has designed, under CNES contract, TOPAS (Tool for Optimal Planning of ADR Sequence), a tool that implements a Branch & Bound method developed in previous work together with a dedicated algorithm for optimizing the "elementary" orbit transfer. A single run of this tool yields an estimation of the Pareto front of the problem, which exhibits the trade-off between mission duration and propellant consumption. We first detail our solution to cope with the combinatorial explosion of complex ADR scenarios with 10 debris. The key point of this approach is to define the orbit transfer strategy through a small set of parameters, allowing an acceptable compromise between the quality of the optimum solution and the calculation cost. Then we present optimization results obtained for various 10 debris removal scenarios involving a 15-ton OTV, using either the deorbiting kit or the disposal orbit strategy. We show that the advantage of one strategy upon the other depends on the propellant margin, the maximum duration allowed

  13. Addressing the targeting range of the ABILHAND-56 in relapsing-remitting multiple sclerosis: A mixed methods psychometric study.

    Science.gov (United States)

    Cleanthous, Sophie; Strzok, Sara; Pompilus, Farrah; Cano, Stefan; Marquis, Patrick; Cohan, Stanley; Goldman, Myla D; Kresa-Reahl, Kiren; Petrillo, Jennifer; Castrillo-Viguera, Carmen; Cadavid, Diego; Chen, Shih-Yin

    2018-01-01

    ABILHAND, a manual ability patient-reported outcome instrument originally developed for stroke patients, has been used in multiple sclerosis clinical trials; however, psychometric analyses indicated the measure's limited measurement range and precision in higher-functioning multiple sclerosis patients. The purpose of this study was to identify candidate items to expand the measurement range of the ABILHAND-56, thus improving its ability to detect differences in manual ability in higher-functioning multiple sclerosis patients. A step-wise mixed methods design strategy was used, comprising two waves of patient interviews, a combination of qualitative (concept elicitation and cognitive debriefing) and quantitative (Rasch measurement theory) analytic techniques, and consultation interviews with three clinical neurologists specializing in multiple sclerosis. Original ABILHAND was well understood in this context of use. Eighty-two new manual ability concepts were identified. Draft supplementary items were generated and refined with patient and neurologist input. Rasch measurement theory psychometric analysis indicated supplementary items improved targeting to higher-functioning multiple sclerosis patients and measurement precision. The final pool of Early Multiple Sclerosis Manual Ability items comprises 20 items. The synthesis of qualitative and quantitative methods used in this study improves the ABILHAND content validity to more effectively identify manual ability changes in early multiple sclerosis and potentially help determine treatment effect in higher-functioning patients in clinical trials.

  14. Effective source of bremsstrahlung with multiple crossing of a thin target by an electron beam

    International Nuclear Information System (INIS)

    Grishin, V.K.; Ishkhanov, B.S.; Shvedunov, V.I.

    1996-01-01

    A basically new scheme of electron beam discharge to the target for x ray and gamma radiation generation is proposed. In this case an accelerated electron beam crosses a thin braking target many times, which substantially increases the integral radiation yield. 3 refs.; 2 figs

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

    Science.gov (United States)

    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).

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

    Directory of Open Access Journals (Sweden)

    Hua Liu

    2017-06-01

    Full Text Available 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.

  17. Detection and Identification of Multiple Stationary Human Targets Via Bio-Radar Based on the Cross-Correlation Method

    Directory of Open Access Journals (Sweden)

    Yang Zhang

    2016-10-01

    Full Text Available Ultra-wideband (UWB radar has been widely used for detecting human physiological signals (respiration, movement, etc. in the fields of rescue, security, and medicine owing to its high penetrability and range resolution. In these applications, especially in rescue after disaster (earthquake, collapse, mine accident, etc., the presence, number, and location of the trapped victims to be detected and rescued are the key issues of concern. Ample research has been done on the first issue, whereas the identification and localization of multi-targets remains a challenge. False positive and negative identification results are two common problems associated with the detection of multiple stationary human targets. This is mainly because the energy of the signal reflected from the target close to the receiving antenna is considerably stronger than those of the targets at further range, often leading to missing or false recognition if the identification method is based on the energy of the respiratory signal. Therefore, a novel method based on cross-correlation is proposed in this paper that is based on the relativity and periodicity of the signals, rather than on the energy. The validity of this method is confirmed through experiments using different scenarios; the results indicate a discernible improvement in the detection precision and identification of the multiple stationary targets.

  18. Detection and Identification of Multiple Stationary Human Targets Via Bio-Radar Based on the Cross-Correlation Method.

    Science.gov (United States)

    Zhang, Yang; Chen, Fuming; Xue, Huijun; Li, Zhao; An, Qiang; Wang, Jianqi; Zhang, Yang

    2016-10-27

    Ultra-wideband (UWB) radar has been widely used for detecting human physiological signals (respiration, movement, etc.) in the fields of rescue, security, and medicine owing to its high penetrability and range resolution. In these applications, especially in rescue after disaster (earthquake, collapse, mine accident, etc.), the presence, number, and location of the trapped victims to be detected and rescued are the key issues of concern. Ample research has been done on the first issue, whereas the identification and localization of multi-targets remains a challenge. False positive and negative identification results are two common problems associated with the detection of multiple stationary human targets. This is mainly because the energy of the signal reflected from the target close to the receiving antenna is considerably stronger than those of the targets at further range, often leading to missing or false recognition if the identification method is based on the energy of the respiratory signal. Therefore, a novel method based on cross-correlation is proposed in this paper that is based on the relativity and periodicity of the signals, rather than on the energy. The validity of this method is confirmed through experiments using different scenarios; the results indicate a discernible improvement in the detection precision and identification of the multiple stationary targets.

  19. Distributed Cooperative Search Control Method of Multiple UAVs for Moving Target

    Directory of Open Access Journals (Sweden)

    Chang-jian Ru

    2015-01-01

    Full Text Available To reduce the impact of uncertainties caused by unknown motion parameters on searching plan of moving targets and improve the efficiency of UAV’s searching, a novel distributed Multi-UAVs cooperative search control method for moving target is proposed in this paper. Based on detection results of onboard sensors, target probability map is updated using Bayesian theory. A Gaussian distribution of target transition probability density function is introduced to calculate prediction probability of moving target existence, and then target probability map can be further updated in real-time. A performance index function combining with target cost, environment cost, and cooperative cost is constructed, and the cooperative searching problem can be transformed into a central optimization problem. To improve computational efficiency, the distributed model predictive control method is presented, and thus the control command of each UAV can be obtained. The simulation results have verified that the proposed method can avoid the blindness of UAV searching better and improve overall efficiency of the team effectively.

  20. Single-Isocenter Multiple-Target Stereotactic Radiosurgery: Risk of Compromised Coverage

    International Nuclear Information System (INIS)

    Roper, Justin; Chanyavanich, Vorakarn; Betzel, Gregory; Switchenko, Jeffrey; Dhabaan, Anees

    2015-01-01

    Purpose: To determine the dosimetric effects of rotational errors on target coverage using volumetric modulated arc therapy (VMAT) for multitarget stereotactic radiosurgery (SRS). Methods and Materials: This retrospective study included 50 SRS cases, each with 2 intracranial planning target volumes (PTVs). Both PTVs were planned for simultaneous treatment to 21 Gy using a single-isocenter, noncoplanar VMAT SRS technique. Rotational errors of 0.5°, 1.0°, and 2.0° were simulated about all axes. The dose to 95% of the PTV (D95) and the volume covered by 95% of the prescribed dose (V95) were evaluated using multivariate analysis to determine how PTV coverage was related to PTV volume, PTV separation, and rotational error. Results: At 0.5° rotational error, D95 values and V95 coverage rates were ≥95% in all cases. For rotational errors of 1.0°, 7% of targets had D95 and V95 values 95% for only 63% of the targets. Multivariate analysis showed that PTV volume and distance to isocenter were strong predictors of target coverage. Conclusions: The effects of rotational errors on target coverage were studied across a broad range of SRS cases. In general, the risk of compromised coverage increased with decreasing target volume, increasing rotational error and increasing distance between targets. Multivariate regression models from this study may be used to quantify the dosimetric effects of rotational errors on target coverage given patient-specific input parameters of PTV volume and distance to isocenter.

  1. Less is more : The effect of multiple implementation intentions targeting unhealthy snacking habits

    NARCIS (Netherlands)

    Verhoeven, A.A.C.; Adriaanse, M.A.; de Ridder, D.T.D.; de Vet, E.; Fennis, B.M.

    Implementation intentions have been shown to effectively change counter-intentional habits. Research has, however, almost solely been concerned with the effectiveness of a single plan. In the present research, we investigated the behavioral and cognitive implications of making multiple

  2. Less is more: The effect of multiple implementation intentions targeting unhealthy snacking habits

    NARCIS (Netherlands)

    Verhoeven, A.A.C.; Adriaanse, M.A.; Ridder, de D.T.D.; Vet, de E.W.M.L.; Fennis, B.M.

    2013-01-01

    Implementation intentions have been shown to effectively change counter-intentional habits. Research has, however, almost solely been concerned with the effectiveness of a single plan. In the present research, we investigated the behavioral and cognitive implications of making multiple

  3. Detection and localization of multiple short range targets using FMCW radar signal

    KAUST Repository

    Jardak, Seifallah; Kiuru, Tero; Metso, Mikko; Pursula, Pekka; Hakli, Janne; Hirvonen, Mervi; Ahmed, Sajid; Alouini, Mohamed-Slim

    2016-01-01

    In this paper, a 24 GHz frequency-modulated continuous wave radar is used to detect and localize both stationary and moving targets. Depending on the application, the implemented software offers different modes of operation. For example, it can

  4. Fine tuning of RFX/DAF-19-regulated target gene expression through binding to multiple sites in Caenorhabditis elegans

    OpenAIRE

    Chu, Jeffery S. C.; Tarailo-Graovac, Maja; Zhang, Di; Wang, Jun; Uyar, Bora; Tu, Domena; Trinh, Joanne; Baillie, David L.; Chen, Nansheng

    2011-01-01

    In humans, mutations of a growing list of regulatory factor X (RFX) target genes have been associated with devastating genetics disease conditions including ciliopathies. However, mechanisms underlying RFX transcription factors (TFs)-mediated gene expression regulation, especially differential gene expression regulation, are largely unknown. In this study, we explore the functional significance of the co-existence of multiple X-box motifs in regulating differential gene expression in Caenorha...

  5. Energy, target, projectile and multiplicity dependences of intermittency behaviour in high energy O(Si,S) induced interactions

    International Nuclear Information System (INIS)

    Adamovich, M.I.; Alexandrov, Y.A.; Chernyavski, M.M.; Gerassimov, S.G.; Kharlamov, S.P.; Larionova, V.G.; Maslennikova, N.V.; Orlova, G.I.; Peresadko, N.G.; Salmanova, N.A.; Tretyakova, M.I.; Ameeva, Z.U.; Andreeva, N.P.; Anzon, Z.V.; Bubnov, V.I.; Chasnikov, I.Y.; Eligbaeva, G.Z.; Eremenko, G.Z.; Gaitinov, A.S.; Kalyachkina, G.S.; Kanygina, E.K.; Skakhova, C.I.; Bhalla, K.B.; Kumar, V.; Lal, P.; Lokanathan, S.; Mookerjee, S.; Raniwala, R.; Raniwala, S.; Burnett, T.H.; Grote, J.; Koss, T.; Lord, J.; Skelding, D.; Strausz, S.C.; Wilkes, R.J.; Cai, X.; Huang, H.; Liu, L.S.; Qian, W.Y.; Wang, H.Q.; Zhou, D.C.; Zhou, J.C.; Chernova, L.P.; Gadzhieva, S.I.; Gulamov, K.G.; Kadyrov, F.G.; Lukicheva, N.S.; Navotny, V.S.; Svechnikova, L.N.; Friedlander, E.M.; Heckman, H.H.; Lindstrom, P.J.; Garpman, S.; Jakobsson, B.; Otterlund, I.; Persson, S.; Soederstroem, K.; Stenlund, E.; Judek, B.; Nasyrov, S.H.; Petrov, N.V.; Xu, G.F.; Zheng, P.Y.

    1991-01-01

    Fluctuations of charged particles in high energy oxygen, silicon and sulphur induced interactions are investigated with the method of scaled factorial moments. It is found that for decreasing bin size down to δη∝0.1 the EMU01 data exhibits intermittent behaviour. The intermittency indexes are found to decrease with increasing incident energy and multiplicity and to increase with increasing target mass. It seems also to increase as the projectile mass increases. (orig.)

  6. Foraging through multiple target categories reveals the flexibility of visual working memory.

    Science.gov (United States)

    Kristjánsson, Tómas; Kristjánsson, Árni

    2018-02-01

    A key assumption in the literature on visual attention is that templates, actively maintained in visual working memory (VWM), guide visual attention. An important question therefore involves the nature and capacity of VWM. According to load theories, more than one search template can be active at the same time and capacity is determined by the total load rather than a precise number of templates. By an alternative account only one search template can be active within visual working memory at any given time, while other templates are in an accessory state - but do not affect visual selection. We addressed this question by varying the number of targets and distractors in a visual foraging task for 40 targets among 40 distractors in two ways: 1) Fixed-distractor-number, involving two distractor types while target categories varied from one to four. 2) Fixed-color-number (7), so that if the target types were two, distractors types were five, while if target number increased to three, distractor types were four (etc.). The two accounts make differing predictions. Under the single-template account, we should expect large switch costs as target types increase to two, but switch-costs should not increase much as target types increase beyond two. Load accounts predict an approximately linear increase in switch costs with increased target type number. The results were that switch costs increased roughly linearly in both conditions, in line with load accounts. The results are discussed in light of recent proposals that working memory reflects lingering neural activity at various sites that operate on the stimuli in each case and findings showing neurally silent working memory representations. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. A multicolor panel of TALE-KRAB based transcriptional repressor vectors enabling knockdown of multiple gene targets.

    Science.gov (United States)

    Zhang, Zhonghui; Wu, Elise; Qian, Zhijian; Wu, Wen-Shu

    2014-12-05

    Stable and efficient knockdown of multiple gene targets is highly desirable for dissection of molecular pathways. Because it allows sequence-specific DNA binding, transcription activator-like effector (TALE) offers a new genetic perturbation technique that allows for gene-specific repression. Here, we constructed a multicolor lentiviral TALE-Kruppel-associated box (KRAB) expression vector platform that enables knockdown of multiple gene targets. This platform is fully compatible with the Golden Gate TALEN and TAL Effector Kit 2.0, a widely used and efficient method for TALE assembly. We showed that this multicolor TALE-KRAB vector system when combined together with bone marrow transplantation could quickly knock down c-kit and PU.1 genes in hematopoietic stem and progenitor cells of recipient mice. Furthermore, our data demonstrated that this platform simultaneously knocked down both c-Kit and PU.1 genes in the same primary cell populations. Together, our results suggest that this multicolor TALE-KRAB vector platform is a promising and versatile tool for knockdown of multiple gene targets and could greatly facilitate dissection of molecular pathways.

  8. The Calibration Target for the Mars 2020 SHERLOC Instrument: Multiple Science Roles for Future Manned and Unmanned Mars Exploration

    Science.gov (United States)

    Fries, M.; Bhartia, R.; Beegle, L.; Burton, A.; Ross, A.; Shahar, A.

    2014-01-01

    The Scanning Habitable Environments with Raman & Luminescence for Organics & Chemicals (SHERLOC) instrument is a deep ultraviolet (UV) Raman/fluorescence instrument selected as part of the Mars 2020 rover instrument suite. SHERLOC will be mounted on the rover arm and its primary role is to identify carbonaceous species in martian samples, which may be selected for inclusion into a returnable sample cache. The SHERLOC instrument will require the use of a calibration target, and by design, multiple science roles will be addressed in the design of the target. Samples of materials used in NASA Extravehicular Mobility unit (EMU, or "space suit") manufacture have been included in the target to serve as both solid polymer calibration targets for SHERLOC instrument function, as well as for testing the resiliency of those materials under martian ambient conditions. A martian meteorite will also be included in the target to serve as a well-characterized example of a martian rock that contains trace carbonaceous material. This rock will be the first rock that we know of that has completed a round trip between planets and will therefore serve an EPO role to attract public attention to science and planetary exploration. The SHERLOC calibration target will address a wide range of NASA goals to include basic science of interest to both the Science Mission Directorate (SMD) and Human Exploration and Operations Mission Directorate (HEOMD).

  9. SAR image dataset of military ground targets with multiple poses for ATR

    Science.gov (United States)

    Belloni, Carole; Balleri, Alessio; Aouf, Nabil; Merlet, Thomas; Le Caillec, Jean-Marc

    2017-10-01

    Automatic Target Recognition (ATR) is the task of automatically detecting and classifying targets. Recognition using Synthetic Aperture Radar (SAR) images is interesting because SAR images can be acquired at night and under any weather conditions, whereas optical sensors operating in the visible band do not have this capability. Existing SAR ATR algorithms have mostly been evaluated using the MSTAR dataset.1 The problem with the MSTAR is that some of the proposed ATR methods have shown good classification performance even when targets were hidden,2 suggesting the presence of a bias in the dataset. Evaluations of SAR ATR techniques are currently challenging due to the lack of publicly available data in the SAR domain. In this paper, we present a high resolution SAR dataset consisting of images of a set of ground military target models taken at various aspect angles, The dataset can be used for a fair evaluation and comparison of SAR ATR algorithms. We applied the Inverse Synthetic Aperture Radar (ISAR) technique to echoes from targets rotating on a turntable and illuminated with a stepped frequency waveform. The targets in the database consist of four variants of two 1.7m-long models of T-64 and T-72 tanks. The gun, the turret position and the depression angle are varied to form 26 different sequences of images. The emitted signal spanned the frequency range from 13 GHz to 18 GHz to achieve a bandwidth of 5 GHz sampled with 4001 frequency points. The resolution obtained with respect to the size of the model targets is comparable to typical values obtained using SAR airborne systems. Single polarized images (Horizontal-Horizontal) are generated using the backprojection algorithm.3 A total of 1480 images are produced using a 20° integration angle. The images in the dataset are organized in a suggested training and testing set to facilitate a standard evaluation of SAR ATR algorithms.

  10. miR-137 inhibits the invasion of melanoma cells through downregulation of multiple oncogenic target genes.

    Science.gov (United States)

    Luo, Chonglin; Tetteh, Paul W; Merz, Patrick R; Dickes, Elke; Abukiwan, Alia; Hotz-Wagenblatt, Agnes; Holland-Cunz, Stefan; Sinnberg, Tobias; Schittek, Birgit; Schadendorf, Dirk; Diederichs, Sven; Eichmüller, Stefan B

    2013-03-01

    MicroRNAs are small noncoding RNAs that regulate gene expression and have important roles in various types of cancer. Previously, miR-137 was reported to act as a tumor suppressor in different cancers, including malignant melanoma. In this study, we show that low miR-137 expression is correlated with poor survival in stage IV melanoma patients. We identified and validated two genes (c-Met and YB1) as direct targets of miR-137 and confirmed two previously known targets, namely enhancer of zeste homolog 2 (EZH2) and microphthalmia-associated transcription factor (MITF). Functional studies showed that miR-137 suppressed melanoma cell invasion through the downregulation of multiple target genes. The decreased invasion caused by miR-137 overexpression could be phenocopied by small interfering RNA knockdown of EZH2, c-Met, or Y box-binding protein 1 (YB1). Furthermore, miR-137 inhibited melanoma cell migration and proliferation. Finally, miR-137 induced apoptosis in melanoma cell lines and decreased BCL2 levels. In summary, our study confirms that miR-137 acts as a tumor suppressor in malignant melanoma and reveals that miR-137 regulates multiple targets including c-Met, YB1, EZH2, and MITF.

  11. DOA Estimation of Low Altitude Target Based on Adaptive Step Glowworm Swarm Optimization-multiple Signal Classification Algorithm

    Directory of Open Access Journals (Sweden)

    Zhou Hao

    2015-06-01

    Full Text Available The traditional MUltiple SIgnal Classification (MUSIC algorithm requires significant computational effort and can not be employed for the Direction Of Arrival (DOA estimation of targets in a low-altitude multipath environment. As such, a novel MUSIC approach is proposed on the basis of the algorithm of Adaptive Step Glowworm Swarm Optimization (ASGSO. The virtual spatial smoothing of the matrix formed by each snapshot is used to realize the decorrelation of the multipath signal and the establishment of a fullorder correlation matrix. ASGSO optimizes the function and estimates the elevation of the target. The simulation results suggest that the proposed method can overcome the low altitude multipath effect and estimate the DOA of target readily and precisely without radar effective aperture loss.

  12. A bio-inspired swarm robot coordination algorithm for multiple target searching

    Science.gov (United States)

    Meng, Yan; Gan, Jing; Desai, Sachi

    2008-04-01

    The coordination of a multi-robot system searching for multi targets is challenging under dynamic environment since the multi-robot system demands group coherence (agents need to have the incentive to work together faithfully) and group competence (agents need to know how to work together well). In our previous proposed bio-inspired coordination method, Local Interaction through Virtual Stigmergy (LIVS), one problem is the considerable randomness of the robot movement during coordination, which may lead to more power consumption and longer searching time. To address these issues, an adaptive LIVS (ALIVS) method is proposed in this paper, which not only considers the travel cost and target weight, but also predicting the target/robot ratio and potential robot redundancy with respect to the detected targets. Furthermore, a dynamic weight adjustment is also applied to improve the searching performance. This new method a truly distributed method where each robot makes its own decision based on its local sensing information and the information from its neighbors. Basically, each robot only communicates with its neighbors through a virtual stigmergy mechanism and makes its local movement decision based on a Particle Swarm Optimization (PSO) algorithm. The proposed ALIVS algorithm has been implemented on the embodied robot simulator, Player/Stage, in a searching target. The simulation results demonstrate the efficiency and robustness in a power-efficient manner with the real-world constraints.

  13. Damage to preheated tungsten targets after multiple plasma impacts simulating ITER ELMs

    Energy Technology Data Exchange (ETDEWEB)

    Garkusha, I.E. [Institute of Plasma Physics of the NSC KIPT, Akademicheskaya 1, 61108 Kharkov (Ukraine)], E-mail: garkusha@ipp.kharkov.ua; Bandura, A.N.; Byrka, O.V.; Chebotarev, V.V. [Institute of Plasma Physics of the NSC KIPT, Akademicheskaya 1, 61108 Kharkov (Ukraine); Landman, I. [Forschungszentrum Karlsruhe, IHM, 76021 Karlsruhe (Germany); Makhlaj, V.A. [Institute of Plasma Physics of the NSC KIPT, Akademicheskaya 1, 61108 Kharkov (Ukraine); Pestchanyi, S. [Forschungszentrum Karlsruhe, IHM, 76021 Karlsruhe (Germany); Tereshin, V.I. [Institute of Plasma Physics of the NSC KIPT, Akademicheskaya 1, 61108 Kharkov (Ukraine)

    2009-04-30

    The behavior of a preheated at 650 deg. C tungsten targets under repetitive ELM-like plasma pulses is studied in simulation experiments with the quasi-stationary plasma accelerator QSPA Kh-50. The targets have been exposed up to 350 pulses of the duration 0.25 ms and the surface heat loads either 0.45 MJ/m{sup 2} or 0.75 MJ/m{sup 2}, which is below and above the melting threshold, respectively. The development of surface morphology of the exposed targets as well as cracking and swelling at the surface is discussed. First comparisons of obtained experimental results with corresponding numerical simulations of the code PEGASUS-3D are presented.

  14. Assessing Multiple Pathways for Achieving China’s National Emissions Reduction Target

    Directory of Open Access Journals (Sweden)

    Mingyue Wang

    2018-06-01

    Full Text Available In order to achieve China’s target of carbon intensity emissions reduction in 2030, there is a need to identify a scientific pathway and feasible strategies. In this study, we used stochastic frontier analysis method of energy efficiency, incorporating energy structure, economic structure, human capital, capital stock and potential energy efficiency to identify an efficient pathway for achieving emissions reduction target. We set up 96 scenarios including single factor scenarios and multi-factors combination scenarios for the simulation. The effects of each scenario on achieving the carbon intensity reduction target are then evaluated. It is found that: (1 Potential energy efficiency has the greatest contribution to the carbon intensity emissions reduction target; (2 they are unlikely to reach the 2030 carbon intensity reduction target of 60% by only optimizing a single factor; (3 in order to achieve the 2030 target, several aspects have to be adjusted: the fossil fuel ratio must be lower than 80%, and its average growth rate must be decreased by 2.2%; the service sector ratio in GDP must be higher than 58.3%, while the growth rate of non-service sectors must be lowered by 2.4%; and both human capital and capital stock must achieve and maintain a stable growth rate and a 1% increase annually in energy efficiency. Finally, the specific recommendations of this research were discussed, including constantly improved energy efficiency; the upgrading of China’s industrial structure must be accelerated; emissions reduction must be done at the root of energy sources; multi-level input mechanisms in overall levels of education and training to cultivate the human capital stock must be established; investment in emerging equipment and accelerate the closure of backward production capacity to accumulate capital stock.

  15. Multivariate linear regression of high-dimensional fMRI data with multiple target variables.

    Science.gov (United States)

    Valente, Giancarlo; Castellanos, Agustin Lage; Vanacore, Gianluca; Formisano, Elia

    2014-05-01

    Multivariate regression is increasingly used to study the relation between fMRI spatial activation patterns and experimental stimuli or behavioral ratings. With linear models, informative brain locations are identified by mapping the model coefficients. This is a central aspect in neuroimaging, as it provides the sought-after link between the activity of neuronal populations and subject's perception, cognition or behavior. Here, we show that mapping of informative brain locations using multivariate linear regression (MLR) may lead to incorrect conclusions and interpretations. MLR algorithms for high dimensional data are designed to deal with targets (stimuli or behavioral ratings, in fMRI) separately, and the predictive map of a model integrates information deriving from both neural activity patterns and experimental design. Not accounting explicitly for the presence of other targets whose associated activity spatially overlaps with the one of interest may lead to predictive maps of troublesome interpretation. We propose a new model that can correctly identify the spatial patterns associated with a target while achieving good generalization. For each target, the training is based on an augmented dataset, which includes all remaining targets. The estimation on such datasets produces both maps and interaction coefficients, which are then used to generalize. The proposed formulation is independent of the regression algorithm employed. We validate this model on simulated fMRI data and on a publicly available dataset. Results indicate that our method achieves high spatial sensitivity and good generalization and that it helps disentangle specific neural effects from interaction with predictive maps associated with other targets. Copyright © 2013 Wiley Periodicals, Inc.

  16. All Set! Evidence of Simultaneous Attentional Control Settings for Multiple Target Colors

    Science.gov (United States)

    Irons, Jessica L.; Folk, Charles L.; Remington, Roger W.

    2012-01-01

    Although models of visual search have often assumed that attention can only be set for a single feature or property at a time, recent studies have suggested that it may be possible to maintain more than one attentional control setting. The aim of the present study was to investigate whether spatial attention could be guided by multiple attentional…

  17. Multiplicities of charged kaons from deep-inelastic muon scattering off an isoscalar target

    Czech Academy of Sciences Publication Activity Database

    Adolph, C.; Aghasyan, M.; Akhunzyanov, R.; Alexeev, M. G.; Alexeev, G. D.; Amoroso, A.; Andrieux, V.; Anfimov, N. V.; Anosov, V.; Augsten, K.; Augustyniak, W.; Austregesilo, A.; Azevedo, C.; Badelek, B.; Balestra, F.; Ball, M.; Barth, J.; Beck, R.; Bedfer, Y.; Bernhard, J.; Bicker, K.; Bielert, E. R.; Birsa, R.; Bodlák, M.; Bordalo, P.; Bradamante, F.; Braun, C.; Bressan, A.; Büchele, M.; Capozza, L.; Chang, W.-C.; Chatterjee, C.; Chiosso, M.; Choi, A.; Chung, S. U.; Cicuttin, A.; Crespo, M.; Curiel, Q.; Dalla Torre, S.; Dasgupta, S. S.; Dasgupta, S.; Denisov, O.; Dhara, L.; Donskov, S. V.; Doshita, N.; Dreisbach, Ch.; Duic, V.; Dünnweber, W.; Dziewiecki, M.; Efremov, A.; Eversheim, P.D.; Eyrich, W.; Faessler, M.; Ferrero, A.; Finger, M.; Finger jr., M.; Fischer, H.; Franco, C.; Fresne von Hohenesche, N.; Friedrich, J. M.; Frolov, V.; Fuchey, E.; Gautheron, F.; Gavrichtchouk, O. P.; Gerassimov, S.; Giordano, F.; Gnesi, I.; Gorzellik, M.; Grabmüller, S.; Grasso, A.; Grosse-Perdekapm, M.; Grube, B.; Grussenmeyer, T.; Guskov, A.; Haas, F.; Hahne, D.; Hamar, G.; von Harrach, D.; Heinsius, F. H.; Heitz, R.; Herrmann, F.; Horikawa, N.; d'Hose, N.; Hsieh, C.-Yu.; Huber, S.; Ishimoto, S.; Ivanov, A.; Ivanshin, Yu.; Iwata, T.; Jarý, V.; Joosten, R.; Jörg, P.; Kabuss, E.; Ketzer, B.; Khaustov, G. V.; Khokhlov, Yu. A.; Kisselev, Y.; Klein, F.; Klimaszewski, K.; Koivuniemi, J. H.; Kolosov, V. N.; Kondo, K.; Königsmann, K.; Konorov, I.; Konstantinov, V. F.; Kotzinian, A. M.; Kouznetsov, O.; Krämer, M.; Kremser, P.; Krinner, F.; Kroumchtein, Z. V.; Kulinich, Y.; Kunne, F.; Kurek, K.; Kurjata, R. P.; Lednev, A. A.; Lehmann, A.; Levillain, M.; Levorato, S.; Lian, Y.-S.; Lichtenstadt, J.; Longo, R.; Maggiora, A.; Magnon, A.; Makins, N.; Makke, N.; Mallot, G.; Marianski, B.; Martin, A.; Marzec, J.; Matoušek, R.; Matsuda, H.; Matsuda, T.; Meshcheryakov, G.; Meyer, M.; Meyer, W.; Mikhailov, Yu. V.; Mikhasenko, M.; Mitrofanov, E.; Mitrofanov, N.; Miyachi, Y.; Nagaytsev, A.; Nerling, F.; Neyret, D.; Nový, J.; Nowak, W. D.; Nukazuka, G.; Nunes, A.S.; Olshevsky, A. G.; Orlov, I.; Ostrick, M.; Panzieri, D.; Parsamyan, B.; Paul, S.; Peng, J.-C.; Pereira, F.; Pešek, M.; Peshekhonov, D. V.; Pierre, N.; Platchkov, S.; Pochodzalla, J.; Polyakov, V. A.; Pretz, J.; Quaresma, M.; Quintans, C.; Ramos, S.; Regali, C.; Reicherz, G.; Riedl, C.; Roskot, M.; Rossiyskaya, N. S.; Ryabchikov, D.; Rybnikov, A.; Rychter, A.; Salač, R.; Samoylenko, V. D.; Sandacz, A.; Santos, C.; Sarkar, S.; Savin, I. A.; Sawada, H.; Sbrizzai, G.; Schiavon, P.; Schmidt, K.; Schmieden, H.; Schönning, K.; Seder, E.; Selyunin, A.; Silva, L.; Sinha, L.; Sirtl, S.; Slunecka, M.; Smolík, J.; Sozzi, F.; Srnka, Aleš; Steffen, D.; Stolarski, M.; Subrt, O.; Sulc, M.; Suzuki, H.; Szabelski, A.; Szameitat, T.; Sznajder, P.; Takekawa, S.; Tasevsky, M.; Tessaro, S.; Tessarotto, F.; Thibaud, F.; Thiel, A.; Tosello, F.; Tskhay, V.; Uhl, S.; Veloso, J.; Virius, M.; Vondra, J.; Wallner, S.; Weisrock, T.; Wilfert, M.; Windmolders, R.; Ter Wolbeek, J.; Zaremba, K.; Závada, P.; Zavertyaev, M.; Zemlyanichkina, E.; Zhuravlev, N.; Ziembicki, M.; Zink, A.

    2017-01-01

    Roč. 767, 10 APRIL (2017), s. 133-141 ISSN 0370-2693 R&D Projects: GA MŠk(CZ) LO1212 Institutional support: RVO:68081731 Keywords : deep inelastic scattering * kaon multiplicities * quark fragmentation functions * strange quark Subject RIV: BM - Solid Matter Physics ; Magnetism OBOR OECD: Nuclear physics Impact factor: 4.807, year: 2016

  18. Managing multimorbidity: profiles of integrated care approaches targeting people with multiple chronic conditions in Europe.

    NARCIS (Netherlands)

    Rijken, M.; Hujala, A.; Ginneken, E. van; Melchiorre, M.G.; Groenewegen, P.; Schellevis, F.

    2018-01-01

    In response to the growing populations of people with multiple chronic diseases, new models of care are currently being developed in European countries to better meet the needs of these people. This paper aims to describe the occurrence and characteristics of various types of integrated care

  19. Data fusion from multiple passive sonar nodes for target localisation and false alarm reduction

    NARCIS (Netherlands)

    Hunter, A.J.; Fillinger, L.; Zampolli, M.; Clarijs, M.C.

    2012-01-01

    A PHD particle filter implementation has been detailed for the fusion of measurements from multiple passive sonar nodes. It has been demonstrated on simulated metadata and on experimental passive acoustic data of divers and small boats collected in an operational port environment. Fusion at the

  20. Development of a real time multiple target, multi camera tracker for civil security applications

    Science.gov (United States)

    Åkerlund, Hans

    2009-09-01

    A surveillance system has been developed that can use multiple TV-cameras to detect and track personnel and objects in real time in public areas. The document describes the development and the system setup. The system is called NIVS Networked Intelligent Video Surveillance. Persons in the images are tracked and displayed on a 3D map of the surveyed area.

  1. New treatment strategies for multiple myeloma by targeting Bcl-2 and the mevalonate pathway

    NARCIS (Netherlands)

    Donk, N.W.C.J. van de

    2003-01-01

    Multiple myeloma is a B-lineage neoplasia. Enhanced proliferation and defects in the regulation of programmed cell death account for the expansion of the malignant clone. Emergence of drug resistance is the primary cause of treatment failure in myeloma. Various studies have indicated that inhibition

  2. A Unique Role of Endogenous Visual-Spatial Attention in Rapid Processing of Multiple Targets

    Science.gov (United States)

    Guzman-Martinez, Emmanuel; Grabowecky, Marcia; Palafox, German; Suzuki, Satoru

    2011-01-01

    Visual spatial attention can be exogenously captured by a salient stimulus or can be endogenously allocated by voluntary effort. Whether these two attention modes serve distinctive functions is debated, but for processing of single targets the literature suggests superiority of exogenous attention (it is faster acting and serves more functions).…

  3. Immuno-Oncology-The Translational Runway for Gene Therapy: Gene Therapeutics to Address Multiple Immune Targets.

    Science.gov (United States)

    Weß, Ludger; Schnieders, Frank

    2017-12-01

    Cancer therapy is once again experiencing a paradigm shift. This shift is based on extensive clinical experience demonstrating that cancer cannot be successfully fought by addressing only single targets or pathways. Even the combination of several neo-antigens in cancer vaccines is not sufficient for successful, lasting tumor eradication. The focus has therefore shifted to the immune system's role in cancer and the striking abilities of cancer cells to manipulate and/or deactivate the immune system. Researchers and pharma companies have started to target the processes and cells known to support immune surveillance and the elimination of tumor cells. Immune processes, however, require novel concepts beyond the traditional "single-target-single drug" paradigm and need parallel targeting of diverse cells and mechanisms. This review gives a perspective on the role of gene therapy technologies in the evolving immuno-oncology space and identifies gene therapy as a major driver in the development and regulation of effective cancer immunotherapy. Present challenges and breakthroughs ranging from chimeric antigen receptor T-cell therapy, gene-modified oncolytic viruses, combination cancer vaccines, to RNA therapeutics are spotlighted. Gene therapy is recognized as the most prominent technology enabling effective immuno-oncology strategies.

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

    Science.gov (United States)

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

    2018-04-05

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

  5. Dependability of Data Derived from Time Sampling Methods with Multiple Observation Targets

    Science.gov (United States)

    Johnson, Austin H.; Chafouleas, Sandra M.; Briesch, Amy M.

    2017-01-01

    In this study, generalizability theory was used to examine the extent to which (a) time-sampling methodology, (b) number of simultaneous behavior targets, and (c) individual raters influenced variance in ratings of academic engagement for an elementary-aged student. Ten graduate-student raters, with an average of 7.20 hr of previous training in…

  6. Charged particles multiplicity in interactions of 3.7 A GeV 28Si with light and heavy target nuclei in nuclear emulsions

    International Nuclear Information System (INIS)

    Singh, B.K.; Tuli, S.K.

    1998-01-01

    Results from measurement of multiplicity of different charged particles emitted from the interactions of 3.7 A GeV 28 Si with different target groups in nuclear emulsion and correlations among them are presented. The nature of the dependence of multiplicities of charged particles on the impact parameter is examined. Analysis of data in terms of specific multiplicity for different target groups is performed and the results are discussed in the light of superposition model. (author)

  7. The Vasa Homolog RDE-12 engages target mRNA and multiple argonaute proteins to promote RNAi in C. elegans.

    Science.gov (United States)

    Shirayama, Masaki; Stanney, William; Gu, Weifeng; Seth, Meetu; Mello, Craig C

    2014-04-14

    Argonaute (AGO) proteins are key nuclease effectors of RNAi. Although purified AGOs can mediate a single round of target RNA cleavage in vitro, accessory factors are required for small interfering RNA (siRNA) loading and to achieve multiple-target turnover. To identify AGO cofactors, we immunoprecipitated the C. elegans AGO WAGO-1, which engages amplified small RNAs during RNAi. These studies identified a robust association between WAGO-1 and a conserved Vasa ATPase-related protein RDE-12. rde-12 mutants are deficient in RNAi, including viral suppression, and fail to produce amplified secondary siRNAs and certain endogenous siRNAs (endo-siRNAs). RDE-12 colocalizes with WAGO-1 in germline P granules and in cytoplasmic and perinuclear foci in somatic cells. These findings and our genetic studies suggest that RDE-12 is first recruited to target mRNA by upstream AGOs (RDE-1 and ERGO-1), where it promotes small RNA amplification and/or WAGO-1 loading. Downstream of these events, RDE-12 forms an RNase-resistant (target mRNA-independent) complex with WAGO-1 and may thus have additional functions in target mRNA surveillance and silencing. Copyright © 2014 Elsevier Ltd. All rights reserved.

  8. A Novel Sensor Selection and Power Allocation Algorithm for Multiple-Target Tracking in an LPI Radar Network

    Directory of Open Access Journals (Sweden)

    Ji She

    2016-12-01

    Full Text Available Radar networks are proven to have numerous advantages over traditional monostatic and bistatic radar. With recent developments, radar networks have become an attractive platform due to their low probability of intercept (LPI performance for target tracking. In this paper, a joint sensor selection and power allocation algorithm for multiple-target tracking in a radar network based on LPI is proposed. It is found that this algorithm can minimize the total transmitted power of a radar network on the basis of a predetermined mutual information (MI threshold between the target impulse response and the reflected signal. The MI is required by the radar network system to estimate target parameters, and it can be calculated predictively with the estimation of target state. The optimization problem of sensor selection and power allocation, which contains two variables, is non-convex and it can be solved by separating power allocation problem from sensor selection problem. To be specific, the optimization problem of power allocation can be solved by using the bisection method for each sensor selection scheme. Also, the optimization problem of sensor selection can be solved by a lower complexity algorithm based on the allocated powers. According to the simulation results, it can be found that the proposed algorithm can effectively reduce the total transmitted power of a radar network, which can be conducive to improving LPI performance.

  9. Endoplasmic reticulum stress response as a potential therapeutic target in multiple sclerosis

    OpenAIRE

    Getts, Meghann Teague; Getts, Daniel R.; Kohm, Adam P.; Miller, Stephen D

    2008-01-01

    Multiple Sclerosis (MS) is an inflammatory demyelinating disorder of the central nervous system (CNS). Since current treatments are aimed at nonspecifically down-regulating inflammation and natural mechanisms of repair and remyelination within the CNS are inadequate for recovery of function, MS patients presently only have available treatments that delay symptom progression. The complex nature of this disease means that only multifaceted treatments hold the promise of a cure. Recent studies i...

  10. On the theory of electromagnetic cascades in thin targets and photon multiplicity measurements

    Energy Technology Data Exchange (ETDEWEB)

    Khokonov, M.Kh.

    2015-02-01

    The partial probabilities of different scenarios of electromagnetic shower processes are calculated in analytical form. It has been shown that these results are important for measurements of the photon multiplicities which occur during above 100 GeV electron radiation in oriented crystals or in the case of interaction of relativistic electrons with powerful Petawatt laser beams. Quantitative analysis of optimal experimental conditions has been performed. The results are applicable for above few GeV electrons and gamma quanta.

  11. Targeting multiple pathogenic mechanisms with polyphenols for the treatment of Alzheimer’s disease: Experimental approach and therapeutic implications

    Directory of Open Access Journals (Sweden)

    Jun eWang

    2014-03-01

    Full Text Available Alzheimer’s disease (AD is the most prevalent neurodegenerative disease of aging and currently has no cure. Its onset and progression are influenced by multiple factors. There is growing consensus that successful treatment will rely on simultaneously targeting multiple pathological features of AD. Polyphenol compounds have many proven health benefits. In this study, we tested the hypothesis that combining three polyphenolic preparations (grape seed extract, resveratrol and Concord grape juice extract, with different polyphenolic compositions and partially redundant bioactivities, may simultaneously and synergistically mitigate amyloid-β (Aβ mediated neuropathology and cognitive impairments in a mouse model of AD. We found that administration of the polyphenols in combination did not alter the profile of bioactive polyphenol metabolites in the brain. We also found that combination treatment resulted in better protection against cognitive impairments compared to individual treatments, in J20 AD mice. Electrophysiological examination showed that acute treatment with select brain penetrating polyphenol metabolites, derived from these polyphenols, improved oligomeric Aβ (oAβ-induced long term potentiation (LTP deficits in hippocampal slices. Moreover, we found greatly reduced total amyloid content in the brain following combination treatment. Our studies provided experimental evidence that application of polyphenols targeting multiple disease-mechanisms may yield a greater likelihood of therapeutic efficacy.

  12. WISDOM-II: Screening against multiple targets implicated in malaria using computational grid infrastructures

    Directory of Open Access Journals (Sweden)

    Kenyon Colin

    2009-05-01

    Full Text Available Abstract Background Despite continuous efforts of the international community to reduce the impact of malaria on developing countries, no significant progress has been made in the recent years and the discovery of new drugs is more than ever needed. Out of the many proteins involved in the metabolic activities of the Plasmodium parasite, some are promising targets to carry out rational drug discovery. Motivation Recent years have witnessed the emergence of grids, which are highly distributed computing infrastructures particularly well fitted for embarrassingly parallel computations like docking. In 2005, a first attempt at using grids for large-scale virtual screening focused on plasmepsins and ended up in the identification of previously unknown scaffolds, which were confirmed in vitro to be active plasmepsin inhibitors. Following this success, a second deployment took place in the fall of 2006 focussing on one well known target, dihydrofolate reductase (DHFR, and on a new promising one, glutathione-S-transferase. Methods In silico drug design, especially vHTS is a widely and well-accepted technology in lead identification and lead optimization. This approach, therefore builds, upon the progress made in computational chemistry to achieve more accurate in silico docking and in information technology to design and operate large scale grid infrastructures. Results On the computational side, a sustained infrastructure has been developed: docking at large scale, using different strategies in result analysis, storing of the results on the fly into MySQL databases and application of molecular dynamics refinement are MM-PBSA and MM-GBSA rescoring. The modeling results obtained are very promising. Based on the modeling results, In vitro results are underway for all the targets against which screening is performed. Conclusion The current paper describes the rational drug discovery activity at large scale, especially molecular docking using FlexX software

  13. Multiplicities of charged pions and unidentified charged hadrons from deep-inelastic scattering of muons off an isoscalar target

    CERN Document Server

    Adolph, C.; Aghasyan, M.; Akhunzyanov, R.; Alexeev, M.G.; Alexeev, G.D.; Amoroso, A.; Andrieux, V.; Anfimov, N.V.; Anosov, V.; Augustyniak, W.; Austregesilo, A.; Azevedo, C.D.R.; Badelek, B.; Balestra, F.; Barth, J.; Beck, R.; Bedfer, Y.; Bernhard, J.; Bicker, K.; Bielert, E.R.; Birsa, R.; Bisplinghoff, J.; Bodlak, M.; Boer, M.; Bordalo, P.; Bradamante, F.; Braun, C.; Bressan, A.; Buechele, M.; Capozza, L.; Chang, W. -C.; Chatterjee, C.; Chiosso, M.; Choi, I.; Chung, S. -U.; Cicuttin, A.; Crespo, M.L.; Curiel, Q.; Dalla Torre, S.; Dasgupta, S.S.; Dasgupta, S.; Denisov, O. Yu.; Dhara, L.; Donskov, S.V.; Doshita, N.; Duic, V.; Duennweber, W.; Dziewiecki, M.; Efremov, A.; Eversheim, P.D.; Eyrich, W.; Faessler, M.; Ferrero, A.; Finger, M.; Fischer, H.; Franco, C.; von Hohenesche, N. du Fresne; Friedrich, J.M.; Frolov, V.; Fuchey, E.; Gautheron, F.; Gavrichtchouk, O.P.; Gerassimov, S.; Giordano, F.; Gnesi, I.; Gorzellik, M.; Grabmueller, S.; Grasso, A.; Grosse Perdekamp, M.; Grube, B.; Grussenmeyer, T.; Guskov, A.; Haas, F.; Hahne, D.; von Harrach, D.; Hashimoto, R.; Heinsius, F.H.; Heitz, R.; Herrmann, F.; Hinterberger, F.; Horikawa, N.; dHose, N.; Hsieh, C. -Y.; Huber, S.; Ishimoto, S.; Ivanov, A.; Ivanshin, Yu.; Iwata, T.; Jahn, R.; Jary, V.; Joosten, R.; Joerg, P.; Kabuss, E.; Ketzer, B.; Khaustov, G.V.; Khokhlov, Yu. A.; Kisselev, Yu.; Klein, F.; Klimaszewski, K.; Koivuniemi, J.H.; Kolosov, V.N.; Kondo, K.; Koenigsmann, K.; Konorov, I.; Konstantinov, V.F.; Kotzinian, A.M.; Kouznetsov, O.M.; Kuhn, R.; Kraemer, M.; Kremser, P.; Krinner, F.; Kroumchtein, Z.V.; Kulinich, Y.; Kunne, F.; Kurek, K.; Kurjata, R.P.; Lednev, A.A.; Lehmann, A.; Levillain, M.; Levorato, S.; Lichtenstadt, J.; Longo, R.; Maggiora, A.; Magnon, A.; Makins, N.; Makke, N.; Mallot, G.K.; Marchand, C.; Marianski, B.; Martin, A.; Marzec, J.; Matousek, J.; Matsuda, H.; Matsuda, T.; Meshcheryakov, G.V.; Meyer, W.; Michigami, T.; Mikhailov, Yu. V.; Mikhasenko, M.; Mitrofanov, E.; Mitrofanov, N.; Miyachi, Y.; Montuenga, P.; Nagaytsev, A.; Nerling, F.; Neyret, D.; Nikolaenko, V.I.; Novy, J.; Nowak, W.-D.; Nukazuka, G.; Nunes, A.S.; Olshevsky, A.G.; Orlov, I.; Ostrick, M.; Panzieri, D.; Parsamyan, B.; Paul, S.; Peng, J. -C.; Pereira, F.; Pesek, M.; Peshekhonov, D.V.; Pierre, N.; Platchkov, S.; Pochodzalla, J.; Polyakov, V.A.; Pretz, J.; Quaresma, M.; Quintans, C.; Ramos, S.; Regali, C.; Reicherz, G.; Riedl, C.; Roskot, M.; Ryabchikov, D.I.; Rybnikov, A.; Rychter, A.; Salac, R.; Samoylenko, V.D.; Sandacz, A.; Santos, C.; Sarkar, S.; Savin, I.A.; Sawada, T.; Sbrizzai, G.; Schiavon, P.; Schmidt, K.; Schmieden, H.; Schoenning, K.; Schopferer, S.; Seder, E.; Selyunin, A.; Shevchenko, O. Yu.; Steffen, D.; Silva, L.; Sinha, L.; Sirtl, S.; Slunecka, M.; Smolik, J.; Sozzi, F.; Srnka, A.; Stolarski, M.; Sulc, M.; Suzuki, H.; Szabelski, A.; Szameitat, T.; Sznajder, P.; Takekawa, S.; Tasevsky, M.; Tessaro, S.; Tessarotto, F.; Thibaud, F.; Tosello, F.; Tskhay, V.; Uhl, S.; Veloso, J.; Virius, M.; Vondra, J.; Weisrock, T.; Wilfert, M.; Windmolders, R.; ter Wolbeek, J.; Zaremba, K.; Zavada, P.; Zavertyaev, M.; Zemlyanichkina, E.; Ziembicki, M.; Zink, A.

    2017-01-10

    Multiplicities of charged pions and unidentified hadrons produced in deep-inelastic scattering were measured in bins of the Bjorken scaling variable $x$, the relative virtual-photon energy $y$ and the relative hadron energy $z$. Data were obtained by the COMPASS Collaboration using a 160 GeV muon beam and an isoscalar target ($^6$LiD). They cover the kinematic domain in the photon virtuality $Q^2$ > 1(GeV/c$)^2$, $0.004 < x < 0.4$, $0.2 < z < 0.85$ and $0.1 < y < 0.7$. In addition, a leading-order pQCD analysis was performed using the pion multiplicity results to extract quark fragmentation functions.

  14. Multiplicities of charged pions and charged hadrons from deep-inelastic scattering of muons off an isoscalar target

    Directory of Open Access Journals (Sweden)

    C. Adolph

    2017-01-01

    Full Text Available Multiplicities of charged pions and charged hadrons produced in deep-inelastic scattering were measured in three-dimensional bins of the Bjorken scaling variable x, the relative virtual-photon energy y and the relative hadron energy z. Data were obtained by the COMPASS Collaboration using a 160GeV muon beam and an isoscalar target (6LiD. They cover the kinematic domain in the photon virtuality Q2>1(GeV/c2, 0.004multiplicity results to extract quark fragmentation functions.

  15. C/EBPβ Mediates Growth Hormone-Regulated Expression of Multiple Target Genes

    Science.gov (United States)

    Cui, Tracy X.; Lin, Grace; LaPensee, Christopher R.; Calinescu, Anda-Alexandra; Rathore, Maanjot; Streeter, Cale; Piwien-Pilipuk, Graciela; Lanning, Nathan; Jin, Hui; Carter-Su, Christin; Qin, Zhaohui S.

    2011-01-01

    Regulation of c-Fos transcription by GH is mediated by CCAAT/enhancer binding protein β (C/EBPβ). This study examines the role of C/EBPβ in mediating GH activation of other early response genes, including Cyr61, Btg2, Socs3, Zfp36, and Socs1. C/EBPβ depletion using short hairpin RNA impaired responsiveness of these genes to GH, as seen for c-Fos. Rescue with wild-type C/EBPβ led to GH-dependent recruitment of the coactivator p300 to the c-Fos promoter. In contrast, rescue with C/EBPβ mutated at the ERK phosphorylation site at T188 failed to induce GH-dependent recruitment of p300, indicating that ERK-mediated phosphorylation of C/EBPβ at T188 is required for GH-induced recruitment of p300 to c-Fos. GH also induced the occupancy of phosphorylated C/EBPβ and p300 on Cyr61, Btg2, and Socs3 at predicted C/EBP-cAMP response element-binding protein motifs in their promoters. Consistent with a role for ERKs in GH-induced expression of these genes, treatment with U0126 to block ERK phosphorylation inhibited their GH-induced expression. In contrast, GH-dependent expression of Zfp36 and Socs1 was not inhibited by U0126. Thus, induction of multiple early response genes by GH in 3T3-F442A cells is mediated by C/EBPβ. A subset of these genes is regulated similarly to c-Fos, through a mechanism involving GH-stimulated ERK 1/2 activation, phosphorylation of C/EBPβ, and recruitment of p300. Overall, these studies suggest that C/EBPβ, like the signal transducer and activator of transcription proteins, regulates multiple genes in response to GH. PMID:21292824

  16. ROCK inhibition as a therapy for spinal muscular atrophy: understanding the repercussions on multiple cellular targets

    Science.gov (United States)

    Coque, Emmanuelle; Raoul, Cédric; Bowerman, Mélissa

    2014-01-01

    Spinal muscular atrophy (SMA) is the most common genetic disease causing infant death, due to an extended loss of motoneurons. This neuromuscular disorder results from deletions and/or mutations within the Survival Motor Neuron 1 (SMN1) gene, leading to a pathological decreased expression of functional full-length SMN protein. Emerging studies suggest that the small GTPase RhoA and its major downstream effector Rho kinase (ROCK), which both play an instrumental role in cytoskeleton organization, contribute to the pathology of motoneuron diseases. Indeed, an enhanced activation of RhoA and ROCK has been reported in the spinal cord of an SMA mouse model. Moreover, the treatment of SMA mice with ROCK inhibitors leads to an increased lifespan as well as improved skeletal muscle and neuromuscular junction pathology, without preventing motoneuron degeneration. Although motoneurons are the primary target in SMA, an increasing number of reports show that other cell types inside and outside the central nervous system contribute to SMA pathogenesis. As administration of ROCK inhibitors to SMA mice was systemic, the improvement in survival and phenotype could therefore be attributed to specific effects on motoneurons and/or on other non-neuronal cell types. In the present review, we will present the various roles of the RhoA/ROCK pathway in several SMA cellular targets including neurons, myoblasts, glial cells, cardiomyocytes and pancreatic cells as well as discuss how ROCK inhibition may ameliorate their health and function. It is most likely a concerted influence of ROCK modulation on all these cell types that ultimately lead to the observed benefits of pharmacological ROCK inhibition in SMA mice. PMID:25221469

  17. ROCK inhibition as a therapy for spinal muscular atrophy: understanding the repercussions on multiple cellular targets

    Directory of Open Access Journals (Sweden)

    Emmanuelle eCoque

    2014-08-01

    Full Text Available Spinal muscular atrophy (SMA is the most common genetic disease causing infant death, due to an extended loss of motoneurons. This neuromuscular disorder results from deletions and/or mutations within the surviving motor neuron 1 (SMN1 gene, leading to a pathological decreased expression of functional full-length SMN protein. Emerging studies suggest that the small GTPase RhoA and its major downstream effector Rho kinase (ROCK, which both play an instrumental role in cytoskeleton organization, contribute to the pathology of motoneuron diseases. Indeed, an enhanced activation of RhoA and ROCK has been reported in the spinal cord of an SMA mouse model. Moreover, the treatment of SMA mice with ROCK inhibitors leads to an increased lifespan as well as improved skeletal muscle and neuromuscular junction pathology, without preventing motoneuron degeneration. Although motoneurons are the primary target in SMA, an increasing number of reports show that other cell types inside and outside the central nervous system contribute to SMA pathogenesis. As administration of ROCK inhibitors to SMA mice was systemic, the improvement in survival and phenotype could therefore be attributed to specific effects on motoneurons and/or on other non-neuronal cell types. In the present review, we will present the various roles of the RhoA/ROCK pathway in several SMA cellular targets including neurons, myocytes, glial cells, cardiomyocytes and pancreatic cells as well as discuss how ROCK inhibition may ameliorate their health and function. It is most likely a concerted influence of ROCK modulation on all these cell types that ultimately lead to the observed benefits of pharmacological ROCK inhibition in SMA mice.

  18. The effects of interventions targeting multiple health behaviors on smoking cessation outcomes: a rapid realist review protocol.

    Science.gov (United States)

    Minian, Nadia; deRuiter, Wayne K; Lingam, Mathangee; Corrin, Tricia; Dragonetti, Rosa; Manson, Heather; Taylor, Valerie H; Zawertailo, Laurie; Ebnahmady, Arezoo; Melamed, Osnat C; Rodak, Terri; Hahn, Margaret; Selby, Peter

    2018-03-01

    Health behaviors directly impact the health of individuals, and populations. Since individuals tend to engage in multiple unhealthy behaviors such as smoking, excessive alcohol use, physical inactivity, and eating an unhealthy diet simultaneously, many large community-based interventions have been implemented to reduce the burden of disease through the modification of multiple health behaviors. Smoking cessation can be particularly challenging as the odds of becoming dependent on nicotine increase with every unhealthy behavior a smoker exhibits. This paper presents a protocol for a rapid realist review which aims to identify factors associated with effectively changing tobacco use and target two or more additional unhealthy behaviors. An electronic literature search will be conducted using the following bibliographic databases: MEDLINE, Embase, PsycINFO, Cumulative Index to Nursing and Allied Health Literature (CINAHL), The Cochrane Library, Social Science Abstracts, Social Work Abstracts, and Web of Science. Two reviewers will screen titles and abstracts for relevant research, and the selected full papers will be used to extract data and assess the quality of evidence. Throughout this process, the rapid realist approach proposed by Saul et al., 2013 will be used to refine our initial program theory and identify contextual factors and mechanisms that are associated with successful multiple health behavior change. This review will provide evidence-based research on the context and mechanisms that may drive the success or failure of interventions designed to support multiple health behavior change. This information will be used to guide curriculum and program development for a government funded project on improving smoking cessation by addressing multiple health behaviors in people in Canada. PROSPERO CRD42017064430.

  19. Molecular diagnostics of a single drug-resistant multiple myeloma case using targeted next-generation sequencing

    Directory of Open Access Journals (Sweden)

    Ikeda H

    2015-10-01

    Full Text Available Hiroshi Ikeda,1 Kazuya Ishiguro,1 Tetsuyuki Igarashi,1 Yuka Aoki,1 Toshiaki Hayashi,1 Tadao Ishida,1 Yasushi Sasaki,1,2 Takashi Tokino,2 Yasuhisa Shinomura1 1Department of Gastroenterology, Rheumatology and Clinical Immunology, 2Medical Genome Sciences, Research Institute for Frontier Medicine, Sapporo Medical University, Sapporo, Japan Abstract: A 69-year-old man was diagnosed with IgG λ-type multiple myeloma (MM, Stage II in October 2010. He was treated with one cycle of high-dose dexamethasone. After three cycles of bortezomib, the patient exhibited slow elevations in the free light-chain levels and developed a significant new increase of serum M protein. Bone marrow cytogenetic analysis revealed a complex karyotype characteristic of malignant plasma cells. To better understand the molecular pathogenesis of this patient, we sequenced for mutations in the entire coding regions of 409 cancer-related genes using a semiconductor-based sequencing platform. Sequencing analysis revealed eight nonsynonymous somatic mutations in addition to several copy number variants, including CCND1 and RB1. These alterations may play roles in the pathobiology of this disease. This targeted next-generation sequencing can allow for the prediction of drug resistance and facilitate improvements in the treatment of MM patients. Keywords: multiple myeloma, drug resistance, genome-wide sequencing, semiconductor sequencer, target therapy

  20. Estimating Accurate Target Coordinates with Magnetic Resonance Images by Using Multiple Phase-Encoding Directions during Acquisition.

    Science.gov (United States)

    Kim, Minsoo; Jung, Na Young; Park, Chang Kyu; Chang, Won Seok; Jung, Hyun Ho; Chang, Jin Woo

    2018-06-01

    Stereotactic procedures are image guided, often using magnetic resonance (MR) images limited by image distortion, which may influence targets for stereotactic procedures. The aim of this work was to assess methods of identifying target coordinates for stereotactic procedures with MR in multiple phase-encoding directions. In 30 patients undergoing deep brain stimulation, we acquired 5 image sets: stereotactic brain computed tomography (CT), T2-weighted images (T2WI), and T1WI in both right-to-left (RL) and anterior-to-posterior (AP) phase-encoding directions. Using CT coordinates as a reference, we analyzed anterior commissure and posterior commissure coordinates to identify any distortion relating to phase-encoding direction. Compared with CT coordinates, RL-directed images had more positive x-axis values (0.51 mm in T1WI, 0.58 mm in T2WI). AP-directed images had more negative y-axis values (0.44 mm in T1WI, 0.59 mm in T2WI). We adopted 2 methods to predict CT coordinates with MR image sets: parallel translation and selective choice of axes according to phase-encoding direction. Both were equally effective at predicting CT coordinates using only MR; however, the latter may be easier to use in clinical settings. Acquiring MR in multiple phase-encoding directions and selecting axes according to the phase-encoding direction allows identification of more accurate coordinates for stereotactic procedures. © 2018 S. Karger AG, Basel.

  1. Identification of targets and new developments in the treatment of multiple sclerosis – focus on cladribine

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    Clemens Warnke

    2010-06-01

    Full Text Available Clemens Warnke1, Heinz Wiendl2, Hans-Peter Hartung1, Olaf Stüve3, Bernd C Kieseier11Department of Neurology, Heinrich-Heine University Düsseldorf, Germany; 2Department of Neurology – Inflammatory Disorders of the Nervous System and Neurooncology, University of Münster, Germany; 3Department of Neurology, Dallas VA Medical Center and UT Southwestern Medical Center, Dallas, Texas, USAAbstract: Orally available disease-modifying drugs for relapsing-remitting multiple sclerosis (MS represent an unmet need for this chronic and debilitating disease. Among 5 currently investigated drugs at phase 3 clinical stage, promising efficacy data for fingolimod and oral cladribine have recently been published. However, benefits need to be weighed against the risks to define the role of these compounds within current treatment regimens. In this review, data on the efficacy of a promising compound, oral cladribine, are discussed and balanced with known and anticipated risks in a postmarketing era, and finally gives an outlook on the potential place of this drug in treatment algorithms for MS in the future.Keywords: immunosuppressant, oral drugs, risk–benefit, safety

  2. Multiple Targets for Novel Therapy of FSGS Associated with Circulating Permeability Factor

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    Virginia J. Savin

    2017-01-01

    Full Text Available A plasma component is responsible for altered glomerular permeability in patients with focal segmental glomerulosclerosis. Evidence includes recurrence after renal transplantation, remission after plasmapheresis, proteinuria in infants of affected mothers, transfer of proteinuria to experimental animals, and impaired glomerular permeability after exposure to patient plasma. Therapy may include decreasing synthesis of the injurious agent, removing or blocking its interaction with cells, or blocking signaling or enhancing cell defenses to restore the permeability barrier and prevent progression. Agents that may prevent the synthesis of the permeability factor include cytotoxic agents or aggressive chemotherapy. Extracorporeal therapies include plasmapheresis, immunoadsorption with protein A or anti-immunoglobulin, or lipopheresis. Oral or intravenous galactose also decreases Palb activity. Studies of glomeruli have shown that several strategies prevent the action of FSGS sera. These include blocking receptor-ligand interactions, modulating cell reactions using indomethacin or eicosanoids 20-HETE or 8,9-EET, and enhancing cytoskeleton and protein interactions using calcineurin inhibitors, glucocorticoids, or rituximab. We have identified cardiotrophin-like cytokine factor 1 (CLCF-1 as a candidate for the permeability factor. Therapies specific to CLCF-1 include potential use of cytokine receptor-like factor (CRLF-1 and inhibition of Janus kinase 2. Combined therapy using multiple modalities offers therapy to reverse proteinuria and prevent scarring.

  3. Whether to target single or multiple CDKs for therapy? That is the question.

    Science.gov (United States)

    Węsierska-Gądek, Józefa; Maurer, Margarita; Zulehner, Nora; Komina, Oxana

    2011-02-01

    Complexes consisting of cyclin-dependent kinases (CDKs) and their regulatory subunits (the cyclins) control the progression of normal mammalian cells through the cell cycle. However, during malignant transformation this regulatory apparatus malfunctions, allowing cells to undergo unchecked proliferation. In many cases, the high mitotic potential of malignant cells is due to the constitutive activation of CDK-cyclin complexes, facilitated by the inactivation of cellular CDK inhibitors, such as p16(INK4A) or p27(Kip1), and the loss of functional tumor suppressors, such as the p53 and pRb proteins. It has recently been suggested that pharmacological intervention based on remedying the deficiency or loss of activity of these negative regulators of the cell cycle could be a very effective therapeutic option in the treatment of cancer. Multiple CDK inhibitors have been synthesized over the last two decades, spanning at least five classes of compounds. While these inhibitors can be classified on the basis of their chemical structure, it may be more interesting to categorize them according to their pharmacological nature, as broad-spectrum unspecific, pan-specific, or very selective antagonists. This review offers a critical assessment of the advantages and disadvantages of both pan-specific and highly selective CDK inhibitors in therapy. © 2010 Wiley-Liss, Inc.

  4. Curcumin induces apoptosis of upper aerodigestive tract cancer cells by targeting multiple pathways.

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    A R M Ruhul Amin

    Full Text Available Curcumin, a natural compound isolated from the Indian spice "Haldi" or "curry powder", has been used for centuries as a traditional remedy for many ailments. Recently, the potential use of curcumin in cancer prevention and therapy urges studies to uncover the molecular mechanisms associated with its anti-tumor effects. In the current manuscript, we investigated the mechanism of curcumin-induced apoptosis in upper aerodigestive tract cancer cell lines and showed that curcumin-induced apoptosis is mediated by the modulation of multiple pathways such as induction of p73, and inhibition of p-AKT and Bcl-2. Treatment of cells with curcumin induced both p53 and the related protein p73 in head and neck and lung cancer cell lines. Inactivation of p73 by dominant negative p73 significantly protected cells from curcumin-induced apoptosis, whereas ablation of p53 by shRNA had no effect. Curcumin treatment also strongly inhibited p-AKT and Bcl-2 and overexpression of constitutively active AKT or Bcl-2 significantly inhibited curcumin-induced apoptosis. Taken together, our findings suggest that curcumin-induced apoptosis is mediated via activating tumor suppressor p73 and inhibiting p-AKT and Bcl-2.

  5. Predicting bat colony survival under controls targeting multiple transmission routes of white-nose syndrome.

    Science.gov (United States)

    Meyer, A D; Stevens, D F; Blackwood, J C

    2016-11-21

    White-nose syndrome (WNS) is a lethal infection of bats caused by the psychrophilic fungus Pseudogymnoascus destructans (Pd). Since the first cases of WNS were documented in 2006, it is estimated that as many as 5.5million bats have succumbed in the United States-one of the fastest mammalian die-offs due to disease ever observed, and the first known sustained epizootic of bats. WNS is contagious between bats, and mounting evidence suggests that a persistent environmental reservoir of Pd plays a significant role in transmission as well. It is unclear, however, the relative contributions of bat-to-bat and environment-to-bat transmission to disease propagation within a colony. We analyze a mathematical model to investigate the consequences of both avenues of transmission on colony survival in addition to the efficacy of disease control strategies. Our model shows that selection of the most effective control strategies is highly dependent on the primary route of WNS transmission. Under all scenarios, however, generalized culling is ineffective and while targeted culling of infected bats may be effective under idealized conditions, it primarily has negative consequences. Thus, understanding the significance of environment-to-bat transmission is paramount to designing effective management plans. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Synthesis, Molecular Modelling and Biological Evaluation of Novel Heterodimeric, Multiple Ligands Targeting Cholinesterases and Amyloid Beta

    Directory of Open Access Journals (Sweden)

    Michalina Hebda

    2016-03-01

    Full Text Available Cholinesterases and amyloid beta are one of the major biological targets in the search for a new and efficacious treatment of Alzheimer’s disease. The study describes synthesis and pharmacological evaluation of new compounds designed as dual binding site acetylcholinesterase inhibitors. Among the synthesized compounds, two deserve special attention—compounds 42 and 13. The former is a saccharin derivative and the most potent and selective acetylcholinesterase inhibitor (EeAChE IC50 = 70 nM. Isoindoline-1,3-dione derivative 13 displays balanced inhibitory potency against acetyl- and butyrylcholinesterase (BuChE (EeAChE IC50 = 0.76 μM, EqBuChE IC50 = 0.618 μM, and it inhibits amyloid beta aggregation (35.8% at 10 μM. Kinetic studies show that the developed compounds act as mixed or non-competitive acetylcholinesterase inhibitors. According to molecular modelling studies, they are able to interact with both catalytic and peripheral active sites of the acetylcholinesterase. Their ability to cross the blood-brain barrier (BBB was confirmed in vitro in the parallel artificial membrane permeability BBB assay. These compounds can be used as a solid starting point for further development of novel multifunctional ligands as potential anti-Alzheimer’s agents.

  7. Mapping multiple components of malaria risk for improved targeting of elimination interventions.

    Science.gov (United States)

    Cohen, Justin M; Le Menach, Arnaud; Pothin, Emilie; Eisele, Thomas P; Gething, Peter W; Eckhoff, Philip A; Moonen, Bruno; Schapira, Allan; Smith, David L

    2017-11-13

    There is a long history of considering the constituent components of malaria risk and the malaria transmission cycle via the use of mathematical models, yet strategic planning in endemic countries tends not to take full advantage of available disease intelligence to tailor interventions. National malaria programmes typically make operational decisions about where to implement vector control and surveillance activities based upon simple categorizations of annual parasite incidence. With technological advances, an enormous opportunity exists to better target specific malaria interventions to the places where they will have greatest impact by mapping and evaluating metrics related to a variety of risk components, each of which describes a different facet of the transmission cycle. Here, these components and their implications for operational decision-making are reviewed. For each component, related mappable malaria metrics are also described which may be measured and evaluated by malaria programmes seeking to better understand the determinants of malaria risk. Implementing tailored programmes based on knowledge of the heterogeneous distribution of the drivers of malaria transmission rather than only consideration of traditional metrics such as case incidence has the potential to result in substantial improvements in decision-making. As programmes improve their ability to prioritize their available tools to the places where evidence suggests they will be most effective, elimination aspirations may become increasingly feasible.

  8. Multi-target QSPR modeling for simultaneous prediction of multiple gas-phase kinetic rate constants of diverse chemicals

    Science.gov (United States)

    Basant, Nikita; Gupta, Shikha

    2018-03-01

    The reactions of molecular ozone (O3), hydroxyl (•OH) and nitrate (NO3) radicals are among the major pathways of removal of volatile organic compounds (VOCs) in the atmospheric environment. The gas-phase kinetic rate constants (kO3, kOH, kNO3) are thus, important in assessing the ultimate fate and exposure risk of atmospheric VOCs. Experimental data for rate constants are not available for many emerging VOCs and the computational methods reported so far address a single target modeling only. In this study, we have developed a multi-target (mt) QSPR model for simultaneous prediction of multiple kinetic rate constants (kO3, kOH, kNO3) of diverse organic chemicals considering an experimental data set of VOCs for which values of all the three rate constants are available. The mt-QSPR model identified and used five descriptors related to the molecular size, degree of saturation and electron density in a molecule, which were mechanistically interpretable. These descriptors successfully predicted three rate constants simultaneously. The model yielded high correlations (R2 = 0.874-0.924) between the experimental and simultaneously predicted endpoint rate constant (kO3, kOH, kNO3) values in test arrays for all the three systems. The model also passed all the stringent statistical validation tests for external predictivity. The proposed multi-target QSPR model can be successfully used for predicting reactivity of new VOCs simultaneously for their exposure risk assessment.

  9. Rationally engineered nanoparticles target multiple myeloma cells, overcome cell-adhesion-mediated drug resistance, and show enhanced efficacy in vivo

    International Nuclear Information System (INIS)

    Kiziltepe, T; Ashley, J D; Stefanick, J F; Qi, Y M; Alves, N J; Handlogten, M W; Suckow, M A; Navari, R M; Bilgicer, B

    2012-01-01

    In the continuing search for effective cancer treatments, we report the rational engineering of a multifunctional nanoparticle that combines traditional chemotherapy with cell targeting and anti-adhesion functionalities. Very late antigen-4 (VLA-4) mediated adhesion of multiple myeloma (MM) cells to bone marrow stroma confers MM cells with cell-adhesion-mediated drug resistance (CAM-DR). In our design, we used micellar nanoparticles as dynamic self-assembling scaffolds to present VLA-4-antagonist peptides and doxorubicin (Dox) conjugates, simultaneously, to selectively target MM cells and to overcome CAM-DR. Dox was conjugated to the nanoparticles through an acid-sensitive hydrazone bond. VLA-4-antagonist peptides were conjugated via a multifaceted synthetic procedure for generating precisely controlled number of targeting functionalities. The nanoparticles were efficiently internalized by MM cells and induced cytotoxicity. Mechanistic studies revealed that nanoparticles induced DNA double-strand breaks and apoptosis in MM cells. Importantly, multifunctional nanoparticles overcame CAM-DR, and were more efficacious than Dox when MM cells were cultured on fibronectin-coated plates. Finally, in a MM xenograft model, nanoparticles preferentially homed to MM tumors with ∼10 fold more drug accumulation and demonstrated dramatic tumor growth inhibition with a reduced overall systemic toxicity. Altogether, we demonstrate the disease driven engineering of a nanoparticle-based drug delivery system, enabling the model of an integrative approach in the treatment of MM

  10. Systemic delivery of microRNA-101 potently inhibits hepatocellular carcinoma in vivo by repressing multiple targets.

    Directory of Open Access Journals (Sweden)

    Fang Zheng

    2015-02-01

    Full Text Available Targeted therapy based on adjustment of microRNA (miRNAs activity takes great promise due to the ability of these small RNAs to modulate cellular behavior. However, the efficacy of miR-101 replacement therapy to hepatocellular carcinoma (HCC remains unclear. In the current study, we first observed that plasma levels of miR-101 were significantly lower in distant metastatic HCC patients than in HCCs without distant metastasis, and down-regulation of plasma miR-101 predicted a worse disease-free survival (DFS, P<0.05. In an animal model of HCC, we demonstrated that systemic delivery of lentivirus-mediated miR-101 abrogated HCC growth in the liver, intrahepatic metastasis and distant metastasis to the lung and to the mediastinum, resulting in a dramatic suppression of HCC development and metastasis in mice without toxicity and extending life expectancy. Furthermore, enforced overexpression of miR-101 in HCC cells not only decreased EZH2, COX2 and STMN1, but also directly down-regulated a novel target ROCK2, inhibited Rho/Rac GTPase activation, and blocked HCC cells epithelial-mesenchymal transition (EMT and angiogenesis, inducing a strong abrogation of HCC tumorigenesis and aggressiveness both in vitro and in vivo. These results provide proof-of-concept support for systemic delivery of lentivirus-mediated miR-101 as a powerful anti-HCC therapeutic modality by repressing multiple molecular targets.

  11. Targeting poly (ADP-ribose polymerase partially contributes to bufalin-induced cell death in multiple myeloma cells.

    Directory of Open Access Journals (Sweden)

    He Huang

    Full Text Available Despite recent pharmaceutical advancements in therapeutic drugs, multiple myeloma (MM remains an incurable disease. Recently, ploy(ADP-ribose polymerase 1 (PARP1 has been shown as a potentially promising target for MM therapy. A previous report suggested bufalin, a component of traditional Chinese medicine ("Chan Su", might target PARP1. However, this hypothesis has not been verified. We here showed that bufalin could inhibit PARP1 activity in vitro and reduce DNA-damage-induced poly(ADP-ribosylation in MM cells. Molecular docking analysis revealed that the active site of bufalin interaction is within the catalytic domain of PAPR1. Thus, PARP1 is a putative target of bufalin. Furthermore, we showed, for the first time that the proliferation of MM cell lines (NCI-H929, U266, RPMI8226 and MM.1S and primary CD138(+ MM cells could be inhibited by bufalin, mainly via apoptosis and G2-M phase cell cycle arrest. MM cell apoptosis was confirmed by apoptotic cell morphology, Annexin-V positive cells, and the caspase3 activation. We further evaluated the role of PARP1 in bufalin-induced apoptosis, discovering that PARP1 overexpression partially suppressed bufalin-induced cell death. Moreover, bufalin can act as chemosensitizer to enhance the cell growth-inhibitory effects of topotecan, camptothecin, etoposide and vorinostat in MM cells. Collectively, our data suggest that bufalin is a novel PARP1 inhibitor and a potentially promising therapeutic agent against MM alone or in combination with other drugs.

  12. Multiple target of hAmylin on rat primary hippocampal neurons.

    Science.gov (United States)

    Zhang, Nan; Yang, Shengchang; Wang, Chang; Zhang, Jianghua; Huo, Lifang; Cheng, Yiru; Wang, Chuan; Jia, Zhanfeng; Ren, Leiming; Kang, Lin; Zhang, Wei

    2017-02-01

    Alzheimer's disease (AD) and type II diabetes mellitus (DM2) are the most common aging-related diseases and are characterized by β-amyloid and amylin accumulation, respectively. Multiple studies have indicated a strong correlation between these two diseases. Amylin oligomerization in the brain appears to be a novel risk factor for developing AD. Although amylin aggregation has been demonstrated to induce cytotoxicity in neurons through altering Ca 2+ homeostasis, the underlying mechanisms have not been fully explored. In this study, we investigated the effects of amylin on rat hippocampal neurons using calcium imaging and whole-cell patch clamp recordings. We demonstrated that the amylin receptor antagonist AC187 abolished the Ca 2+ response induced by low concentrations of human amylin (hAmylin). However, the Ca 2+ response induced by higher concentrations of hAmylin was independent of the amylin receptor. This effect was dependent on extracellular Ca 2+ . Additionally, blockade of L-type Ca 2+ channels partially reduced hAmylin-induced Ca 2+ response. In whole-cell recordings, hAmylin depolarized the membrane potential. Moreover, application of the transient receptor potential (TRP) channel antagonist ruthenium red (RR) attenuated the hAmylin-induced increase in Ca 2+ . Single-cell RT-PCR demonstrated that transient receptor potential vanilloid 4 (TRPV4) mRNA was expressed in most of the hAmylin-responsive neurons. In addition, selective knockdown of TRPV4 channels inhibited the hAmylin-evoked Ca 2+ response. These results indicated that different concentrations of hAmylin act through different pathways. The amylin receptor mediates the excitatory effects of low concentrations of hAmylin. In contrast, for high concentrations of hAmylin, hAmylin aggregates precipitated on the neuronal membrane, activated TRPV4 channels and subsequently triggered membrane voltage-gated calcium channel opening followed by membrane depolarization. Therefore, our data suggest that

  13. Sensitive targeted multiple protein quantification based on elemental detection of Quantum Dots

    Energy Technology Data Exchange (ETDEWEB)

    Montoro Bustos, Antonio R.; Garcia-Cortes, Marta [Department of Physical and Analytical Chemistry, University of Oviedo, Julián Clavería 8, Oviedo 33006 (Spain); González-Iglesias, Hector [Fundación de Investigación Oftalmológica, Instituto Oftalmológico Fernandez-Vega, Avenida Doctores Fernández-Vega, 34, Oviedo 33012 (Spain); Ruiz Encinar, Jorge, E-mail: ruizjorge@uniovi.es [Department of Physical and Analytical Chemistry, University of Oviedo, Julián Clavería 8, Oviedo 33006 (Spain); Costa-Fernández, José M. [Department of Physical and Analytical Chemistry, University of Oviedo, Julián Clavería 8, Oviedo 33006 (Spain); Coca-Prados, Miguel [Fundación de Investigación Oftalmológica, Instituto Oftalmológico Fernandez-Vega, Avenida Doctores Fernández-Vega, 34, Oviedo 33012 (Spain); Department of Ophthalmology and Visual Science, Yale University School of Medicine, New Haven, CT 06510 (United States); Sanz-Medel, Alfredo, E-mail: asm@uniovi.es [Department of Physical and Analytical Chemistry, University of Oviedo, Julián Clavería 8, Oviedo 33006 (Spain)

    2015-06-16

    Highlights: • Novel generic platform for multiparametric quantification of proteins. • QDs labeling and ICP-MS detection allow significant analytical signal amplification. • ICP-MS mass balances information provided an internal validation of the immunoassay. • Multiparametric determination of 5 proteins in human serum samples. • ICP-MS reduced matrix effects as compared to other conventional detection techniques. - Abstract: A generic strategy based on the use of CdSe/ZnS Quantum Dots (QDs) as elemental labels for protein quantification, using immunoassays with elemental mass spectrometry (ICP-MS), detection is presented. In this strategy, streptavidin modified QDs (QDs-SA) are bioconjugated to a biotinylated secondary antibody (b-Ab{sub 2}). After a multi-technique characterization of the synthesized generic platform (QDs-SA-b-Ab{sub 2}) it was applied to the sequential quantification of five proteins (transferrin, complement C3, apolipoprotein A1, transthyretin and apolipoprotein A4) at different concentration levels in human serum samples. It is shown how this generic strategy does only require the appropriate unlabeled primary antibody for each protein to be detected. Therefore, it introduces a way out to the need for the cumbersome and specific bioconjugation of the QDs to the corresponding specific recognition antibody for every target analyte (protein). Results obtained were validated with those obtained using UV–vis spectrophotometry and commercial ELISA Kits. As expected, ICP-MS offered one order of magnitude lower DL (0.23 fmol absolute for transferrin) than the classical spectrophotometric detection (3.2 fmol absolute). ICP-MS precision and detection limits, however turned out to be compromised by procedural blanks. The full analytical performance of the ICP-MS-based immunoassay proposed was assessed for detection of transferrin (Tf), present at the low ng mL{sup −1} range in a complex “model” synthetic matrix, where the total protein

  14. Multiple D2 heteroreceptor complexes: new targets for treatment of schizophrenia

    Science.gov (United States)

    Borroto-Escuela, Dasiel O.; Pintsuk, Julia; Schäfer, Thorsten; Friedland, Kristina; Ferraro, Luca; Tanganelli, Sergio; Liu, Fang; Fuxe, Kjell

    2016-01-01

    The dopamine (DA) neuron system most relevant for schizophrenia is the meso-limbic-cortical DA system inter alia densely innervating subcortical limbic regions. The field of dopamine D2 receptors and schizophrenia changed markedly with the discovery of many types of D2 heteroreceptor complexes in subcortical limbic areas as well as the dorsal striatum. The results indicate that the D2 is a hub receptor which interacts not only with many other G protein-coupled receptors (GPCRs) including DA isoreceptors but also with ion-channel receptors, receptor tyrosine kinases, scaffolding proteins and DA transporters. Disturbances in several of these D2 heteroreceptor complexes may contribute to the development of schizophrenia through changes in the balance of diverse D2 homo- and heteroreceptor complexes mediating the DA signal, especially to the ventral striato-pallidal γ-aminobutyric acid (GABA) pathway. This will have consequences for the control of this pathway of the glutamate drive to the prefrontal cortex via the mediodorsal thalamic nucleus which can contribute to psychotic processes. Agonist activation of the A2A protomer in the A2A–D2 heteroreceptor complex inhibits D2 Gi/o mediated signaling but increases the D2 β-arrestin2 mediated signaling. Through this allosteric receptor–receptor interaction, the A2A agonist becomes a biased inhibitory modulator of the Gi/o mediated D2 signaling, which may the main mechanism for its atypical antipsychotic properties especially linked to the limbic A2A–D2 heterocomplexes. The DA and glutamate hypotheses of schizophrenia come together in the signal integration in D2–N-methyl-d-aspartate (NMDA) and A2A–D2–metabotropic glutamate receptor 5 (mGlu5) heteroreceptor complexes, especially in the ventral striatum. 5-Hydroxytryptamine 2A (5-HT2A)–D2 heteroreceptor complexes are special targets for atypical antipsychotics with high potency to block their 5-HT2A protomer signaling in view of the potential development of

  15. Forward-backward multiplicity correlations of target fragments in nucleus-emulsion collisions at a few hundred MeV/u

    International Nuclear Information System (INIS)

    Zhang Donghai; Chen Yanling; Wang Guorong; Li Wangdong; Wang Qing; Yao Jijie; Zhou Jianguo; Li Rong; Li Junsheng; Li Huiling

    2015-01-01

    The forward-backward multiplicity and correlations of a target evaporated fragment (black track particle) and target recoiled proton (grey track particle) emitted from 150 A MeV "4He, 290 A MeV "1"2C, 400 A MeV "1"2C, 400 A MeV "2"0Ne and 500 A MeV "5"6Fe induced different types of nuclear emulsion target interactions are investigated. It is found that the forward and backward averaged multiplicity of a grey, black and heavily ionized track particle increases with the increase of the target size. The averaged multiplicity of a forward black track particle, backward black track particle, and backward grey track particle do not depend on the projectile size and energy, but the averaged multiplicity of a forward grey track particle increases with an increase of projectile size and energy. The backward grey track particle multiplicity distribution follows an exponential decay law and the decay constant decreases with an increase of target size. The backward-forward multiplicity correlations follow linear law which is independent of the projectile size and energy, and the saturation effect is observed in some heavy target data sets. (authors)

  16. Identification of the APC/C co-factor FZR1 as a novel therapeutic target for multiple myeloma.

    Science.gov (United States)

    Crawford, Lisa J; Anderson, Gordon; Johnston, Cliona K; Irvine, Alexandra E

    2016-10-25

    Multiple Myeloma (MM) is a haematological neoplasm characterised by the clonal proliferation of malignant plasma cells in the bone marrow. The success of proteasome inhibitors in the treatment of MM has highlighted the importance of the ubiquitin proteasome system (UPS) in the pathogenesis of this disease. In this study, we analysed gene expression of UPS components to identify novel therapeutic targets within this pathway in MM. Here we demonstrate how this approach identified previously validated and novel therapeutic targets. In addition we show that FZR1 (Fzr), a cofactor of the multi-subunit E3 ligase complex anaphase-promoting complex/cyclosome (APC/C), represents a novel therapeutic target in myeloma. The APC/C associates independently with two cofactors, Fzr and Cdc20, to control cell cycle progression. We found high levels of FZR1 in MM primary cells and cell lines and demonstrate that expression is further increased on adhesion to bone marrow stromal cells (BMSCs). Specific knockdown of either FZR1 or CDC20 reduced viability and induced growth arrest of MM cell lines, and resulted in accumulation of APC/CFzr substrate Topoisomerase IIα (TOPIIα) or APC/CCdc20 substrate Cyclin B. Similar effects were observed following treatment with proTAME, an inhibitor of both APC/CFzr and APC/CCdc20. Combinations of proTAME with topoisomerase inhibitors, etoposide and doxorubicin, significantly increased cell death in MM cell lines and primary cells, particularly if TOPIIα levels were first increased through pre-treatment with proTAME. Similarly, combinations of proTAME with the microtubule inhibitor vincristine resulted in enhanced cell death. This study demonstrates the potential of targeting the APC/C and its cofactors as a therapeutic approach in MM.

  17. Enhanced Algorithms for EO/IR Electronic Stabilization, Clutter Suppression, and Track-Before-Detect for Multiple Low Observable Targets

    Science.gov (United States)

    Tartakovsky, A.; Brown, A.; Brown, J.

    The paper describes the development and evaluation of a suite of advanced algorithms which provide significantly-improved capabilities for finding, fixing, and tracking multiple ballistic and flying low observable objects in highly stressing cluttered environments. The algorithms have been developed for use in satellite-based staring and scanning optical surveillance suites for applications including theatre and intercontinental ballistic missile early warning, trajectory prediction, and multi-sensor track handoff for midcourse discrimination and intercept. The functions performed by the algorithms include electronic sensor motion compensation providing sub-pixel stabilization (to 1/100 of a pixel), as well as advanced temporal-spatial clutter estimation and suppression to below sensor noise levels, followed by statistical background modeling and Bayesian multiple-target track-before-detect filtering. The multiple-target tracking is performed in physical world coordinates to allow for multi-sensor fusion, trajectory prediction, and intercept. Output of detected object cues and data visualization are also provided. The algorithms are designed to handle a wide variety of real-world challenges. Imaged scenes may be highly complex and infinitely varied -- the scene background may contain significant celestial, earth limb, or terrestrial clutter. For example, when viewing combined earth limb and terrestrial scenes, a combination of stationary and non-stationary clutter may be present, including cloud formations, varying atmospheric transmittance and reflectance of sunlight and other celestial light sources, aurora, glint off sea surfaces, and varied natural and man-made terrain features. The targets of interest may also appear to be dim, relative to the scene background, rendering much of the existing deployed software useless for optical target detection and tracking. Additionally, it may be necessary to detect and track a large number of objects in the threat cloud

  18. Lack of magnetic resonance imaging lesion activity as a treatment target in multiple sclerosis: An evaluation using electronically collected outcomes.

    Science.gov (United States)

    Conway, Devon S; Thompson, Nicolas R; Cohen, Jeffrey A

    2016-09-01

    The appropriate treatment target in multiple sclerosis (MS) is unclear. Lack of magnetic resonance imaging (MRI) lesion activity, a component of the no evidence of disease activity concept, has been proposed as a treatment target in MS. We used our MS database to investigate whether aggressively pursuing MRI stability by changing disease modifying therapy (DMT) when MRI activity is observed leads to better clinical and imaging outcomes. The Knowledge Program (KP) is a database linked to our electronic medical record allowing capture of patient and clinician reported outcomes. Through KP query and chart review, we identified all relapsing-remitting MS patients visiting between 1 January 2008 and 31 December 2014 with active MRIs despite DMT. Propensity modeling based on demographic and disease characteristics was used to match DMT switchers to non-switchers. KP and MRI outcomes were compared 18 months after the active MRI using mixed-effects linear regression models. We identified 417 patients who met criteria for our analysis. After propensity matching, 78 switchers and 91 non-switchers were analyzed. There was no difference in clinical or radiologic outcomes between these groups at 18 months. We did not find a short-term benefit of changing DMT to pursue MRI stability. Copyright © 2016 Elsevier B.V. All rights reserved.

  19. Multiple polysaccharide-drug complex-loaded liposomes: A unique strategy in drug loading and cancer targeting.

    Science.gov (United States)

    Ruttala, Hima Bindu; Ramasamy, Thiruganesh; Gupta, Biki; Choi, Han-Gon; Yong, Chul Soon; Kim, Jong Oh

    2017-10-01

    In the present study, a unique strategy was developed to develop nanocarriers containing multiple therapeutics with controlled release characteristics. In this study, we demonstrated the synthesis of dextran sulfate-doxorubicin (DS-DOX) and alginate-cisplatin (AL-CIS) polymer-drug complexes to produce a transferrin ligand-conjugated liposome. The targeted nanoparticles (TL-DDAC) were nano-sized and spherical. The targeted liposome exhibited a specific receptor-mediated endocytic uptake in cancer cells. The enhanced cellular uptake of TL-DDAC resulted in a significantly better anticancer effect in resistant and sensitive breast cancer cells compared to that of the free drugs. Specifically, DOX and CIS at a molar ratio of 1:1 exhibited better therapeutic performance compared to that of other combinations. The combination of an anthracycline-based topoisomerase II inhibitor (DOX) and a platinum compound (CIS) resulted in significantly higher cell apoptosis (early and late) in both types of cancer cells. In conclusion, treatment with DS-DOX and AL-CIS based combination liposomes modified with transferrin (TL-DDAC) was an effective cancer treatment strategy. Further investigation in clinically relevant animal models is warranted to prove the therapeutic efficacy of this unique strategy. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Double ionization of the hydrogen sulfide molecule by electron impact: Influence of the target orientation on multiple differential cross sections

    Energy Technology Data Exchange (ETDEWEB)

    Imadouchene, N. [Laboratoire de Mécanique, Structures et Energétique Université Mouloud Mammeri de Tizi-Ouzou, B.P. 17, Tizi-Ouzou 15000 (Algeria); Aouchiche, H., E-mail: h_aouchiche@yahoo.fr [Laboratoire de Mécanique, Structures et Energétique Université Mouloud Mammeri de Tizi-Ouzou, B.P. 17, Tizi-Ouzou 15000 (Algeria); Champion, C. [Centre d’Etudes Nucléaires de Bordeaux Gradignan, Université Bordeaux, CNRS/IN2P3, Boîte Postale 120, Gradignan 33175 (France)

    2016-07-15

    Highlights: • The double ionization of the H{sub 2}S molecule is here theoretically studied. • The orientation dependence of the differential cross sections is scrutinized. • The specific double ionizing mechanisms are clearly identified. - Abstract: Multiple differential cross sections of double ionization of hydrogen sulfide molecule impacted by electrons are here investigated within the first Born approximation. In the initial state, the incident electron is represented by a plane wave function whereas the target is described by means of a single-center molecular wave function. In the final state, the two ejected electrons are described by Coulomb wave functions coupled by the Gamow factor, whereas the scattered electron is described by a plane wave. In this work, we analyze the role played by the molecular target orientation in the double ionization of the four outermost orbitals, namely 2b{sub 1}, 5a{sub 1}, 2b{sub 2} and 4a{sub 1} in considering the particular case of two electrons ejected from the same orbital. The contribution of each final state to the double ionization process is studied in terms of shape and magnitude for specific molecular orientations and for each molecular orbital we identified the mechanisms involved in the double ionization process, namely, the Shake-Off and the Two-Step 1.

  1. The Rho Kinases: Critical Mediators of Multiple Profibrotic Processes and Rational Targets for New Therapies for Pulmonary Fibrosis

    Science.gov (United States)

    Knipe, Rachel S.; Tager, Andrew M.

    2015-01-01

    Idiopathic pulmonary fibrosis (IPF) is characterized by progressive lung scarring, short median survival, and limited therapeutic options, creating great need for new pharmacologic therapies. IPF is thought to result from repetitive environmental injury to the lung epithelium, in the context of aberrant host wound healing responses. Tissue responses to injury fundamentally involve reorganization of the actin cytoskeleton of participating cells, including epithelial cells, fibroblasts, endothelial cells, and macrophages. Actin filament assembly and actomyosin contraction are directed by the Rho-associated coiled-coil forming protein kinase (ROCK) family of serine/threonine kinases (ROCK1 and ROCK2). As would therefore be expected, lung ROCK activation has been demonstrated in humans with IPF and in animal models of this disease. ROCK inhibitors can prevent fibrosis in these models, and more importantly, induce the regression of already established fibrosis. Here we review ROCK structure and function, upstream activators and downstream targets of ROCKs in pulmonary fibrosis, contributions of ROCKs to profibrotic cellular responses to lung injury, ROCK inhibitors and their efficacy in animal models of pulmonary fibrosis, and potential toxicities of ROCK inhibitors in humans, as well as involvement of ROCKs in fibrosis in other organs. As we discuss, ROCK activation is required for multiple profibrotic responses, in the lung and multiple other organs, suggesting ROCK participation in fundamental pathways that contribute to the pathogenesis of a broad array of fibrotic diseases. Multiple lines of evidence therefore indicate that ROCK inhibition has great potential to be a powerful therapeutic tool in the treatment of fibrosis, both in the lung and beyond. PMID:25395505

  2. GLUT2 in pancreatic islets: crucial target molecule in diabetes induced with multiple low doses of streptozotocin in mice.

    Science.gov (United States)

    Wang, Z; Gleichmann, H

    1998-01-01

    In mice, diabetes can be induced by multiple low doses of streptozotocin (MLD-STZ), i.e., 40 mg/kg body wt on each of 5 consecutive days. In this model, diabetes develops only when STZ induces both beta-cell toxicity and T-cell-dependent immune reactions. The target molecule(s) of MLD-STZ-induced beta-cell toxicity are not known, however. In this study, we report that GLUT2 is a target molecule for MLD-STZ toxicity. Ex vivo, a gradual decrement of both GLUT2 protein and mRNA expression was found in pancreatic islets isolated from MLD-STZ-treated C57BL/6 male mice, whereas mRNA expression of beta-actin, glucokinase, and proinsulin remained unaffected. Significant reduction of both GLUT2 protein and mRNA expression was first noted 1 day after the third STZ injection, clearly preceding the onset of hyperglycemia. The extent of reduction increased with the number of STZ injections administered and increased over time, after the last, i.e., fifth, STZ injection. The STZ-induced reduction of GLUT2 protein and mRNA was not due to an essential loss of beta-cells, because ex vivo, not only the total RNA yield and protein content in isolated islets, but also proinsulin mRNA expression, failed to differ significantly in the differently treated groups. Furthermore, islets isolated from MLD-STZ-treated donors responded to the nonglucose secretagogue arginine in a pattern similar to that of solvent-treated donors. Interestingly, the MLD-STZ-induced reduction of both GLUT2 protein and mRNA was prevented by preinjecting mice with 5-thio-D-glucose before each STZ injection. Apparently, GLUT2 is a crucial target molecule of MLD-STZ toxicity, and this toxicity seems to precede the immune reactions against beta-cells.

  3. Targeting multiple cannabinoid anti-tumour pathways with a resorcinol derivative leads to inhibition of advanced stages of breast cancer.

    Science.gov (United States)

    Murase, Ryuichi; Kawamura, Rumi; Singer, Eric; Pakdel, Arash; Sarma, Pranamee; Judkins, Jonathon; Elwakeel, Eiman; Dayal, Sonali; Martinez-Martinez, Esther; Amere, Mukkanti; Gujjar, Ramesh; Mahadevan, Anu; Desprez, Pierre-Yves; McAllister, Sean D

    2014-10-01

    The psychoactive cannabinoid Δ(9) -tetrahydrocannabinol (THC) and the non-psychoactive cannabinoid cannabidiol (CBD) can both reduce cancer progression, each through distinct anti-tumour pathways. Our goal was to discover a compound that could efficiently target both cannabinoid anti-tumour pathways. To measure breast cancer cell proliferation/viability and invasion, MTT and Boyden chamber assays were used. Modulation of reactive oxygen species (ROS) and apoptosis was measured using dichlorodihydrofluorescein and annexin/propidium iodide, respectively, in combination with cell flow cytometry. Changes in protein levels were evaluated using Western analysis. Orthotopic and i.v. mouse models of breast cancer metastasis were used to test the activity of cannabinoids in vivo. CBD reduced breast cancer metastasis in advanced stages of the disease as the direct result of down-regulating the transcriptional regulator Id1. However, this was associated with moderate increases in survival. We therefore screened for analogues that could co-target cannabinoid anti-tumour pathways (CBD- and THC-associated) and discovered the compound O-1663. This analogue inhibited Id1, produced a marked stimulation of ROS, up-regulated autophagy and induced apoptosis. Of all the compounds tested, it was the most potent at inhibiting breast cancer cell proliferation and invasion in culture and metastasis in vivo. O-1663 prolonged survival in advanced stages of breast cancer metastasis. Developing compounds that can simultaneously target multiple cannabinoid anti-tumour pathways efficiently may provide a novel approach for the treatment of patients with metastatic breast cancer. © 2014 The British Pharmacological Society.

  4. Managing multiple diffuse pressures on water quality and ecological habitat: Spatially targeting effective mitigation actions at the landscape scale.

    Science.gov (United States)

    Joyce, Hannah; Reaney, Sim

    2015-04-01

    Catchment systems provide multiple benefits for society, including: land for agriculture, climate regulation and recreational space. Yet, these systems also have undesirable externalities, such as flooding, and the benefits they create can be compromised through societal use. For example, agriculture, forestry and urban land use practices can increase the export of fine sediment and faecal indicator organisms (FIO) delivered to river systems. These diffuse landscape pressures are coupled with pressures on the in stream temperature environment from projected climate change. Such pressures can have detrimental impacts on water quality and ecological habitat and consequently the benefits they provide for society. These diffuse and in-stream pressures can be reduced through actions at the landscape scale but are commonly tackled individually. Any intervention may have benefits for other pressures and hence the challenge is to consider all of the different pressures simultaneously to find solutions with high levels of cross-pressure benefits. This research presents (1) a simple but spatially distributed model to predict the pattern of multiple pressures at the landscape scale, and (2) a method for spatially targeting the optimum location for riparian woodland planting as mitigation action against these pressures. The model follows a minimal information requirement approach along the lines of SCIMAP (www.scimap.org.uk). This approach defines the critical source areas of fine sediment diffuse pollution, rapid overland flow and FIOs, based on the analysis of the pattern of the pressure in the landscape and the connectivity from source areas to rivers. River temperature was modeled using a simple energy balance equation; focusing on temperature of inflowing and outflowing water across a catchment. The model has been calibrated using a long term observed temperature record. The modelling outcomes enabled the identification of the severity of each pressure in relative rather

  5. Targeting p53 via JNK pathway: a novel role of RITA for apoptotic signaling in multiple myeloma.

    Science.gov (United States)

    Saha, Manujendra N; Jiang, Hua; Yang, Yijun; Zhu, Xiaoyun; Wang, Xiaoming; Schimmer, Aaron D; Qiu, Lugui; Chang, Hong

    2012-01-01

    The low frequency of p53 alterations e.g., mutations/deletions (∼10%) in multiple myeloma (MM) makes this tumor type an ideal candidate for p53-targeted therapies. RITA is a small molecule which can induce apoptosis in tumor cells by activating the p53 pathway. We previously showed that RITA strongly activates p53 while selectively inhibiting growth of MM cells without inducing genotoxicity, indicating its potential as a drug lead for p53-targeted therapy in MM. However, the molecular mechanisms underlying the pro-apoptotic effect of RITA are largely undefined. Gene expression analysis by microarray identified a significant number of differentially expressed genes associated with stress response including c-Jun N-terminal kinase (JNK) signaling pathway. By Western blot analysis we further confirmed that RITA induced activation of p53 in conjunction with up-regulation of phosphorylated ASK-1, MKK-4 and c-Jun. These results suggest that RITA induced the activation of JNK signaling. Chromatin immunoprecipitation (ChIP) analysis showed that activated c-Jun binds to the activator protein-1 (AP-1) binding site of the p53 promoter region. Disruption of the JNK signal pathway by small interfering RNA (siRNA) against JNK or JNK specific inhibitor, SP-600125 inhibited the activation of p53 and attenuated apoptosis induced by RITA in myeloma cells carrying wild type p53. On the other hand, p53 transcriptional inhibitor, PFT-α or p53 siRNA not only inhibited the activation of p53 transcriptional targets but also blocked the activation of c-Jun suggesting the presence of a positive feedback loop between p53 and JNK. In addition, RITA in combination with dexamethasone, known as a JNK activator, displays synergistic cytotoxic responses in MM cell lines and patient samples. Our study unveils a previously undescribed mechanism of RITA-induced p53-mediated apoptosis through JNK signaling pathway and provides the rationale for combination of p53 activating drugs with JNK

  6. Targeting p53 via JNK pathway: a novel role of RITA for apoptotic signaling in multiple myeloma.

    Directory of Open Access Journals (Sweden)

    Manujendra N Saha

    Full Text Available The low frequency of p53 alterations e.g., mutations/deletions (∼10% in multiple myeloma (MM makes this tumor type an ideal candidate for p53-targeted therapies. RITA is a small molecule which can induce apoptosis in tumor cells by activating the p53 pathway. We previously showed that RITA strongly activates p53 while selectively inhibiting growth of MM cells without inducing genotoxicity, indicating its potential as a drug lead for p53-targeted therapy in MM. However, the molecular mechanisms underlying the pro-apoptotic effect of RITA are largely undefined. Gene expression analysis by microarray identified a significant number of differentially expressed genes associated with stress response including c-Jun N-terminal kinase (JNK signaling pathway. By Western blot analysis we further confirmed that RITA induced activation of p53 in conjunction with up-regulation of phosphorylated ASK-1, MKK-4 and c-Jun. These results suggest that RITA induced the activation of JNK signaling. Chromatin immunoprecipitation (ChIP analysis showed that activated c-Jun binds to the activator protein-1 (AP-1 binding site of the p53 promoter region. Disruption of the JNK signal pathway by small interfering RNA (siRNA against JNK or JNK specific inhibitor, SP-600125 inhibited the activation of p53 and attenuated apoptosis induced by RITA in myeloma cells carrying wild type p53. On the other hand, p53 transcriptional inhibitor, PFT-α or p53 siRNA not only inhibited the activation of p53 transcriptional targets but also blocked the activation of c-Jun suggesting the presence of a positive feedback loop between p53 and JNK. In addition, RITA in combination with dexamethasone, known as a JNK activator, displays synergistic cytotoxic responses in MM cell lines and patient samples. Our study unveils a previously undescribed mechanism of RITA-induced p53-mediated apoptosis through JNK signaling pathway and provides the rationale for combination of p53 activating drugs with

  7. Targeting demyelination and virtual hypoxia with high-dose biotin as a treatment for progressive multiple sclerosis.

    Science.gov (United States)

    Sedel, Frédéric; Bernard, Delphine; Mock, Donald M; Tourbah, Ayman

    2016-11-01

    Progressive multiple sclerosis (MS) is a severely disabling neurological condition, and an effective treatment is urgently needed. Recently, high-dose biotin has emerged as a promising therapy for affected individuals. Initial clinical data have shown that daily doses of biotin of up to 300 mg can improve objective measures of MS-related disability. In this article, we review the biology of biotin and explore the properties of this ubiquitous coenzyme that may explain the encouraging responses seen in patients with progressive MS. The gradual worsening of neurological disability in patients with progressive MS is caused by progressive axonal loss or damage. The triggers for axonal loss in MS likely include both inflammatory demyelination of the myelin sheath and primary neurodegeneration caused by a state of virtual hypoxia within the neuron. Accordingly, targeting both these pathological processes could be effective in the treatment of progressive MS. Biotin is an essential co-factor for five carboxylases involved in fatty acid synthesis and energy production. We hypothesize that high-dose biotin is exerting a therapeutic effect in patients with progressive MS through two different and complementary mechanisms: by promoting axonal remyelination by enhancing myelin production and by reducing axonal hypoxia through enhanced energy production. This article is part of the Special Issue entitled 'Oligodendrocytes in Health and Disease'. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  8. Two (or three) is one too many: testing the flexibility of contextual cueing with multiple target locations.

    Science.gov (United States)

    Zellin, Martina; Conci, Markus; von Mühlenen, Adrian; Müller, Hermann J

    2011-10-01

    Visual search for a target object is facilitated when the object is repeatedly presented within an invariant context of surrounding items ("contextual cueing"; Chun & Jiang, Cognitive Psychology, 36, 28-71, 1998). The present study investigated whether such invariant contexts can cue more than one target location. In a series of three experiments, we showed that contextual cueing is significantly reduced when invariant contexts are paired with two rather than one possible target location, whereas no contextual cueing occurs with three distinct target locations. Closer data inspection revealed that one "dominant" target always exhibited substantially more contextual cueing than did the other, "minor" target(s), which caused negative contextual-cueing effects. However, minor targets could benefit from the invariant context when they were spatially close to the dominant target. In sum, our experiments suggest that contextual cueing can guide visual attention to a spatially limited region of the display, only enhancing the detection of targets presented inside that region.

  9. Multiple reaction monitoring targeted LC-MS analysis of potential cell death marker proteins for increased bioprocess control.

    Science.gov (United States)

    Albrecht, Simone; Kaisermayer, Christian; Reinhart, David; Ambrose, Monica; Kunert, Renate; Lindeberg, Anna; Bones, Jonathan

    2018-05-01

    The monitoring of protein biomarkers for the early prediction of cell stress and death is a valuable tool for process characterization and efficient biomanufacturing control. A representative set of six proteins, namely GPDH, PRDX1, LGALS1, CFL1, TAGLN2 and MDH, which were identified in a previous CHO-K1 cell death model using discovery LC-MS E was translated into a targeted liquid chromatography multiple reaction monitoring mass spectrometry (LC-MRM-MS) platform and verified. The universality of the markers was confirmed in a cell growth model for which three Chinese hamster ovary host cell lines (CHO-K1, CHO-S, CHO-DG44) were grown in batch culture in two different types of basal media. LC-MRM-MS was also applied to spent media (n = 39) from four perfusion biomanufacturing series. Stable isotope-labelled peptide analogues and a stable isotope-labelled monoclonal antibody were used for improved protein quantitation and simultaneous monitoring of the workflow reproducibility. Significant increases in protein concentrations were observed for all viability marker proteins upon increased dead cell numbers and allowed for discrimination of spent media with dead cell densities below and above 1 × 10 6  dead cells/mL which highlights the potential of the selected viability marker proteins in bioprocess control. Graphical abstract Overview of the LC-MRM-MS workflow for the determination of proteomic markers in conditioned media from the bioreactor that correlate with CHO cell death.

  10. D- production by multiple charge-transfer collisions in metal-vapor targets. [1 to 50 keV D/sup +/

    Energy Technology Data Exchange (ETDEWEB)

    Schlachter, A.S.

    1977-09-01

    A beam of D/sup -/ions can be produced by multiple charge-transfer collisions of a D/sup +/ beam in a thick metal-vapor target. Cross sections and equilibrium charge-state fractions are presented and discussed.

  11. Technical Note: Using k-means clustering to determine the number and position of isocenters in MLC-based multiple target intracranial radiosurgery.

    Science.gov (United States)

    Yock, Adam D; Kim, Gwe-Ya

    2017-09-01

    To present the k-means clustering algorithm as a tool to address treatment planning considerations characteristic of stereotactic radiosurgery using a single isocenter for multiple targets. For 30 patients treated with stereotactic radiosurgery for multiple brain metastases, the geometric centroids and radii of each met were determined from the treatment planning system. In-house software used this as well as weighted and unweighted versions of the k-means clustering algorithm to group the targets to be treated with a single isocenter, and to position each isocenter. The algorithm results were evaluated using within-cluster sum of squares as well as a minimum target coverage metric that considered the effect of target size. Both versions of the algorithm were applied to an example patient to demonstrate the prospective determination of the appropriate number and location of isocenters. Both weighted and unweighted versions of the k-means algorithm were applied successfully to determine the number and position of isocenters. Comparing the two, both the within-cluster sum of squares metric and the minimum target coverage metric resulting from the unweighted version were less than those from the weighted version. The average magnitudes of the differences were small (-0.2 cm 2 and 0.1% for the within cluster sum of squares and minimum target coverage, respectively) but statistically significant (Wilcoxon signed-rank test, P k-means clustering algorithm represented an advantage of the unweighted version for the within-cluster sum of squares metric, and an advantage of the weighted version for the minimum target coverage metric. While additional treatment planning considerations have a large influence on the final treatment plan quality, both versions of the k-means algorithm provide automatic, consistent, quantitative, and objective solutions to the tasks associated with SRS treatment planning using a single isocenter for multiple targets. © 2017 The Authors. Journal

  12. Ibrutinib targets microRNA-21 in multiple myeloma cells by inhibiting NF-κB and STAT3.

    Science.gov (United States)

    Ma, Jing; Gong, Wei; Liu, Su; Li, Qian; Guo, Mengzheng; Wang, Jinhan; Wang, Suying; Chen, Naiyao; Wang, Yafei; Liu, Qiang; Zhao, Hui

    2018-01-01

    The oncogenic microRNA-21 contributes to the pathogenesis of multiple myeloma. Ibrutinib (also referred to as PCI-32765), an inhibitor of Bruton's tyrosine kinase, while its effects on multiple myeloma have not been well described. Here, we show that microRNA-21 is an oncogenic marker closely linked with progression of multiple myeloma. Moreover, ibrutinib attenuates microRNA-21 expression in multiple myeloma cells by inhibiting nuclear factor-κB and signal transducer and activator of transcription 3 signaling pathways. Taken together, our results suggest that ibrutinib is a promising potential treatment for multiple myeloma. Further investigation of mechanisms of ibrutinib function in multiple myeloma will be necessary to evaluate its use as a novel multiple myeloma treatment.

  13. Feature-space assessment of electrical impedance tomography coregistered with computed tomography in detecting multiple contrast targets

    International Nuclear Information System (INIS)

    Krishnan, Kalpagam; Liu, Jeff; Kohli, Kirpal

    2014-01-01

    Purpose: Fusion of electrical impedance tomography (EIT) with computed tomography (CT) can be useful as a clinical tool for providing additional physiological information about tissues, but requires suitable fusion algorithms and validation procedures. This work explores the feasibility of fusing EIT and CT images using an algorithm for coregistration. The imaging performance is validated through feature space assessment on phantom contrast targets. Methods: EIT data were acquired by scanning a phantom using a circuit, configured for injecting current through 16 electrodes, placed around the phantom. A conductivity image of the phantom was obtained from the data using electrical impedance and diffuse optical tomography reconstruction software (EIDORS). A CT image of the phantom was also acquired. The EIT and CT images were fused using a region of interest (ROI) coregistration fusion algorithm. Phantom imaging experiments were carried out on objects of different contrasts, sizes, and positions. The conductive medium of the phantoms was made of a tissue-mimicking bolus material that is routinely used in clinical radiation therapy settings. To validate the imaging performance in detecting different contrasts, the ROI of the phantom was filled with distilled water and normal saline. Spatially separated cylindrical objects of different sizes were used for validating the imaging performance in multiple target detection. Analyses of the CT, EIT and the EIT/CT phantom images were carried out based on the variations of contrast, correlation, energy, and homogeneity, using a gray level co-occurrence matrix (GLCM). A reference image of the phantom was simulated using EIDORS, and the performances of the CT and EIT imaging systems were evaluated and compared against the performance of the EIT/CT system using various feature metrics, detectability, and structural similarity index measures. Results: In detecting distilled and normal saline water in bolus medium, EIT as a stand

  14. Targeting Accuracy of Image-Guided Radiosurgery for Intracranial Lesions: A Comparison Across Multiple Linear Accelerator Platforms.

    Science.gov (United States)

    Huang, Yimei; Zhao, Bo; Chetty, Indrin J; Brown, Stephen; Gordon, James; Wen, Ning

    2016-04-01

    To evaluate the overall positioning accuracy of image-guided intracranial radiosurgery across multiple linear accelerator platforms. A computed tomography scan with a slice thickness of 1.0 mm was acquired of an anthropomorphic head phantom in a BrainLAB U-frame mask. The phantom was embedded with three 5-mm diameter tungsten ball bearings, simulating a central, a left, and an anterior cranial lesion. The ball bearings were positioned to radiation isocenter under ExacTrac X-ray or cone-beam computed tomography image guidance on 3 Linacs: (1) ExacTrac X-ray localization on a Novalis Tx; (2) cone-beam computed tomography localization on the Novalis Tx; (3) cone-beam computed tomography localization on a TrueBeam; and (4) cone-beam computed tomography localization on an Edge. Each ball bearing was positioned 5 times to the radiation isocenter with different initial setup error following the 4 image guidance procedures on the 3 Linacs, and the mean (µ) and one standard deviation (σ) of the residual error were compared. Averaged overall 3 ball bearing locations, the vector length of the residual setup error in mm (µ ± σ) was 0.6 ± 0.2, 1.0 ± 0.5, 0.2 ± 0.1, and 0.3 ± 0.1 on ExacTrac X-ray localization on a Novalis Tx, cone-beam computed tomography localization on the Novalis Tx, cone-beam computed tomography localization on a TrueBeam, and cone-beam computed tomography localization on an Edge, with their range in mm being 0.4 to 1.1, 0.4 to 1.9, 0.1 to 0.5, and 0.2 to 0.6, respectively. The congruence between imaging and radiation isocenters in mm was 0.6 ± 0.1, 0.7 ± 0.1, 0.3 ± 0.1, and 0.2 ± 0.1, for the 4 systems, respectively. Targeting accuracy comparable to frame-based stereotactic radiosurgery can be achieved with image-guided intracranial stereotactic radiosurgery treatment. © The Author(s) 2015.

  15. Two (or three) is one too many : testing the flexibility of contextual cueing with multiple target locations

    OpenAIRE

    Zellin, Martina; Conci, Markus; von Mühlenen, Adrian; Müller, Hermann J.

    2011-01-01

    Visual search for a target object is facilitated when the object is repeatedly presented within an invariant context of surrounding items ("contextual cueing"; Chun & Jiang, Cognitive Psychology, 36, 28-71, 1998). The present study investigated whether such invariant contexts can cue more than one target location. In a series of three experiments, we showed that contextual cueing is significantly reduced when invariant contexts are paired with two rather than one possible target location, whe...

  16. Lorazepam induces multiple disturbances in selective attention: attentional overload, decrement in target processing efficiency, and shifts in perceptual discrimination and response bias.

    Science.gov (United States)

    Michael, George Andrew; Bacon, Elisabeth; Offerlin-Meyer, Isabelle

    2007-09-01

    There is a general consensus that benzodiazepines affect attentional processes, yet only few studies have tried to investigate these impairments in detail. The purpose of the present study was to investigate the effects of a single dose of Lorazepam on performance in a target cancellation task with important time constraints. We measured correct target detections and correct distractor rejections, misses and false positives. The results show that Lorazepam produces multiple kinds of shifts in performance, which suggests that it impairs multipLe processes: (a) the evolution of performance over time was not the same between the placebo and the Lorazepam groups, with the Lorazepam affecting performance quite early after the beginning of the test. This is suggestive of a depletion of attentional resources during sequential attentional processing; (b) Lorazepam affected differently target and distractor processing, with target detection being the most impaired; (c) misses were more frequent under Lorazepam than under placebo, but no such difference was observed as far as false positives were concerned. Signal detection analyses showed that Lorazepam (d) decreased perceptual discrimination, and (e) reliably increased response bias. Our results bring new insights on the multiple effects of Lorazepam on selective attention which, when combined, may have deleterious effects on human performance.

  17. 'Multi-epitope-targeted' immune-specific therapy for a multiple sclerosis-like disease via engineered multi-epitope protein is superior to peptides.

    Directory of Open Access Journals (Sweden)

    Nathali Kaushansky

    Full Text Available Antigen-induced peripheral tolerance is potentially one of the most efficient and specific therapeutic approaches for autoimmune diseases. Although highly effective in animal models, antigen-based strategies have not yet been translated into practicable human therapy, and several clinical trials using a single antigen or peptidic-epitope in multiple sclerosis (MS yielded disappointing results. In these clinical trials, however, the apparent complexity and dynamics of the pathogenic autoimmunity associated with MS, which result from the multiplicity of potential target antigens and "epitope spread", have not been sufficiently considered. Thus, targeting pathogenic T-cells reactive against a single antigen/epitope is unlikely to be sufficient; to be effective, immunospecific therapy to MS should logically neutralize concomitantly T-cells reactive against as many major target antigens/epitopes as possible. We investigated such "multi-epitope-targeting" approach in murine experimental autoimmune encephalomyelitis (EAE associated with a single ("classical" or multiple ("complex" anti-myelin autoreactivities, using cocktail of different encephalitogenic peptides vis-a-vis artificial multi-epitope-protein (designated Y-MSPc encompassing rationally selected MS-relevant epitopes of five major myelin antigens, as "multi-epitope-targeting" agents. Y-MSPc was superior to peptide(s in concomitantly downregulating pathogenic T-cells reactive against multiple myelin antigens/epitopes, via inducing more effective, longer lasting peripheral regulatory mechanisms (cytokine shift, anergy, and Foxp3+ CTLA4+ regulatory T-cells. Y-MSPc was also consistently more effective than the disease-inducing single peptide or peptide cocktail, not only in suppressing the development of "classical" or "complex EAE" or ameliorating ongoing disease, but most importantly, in reversing chronic EAE. Overall, our data emphasize that a "multi-epitope-targeting" strategy is required for

  18. Targeting of OSBP-related protein 3 (ORP3) to endoplasmic reticulum and plasma membrane is controlled by multiple determinants

    International Nuclear Information System (INIS)

    Lehto, Markku; Hynynen, Riikka; Karjalainen, Katja; Kuismanen, Esa; Hyvaerinen, Kati; Olkkonen, Vesa M.

    2005-01-01

    The intracellular targeting determinants of oxysterol binding protein (OSBP)-related protein 3 (ORP3) were studied using a series of truncated and point mutated constructs. The pleckstrin homology (PH) domain of ORP3 binds the phosphoinositide-3-kinase (PI3K) products, PI(3,4)P 2 and PI(3,4,5)P 3 . A functional PH domain and flanking sequences are crucial for the plasma membrane (PM) targeting of ORP3. The endoplasmic reticulum (ER) targeting of ORP3 is regulated the by a FFAT motif (EFFDAxE), which mediates interaction with VAMP-associated protein (VAP)-A. The targeting function of the FFAT motif dominates over that of the PH domain. In addition, the exon 10/11 region modulates interaction of ORP3 with the ER and the nuclear membrane. Analysis of a chimeric ORP3:OSBP protein suggests that ligand binding by the C-terminal domain of OSBP induces allosteric changes that activate the N-terminal targeting modules of ORP3. Notably, over-expression of ORP3 together with VAP-A induces stacked ER membrane structures also known as organized smooth ER (OSER). Moreover, lipid starvation promotes formation of dilated peripheral ER (DPER) structures dependent on the ORP3 protein. Based on the present data, we introduce a model for the inter-relationships of the functional domains of ORP3 in the membrane targeting of the protein

  19. Glatiramer Acetate in Treatment of Multiple Sclerosis: A Toolbox of Random Co-Polymers for Targeting Inflammatory Mechanisms of both the Innate and Adaptive Immune System?

    Directory of Open Access Journals (Sweden)

    Thomas Vorup-Jensen

    2012-11-01

    Full Text Available Multiple sclerosis is a disease of the central nervous system, resulting in the demyelination of neurons, causing mild to severe symptoms. Several anti-inflammatory treatments now play a significant role in ameliorating the disease. Glatiramer acetate (GA is a formulation of random polypeptide copolymers for the treatment of relapsing-remitting MS by limiting the frequency of attacks. While evidence suggests the influence of GA on inflammatory responses, the targeted molecular mechanisms remain poorly understood. Here, we review the multiple pharmacological modes-of-actions of glatiramer acetate in treatment of multiple sclerosis. We discuss in particular a newly discovered interaction between the leukocyte-expressed integrin αMβ2 (also called Mac-1, complement receptor 3, or CD11b/CD18 and perspectives on the GA co-polymers as an influence on the function of the innate immune system.

  20. In Silico Design and Experimental Validation of siRNAs Targeting Conserved Regions of Multiple Hepatitis C Virus Genotypes.

    Directory of Open Access Journals (Sweden)

    Mahmoud ElHefnawi

    Full Text Available RNA interference (RNAi is a post-transcriptional gene silencing mechanism that mediates the sequence-specific degradation of targeted RNA and thus provides a tremendous opportunity for development of oligonucleotide-based drugs. Here, we report on the design and validation of small interfering RNAs (siRNAs targeting highly conserved regions of the hepatitis C virus (HCV genome. To aim for therapeutic applications by optimizing the RNAi efficacy and reducing potential side effects, we considered different factors such as target RNA variations, thermodynamics and accessibility of the siRNA and target RNA, and off-target effects. This aim was achieved using an in silico design and selection protocol complemented by an automated MysiRNA-Designer pipeline. The protocol included the design and filtration of siRNAs targeting highly conserved and accessible regions within the HCV internal ribosome entry site, and adjacent core sequences of the viral genome with high-ranking efficacy scores. Off-target analysis excluded siRNAs with potential binding to human mRNAs. Under this strict selection process, two siRNAs (HCV353 and HCV258 were selected based on their predicted high specificity and potency. These siRNAs were tested for antiviral efficacy in HCV genotype 1 and 2 replicon cell lines. Both in silico-designed siRNAs efficiently inhibited HCV RNA replication, even at low concentrations and for short exposure times (24h; they also exceeded the antiviral potencies of reference siRNAs targeting HCV. Furthermore, HCV353 and HCV258 siRNAs also inhibited replication of patient-derived HCV genotype 4 isolates in infected Huh-7 cells. Prolonged treatment of HCV replicon cells with HCV353 did not result in the appearance of escape mutant viruses. Taken together, these results reveal the accuracy and strength of our integrated siRNA design and selection protocols. These protocols could be used to design highly potent and specific RNAi-based therapeutic

  1. Multiplicities of charged pions and charged hadrons from deep-inelastic scattering of muons off an isoscalar target

    Czech Academy of Sciences Publication Activity Database

    Adolph, C.; Aghasyan, M.; Akhunzyanov, R.; Alexeev, G. D.; Alexeev, M.; Amoroso, A.; Andrieux, V.; Anfimov, N. V.; Anosov, V.; Augsten, K.; Augustyniak, W.; Austregesilo, A.; Azevedo, C.; Badelek, B.; Balestra, F.; Barth, J.; Beck, D.; Bedfer, Y.; Bernhard, J.; Bicker, K.; Bielert, E. R.; Birsa, R.; Bisplinghoff, J.; Bodlák, M.; Boer, M.; Bordalo, P.; Bradamante, F.; Braun, C.; Bressan, A.; Büchele, M.; Capozza, L.; Chang, W.-C.; Chatterjee, C.; Chiosso, M.; Choi, I.; Chung, S.U.; Cicuttin, A.; Crespo, M.; Curiel, Q.; Dalla Torre, S.; Dasgupta, S. S.; Dasgupta, S.; Denisov, O.; Dhara, L.; Donskov, S. V.; Doshita, N.; Duic, V.; Dünnweber, W.; Dziewiecki, M.; Efremov, A.; Eversheim, P.D.; Eyrich, W.; Faessler, M.; Ferrero, A.; Finger, M.; Finger jr., M.; Fischer, H.; Franco, C.; Fresne von Hohenesche, N.; Friedrich, J. M.; Frolov, V.; Fuchey, E.; Gautheron, F.; Gavrichtchouk, O. P.; Gerassimov, S.; Giordano, F.; Gnesi, I.; Gorzellik, M.; Grabmüller, S.; Grasso, A.; Grosse-Perdekapm, M.; Grube, B.; Grussenmeyer, T.; Guskov, A.; Haas, F.; Hahne, D.; von Harrach, D.; Hashimoto, R.; Heinsius, F. H.; Heitz, R.; Herrmann, E.; Hinterberger, F.; Horikawa, N.; d'Hose, N.; Hsieh, C.-Yu.; Huber, S.; Ishimoto, S.; Ivanov, A.; Ivanshin, Yu.; Iwata, T.; Jahn, R.; Jarý, V.; Joosten, R.; Jörg, P.; Kabuss, E.; Ketzer, B.; Khaustov, G. V.; Khokhlov, Yu. A.; Kisselev, Y.; Klein, F.; Klimaszewski, K.; Koivuniemi, J. H.; Kolosov, V. N.; Kondo, K.; Königsmann, K.; Konorov, I.; Konstantinov, V. F.; Kotzinian, A. M.; Kouznetsov, O.; Krämer, M.; Kremser, P.; Krinner, F.; Kroumchtein, Z. V.; Kuhn, R.; Kulinich, Y.; Kunne, F.; Kurek, K.; Kurjata, R. P.; Lednev, A. A.; Lehmann, A.; Levillain, M.; Levorato, S.; Lian, Y.-S.; Lichtenstadt, J.; Longo, R.; Maggiora, A.; Magnon, A.; Makins, N.; Makke, N.; Mallot, G. K.; Marchand, C.; Marianski, B.; Martin, A.; Marzec, J.; Matoušek, J.; Matsuda, H.; Matsuda, T.; Meshcheryakov, G.; Meyer, M.; Meyer, W.; Michigami, T.; Mikhailov, Yu. V.; Mikhasenko, M.; Mitrofanov, E.; Mitrofanov, N.; Miyachi, Y.; Montuenga, P.; Nagaytsev, A.; Nerling, F.; Neyret, D.; Nikolaenko, V. I.; Nový, J.; Nowak, W. D.; Nukazuka, G.; Nunes, A.S.; Olshevsky, A. G.; Orlov, I.; Ostrick, M.; Panzieri, D.; Parsamyan, B.; Paul, S.; Peng, J.-C.; Pereira, F.; Pešek, M.; Peshekhonov, D. V.; Pierre, N.; Platchkov, S.; Pochodzalla, J.; Polyakov, V. A.; Pretz, J.; Quaresma, M.; Quintans, C.; Ramos, S.; Regali, C.; Reicherz, G.; Riedl, C.; Roskot, M.; Rossiyskaya, N. S.; Ryabchikov, D.; Rybnikov, A.; Rychter, A.; Salač, R.; Samoylenko, V. D.; Sandacz, A.; Santos, C.; Sarkar, S.; Savin, I. A.; Sawada, T.; Sbrizzai, G.; Schiavon, P.; Schmidt, K.; Schmieden, H.; Schönning, K.; Schopferer, S.; Seder, E.; Selyunin, A.; Shevchenko, O. Yu.; Silva, L.; Sinha, L.; Sirtl, S.; Slunecka, M.; Smolík, J.; Sozzi, F.; Srnka, Aleš; Steffen, D.; Stolarski, M.; Šulc, M.; Suzuki, H.; Szabelski, A.; Szameitat, T.; Sznajder, P.; Takekawa, S.; Tasevsky, M.; Tessaro, S.; Tessarotto, F.; Thibaud, F.; Tosello, F.; Tskhay, V.; Uhl, S.; Veloso, J.; Virius, M.; Vondra, J.; Weisrock, T.; Wilfert, M.; Windmolders, R.; Ter Wolbeek, J.; Zaremba, K.; Závada, P.; Zavertyaev, M.; Zemlyanichkina, E.; Zhuravlev, N.; Ziembicki, M.; Zink, A.

    2017-01-01

    Roč. 764, JAN (2017), s. 1-10 ISSN 0370-2693 R&D Projects: GA MŠk(CZ) LO1212 Institutional support: RVO:68081731 Keywords : deep inelastic scattering * pion multiplicities * fragmentation functions Subject RIV: BM - Solid Matter Physics ; Magnetism OBOR OECD: Nuclear physics Impact factor: 4.807, year: 2016

  2. Target intervention against multiple-risk markers to reduce cardiovascular disease in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Gaede, Peter; Pedersen, Oluf

    2004-01-01

    The risk of cardiovascular disease is markedly increased in patients with type 2 diabetes with a prevalence twice as high compared to the background population. With the recognition of multiple concomitant risk factors for both microvascular as well as cardiovascular disease in type 2 diabetic pa...

  3. Multiple cues on the physiochemical, mesenchymal, and intracellular trafficking interactions with nanocarriers to maximize tumor target efficiency

    Directory of Open Access Journals (Sweden)

    Kim SW

    2015-06-01

    Full Text Available Sang-Woo Kim, Dongwoo Khang Nanomedicine Laboratory, Department of Molecular Medicine, School of Medicine, Gachon University, Incheon, South Korea Abstract: Over the past 60 years, numerous medical strategies have been employed to overcome neoplasms. In fact, with the exception of lung, bronchial, and pancreatic cancers, the 5-year survival rate of most cancers currently exceeds 70%. However, the quality of life of patients during chemotherapy remains unsatisfactory despite the increase in survival rate. The side effects of current chemotherapies stem from poor target efficiency at tumor sites due to the uncontrolled biodistribution of anticancer agents (ie, conventional or current approved nanodrugs. This review discusses the effective physiochemical factors for determining biodistribution of nanocarriers and, ultimately, increasing tumor-targeting probability by avoiding the reticuloendothelial system. Second, stem cell-conjugated nanotherapeutics was addressed to maximize the tumor searching ability and to inhibit tumor growth. Lastly, physicochemical material properties of anticancer nanodrugs were discussed for targeting cellular organelles with modulation of drug-release time. A better understanding of suggested topics will increase the tumor-targeting ability of anticancer drugs and, ultimately, promote the quality of life of cancer patients during chemotherapy. Keywords: cancer, anticancer nanodrugs, mesenchymal stem cell, intracellular trafficking

  4. Myosin-1A Targets to Microvilli Using Multiple Membrane Binding Motifs in the Tail Homology 1 (TH1) Domain*

    Science.gov (United States)

    Mazerik, Jessica N.; Tyska, Matthew J.

    2012-01-01

    One of the most abundant components of the enterocyte brush border is the actin-based monomeric motor, myosin-1a (Myo1a). Within brush border microvilli, Myo1a carries out a number of critical functions at the interface between membrane and actin cytoskeleton. Proper physiological function of Myo1a depends on its ability to bind to microvillar membrane, an interaction mediated by a C-terminal tail homology 1 (TH1) domain. However, little is known about the mechanistic details of the Myo1a-TH1/membrane interaction. Structure-function analysis of Myo1a-TH1 targeting in epithelial cells revealed that an N-terminal motif conserved among class I myosins and a C-terminal motif unique to Myo1a-TH1 are both required for steady state microvillar enrichment. Purified Myo1a bound to liposomes composed of phosphatidylserine and phosphoinositol 4,5-bisphosphate, with moderate affinity in a charge-dependent manner. Additionally, peptides of the N- and C-terminal regions required for targeting were able to compete with Myo1a for binding to highly charged liposomes in vitro. Single molecule total internal reflection fluorescence microscopy showed that these motifs are also necessary for slowing the membrane detachment rate in cells. Finally, Myo1a-TH1 co-localized with both lactadherin-C2 (a phosphatidylserine-binding protein) and PLCδ1-PH (a phosphoinositol 4,5-bisphosphate-binding protein) in microvilli, but only lactaderin-C2 expression reduced brush border targeting of Myo1a-TH1. Together, our results suggest that Myo1a targeting to microvilli is driven by membrane binding potential that is distributed throughout TH1 rather than localized to a single motif. These data highlight the diversity of mechanisms that enable different class I myosins to target membranes in distinct biological contexts. PMID:22367206

  5. Hindsight regulates photoreceptor axon targeting through transcriptional control of jitterbug/Filamin and multiple genes involved in axon guidance in Drosophila.

    Science.gov (United States)

    Oliva, Carlos; Molina-Fernandez, Claudia; Maureira, Miguel; Candia, Noemi; López, Estefanía; Hassan, Bassem; Aerts, Stein; Cánovas, José; Olguín, Patricio; Sierralta, Jimena

    2015-09-01

    During axon targeting, a stereotyped pattern of connectivity is achieved by the integration of intrinsic genetic programs and the response to extrinsic long and short-range directional cues. How this coordination occurs is the subject of intense study. Transcription factors play a central role due to their ability to regulate the expression of multiple genes required to sense and respond to these cues during development. Here we show that the transcription factor HNT regulates layer-specific photoreceptor axon targeting in Drosophila through transcriptional control of jbug/Filamin and multiple genes involved in axon guidance and cytoskeleton organization.Using a microarray analysis we identified 235 genes whose expression levels were changed by HNT overexpression in the eye primordia. We analyzed nine candidate genes involved in cytoskeleton regulation and axon guidance, six of which displayed significantly altered gene expression levels in hnt mutant retinas. Functional analysis confirmed the role of OTK/PTK7 in photoreceptor axon targeting and uncovered Tiggrin, an integrin ligand, and Jbug/Filamin, a conserved actin- binding protein, as new factors that participate of photoreceptor axon targeting. Moreover, we provided in silico and molecular evidence that supports jbug/Filamin as a direct transcriptional target of HNT and that HNT acts partially through Jbug/Filamin in vivo to regulate axon guidance. Our work broadens the understanding of how HNT regulates the coordinated expression of a group of genes to achieve the correct connectivity pattern in the Drosophila visual system. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 75: 1018-1032, 2015. © 2015 Wiley Periodicals, Inc.

  6. The microRNA-132/212 family fine-tunes multiple targets in Angiotensin II signalling in cardiac fibroblasts

    DEFF Research Database (Denmark)

    Eskildsen, Tilde V; Schneider, Mikael; Sandberg, Maria B

    2015-01-01

    INTRODUCTION: MicroRNAs (miRNAs) are emerging as key regulators of cardiovascular development and disease; however, the cardiac miRNA target molecules are not well understood. We and others have described the Angiotensin II (AngII)-induced miR-132/212 family as novel regulators of cardiovascular...... in silico and in vitro experiments to identify miR-132/212 molecular targets in primary rat cardiac fibroblasts. RESULTS: MiR-132/212 overexpression increased fibroblast cell size and mRNA arrays detected several hundred genes that were differentially expressed, including a wide panel of receptors...... pathways that fine-tuned by miR-132/212, suggesting a role for this miRNA family as master signalling switches in cardiac fibroblasts. Our data underscore the potential for miRNA tools to manipulate a large array of molecules and thereby control biological function....

  7. Selected Arterial Infusion Chemotherapy Combined with Target Drugs 
for Non-small Cell Lung Cancer with Multiple Brain Metastase

    Directory of Open Access Journals (Sweden)

    Jinduo LI

    2012-05-01

    Full Text Available Background and objective The aim of this study is to evaluate the efficacy of selected arterial infusion chemotherapy in treating non-small cell lung cancer (NSCLC with multiple brain metastases and corresponding factors to influencing prognosis. Methods From September 2008 to October 2011, a total of 31 patients of NSCLC with multiple brain metastases (≥3 received selected incranial, bronchial and corresponding target arterial infusion chemotherapy combined with EGFR-TKIs. Interventional treatment was performed every four weeks, two-six cycles with synchronized or sequential targeted drugs (erlotinib, gefitinib or icotinib. Follow-up CT and MRI were regularly finished at interval of four weeks after two cycles of interventional treatment were finished or during taking targeted drugs in order to evaluate efficacy of the therapy. The procedure was stopped for the tumor disease was worse or the patient could not tolerate the toxity of drugs any longer. Results 31 patients was performed two to six cycles of interventional therapy, 3cycles at average. Response assessment showed that 5 (16.1% patients got a complete response (CR, 7 (22.6% had a partial response (PR, 11 (35.5% had a stable disease (SD and 8 (25.8% had a progressive disease (PD. The objective response rate (ORR was 38.7%, and the disease control rate was 74.2%. The median progression free survival (PFS and overall survival (OS were 13.1 months and 15.1 months. The 6-month survival rate, one-year survival rate and two-year survival rate were 79%, 61.1%, and 31.1%, respectively. The patients’ OS and PFS were influenced by smoking state, tumor pathology, extracranial metastases, period of targeted drug taking and performance status, not by sex, age, before therapy and the total of brain metastases. Conclusion Selected arterial infusion chemotherapy with targeted drugs is one of the most effective and safe treatment to NSCLC with multiple brain metastases. Smoking status, tumor

  8. Silver nanoclusters-assisted ion-exchange reaction with CdTe quantum dots for photoelectrochemical detection of adenosine by target-triggering multiple-cycle amplification strategy.

    Science.gov (United States)

    Zhao, Yang; Tan, Lu; Gao, Xiaoshan; Jie, Guifen; Huang, Tingyu

    2018-07-01

    Herein, we successfully devised a novel photoelectrochemical (PEC) platform for ultrasensitive detection of adenosine by target-triggering cascade multiple cycle amplification based on the silver nanoparticles-assisted ion-exchange reaction with CdTe quantum dots (QDs). In the presence of target adenosine, DNA s1 is released from the aptamer and then hybridizes with hairpin DNA (HP1), which could initiate the cycling cleavage process under the reaction of nicking endonuclease. Then the product (DNA b) of cycle I could act as the "DNA trigger" of cycle II to further generate a large number of DNA s1, which again go back to cycle I, thus a cascade multiple DNA cycle amplification was carried out to produce abundant DNA c. These DNA c fragments with the cytosine (C)-rich loop were captured by magnetic beads, and numerous silver nanoclusters (Ag NCs) were synthesized by AgNO 3 and sodium borohydride. The dissolved AgNCs released numerous silver ions which could induce ion exchange reaction with the CdTe QDs, thus resulting in greatly amplified change of photocurrent for target detection. The detection linear range for adenosine was 1.0 fM ~10 nM with the detection limit of 0.5 fM. The present PEC strategy combining cascade multiple DNA cycle amplification and AgNCs-induced ion-exchange reaction with QDs provides new insight into rapid, and ultrasensitive PEC detection of different biomolecules, which showed great potential for detecting trace amounts in bioanalysis and clinical biomedicine. Copyright © 2018 Elsevier B.V. All rights reserved.

  9. ApicoAP: the first computational model for identifying apicoplast-targeted proteins in multiple species of Apicomplexa.

    Directory of Open Access Journals (Sweden)

    Gokcen Cilingir

    Full Text Available Most of the parasites of the phylum Apicomplexa contain a relict prokaryotic-derived plastid called the apicoplast. This organelle is important not only for the survival of the parasite, but its unique properties make it an ideal drug target. The majority of apicoplast-associated proteins are nuclear encoded and targeted post-translationally to the organellar lumen via a bipartite signaling mechanism that requires an N-terminal signal and transit peptide (TP. Attempts to define a consensus motif that universally identifies apicoplast TPs have failed.In this study, we propose a generalized rule-based classification model to identify apicoplast-targeted proteins (ApicoTPs that use a bipartite signaling mechanism. Given a training set specific to an organism, this model, called ApicoAP, incorporates a procedure based on a genetic algorithm to tailor a discriminating rule that exploits the known characteristics of ApicoTPs. Performance of ApicoAP is evaluated for four labeled datasets of Plasmodium falciparum, Plasmodium yoelii, Babesia bovis, and Toxoplasma gondii proteins. ApicoAP improves the classification accuracy of the published dataset for P. falciparum to 94%, originally 90% using PlasmoAP.We present a parametric model for ApicoTPs and a procedure to optimize the model parameters for a given training set. A major asset of this model is that it is customizable to different parasite genomes. The ApicoAP prediction software is available at http://code.google.com/p/apicoap/ and http://bcb.eecs.wsu.edu.

  10. Cerebroside D, a glycoceramide compound, improves experimental colitis in mice with multiple targets against activated T lymphocytes

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Xue-Feng; Wu, Xing-Xin; Guo, Wen-Jie; Luo, Qiong [State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093 (China); Gu, Yan-Hong [Department of Clinical Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029 (China); Shen, Yan; Tan, Ren-Xiang [State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093 (China); Sun, Yang, E-mail: yangsun@nju.edu.cn [State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093 (China); Xu, Qiang, E-mail: molpharm@163.com [State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093 (China)

    2012-09-15

    In the present paper, we aimed to examine the novel effects of cerebroside D, a glycoceramide compound, on murine experimental colitis. Cerebroside D significantly reduced the weight loss, mortality rate and alleviated the macroscopic and microscopic appearances of colitis induced by dexran sulfate sodium. This compound also decreased the levels of TNF-α, IFN-γ and IL-1β in intestinal tissue of mice with experimental colitis in a concentration-dependent manner, accompanied with markedly increased serum level of IL-10. Cerebroside D inhibited proliferation and induced apoptosis of T cells activated by concanavalin A or anti-CD3 plus anti-CD28 antibodies. The compound did not show an effect on naive lymphocytes but prevented cells from entering S phase and G2/M phase during T cells activation. Moreover, the treatment of cerebroside D led to apoptosis of activated T cells with the cleavage of caspase 3, 9, 12 and PARP. These results showed multiple effects of cerebroside D against activated T cells for a novel approach to treatment of colonic inflammation. Highlights: ► Cerebroside D, a glycoceramide compound, alleviated DSS induced colitis. ► The mechanism of the compound involved multiple effects against activated T cells. ► It regulated cytokine profiles in mice with experimental colitis. ► It prevented T cells from entering S and G2/M phases during activation. ► It led to apoptosis of activated T cells with the cleavage of caspases and PARP.

  11. Cerebroside D, a glycoceramide compound, improves experimental colitis in mice with multiple targets against activated T lymphocytes

    International Nuclear Information System (INIS)

    Wu, Xue-Feng; Wu, Xing-Xin; Guo, Wen-Jie; Luo, Qiong; Gu, Yan-Hong; Shen, Yan; Tan, Ren-Xiang; Sun, Yang; Xu, Qiang

    2012-01-01

    In the present paper, we aimed to examine the novel effects of cerebroside D, a glycoceramide compound, on murine experimental colitis. Cerebroside D significantly reduced the weight loss, mortality rate and alleviated the macroscopic and microscopic appearances of colitis induced by dexran sulfate sodium. This compound also decreased the levels of TNF-α, IFN-γ and IL-1β in intestinal tissue of mice with experimental colitis in a concentration-dependent manner, accompanied with markedly increased serum level of IL-10. Cerebroside D inhibited proliferation and induced apoptosis of T cells activated by concanavalin A or anti-CD3 plus anti-CD28 antibodies. The compound did not show an effect on naive lymphocytes but prevented cells from entering S phase and G2/M phase during T cells activation. Moreover, the treatment of cerebroside D led to apoptosis of activated T cells with the cleavage of caspase 3, 9, 12 and PARP. These results showed multiple effects of cerebroside D against activated T cells for a novel approach to treatment of colonic inflammation. Highlights: ► Cerebroside D, a glycoceramide compound, alleviated DSS induced colitis. ► The mechanism of the compound involved multiple effects against activated T cells. ► It regulated cytokine profiles in mice with experimental colitis. ► It prevented T cells from entering S and G2/M phases during activation. ► It led to apoptosis of activated T cells with the cleavage of caspases and PARP.

  12. Automatic detection of multiple UXO-like targets using magnetic anomaly inversion and self-adaptive fuzzy c-means clustering

    Science.gov (United States)

    Yin, Gang; Zhang, Yingtang; Fan, Hongbo; Ren, Guoquan; Li, Zhining

    2017-12-01

    We have developed a method for automatically detecting UXO-like targets based on magnetic anomaly inversion and self-adaptive fuzzy c-means clustering. Magnetic anomaly inversion methods are used to estimate the initial locations of multiple UXO-like sources. Although these initial locations have some errors with respect to the real positions, they form dense clouds around the actual positions of the magnetic sources. Then we use the self-adaptive fuzzy c-means clustering algorithm to cluster these initial locations. The estimated number of cluster centroids represents the number of targets and the cluster centroids are regarded as the locations of magnetic targets. Effectiveness of the method has been demonstrated using synthetic datasets. Computational results show that the proposed method can be applied to the case of several UXO-like targets that are randomly scattered within in a confined, shallow subsurface, volume. A field test was carried out to test the validity of the proposed method and the experimental results show that the prearranged magnets can be detected unambiguously and located precisely.

  13. Specific emotions as mediators of the effect of intergroup contact on prejudice: findings across multiple participant and target groups.

    Science.gov (United States)

    Seger, Charles R; Banerji, Ishani; Park, Sang Hee; Smith, Eliot R; Mackie, Diane M

    2017-08-01

    Emotions are increasingly being recognised as important aspects of prejudice and intergroup behaviour. Specifically, emotional mediators play a key role in the process by which intergroup contact reduces prejudice towards outgroups. However, which particular emotions are most important for prejudice reduction, as well as the consistency and generality of emotion-prejudice relations across different in-group-out-group relations, remain uncertain. To address these issues, in Study 1 we examined six distinct positive and negative emotions as mediators of the contact-prejudice relations using representative samples of U.S. White, Black, and Asian American respondents (N = 639). Admiration and anger (but not other emotions) were significant mediators of the effects of previous contact on prejudice, consistently across different perceiver and target ethnic groups. Study 2 examined the same relations with student participants and gay men as the out-group. Admiration and disgust mediated the effect of past contact on attitude. The findings confirm that not only negative emotions (anger or disgust, based on the specific types of threat perceived to be posed by an out-group), but also positive, status- and esteem-related emotions (admiration) mediate effects of contact on prejudice, robustly across several different respondent and target groups.

  14. Pyrosequencing the transcriptome of the greenhouse whitefly, Trialeurodes vaporariorum reveals multiple transcripts encoding insecticide targets and detoxifying enzymes

    Directory of Open Access Journals (Sweden)

    Gorman Kevin

    2011-01-01

    Full Text Available Abstract Background The whitefly Trialeurodes vaporariorum is an economically important crop pest in temperate regions that has developed resistance to most classes of insecticides. However, the molecular mechanisms underlying resistance have not been characterised and, to date, progress has been hampered by a lack of nucleotide sequence data for this species. Here, we use pyrosequencing on the Roche 454-FLX platform to produce a substantial and annotated EST dataset. This 'unigene set' will form a critical reference point for quantitation of over-expressed messages via digital transcriptomics. Results Pyrosequencing produced around a million sequencing reads that assembled into 54,748 contigs, with an average length of 965 bp, representing a dramatic expansion of existing cDNA sequences available for T. vaporariorum (only 43 entries in GenBank at the time of this publication. BLAST searching of non-redundant databases returned 20,333 significant matches and those gene families potentially encoding gene products involved in insecticide resistance were manually curated and annotated. These include, enzymes potentially involved in the detoxification of xenobiotics and those encoding the targets of the major chemical classes of insecticides. A total of 57 P450s, 17 GSTs and 27 CCEs were identified along with 30 contigs encoding the target proteins of six different insecticide classes. Conclusion Here, we have developed new transcriptomic resources for T. vaporariorum. These include a substantial and annotated EST dataset that will serve the community studying this important crop pest and will elucidate further the molecular mechanisms underlying insecticide resistance.

  15. Androgen receptor-dependent and -independent mechanisms driving prostate cancer progression: Opportunities for therapeutic targeting from multiple angles

    Science.gov (United States)

    Hoang, David T; Iczkowski, Kenneth A; Kilari, Deepak; See, William; Nevalainen, Marja T

    2017-01-01

    Despite aggressive treatment for localized cancer, prostate cancer (PC) remains a leading cause of cancer-related death for American men due to a subset of patients progressing to lethal and incurable metastatic castrate-resistant prostate cancer (CRPC). Organ-confined PC is treated by surgery or radiation with or without androgen deprivation therapy (ADT), while options for locally advanced and disseminated PC include radiation combined with ADT, or systemic treatments including chemotherapy. Progression to CRPC results from failure of ADT, which targets the androgen receptor (AR) signaling axis and inhibits AR-driven proliferation and survival pathways. The exact mechanisms underlying the transition from androgen-dependent PC to CRPC remain incompletely understood. Reactivation of AR has been shown to occur in CRPC despite depletion of circulating androgens by ADT. At the same time, the presence of AR-negative cell populations in CRPC has also been identified. While AR signaling has been proposed as the primary driver of CRPC, AR-independent signaling pathways may represent additional mechanisms underlying CRPC progression. Identification of new therapeutic strategies to target both AR-positive and AR-negative PC cell populations and, thereby, AR-driven as well as non-AR-driven PC cell growth and survival mechanisms would provide a two-pronged approach to eliminate CRPC cells with potential for synthetic lethality. In this review, we provide an overview of AR-dependent and AR-independent molecular mechanisms which drive CRPC, with special emphasis on the role of the Jak2-Stat5a/b signaling pathway in promoting castrate-resistant growth of PC through both AR-dependent and AR-independent mechanisms. PMID:27741508

  16. Integrated microarray and ChIP analysis identifies multiple Foxa2 dependent target genes in the notochord.

    Science.gov (United States)

    Tamplin, Owen J; Cox, Brian J; Rossant, Janet

    2011-12-15

    The node and notochord are key tissues required for patterning of the vertebrate body plan. Understanding the gene regulatory network that drives their formation and function is therefore important. Foxa2 is a key transcription factor at the top of this genetic hierarchy and finding its targets will help us to better understand node and notochord development. We performed an extensive microarray-based gene expression screen using sorted embryonic notochord cells to identify early notochord-enriched genes. We validated their specificity to the node and notochord by whole mount in situ hybridization. This provides the largest available resource of notochord-expressed genes, and therefore candidate Foxa2 target genes in the notochord. Using existing Foxa2 ChIP-seq data from adult liver, we were able to identify a set of genes expressed in the notochord that had associated regions of Foxa2-bound chromatin. Given that Foxa2 is a pioneer transcription factor, we reasoned that these sites might represent notochord-specific enhancers. Candidate Foxa2-bound regions were tested for notochord specific enhancer function in a zebrafish reporter assay and 7 novel notochord enhancers were identified. Importantly, sequence conservation or predictive models could not have readily identified these regions. Mutation of putative Foxa2 binding elements in two of these novel enhancers abrogated reporter expression and confirmed their Foxa2 dependence. The combination of highly specific gene expression profiling and genome-wide ChIP analysis is a powerful means of understanding developmental pathways, even for small cell populations such as the notochord. Copyright © 2011 Elsevier Inc. All rights reserved.

  17. Systematic approach to optimize a pretreatment method for ultrasensitive liquid chromatography with tandem mass spectrometry analysis of multiple target compounds in biological samples.

    Science.gov (United States)

    Togashi, Kazutaka; Mutaguchi, Kuninori; Komuro, Setsuko; Kataoka, Makoto; Yamazaki, Hiroshi; Yamashita, Shinji

    2016-08-01

    In current approaches for new drug development, highly sensitive and robust analytical methods for the determination of test compounds in biological samples are essential. These analytical methods should be optimized for every target compound. However, for biological samples that contain multiple compounds as new drug candidates obtained by cassette dosing tests, it would be preferable to develop a single method that allows the determination of all compounds at once. This study aims to establish a systematic approach that enables a selection of the most appropriate pretreatment method for multiple target compounds without the use of their chemical information. We investigated the retention times of 27 known compounds under different mobile phase conditions and determined the required pretreatment of human plasma samples using several solid-phase and liquid-liquid extractions. From the relationship between retention time and recovery in a principal component analysis, appropriate pretreatments were categorized into several types. Based on the category, we have optimized a pretreatment method for the identification of three calcium channel blockers in human plasma. Plasma concentrations of these drugs in a cassette-dose clinical study at microdose level were successfully determined with a lower limit of quantitation of 0.2 pg/mL for diltiazem, 1 pg/mL for nicardipine, and 2 pg/mL for nifedipine. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Treatment simulations with a statistical deformable motion model to evaluate margins for multiple targets in radiotherapy for high-risk prostate cancer

    International Nuclear Information System (INIS)

    Thörnqvist, Sara; Hysing, Liv B.; Zolnay, Andras G.; Söhn, Matthias; Hoogeman, Mischa S.; Muren, Ludvig P.; Bentzen, Lise; Heijmen, Ben J.M.

    2013-01-01

    Background and purpose: Deformation and correlated target motion remain challenges for margin recipes in radiotherapy (RT). This study presents a statistical deformable motion model for multiple targets and applies it to margin evaluations for locally advanced prostate cancer i.e. RT of the prostate (CTV-p), seminal vesicles (CTV-sv) and pelvic lymph nodes (CTV-ln). Material and methods: The 19 patients included in this study, all had 7–10 repeat CT-scans available that were rigidly aligned with the planning CT-scan using intra-prostatic implanted markers, followed by deformable registrations. The displacement vectors from the deformable registrations were used to create patient-specific statistical motion models. The models were applied in treatment simulations to determine probabilities for adequate target coverage, e.g. by establishing distributions of the accumulated dose to 99% of the target volumes (D 99 ) for various CTV–PTV expansions in the planning-CTs. Results: The method allowed for estimation of the expected accumulated dose and its variance of different DVH parameters for each patient. Simulations of inter-fractional motion resulted in 7, 10, and 18 patients with an average D 99 >95% of the prescribed dose for CTV-p expansions of 3 mm, 4 mm and 5 mm, respectively. For CTV-sv and CTV-ln, expansions of 3 mm, 5 mm and 7 mm resulted in 1, 11 and 15 vs. 8, 18 and 18 patients respectively with an average D 99 >95% of the prescription. Conclusions: Treatment simulations of target motion revealed large individual differences in accumulated dose mainly for CTV-sv, demanding the largest margins whereas those required for CTV-p and CTV-ln were comparable

  19. Importance of Neutralizing Monoclonal Antibodies Targeting Multiple Antigenic Sites on the Middle East Respiratory Syndrome Coronavirus Spike Glycoprotein To Avoid Neutralization Escape

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Lingshu; Shi, Wei; Chappell, James D.; Joyce, M. Gordon; Zhang, Yi; Kanekiyo, Masaru; Becker, Michelle M.; van Doremalen, Neeltje; Fischer, Robert; Wang, Nianshuang; Corbett, Kizzmekia S.; Choe, Misook; Mason, Rosemarie D.; Van Galen, Joseph G.; Zhou, Tongqing; Saunders, Kevin O.; Tatti, Kathleen M.; Haynes, Lia M.; Kwong, Peter D.; Modjarrad, Kayvon; Kong, Wing-Pui; McLellan, Jason S.; Denison, Mark R.; Munster, Vincent J.; Mascola, John R.; Graham, Barney S.; Gallagher, Tom

    2018-03-07

    ABSTRACT

    Middle East respiratory syndrome coronavirus (MERS-CoV) causes a highly lethal pulmonary infection with ~35% mortality. The potential for a future pandemic originating from animal reservoirs or health care-associated events is a major public health concern. There are no vaccines or therapeutic agents currently available for MERS-CoV. Using a probe-based single B cell cloning strategy, we have identified and characterized multiple neutralizing monoclonal antibodies (MAbs) specifically binding to the receptor-binding domain (RBD) or S1 (non-RBD) regions from a convalescent MERS-CoV-infected patient and from immunized rhesus macaques. RBD-specific MAbs tended to have greater neutralizing potency than non-RBD S1-specific MAbs. Six RBD-specific and five S1-specific MAbs could be sorted into four RBD and three non-RBD distinct binding patterns, based on competition assays, mapping neutralization escape variants, and structural analysis. We determined cocrystal structures for two MAbs targeting the RBD from different angles and show they can bind the RBD only in the “out” position. We then showed that selected RBD-specific, non-RBD S1-specific, and S2-specific MAbs given prophylactically prevented MERS-CoV replication in lungs and protected mice from lethal challenge. Importantly, combining RBD- and non-RBD MAbs delayed the emergence of escape mutations in a cell-based virus escape assay. These studies identify MAbs targeting different antigenic sites on S that will be useful for defining mechanisms of MERS-CoV neutralization and for developing more effective interventions to prevent or treat MERS-CoV infections.

    IMPORTANCEMERS-CoV causes a highly lethal respiratory infection for which no vaccines or antiviral therapeutic options are currently available. Based on continuing exposure from established reservoirs in dromedary camels and bats, transmission of MERS-CoV into humans and future outbreaks are expected. Using

  20. Novel VEGF decoy receptor fusion protein conbercept targeting multiple VEGF isoforms provide remarkable anti-angiogenesis effect in vivo.

    Directory of Open Access Journals (Sweden)

    Qin Wang

    Full Text Available VEGF family factors are known to be the principal stimulators of abnormal angiogenesis, which play a fundamental role in tumor and various ocular diseases. Inhibition of VEGF is widely applied in antiangiogenic therapy. Conbercept is a novel decoy receptor protein constructed by fusing VEGF receptor 1 and VEGF receptor 2 extracellular domains with the Fc region of human immunoglobulin. In this study, we systematically evaluated the binding affinity of conbercept with VEGF isoforms and PlGF by using anti-VEGF antibody (Avastin as reference. BIACORE and ELISA assay results indicated that conbercept could bind different VEGF-A isoforms with higher affinity than reference. Furthermore, conbercept could also bind VEGF-B and PlGF, whereas Avastin showed no binding. Oxygen-induced retinopathy model showed that conbercept could inhibit the formation of neovasularizations. In tumor-bearing nude mice, conbercept could also suppress tumor growth very effectively in vivo. Overall, our study have demonstrated that conbercept could bind with high affinity to multiple VEGF isoforms and consequently provide remarkable anti-angiogenic effect, suggesting the possibility to treat angiogenesis-related diseases such as cancer and wet AMD etc.

  1. A targeted sequencing panel identifies rare damaging variants in multiple genes in the cranial neural tube defect, anencephaly.

    Science.gov (United States)

    Ishida, M; Cullup, T; Boustred, C; James, C; Docker, J; English, C; Lench, N; Copp, A J; Moore, G E; Greene, N D E; Stanier, P

    2018-04-01

    Neural tube defects (NTDs) affecting the brain (anencephaly) are lethal before or at birth, whereas lower spinal defects (spina bifida) may lead to lifelong neurological handicap. Collectively, NTDs rank among the most common birth defects worldwide. This study focuses on anencephaly, which despite having a similar frequency to spina bifida and being the most common type of NTD observed in mouse models, has had more limited inclusion in genetic studies. A genetic influence is strongly implicated in determining risk of NTDs and a molecular diagnosis is of fundamental importance to families both in terms of understanding the origin of the condition and for managing future pregnancies. Here we used a custom panel of 191 NTD candidate genes to screen 90 patients with cranial NTDs (n = 85 anencephaly and n = 5 craniorachischisis) with a targeted exome sequencing platform. After filtering and comparing to our in-house control exome database (N = 509), we identified 397 rare variants (minor allele frequency, MAF < 1%), 21 of which were previously unreported and predicted damaging. This included 1 frameshift (PDGFRA), 2 stop-gained (MAT1A; NOS2) and 18 missense variations. Together with evidence for oligogenic inheritance, this study provides new information on the possible genetic causation of anencephaly. © 2017 The Authors. Clinical Genetics published by John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  2. Oridonin Targets Multiple Drug-Resistant Tumor Cells as Determined by in Silico and in Vitro Analyses

    Directory of Open Access Journals (Sweden)

    Onat Kadioglu

    2018-04-01

    Full Text Available Drug resistance is one of the main reasons of chemotherapy failure. Therefore, overcoming drug resistance is an invaluable approach to identify novel anticancer drugs that have the potential to bypass or overcome resistance to established drugs and to substantially increase life span of cancer patients for effective chemotherapy. Oridonin is a cytotoxic diterpenoid isolated from Rabdosia rubescens with in vivo anticancer activity. In the present study, we evaluated the cytotoxicity of oridonin toward a panel of drug-resistant cancer cells overexpressing ABCB1, ABCG2, or ΔEGFR or with a knockout deletion of TP53. Interestingly, oridonin revealed lower degree of resistance than the control drug, doxorubicin. Molecular docking analyses pointed out that oridonin can interact with Akt/EGFR pathway proteins with comparable binding energies and similar docking poses as the known inhibitors. Molecular dynamics results validated the stable conformation of oridonin docking pose on Akt kinase domain. Western blot experiments clearly revealed dose-dependent downregulation of Akt and STAT3. Pharmacogenomics analyses pointed to a mRNA signature that predicted sensitivity and resistance to oridonin. In conclusion, oridonin bypasses major drug resistance mechanisms and targets Akt pathway and might be effective toward drug refractory tumors. The identification of oridonin-specific gene expressions may be useful for the development of personalized treatment approaches.

  3. Comparative analysis of CD138 antigen targeting for the treatment of multiple myeloma with bismuth-213 and Melphalan chemotherapy

    International Nuclear Information System (INIS)

    Gouard, S.; Gaschet, J.; Maurel, C.; Barbet, J.; Davodeau, F.; Pallardy, A.; Faivre-Chauvet, A.; Kraeber-Bodere, F.; Bruchertseifer, F.; Morgenstern, A.; Cherel, M.

    2015-01-01

    Full text of publication follows. Aim: multiple myeloma (MM) is a B-cell malignancy of terminally differentiated plasma cells within the bone marrow, with the presence of a monoclonal immunoglobulin in serum and/or urine and development of osteolytic bone lesions in human. Despite intense research to develop new treatments, cure is almost never achieved. Alpha-radioimmunotherapy (RIT) has been shown to be effective in vivo in a multiple myeloma model and seems particularly suited for disseminated tumour cells or small clusters of tumour cells. CD138 (Syndecan-1) is found mainly in epithelial cells, but has been shown to be expressed by most myeloma cells, both in human and in mouse. In order to define where alpha RIT stands in MM treatment, the aim of this study was to compare Melphalan, MM standard treatment, with alpha RIT using a bismuth-213-labelled anti-mouse CD138 rat antibody in a syngeneic mouse MM model. Material and Methods: C57BL/KaLwRij mice were grafted with 10 6 5T33 cells (murine myeloma cells). Luciferase transfected 5T33 were used for in vivo localization of the cells during the course of disease. The first step of the study was to assess the dose-response of Melphalan (100, 200 et 300 μg/mouse), 21 days after engraftment. The second step consisted in therapeutic association: Melphalan followed by RIT at d22 et d25 after engraftment. Toxicity (animal weight, blood cell counts) and treatment efficacy were studied in animals receiving no treatment, injected with Melphalan alone (200 μg), RIT alone at d22 and d25 (3.7 MBq of 213 Bi-anti-CD138) and Melphalan combined with alpha RIT. Results: fifty percent of untreated mice died by d64 after MM engraftment. In mice treated with Melphalan alone, only the 200 μg dose improved median survival. No animal was cured after Melphalan treatment whereas 60% of the mice survived with RIT alone at d22 after tumour engraftment. However, the therapeutic window seems to be narrow, indeed no effect was observed with

  4. Combining multiple FDG-PET radiotherapy target segmentation methods to reduce the effect of variable performance of individual segmentation methods

    Energy Technology Data Exchange (ETDEWEB)

    McGurk, Ross J. [Medical Physics Graduate Program, Duke University, Durham, North Carolina 27705 (United States); Bowsher, James; Das, Shiva K. [Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27705 (United States); Lee, John A [Molecular Imaging and Experimental Radiotherapy Unit, Universite Catholique de Louvain, 1200 Brussels (Belgium)

    2013-04-15

    different between 128 Multiplication-Sign 128 and 256 Multiplication-Sign 256 grid sizes for either method (MJV, p= 0.0519; STAPLE, p= 0.5672) but was for SMASD values (MJV, p < 0.0001; STAPLE, p= 0.0164). The best individual method varied depending on object characteristics. However, both MJV and STAPLE provided essentially equivalent accuracy to using the best independent method in every situation, with mean differences in DSC of 0.01-0.03, and 0.05-0.12 mm for SMASD. Conclusions: Combining segmentations offers a robust approach to object segmentation in PET. Both MJV and STAPLE improved accuracy and were robust against the widely varying performance of individual segmentation methods. Differences between MJV and STAPLE are such that either offers good performance when combining volumes. Neither method requires a training dataset but MJV is simpler to interpret, easy to implement and fast.

  5. Activating receptor NKG2D targets RAE-1-expressing allogeneic neural precursor cells in a viral model of multiple sclerosis.

    Science.gov (United States)

    Weinger, Jason G; Plaisted, Warren C; Maciejewski, Sonia M; Lanier, Lewis L; Walsh, Craig M; Lane, Thomas E

    2014-10-01

    Transplantation of major histocompatibility complex-mismatched mouse neural precursor cells (NPCs) into mice persistently infected with the neurotropic JHM strain of mouse hepatitis virus (JHMV) results in rapid rejection that is mediated, in part, by T cells. However, the contribution of the innate immune response to allograft rejection in a model of viral-induced neurological disease has not been well defined. Herein, we demonstrate that the natural killer (NK) cell-expressing-activating receptor NKG2D participates in transplanted allogeneic NPC rejection in mice persistently infected with JHMV. Cultured NPCs derived from C57BL/6 (H-2(b) ) mice express the NKG2D ligand retinoic acid early precursor transcript (RAE)-1 but expression was dramatically reduced upon differentiation into either glia or neurons. RAE-1(+) NPCs were susceptible to NK cell-mediated killing whereas RAE-1(-) cells were resistant to lysis. Transplantation of C57BL/6-derived NPCs into JHMV-infected BALB/c (H-2(d) ) mice resulted in infiltration of NKG2D(+) CD49b(+) NK cells and treatment with blocking antibody specific for NKG2D increased survival of allogeneic NPCs. Furthermore, transplantation of differentiated RAE-1(-) allogeneic NPCs into JHMV-infected BALB/c mice resulted in enhanced survival, highlighting a role for the NKG2D/RAE-1 signaling axis in allograft rejection. We also demonstrate that transplantation of allogeneic NPCs into JHMV-infected mice resulted in infection of the transplanted cells suggesting that these cells may be targets for infection. Viral infection of cultured cells increased RAE-1 expression, resulting in enhanced NK cell-mediated killing through NKG2D recognition. Collectively, these results show that in a viral-induced demyelination model, NK cells contribute to rejection of allogeneic NPCs through an NKG2D signaling pathway. © 2014 AlphaMed Press.

  6. Multiple insecticide resistance mechanisms involving metabolic changes and insensitive target sites selected in anopheline vectors of malaria in Sri Lanka

    Directory of Open Access Journals (Sweden)

    Karunaratne SHP Parakrama

    2008-08-01

    Full Text Available Abstract Background The current status of insecticide resistance and the underlying resistance mechanisms were studied in the major vector of malaria, Anopheles culicifacies, and the secondary vector, Anopheles subpictus in five districts (Anuradhapura, Kurunegala, Moneragala, Puttalam and Trincomalee of Sri Lanka. Eight other anophelines, Anopheles annularis, Anopheles barbirostris, Anopheles jamesii, Anopheles nigerrimus, Anopheles peditaeniatus, Anopheles tessellatus, Anopheles vagus and Anopheles varuna from Anuradhapura district were also tested. Methods Adult females were exposed to the WHO discriminating dosages of DDT, malathion, fenitrothion, propoxur, λ-cyhalothrin, cyfluthrin, cypermethrin, deltamethrin, permethrin and etofenprox. The presence of metabolic resistance by esterase, glutathione S-transferase (GST and monooxygenase-based mechanisms, and the sensitivity of the acetylcholinesterase target site were assessed using synergists, and biochemical, and metabolic techniques. Results All the anopheline species had high DDT resistance. All An. culicifacies and An. subpictus populations were resistant to malathion, except An. culicifacies from Kurunegala, where there was no malathion carboxylesterase activity. Kurunegala and Puttalam populations of An. culicifacies were susceptible to fenitrothion. All the An. culicifacies populations were susceptible to carbamates. Both species were susceptible to the discriminating dosages of cypermethrin and cyfluthrin, but had different levels of resistance to other pyrethroids. Of the 8 other anophelines, only An. nigerrimus and An. peditaeniatus were resistant to all the insecticides tested, probably due to their high exposure to the insecticides used in agriculture. An. vagus showed some resistance to permethrin. Esterases, GSTs and monooxygenases were elevated in both An. culicifacies and An. subpictus. AChE was most sensitive to insecticides in Kurunegala and Trincomalee An. culicifacies

  7. Targeted deep sequencing of mucinous ovarian tumors reveals multiple overlapping RAS-pathway activating mutations in borderline and cancerous neoplasms

    International Nuclear Information System (INIS)

    Mackenzie, Robertson; Kommoss, Stefan; Winterhoff, Boris J.; Kipp, Benjamin R.; Garcia, Joaquin J.; Voss, Jesse; Halling, Kevin; Karnezis, Anthony; Senz, Janine; Yang, Winnie; Prigge, Elena-Sophie; Reuschenbach, Miriam; Doeberitz, Magnus Von Knebel; Gilks, Blake C.; Huntsman, David G.; Bakkum-Gamez, Jamie; McAlpine, Jessica N.; Anglesio, Michael S.

    2015-01-01

    populations, while consistency of KRAS allelic frequency in both ERBB2 amplified and non-amplified regions suggests this mutation occurred in advance of the amplification event. Overall, the prevalence of RAS-alteration and striking co-occurrence of pathway “double-hits” supports a critical role for tumor progression in this ovarian malignancy. Given the spectrum of RAS-activating mutations, it is clear that targeting this pathway may be a viable therapeutic option for patients with recurrent or advanced stage mucinous ovarian carcinoma, however caution should be exercised in selecting one or more personalized therapeutics given the frequency of non-redundant RAS-activating alterations. The online version of this article (doi:10.1186/s12885-015-1421-8) contains supplementary material, which is available to authorized users

  8. MO-C-17A-06: Online Adaptive Re-Planning to Account for Independent Motions Between Multiple Targets During Radiotherapy of Lung Cancer

    International Nuclear Information System (INIS)

    Liu, F; Tai, A; Ahunbay, E; Gore, E; Johnstone, C; Li, X

    2014-01-01

    Purpose: To quantify interfractional independent motions between multiple targets in radiotherapy (RT) of lung cancer, and to study the dosimetric benefits of an online adaptive replanning method to account for these variations. Methods: Ninety five diagnostic-quality daily CTs acquired for 9 lung cancer patients treated with IGRT using an in-room CT (CTVision, Siemens) were analyzed. On each daily CT set, contours of the targets (GTV, CTV, or involved nodes) and organs at risk were generated by populating the planning contours using an auto-segmentation tool (ABAS, Elekta) with manual editing. For each patient, an IMRT plan was generated based on the planning CT with a prescription dose of 60 Gy in 2Gy fractions. Three plans were generated and compared for each daily CT set: an IGRT (repositioning) plan by copying the original plan with the required shifts, an online adaptive plan by rapidly modifying the aperture shapes and segment weights of the original plan to conform to the daily anatomy, and a new fully re-optimized plan based on the daily CT using a planning system (Panther, Prowess). Results: The daily deviations of the distance between centers of masses of the targets from the plans varied daily from -10 to 8 mm with an average −0.9±4.1 mm (one standard deviation). The average CTV V100 are 99.0±0.7%, 97.9±2.8%, 99.0±0.6%, and 99.1±0.6%, and the lung V20 Gy 928±332 cc, 944±315 cc, 917±300 cc, and 891±295 cc for the original, repositioning, adaptive, and re-optimized plans, respectively. Wilcoxon signed-rank tests show that the adaptive plans are statistically significantly better than the repositioning plans and comparable with the reoptimized plans. Conclusion: There exist unpredictable, interfractional, relative volume changes and independent motions between multiple targets during lung cancer RT which cannot be accounted for by the current IGRT repositioning but can be corrected by the online adaptive replanning method

  9. MO-C-17A-06: Online Adaptive Re-Planning to Account for Independent Motions Between Multiple Targets During Radiotherapy of Lung Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Liu, F; Tai, A; Ahunbay, E; Gore, E; Johnstone, C; Li, X [Medical College of Wisconsin, Milwaukee, WI (United States)

    2014-06-15

    Purpose: To quantify interfractional independent motions between multiple targets in radiotherapy (RT) of lung cancer, and to study the dosimetric benefits of an online adaptive replanning method to account for these variations. Methods: Ninety five diagnostic-quality daily CTs acquired for 9 lung cancer patients treated with IGRT using an in-room CT (CTVision, Siemens) were analyzed. On each daily CT set, contours of the targets (GTV, CTV, or involved nodes) and organs at risk were generated by populating the planning contours using an auto-segmentation tool (ABAS, Elekta) with manual editing. For each patient, an IMRT plan was generated based on the planning CT with a prescription dose of 60 Gy in 2Gy fractions. Three plans were generated and compared for each daily CT set: an IGRT (repositioning) plan by copying the original plan with the required shifts, an online adaptive plan by rapidly modifying the aperture shapes and segment weights of the original plan to conform to the daily anatomy, and a new fully re-optimized plan based on the daily CT using a planning system (Panther, Prowess). Results: The daily deviations of the distance between centers of masses of the targets from the plans varied daily from -10 to 8 mm with an average −0.9±4.1 mm (one standard deviation). The average CTV V100 are 99.0±0.7%, 97.9±2.8%, 99.0±0.6%, and 99.1±0.6%, and the lung V20 Gy 928±332 cc, 944±315 cc, 917±300 cc, and 891±295 cc for the original, repositioning, adaptive, and re-optimized plans, respectively. Wilcoxon signed-rank tests show that the adaptive plans are statistically significantly better than the repositioning plans and comparable with the reoptimized plans. Conclusion: There exist unpredictable, interfractional, relative volume changes and independent motions between multiple targets during lung cancer RT which cannot be accounted for by the current IGRT repositioning but can be corrected by the online adaptive replanning method.

  10. Performance of the multiple target He/PbI sub 2 aerosol jet system for mass separation of neutron-deficient actinide isotopes

    CERN Document Server

    Ichikawa, S; Asai, M; Haba, H; Sakama, M; Kojima, Y; Shibata, M; Nagame, Y; Oura, Y; Kawade, K

    2002-01-01

    A multiple target He/PbI sub 2 aerosol jet system coupled with a thermal ion source was installed in the isotope separator on line (JAERI-ISOL) at the JAERI tandem accelerator facility. The neutron-deficient americium and curium isotopes produced in the sup 2 sup 3 sup 3 sup , sup 2 sup 3 sup 5 U( sup 6 Li, xn) and sup 2 sup 3 sup 7 Np( sup 6 Li, xn) reactions were successfully mass-separated and the overall efficiency including the ionization of Am atoms was evaluated to be 0.3-0.4%. The identification of a new isotope sup 2 sup 3 sup 7 Cm with the present system is reported.

  11. A Challenge to Aging Society by microRNA in Extracellular Vesicles: microRNA in Extracellular Vesicles as Promising Biomarkers and Novel Therapeutic Targets in Multiple Myeloma

    Directory of Open Access Journals (Sweden)

    Tomofumi Yamamoto

    2018-03-01

    Full Text Available Multiple myeloma (MM is a malignancy of terminally differentiated plasma cells and is the second most common hematological cancer. MM frequently occurs in the elderly population with the median age as the middle sixties. Over the last 10 years, the prognosis of MM has been dramatically improved by new therapeutic drugs; however, MM is still incurable. The pathogenesis of MM is still unclear, thus greater understanding of the molecular mechanisms of MM malignancy is desirable. Recently, microRNAs (miRNAs were shown to modulate the expression of genes critical for MM pathogenesis. In addition, miRNAs are secreted via extracellular vesicles (EVs, which are released from various cell types including MM cells, and these miRNAs are involved in multiple types of cell-cell interactions, which lead to the malignancy of MM. In this review, we summarize the current knowledge regarding the role of miRNA secretion via EVs and of EVs themselves in MM development. We also discuss the potential clinical applications of EVs as promising biomarkers and new therapeutic targets for improving the outcome of MM, resulting in a brighter future for aging societies.

  12. Single-photon sensitive fast ebCMOS camera system for multiple-target tracking of single fluorophores: application to nano-biophotonics

    Science.gov (United States)

    Cajgfinger, Thomas; Chabanat, Eric; Dominjon, Agnes; Doan, Quang T.; Guerin, Cyrille; Houles, Julien; Barbier, Remi

    2011-03-01

    Nano-biophotonics applications will benefit from new fluorescent microscopy methods based essentially on super-resolution techniques (beyond the diffraction limit) on large biological structures (membranes) with fast frame rate (1000 Hz). This trend tends to push the photon detectors to the single-photon counting regime and the camera acquisition system to real time dynamic multiple-target tracing. The LUSIPHER prototype presented in this paper aims to give a different approach than those of Electron Multiplied CCD (EMCCD) technology and try to answer to the stringent demands of the new nano-biophotonics imaging techniques. The electron bombarded CMOS (ebCMOS) device has the potential to respond to this challenge, thanks to the linear gain of the accelerating high voltage of the photo-cathode, to the possible ultra fast frame rate of CMOS sensors and to the single-photon sensitivity. We produced a camera system based on a 640 kPixels ebCMOS with its acquisition system. The proof of concept for single-photon based tracking for multiple single-emitters is the main result of this paper.

  13. Parallel solid-phase isothermal amplification and detection of multiple DNA targets in microliter-sized wells of a digital versatile disc

    International Nuclear Information System (INIS)

    Santiago-Felipe, Sara; Tortajada-Genaro, Luis Antonio; Puchades, Rosa; Maquieira, Ángel

    2016-01-01

    An integrated method for the parallelized detection of multiple DNA target sequences is presented by using microstructures in a digital versatile disc (DVD). Samples and reagents were managed by using both the capillary and centrifugal forces induced by disc rotation. Recombinase polymerase amplification (RPA), in a bridge solid phase format, took place in separate wells, which thereby modified their optical properties. Then the DVD drive reader recorded the modifications of the transmitted laser beam. The strategy allowed tens of genetic determinations to be made simultaneously within <2 h, with small sample volumes (3 μL), low manipulation and at low cost. The method was applied to high-throughput screening of relevant safety threats (allergens, GMOs and pathogenic bacteria) in food samples. Satisfactory results were obtained in terms of sensitivity (48.7 fg of DNA) and reproducibility (below 18 %). This scheme warrants cost-effective multiplex amplification and detection and is perceived to represent a viable tool for screening of nucleic acid targets. (author)

  14. Activator Gcn4 employs multiple segments of Med15/Gal11, including the KIX domain, to recruit mediator to target genes in vivo.

    Science.gov (United States)

    Jedidi, Iness; Zhang, Fan; Qiu, Hongfang; Stahl, Stephen J; Palmer, Ira; Kaufman, Joshua D; Nadaud, Philippe S; Mukherjee, Sujoy; Wingfield, Paul T; Jaroniec, Christopher P; Hinnebusch, Alan G

    2010-01-22

    Mediator is a multisubunit coactivator required for initiation by RNA polymerase II. The Mediator tail subdomain, containing Med15/Gal11, is a target of the activator Gcn4 in vivo, critical for recruitment of native Mediator or the Mediator tail subdomain present in sin4Delta cells. Although several Gal11 segments were previously shown to bind Gcn4 in vitro, the importance of these interactions for recruitment of Mediator and transcriptional activation by Gcn4 in cells was unknown. We show that interaction of Gcn4 with the Mediator tail in vitro and recruitment of this subcomplex and intact Mediator to the ARG1 promoter in vivo involve additive contributions from three different segments in the N terminus of Gal11. These include the KIX domain, which is a critical target of other activators, and a region that shares a conserved motif (B-box) with mammalian coactivator SRC-1, and we establish that B-box is a critical determinant of Mediator recruitment by Gcn4. We further demonstrate that Gcn4 binds to the Gal11 KIX domain directly and, by NMR chemical shift analysis combined with mutational studies, we identify the likely binding site for Gcn4 on the KIX surface. Gcn4 is distinctive in relying on comparable contributions from multiple segments of Gal11 for efficient recruitment of Mediator in vivo.

  15. Apigenin inhibits proliferation and induces apoptosis in human multiple myeloma cells through targeting the trinity of CK2, Cdc37 and Hsp90

    Directory of Open Access Journals (Sweden)

    Xu Yuan-Ji

    2011-08-01

    Full Text Available Abstract Background Multiple myeloma (MM is a B-cell malignancy that is largely incurable and is characterized by the accumulation of malignant plasma cells in the bone marrow. Apigenin, a common flavonoid, has been reported to suppress proliferation in a wide variety of solid tumors and hematological cancers; however its mechanism is not well understood and its effect on MM cells has not been determined. Results In this study, we investigated the effects of apigenin on MM cell lines and on primary MM cells. Cell viability assays demonstrated that apigenin exhibited cytotoxicity against both MM cell lines and primary MM cells but not against normal peripheral blood mononuclear cells. Together, kinase assays, immunoprecipitation and western blot analysis showed that apigenin inhibited CK2 kinase activity, decreased phosphorylation of Cdc37, disassociated the Hsp90/Cdc37/client complex and induced the degradation of multiple kinase clients, including RIP1, Src, Raf-1, Cdk4 and AKT. By depleting these kinases, apigenin suppressed both constitutive and inducible activation of STAT3, ERK, AKT and NF-κB. The treatment also downregulated the expression of the antiapoptotic proteins Mcl-1, Bcl-2, Bcl-xL, XIAP and Survivin, which ultimately induced apoptosis in MM cells. In addition, apigenin had a greater effects in depleting Hsp90 clients when used in combination with the Hsp90 inhibitor geldanamycin and the histone deacetylase inhibitor vorinostat. Conclusions Our results suggest that the primary mechanisms by which apigenin kill MM cells is by targeting the trinity of CK2-Cdc37-Hsp90, and this observation reveals the therapeutic potential of apigenin in treating multiple myeloma.

  16. miR-320a regulates cell proliferation and apoptosis in multiple myeloma by targeting pre-B-cell leukemia transcription factor 3

    Energy Technology Data Exchange (ETDEWEB)

    Lu, Yinghao [Jiangsu Institute of Hematology, First Affiliated Hospital of Soochow University, Key Laboratory of Thrombosis and Hemostasis Under Ministry of Health, Collaborative Innovation Center of Hematology, Suzhou, 215006 (China); Department of Hematology, Affiliated Hospital of Guizhou Medical University, The Hematopoietic Stem Cell Transplant Center of Guizhou Province, Blood Diseases Diagnosis and Treatment Center of Guizhou Province, Guiyang, 550004, Guizhou Province (China); Wu, Depei, E-mail: wudepei@medmail.com.cn [Jiangsu Institute of Hematology, First Affiliated Hospital of Soochow University, Key Laboratory of Thrombosis and Hemostasis Under Ministry of Health, Collaborative Innovation Center of Hematology, Suzhou, 215006 (China); Wang, Jishi, E-mail: lgylhlyh@aliyun.com [Department of Hematology, Affiliated Hospital of Guizhou Medical University, The Hematopoietic Stem Cell Transplant Center of Guizhou Province, Blood Diseases Diagnosis and Treatment Center of Guizhou Province, Guiyang, 550004, Guizhou Province (China); Li, Yan; Chai, Xiao; Kang, Qian [Department of Hematology, Affiliated Hospital of Guizhou Medical University, The Hematopoietic Stem Cell Transplant Center of Guizhou Province, Blood Diseases Diagnosis and Treatment Center of Guizhou Province, Guiyang, 550004, Guizhou Province (China)

    2016-05-13

    Aberrant expression of microRNAs (miRNAs) is implicated in cancer development and progression. While miR-320a is reported to be deregulated in many malignancy types, its biological role in multiple myeloma (MM) remains unclear. Here, we observed reduced expression of miR-320a in MM samples and cell lines. Ectopic expression of miR-320a dramatically suppressed cell viability and clonogenicity and induced apoptosis in vitro. Mechanistic investigation led to the identification of Pre-B-cellleukemia transcription factor 3 (PBX3) as a novel and direct downstream target of miR-320a. Interestingly, reintroduction of PBX3 abrogated miR-320a-induced MM cell growth inhibition and apoptosis. In a mouse xenograft model, miR-320a overexpression inhibited tumorigenicity and promoted apoptosis. Our findings collectively indicate that miR-320a inhibits cell proliferation and induces apoptosis in MM cells by directly targeting PBX3, supporting its utility as a novel and potential therapeutic agent for miRNA-based MM therapy. -- Highlights: •Expression of miR-320a in MM cell induces apoptosis in vitro. •miR-320a represses PBX3 via targeting specific sequences in the 3′UTR region. •Exogenous expression of PBX3 reverses the effects of miR-320a in inhibiting MM cell growth and promoting apoptosis. •Overexpression of miR-320a inhibits tumor growth and increases apoptosis in vivo.

  17. Identifying Patient-Specific Epstein-Barr Nuclear Antigen-1 Genetic Variation and Potential Autoreactive Targets Relevant to Multiple Sclerosis Pathogenesis.

    Directory of Open Access Journals (Sweden)

    Monika Tschochner

    Full Text Available Epstein-Barr virus (EBV infection represents a major environmental risk factor for multiple sclerosis (MS, with evidence of selective expansion of Epstein-Barr Nuclear Antigen-1 (EBNA1-specific CD4+ T cells that cross-recognize MS-associated myelin antigens in MS patients. HLA-DRB1*15-restricted antigen presentation also appears to determine susceptibility given its role as a dominant risk allele. In this study, we have utilised standard and next-generation sequencing techniques to investigate EBNA-1 sequence variation and its relationship to HLA-DR15 binding affinity, as well as examining potential cross-reactive immune targets within the central nervous system proteome.Sanger sequencing was performed on DNA isolated from peripheral blood samples from 73 Western Australian MS cases, without requirement for primary culture, with additional FLX 454 Roche sequencing in 23 samples to identify low-frequency variants. Patient-derived viral sequences were used to predict HLA-DRB1*1501 epitopes (NetMHCII, NetMHCIIpan and candidates were evaluated for cross recognition with human brain proteins.EBNA-1 sequence variation was limited, with no evidence of multiple viral strains and only low levels of variation identified by FLX technology (8.3% nucleotide positions at a 1% cut-off. In silico epitope mapping revealed two known HLA-DRB1*1501-restricted epitopes ('AEG': aa 481-496 and 'MVF': aa 562-577, and two putative epitopes between positions 502-543. We identified potential cross-reactive targets involving a number of major myelin antigens including experimentally confirmed HLA-DRB1*15-restricted epitopes as well as novel candidate antigens within myelin and paranodal assembly proteins that may be relevant to MS pathogenesis.This study demonstrates the feasibility of obtaining autologous EBNA-1 sequences directly from buffy coat samples, and confirms divergence of these sequences from standard laboratory strains. This approach has identified a number of

  18. Damage to tungsten macro-brush targets under multiple ELM-like heat loads. Experiments vs. numerical simulations and extrapolation to ITER

    Energy Technology Data Exchange (ETDEWEB)

    Bazylev, B.; Landman, I. [Forschungszentrum Karlsruhe (Germany). IHM; Janeschitz, G. [Forschungszentrum Karlsruhe (DE). Fusion EURATOM] (and others)

    2007-07-01

    Operation of ITER at high fusion gain is assumed to be the H-mode. A characteristic feature of this regime is the transient release of energy from the confined plasma onto PFCs by multiple ELMs (about 104 ELMs per ITER discharge), which can play a determining role in the erosion rate and lifetime of these components. The expected energy heat loads on the ITER divertor during Type I ELM are in range 0.5-4 MJ/m{sup 2} in timescales of 0.3-0.6 ms. Tungsten macro-brush armour (W-brushes) is foreseen as one of plasma facing components (PFC) for ITER divertor and dome. During the intense transient events in ITER the surface melting, melt motion, melt splashing and evaporation are seen as the main mechanisms of W erosion. The expected erosion of the ITER plasma facing components under transient energy loads can be properly estimated by numerical simulations validated against target erosion of the experiments at the plasma gun facility QSPA-T. Within the collaboration established between EU fusion programme and the Russian Federation, W-brush targets (produced either from pure tungsten or tungsten with 1% of La{sub 2}O{sub 3}) manufactured according to the EU specifications for the ITER divertor targets, have been exposed to multiple ITER ELM-like loads in plasma gun facilities at TRINITI in the range 0.5 - 2.2 MJ/m2 with pulse duration of 0.5 ms. The measured material erosion data have been used to validate the codes MEMOS and PHEMOBRID. Numerical simulations, including 3D-simulations (codes MEMOS and PHEMOBRID), carried out for the conditions of the QSPA-T experiments with heat loads in the range 0.5-2.2 MJ/m{sup 2} and the timescale 0.5 ms demonstrated a rather good agreement with the data obtained at the plasma gun facility QSPA: melting of brush edges at low heat loads, intense melt motion and bridge formation caused by the Rayleigh-Taylor instability at heat loads Q>1.3 MJ/m{sup 2}. The melt splashing generated by the Kelvin-Helmholtz, and Rayleigh

  19. Concomitant targeting of multiple key transcription factors effectively disrupts cancer stem cells enriched in side population of human pancreatic cancer cells.

    Directory of Open Access Journals (Sweden)

    Xiyan Wang

    Full Text Available A major challenge in the treatment of pancreatic ductal adenocarcinoma is the failure of chemotherapy, which is likely due to the presence of the cancer stem cells (CSCs.To identify side population (SP cells and characterize s-like properties in human pancreatic cancer cell lines (h-PCCLs and to exploit the efficacy of concomitant targeting of multiple key transcription factors governing the stemness of pancreatic CSCs in suppressing CSC-like phenotypes.Flow cytometry and Hoechst 33342 DNA-binding dye efflux assay were used to sort SP and non-SP (NSP cells from three h-PCCLs: PANC-1, SW1990, and BxPc-3. The self-renewal ability, invasiveness, migration and drug resistance of SP cells were evaluated. Expression of CSC marker genes was analyzed. Tumorigenicity was assessed using a xenograft model in nude mice. Effects of a complex decoy oligonucleotide (cdODN-SCO designed to simultaneously targeting Sox2, Oct4 and c-Myc were assessed.CSCs were enriched in the side proportion (SP cells contained in the h-PCCLs and they possessed aggressive growth, invasion, migration and drug-resistance properties, compared with NSP cells. SP cells overexpressed stem cell markers CD133 and ALDH1, pluripotency maintaining factors Nanog, Sox2 and Oct4, oncogenic transcription factor c-Myc, signaling molecule Notch1, and drug resistant gene ABCG2. Moreover, SP cells consistently demonstrated significantly greater tumorigenicity than NSP cells in xenograft model of nude mice. CdODN-SOC efficiently suppressed all CSC properties and phenotypes, and minimized the tumorigenic capability of the SP cells and the resistance to chemotherapy. By comparison, the negative control failed to do so.The findings indicate that targeting the key genes conferring the stemness of CSCs can efficiently eliminate CSC-like phenotypes, and thus may be considered a new approach for cancer therapy. Specifically, the present study establishes the combination of Sox2/Oct4/c-Myc targeting as a

  20. Vascular targeting of LIGHT normalizes blood vessels in primary brain cancer and induces intratumoural high endothelial venules.

    Science.gov (United States)

    He, Bo; Jabouille, Arnaud; Steri, Veronica; Johansson-Percival, Anna; Michael, Iacovos P; Kotamraju, Venkata Ramana; Junckerstorff, Reimar; Nowak, Anna K; Hamzah, Juliana; Lee, Gabriel; Bergers, Gabriele; Ganss, Ruth

    2018-06-01

    High-grade brain cancer such as glioblastoma (GBM) remains an incurable disease. A common feature of GBM is the angiogenic vasculature, which can be targeted with selected peptides for payload delivery. We assessed the ability of micelle-tagged, vascular homing peptides RGR, CGKRK and NGR to specifically bind to blood vessels in syngeneic orthotopic GBM models. By using the peptide CGKRK to deliver the tumour necrosis factor (TNF) superfamily member LIGHT (also known as TNF superfamily member 14; TNFSF14) to angiogenic tumour vessels, we have generated a reagent that normalizes the brain cancer vasculature by inducing pericyte contractility and re-establishing endothelial barrier integrity. LIGHT-mediated vascular remodelling also activates endothelia and induces intratumoural high endothelial venules (HEVs), which are specialized blood vessels for lymphocyte infiltration. Combining CGKRK-LIGHT with anti-vascular endothelial growth factor and checkpoint blockade amplified HEV frequency and T-cell accumulation in GBM, which is often sparsely infiltrated by immune effector cells, and reduced tumour burden. Furthermore, CGKRK and RGR peptides strongly bound to blood vessels in freshly resected human GBM, demonstrating shared peptide-binding activities in mouse and human primary brain tumour vessels. Thus, peptide-mediated LIGHT targeting is a highly translatable approach in primary brain cancer to reduce vascular leakiness and enhance immunotherapy. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  1. 'Compromise position' image alignment to accommodate independent motion of multiple clinical target volumes during radiotherapy: A high risk prostate cancer example

    International Nuclear Information System (INIS)

    Rosewall, Tara; Alasti, Hamideh; Bayley, Andrew; Yan, Jing

    2017-01-01

    Inclusion of multiple independently moving clinical target volumes (CTVs) in the irradiated volume causes an image guidance conundrum. The purpose of this research was to use high risk prostate cancer as a clinical example to evaluate a 'compromise' image alignment strategy. The daily pre-treatment orthogonal EPI for 14 consecutive patients were included in this analysis. Image matching was performed by aligning to the prostate only, the bony pelvis only and using the 'compromise' strategy. Residual CTV surrogate displacements were quantified for each of the alignment strategies. Analysis of the 388 daily fractions indicated surrogate displacements were well-correlated in all directions (r 2 = 0.95 (LR), 0.67 (AP) and 0.59 (SI). Differences between the surrogates displacements (95% range) were −0.4 to 1.8 mm (LR), −1.2 to 5.2 mm (SI) and −1.2 to 5.2 mm (AP). The distribution of the residual displacements was significantly smaller using the 'compromise' strategy, compared to the other strategies (p 0.005). The 'compromise' strategy ensured the CTV was encompassed by the PTV in all fractions, compared to 47 PTV violations when aligned to prostate only. This study demonstrated the feasibility of a compromise position image guidance strategy to accommodate simultaneous displacements of two independently moving CTVs. Application of this strategy was facilitated by correlation between the CTV displacements and resulted in no geometric excursions of the CTVs beyond standard sized PTVs. This simple image guidance strategy may also be applicable to other disease sites that concurrently irradiate multiple CTVs, such as head and neck, lung and cervix cancer.

  2. 'Compromise position' image alignment to accommodate independent motion of multiple clinical target volumes during radiotherapy: A high risk prostate cancer example.

    Science.gov (United States)

    Rosewall, Tara; Yan, Jing; Alasti, Hamideh; Cerase, Carla; Bayley, Andrew

    2017-04-01

    Inclusion of multiple independently moving clinical target volumes (CTVs) in the irradiated volume causes an image guidance conundrum. The purpose of this research was to use high risk prostate cancer as a clinical example to evaluate a 'compromise' image alignment strategy. The daily pre-treatment orthogonal EPI for 14 consecutive patients were included in this analysis. Image matching was performed by aligning to the prostate only, the bony pelvis only and using the 'compromise' strategy. Residual CTV surrogate displacements were quantified for each of the alignment strategies. Analysis of the 388 daily fractions indicated surrogate displacements were well-correlated in all directions (r 2  = 0.95 (LR), 0.67 (AP) and 0.59 (SI). Differences between the surrogates displacements (95% range) were -0.4 to 1.8 mm (LR), -1.2 to 5.2 mm (SI) and -1.2 to 5.2 mm (AP). The distribution of the residual displacements was significantly smaller using the 'compromise' strategy, compared to the other strategies (p 0.005). The 'compromise' strategy ensured the CTV was encompassed by the PTV in all fractions, compared to 47 PTV violations when aligned to prostate only. This study demonstrated the feasibility of a compromise position image guidance strategy to accommodate simultaneous displacements of two independently moving CTVs. Application of this strategy was facilitated by correlation between the CTV displacements and resulted in no geometric excursions of the CTVs beyond standard sized PTVs. This simple image guidance strategy may also be applicable to other disease sites that concurrently irradiate multiple CTVs, such as head and neck, lung and cervix cancer. © 2016 The Royal Australian and New Zealand College of Radiologists.

  3. The novel orally bioavailable inhibitor of phosphoinositol-3-kinase and mammalian target of rapamycin, NVP-BEZ235, inhibits growth and proliferation in multiple myeloma

    International Nuclear Information System (INIS)

    Baumann, Philipp; Mandl-Weber, Sonja; Oduncu, Fuat; Schmidmaier, Ralf

    2009-01-01

    NVP-BEZ235 is a new inhibitor of phosphoinositol-3-kinase (PI3 kinase) and mammalian target of rapamycin (mTOR) whose efficacy in advanced solid tumours is currently being evaluated in a phase I/II clinical trial. Here we show that NVP-BEZ235 inhibits growth in common myeloma cell lines as well as primary myeloma cells at nanomolar concentrations in a time and dose dependent fashion. Further experiments revealed induction of apoptosis in three of four cell lines. Inhibition of cell growth was mainly due to inhibition of myeloma cell proliferation, as shown by the BrdU assay. Cell cycle analysis revealed induction of cell cycle arrest in the G1 phase, which was due to downregulation of cyclin D1, pRb and cdc25a. NVP-BEZ235 inhibited phosphorylation of protein kinase B (Akt), P70S6k and 4E-BP-1. Furthermore we show that the stimulatory effect of CD40-ligand (CD40L), insulin-like growth factor 1 (IGF-1), interleukin-6 (IL-6) and conditioned medium of HS-5 stromal cells on myeloma cell growth is completely abrogated by NVP-BEZ235. In addition, synergism studies revealed synergistic and additive activity of NVP-BEZ235 together with melphalan, doxorubicin and bortezomib. Taken together, inhibition of PI3 kinase/mTOR by NVP-BEZ235 is highly effective and NVP-BEZ235 represents a potential new candidate for targeted therapy in multiple myeloma

  4. MiR-17-5p impairs trafficking of H-ERG K+ channel protein by targeting multiple er stress-related chaperones during chronic oxidative stress.

    Directory of Open Access Journals (Sweden)

    Qi Wang

    Full Text Available BACKGROUND: To investigate if microRNAs (miRNAs play a role in regulating h-ERG trafficking in the setting of chronic oxidative stress as a common deleterious factor for many cardiac disorders. METHODS: We treated neonatal rat ventricular myocytes and HEK293 cells with stable expression of h-ERG with H2O2 for 12 h and 48 h. Expression of miR-17-5p seed miRNAs was quantified by real-time RT-PCR. Protein levels of chaperones and h-ERG trafficking were measured by Western blot analysis. Luciferase reporter gene assay was used to study miRNA and target interactions. Whole-cell patch-clamp techniques were employed to record h-ERG K(+ current. RESULTS: H-ERG trafficking was impaired by H2O2 after 48 h treatment, accompanied by reciprocal changes of expression between miR-17-5p seed miRNAs and several chaperones (Hsp70, Hsc70, CANX, and Golga2, with the former upregulated and the latter downregulated. We established these chaperones as targets for miR-17-5p. Application miR-17-5p inhibitor rescued H2O2-induced impairment of h-ERG trafficking. Upregulation of endogenous by H2O2 or forced miR-17-5p expression either reduced h-ERG current. Sequestration of AP1 by its decoy molecule eliminated the upregulation of miR-17-5p, and ameliorated impairment of h-ERG trafficking. CONCLUSIONS: Collectively, deregulation of the miR-17-5p seed family miRNAs can cause severe impairment of h-ERG trafficking through targeting multiple ER stress-related chaperones, and activation of AP1 likely accounts for the deleterious upregulation of these miRNAs, in the setting of prolonged duration of oxidative stress. These findings revealed the role of miRNAs in h-ERG trafficking, which may contribute to the cardiac electrical disturbances associated with oxidative stress.

  5. MiR-17-5p impairs trafficking of H-ERG K+ channel protein by targeting multiple er stress-related chaperones during chronic oxidative stress.

    Science.gov (United States)

    Wang, Qi; Hu, Weina; Lei, Mingming; Wang, Yong; Yan, Bing; Liu, Jun; Zhang, Ren; Jin, Yuanzhe

    2013-01-01

    To investigate if microRNAs (miRNAs) play a role in regulating h-ERG trafficking in the setting of chronic oxidative stress as a common deleterious factor for many cardiac disorders. We treated neonatal rat ventricular myocytes and HEK293 cells with stable expression of h-ERG with H2O2 for 12 h and 48 h. Expression of miR-17-5p seed miRNAs was quantified by real-time RT-PCR. Protein levels of chaperones and h-ERG trafficking were measured by Western blot analysis. Luciferase reporter gene assay was used to study miRNA and target interactions. Whole-cell patch-clamp techniques were employed to record h-ERG K(+) current. H-ERG trafficking was impaired by H2O2 after 48 h treatment, accompanied by reciprocal changes of expression between miR-17-5p seed miRNAs and several chaperones (Hsp70, Hsc70, CANX, and Golga2), with the former upregulated and the latter downregulated. We established these chaperones as targets for miR-17-5p. Application miR-17-5p inhibitor rescued H2O2-induced impairment of h-ERG trafficking. Upregulation of endogenous by H2O2 or forced miR-17-5p expression either reduced h-ERG current. Sequestration of AP1 by its decoy molecule eliminated the upregulation of miR-17-5p, and ameliorated impairment of h-ERG trafficking. Collectively, deregulation of the miR-17-5p seed family miRNAs can cause severe impairment of h-ERG trafficking through targeting multiple ER stress-related chaperones, and activation of AP1 likely accounts for the deleterious upregulation of these miRNAs, in the setting of prolonged duration of oxidative stress. These findings revealed the role of miRNAs in h-ERG trafficking, which may contribute to the cardiac electrical disturbances associated with oxidative stress.

  6. Quantitative changes in proteins responsible for flavonoid and anthocyanin biosynthesis in strawberry fruit at different ripening stages: A targeted quantitative proteomic investigation employing multiple reaction monitoring.

    Science.gov (United States)

    Song, Jun; Du, Lina; Li, Li; Kalt, Wilhelmina; Palmer, Leslie Campbell; Fillmore, Sherry; Zhang, Ying; Zhang, ZhaoQi; Li, XiHong

    2015-06-03

    To better understand the regulation of flavonoid and anthocyanin biosynthesis, a targeted quantitative proteomic investigation employing LC-MS with multiple reaction monitoring was conducted on two strawberry cultivars at three ripening stages. This quantitative proteomic workflow was improved through an OFFGEL electrophoresis to fractionate peptides from total protein digests. A total of 154 peptide transitions from 47 peptides covering 21 proteins and isoforms related to anthocyanin biosynthesis were investigated. The normalized protein abundance, which was measured using isotopically-labeled standards, was significantly changed concurrently with increased anthocyanin content and advanced fruit maturity. The protein abundance of phenylalanine ammonia-lyase; anthocyanidin synthase, chalcone isomerase; flavanone 3-hydroxylase; dihydroflavonol 4-reductase, UDP-glucose:flavonoid-3-O-glucosyltransferase, cytochrome c and cytochrome C oxidase subunit 2, was all significantly increased in fruit of more advanced ripeness. An interaction between cultivar and maturity was also shown with respect to chalcone isomerase. The good correlation between protein abundance and anthocyanin content suggested that a metabolic control point may exist for anthocyanin biosynthesis. This research provides insights into the process of anthocyanin formation in strawberry fruit at the level of protein concentration and reveals possible candidates in the regulation of anthocyanin formation during fruit ripening. To gain insight into the molecular mechanisms contributing to flavonoids and anthocyanin biosynthesis and regulation of strawberry fruit during ripening is challenging due to limited molecular biology tools and established hypothesis. Our targeted proteomic approach employing LC-MS/MS analysis and MRM technique to quantify proteins in relation to flavonoids and anthocyanin biosynthesis and regulation in strawberry fruit during fruit ripening is novel. The identification of peptides

  7. Parent-administered computer-assisted tutoring targeting letter-sound knowledge: Evaluation via multiple-baseline across three preschool students.

    Science.gov (United States)

    DuBois, Matthew R; Volpe, Robert J; Burns, Matthew K; Hoffman, Jessica A

    2016-12-01

    Knowledge of letters sounds has been identified as a primary objective of preschool instruction and intervention. Despite this designation, large disparities exist in the number of letter sounds children know at school entry. Enhancing caregivers' ability to teach their preschool-aged children letter sounds may represent an effective practice for reducing this variability and ensuring that more children are prepared to experience early school success. This study used a non-concurrent multiple-baseline-across-participants design to evaluate the effectiveness of caregivers (N=3) delivering a computer-assisted tutoring program (Tutoring Buddy) targeting letter sound knowledge to their preschool-aged children. Visual analyses and effect size estimates derived from Percentage of All Non-Overlapping Data (PAND) statistics indicated consistent results for letter sound acquisition, as 6weeks of intervention yielded large effects for letter sound knowledge (LSK) across all three children. Large effect sizes were also found for letter sound fluency (LSF) and nonsense word fluency (NWF) for two children. All three caregivers rated the intervention as highly usable and were able to administer it with high levels of fidelity. Taken together, the results of the present study found Tutoring Buddy to be an effective, simple, and usable way for the caregivers to support their children's literacy development. Copyright © 2016 Society for the Study of School Psychology. Published by Elsevier Ltd. All rights reserved.

  8. Targeted Quantitation of Site-Specific Cysteine Oxidation in Endogenous Proteins Using a Differential Alkylation and Multiple Reaction Monitoring Mass Spectrometry Approach

    Science.gov (United States)

    Held, Jason M.; Danielson, Steven R.; Behring, Jessica B.; Atsriku, Christian; Britton, David J.; Puckett, Rachel L.; Schilling, Birgit; Campisi, Judith; Benz, Christopher C.; Gibson, Bradford W.

    2010-01-01

    Reactive oxygen species (ROS) are both physiological intermediates in cellular signaling and mediators of oxidative stress. The cysteine-specific redox-sensitivity of proteins can shed light on how ROS are regulated and function, but low sensitivity has limited quantification of the redox state of many fundamental cellular regulators in a cellular context. Here we describe a highly sensitive and reproducible oxidation analysis approach (OxMRM) that combines protein purification, differential alkylation with stable isotopes, and multiple reaction monitoring mass spectrometry that can be applied in a targeted manner to virtually any cysteine or protein. Using this approach, we quantified the site-specific cysteine oxidation status of endogenous p53 for the first time and found that Cys182 at the dimerization interface of the DNA binding domain is particularly susceptible to diamide oxidation intracellularly. OxMRM enables analysis of sulfinic and sulfonic acid oxidation levels, which we validate by assessing the oxidation of the catalytic Cys215 of protein tyrosine phosphatase-1B under numerous oxidant conditions. OxMRM also complements unbiased redox proteomics discovery studies as a verification tool through its high sensitivity, accuracy, precision, and throughput. PMID:20233844

  9. MiR-7 triggers cell cycle arrest at the G1/S transition by targeting multiple genes including Skp2 and Psme3.

    Directory of Open Access Journals (Sweden)

    Noelia Sanchez

    Full Text Available MiR-7 acts as a tumour suppressor in many cancers and abrogates proliferation of CHO cells in culture. In this study we demonstrate that miR-7 targets key regulators of the G1 to S phase transition, including Skp2 and Psme3, to promote increased levels of p27(KIP and temporary growth arrest of CHO cells in the G1 phase. Simultaneously, the down-regulation of DNA repair-specific proteins via miR-7 including Rad54L, and pro-apoptotic regulators such as p53, combined with the up-regulation of anti-apoptotic factors like p-Akt, promoted cell survival while arrested in G1. Thus miR-7 can co-ordinate the levels of multiple genes and proteins to influence G1 to S phase transition and the apoptotic response in order to maintain cellular homeostasis. This work provides further mechanistic insight into the role of miR-7 as a regulator of cell growth in times of cellular stress.

  10. Clinical Validation of Atlas-Based Auto-Segmentation of Multiple Target Volumes and Normal Tissue (Swallowing/Mastication) Structures in the Head and Neck

    International Nuclear Information System (INIS)

    Teguh, David N.; Levendag, Peter C.; Voet, Peter W.J.; Al-Mamgani, Abrahim; Han Xiao; Wolf, Theresa K.; Hibbard, Lyndon S.; Nowak, Peter; Akhiat, Hafid; Dirkx, Maarten L.P.; Heijmen, Ben J.M.; Hoogeman, Mischa S.

    2011-01-01

    . Conclusion: Multiple-subject ABAS of computed tomography images proved to be a useful novel tool in the rapid delineation of target and normal tissues. Although editing of the autocontours is inevitable, a substantial time reduction was achieved using editing, instead of manual contouring (180 vs. 66 min).

  11. Abundant and diverse clustered regularly interspaced short palindromic repeat spacers in Clostridium difficile strains and prophages target multiple phage types within this pathogen.

    Science.gov (United States)

    Hargreaves, Katherine R; Flores, Cesar O; Lawley, Trevor D; Clokie, Martha R J

    2014-08-26

    Clostridium difficile is an important human-pathogenic bacterium causing antibiotic-associated nosocomial infections worldwide. Mobile genetic elements and bacteriophages have helped shape C. difficile genome evolution. In many bacteria, phage infection may be controlled by a form of bacterial immunity called the clustered regularly interspaced short palindromic repeats/CRISPR-associated (CRISPR/Cas) system. This uses acquired short nucleotide sequences (spacers) to target homologous sequences (protospacers) in phage genomes. C. difficile carries multiple CRISPR arrays, and in this paper we examine the relationships between the host- and phage-carried elements of the system. We detected multiple matches between spacers and regions in 31 C. difficile phage and prophage genomes. A subset of the spacers was located in prophage-carried CRISPR arrays. The CRISPR spacer profiles generated suggest that related phages would have similar host ranges. Furthermore, we show that C. difficile strains of the same ribotype could either have similar or divergent CRISPR contents. Both synonymous and nonsynonymous mutations in the protospacer sequences were identified, as well as differences in the protospacer adjacent motif (PAM), which could explain how phages escape this system. This paper illustrates how the distribution and diversity of CRISPR spacers in C. difficile, and its prophages, could modulate phage predation for this pathogen and impact upon its evolution and pathogenicity. Clostridium difficile is a significant bacterial human pathogen which undergoes continual genome evolution, resulting in the emergence of new virulent strains. Phages are major facilitators of genome evolution in other bacterial species, and we use sequence analysis-based approaches in order to examine whether the CRISPR/Cas system could control these interactions across divergent C. difficile strains. The presence of spacer sequences in prophages that are homologous to phage genomes raises an

  12. Auger electron emitter against multiple myeloma - targeted endo-radio-therapy with 125I-labeled thymidine analogue 5-iodo-4'-thio-2'-deoxyuridine

    International Nuclear Information System (INIS)

    Morgenroth, Agnieszka; Dinger, Cornelia; Zlatopolskiy, Boris D.; Al-Momani, Ehab; Glatting, Gerhard; Mottaghy, Felix M.; Reske, Sven N.

    2011-01-01

    Introduction: Multiple myeloma (MM) is a plasma cell malignancy characterized by accumulation of malignant, terminally differentiated B cells in the bone marrow. Despite advances in therapy, MM remains an incurable disease. Novel therapeutic approaches are, therefore, urgently needed. Auger electron-emitting radiopharmaceuticals are attractive for targeted nano-irradiation therapy, given that DNA of malignant cells is selectively addressed. Here we evaluated the antimyeloma potential of the Auger electron-emitting thymidine analogue 125 I-labeled 5-iodo-4'-thio-2'-deoxyuridine ([ 125 I]ITdU). Methods: Cellular uptake and DNA incorporation of [ 125 I]ITdU were determined in fluorodeoxyuridine-pretreated KMS12BM, U266, dexamethasone-sensitive MM1.S and -resistant MM1.R cell lines. The effect of stimulation with interleukin 6 (IL6) or insulin-like growth factor 1 (IGF1) on the intracellular incorporation of [ 125 I]ITdU was investigated in cytokine-sensitive MM1.S and MM1.R cell lines. Apoptotic cells were identified using Annexin V. Cleavage of caspase 3 and PARP was visualized by Western blot. DNA fragmentation was investigated using laddering assay. Therapeutic efficiency of [ 125 I]ITdU was proven by clonogenic assay. Results: [ 125 I]ITdU was shown to be efficiently incorporated into DNA of malignant cells, providing a promising mechanism for delivering highly toxic Auger radiation emitters into tumor DNA. [ 125 I]ITdU had a potent antimyeloma effect in cell lines representing distinct disease stages and, importantly, in cell lines sensitive or resistant to the conventional therapeutic agent, but was not toxic for normal plasma and bone marrow stromal cells. Furthermore, [ 125 I]ITdU abrogated the protective actions of IL6 and IGF1 on MM cells. [ 125 I]ITdU induced massive damage in the DNA of malignant plasma cells, which resulted in efficient inhibition of clonogenic growth. Conclusion: These studies may provide a novel treatment strategy for overcoming

  13. Clinical Validation of Atlas-Based Auto-Segmentation of Multiple Target Volumes and Normal Tissue (Swallowing/Mastication) Structures in the Head and Neck

    Energy Technology Data Exchange (ETDEWEB)

    Teguh, David N. [Department of Radiation Oncology, Erasmus Medical Center-Daniel den Hoed Cancer Center, Rotterdam (Netherlands); Levendag, Peter C., E-mail: p.levendag@erasmusmc.nl [Department of Radiation Oncology, Erasmus Medical Center-Daniel den Hoed Cancer Center, Rotterdam (Netherlands); Voet, Peter W.J.; Al-Mamgani, Abrahim [Department of Radiation Oncology, Erasmus Medical Center-Daniel den Hoed Cancer Center, Rotterdam (Netherlands); Han Xiao; Wolf, Theresa K.; Hibbard, Lyndon S. [Elekta-CMS Software, Maryland Heights, MO 63043 (United States); Nowak, Peter; Akhiat, Hafid; Dirkx, Maarten L.P.; Heijmen, Ben J.M.; Hoogeman, Mischa S. [Department of Radiation Oncology, Erasmus Medical Center-Daniel den Hoed Cancer Center, Rotterdam (Netherlands)

    2011-11-15

    . Conclusion: Multiple-subject ABAS of computed tomography images proved to be a useful novel tool in the rapid delineation of target and normal tissues. Although editing of the autocontours is inevitable, a substantial time reduction was achieved using editing, instead of manual contouring (180 vs. 66 min).

  14. Boswellic acid suppresses growth and metastasis of human pancreatic tumors in an orthotopic nude mouse model through modulation of multiple targets.

    Directory of Open Access Journals (Sweden)

    Byoungduck Park

    Full Text Available Pancreatic cancer (PaCa is one of the most lethal cancers, with an estimated 5-year survival of <5% even when patients are given the best treatment available. In addition, these treatments are often toxic and expensive, thus new agents which are safe, affordable and effective are urgently needed. We describe here the results of our study with acetyl-11-keto-β-boswellic acid (AKBA, an agent obtained from an Ayurvedic medicine, gum resin of Boswellia serrata. Whether AKBA has an activity against human PaCa, was examined in in vitro models and in an orthotopic nude mouse model of PaCa. We found that AKBA inhibited the proliferation of four different PaCa cell lines (AsPC-1, PANC-28, and MIA PaCa-2 with K-Ras and p53 mutations, and BxPC-3 with wild-type K-Ras and p53 mutation. These effects correlated with an inhibition of constitutively active NF-κB and suppression of NF-κB regulating gene expression. AKBA also induced apoptosis, and sensitized the cells to apoptotic effects of gemcitabine. In the orthotopic nude mouse model of PaCa, p.o. administration of AKBA alone (100 mg/kg significantly inhibited the tumor growth; this activity was enhanced by gemcitabine. In addition, AKBA inhibited the metastasis of the PaCa to spleen, liver, and lungs. This correlated with decreases in Ki-67, a biomarker of proliferation, and CD31, a biomarker of microvessel density, in the tumor tissue. AKBA produced significant decreases in the expression of NF-κB regulating genes in the tissues. Immunohistochemical analysis also showed AKBA downregulated the expression of COX-2, MMP-9, CXCR4, and VEGF in the tissues. Overall these results demonstrate that AKBA can suppress the growth and metastasis of human pancreatic tumors in an orthotopic nude mouse model that correlates with modulation of multiple targets.

  15. Mitochondrial-Targeted Decyl-Triphenylphosphonium Enhances 2-Deoxy-D-Glucose Mediated Oxidative Stress and Clonogenic Killing of Multiple Myeloma Cells.

    Directory of Open Access Journals (Sweden)

    Jeanine Schibler

    Full Text Available Therapeutic advances have markedly prolonged overall survival in multiple myeloma (MM but the disease currently remains incurable. In a panel of MM cell lines (MM.1S, OPM-2, H929, and U266, using CD138 immunophenotyping, side population staining, and stem cell-related gene expression, we demonstrate the presence of stem-like tumor cells. Hypoxic culture conditions further increased CD138low stem-like cells with upregulated expression of OCT4 and NANOG. Compared to MM cells, these stem-like cells maintained lower steady-state pro-oxidant levels with increased uptake of the fluorescent deoxyglucose analog. In primary human MM samples, increased glycolytic gene expression correlated with poorer overall and event-free survival outcomes. Notably, stem-like cells showed increased mitochondrial mass, rhodamine 123 accumulation, and orthodox mitochondrial configuration while more condensed mitochondria were noted in the CD138high cells. Glycolytic inhibitor 2-deoxyglucose (2-DG induced ER stress as detected by qPCR (BiP, ATF4 and immunoblotting (BiP, CHOP and increased dihydroethidium probe oxidation both CD138low and CD138high cells. Treatment with a mitochondrial-targeting agent decyl-triphenylphosphonium (10-TPP increased intracellular steady-state pro-oxidant levels in stem-like and mature MM cells. Furthermore, 10-TPP mediated increases in mitochondrial oxidant production were suppressed by ectopic expression of manganese superoxide dismutase. Relative to 2-DG or 10-TPP alone, 2-DG plus 10-TPP combination showed increased caspase 3 activation in MM cells with minimal toxicity to the normal hematopoietic progenitor cells. Notably, treatment with polyethylene glycol conjugated catalase significantly reduced 2-DG and/or 10-TPP-induced apoptosis of MM cells. Also, the combination of 2-DG with 10-TPP decreased clonogenic survival of MM cells. Taken together, this study provides a novel strategy of metabolic oxidative stress-induced cytotoxicity of MM

  16. Target preparation

    International Nuclear Information System (INIS)

    Hinn, G.M.

    1984-01-01

    A few of the more interesting of the 210 targets prepared in the Laboratory last year are listed. In addition the author continues to use powdered silver mixed with /sup 9,10/BeO to produce sources for accelerator radio dating of Alaskan and South Polar snow. Currently, he is trying to increase production by multiple sample processing. Also the author routinely makes 3 μg/cm 2 cracked slacked carbon stripper foils and is continuing research with some degree of success in making enriched 28 Si targets starting with the oxide

  17. Preclinical Evidence for the Therapeutic Potential of CD38-Targeted Immuno-Chemotherapy in Multiple Myeloma Patients Refractory to Lenalidomide and Bortezomib

    DEFF Research Database (Denmark)

    Nijhof, I. S.; Groen, R. W. J.; Noort, W. A.

    2015-01-01

    lenalidomide- and/or bortezomib-refractory patients. In these assays, lenalidomide but not bortezomib, synergistically enhanced daratumumab-mediated multiple myeloma lysis through activation of natural killer cells. Finally, in an in vivo xenograft model, only the combination of daratumumab with lenalidomide......Purpose: Novel therapeutic agents have significantly improved the survival of patients with multiple myeloma. Nonetheless, the prognosis of patients with multiple myeloma who become refractory to the novel agents lenalidomide and bortezomib is very poor, indicating the urgent need for new...... therapeutic options for these patients. The human CD38 monoclonal antibody daratumumab is being evaluated as a novel therapy for multiple myeloma. Prompted with the encouraging results of ongoing clinical phase I/II trials, we now addressed the potential value of daratumumab alone or in combination...

  18. Systemic Responses of Multidrug-Resistant Pseudomonas aeruginosa and Acinetobacter baumannii Following Exposure to the Antimicrobial Peptide Cathelicidin-BF Imply Multiple Intracellular Targets

    Directory of Open Access Journals (Sweden)

    Cunbao Liu

    2017-11-01

    Full Text Available Cathelicidin-BF, derived from the banded krait (Bungarus fasciatus, is a typically cationic, amphiphilic and α-helical antimicrobial peptide (AMP with 30 amino acids that exerts powerful effects on multidrug-resistant (MDR clinical isolates, including Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae, but whether it targets plasma membranes or intracellular targets to kill bacteria is still controversial. In the present study, we demonstrated that the disruption of bacterial membranes with high concentrations of cathelicidin-BF was the cause of bacterial death, as with conventional antibiotics at high concentrations. At lower concentrations, cathelicidin-BF did not cause bacterial plasma membrane disruption, but it was able to cross the membrane and aggregate at the nucleoid regions. Functional proteins of the transcription processes of P. aeruginosa and A. baumannii were affected by sublethal doses of cathelicidin-BF, as demonstrated by comparative proteomics using isobaric tags for relative and absolute quantification and subsequent gene ontology (GO analysis. Analysis using the Kyoto Encyclopedia of Genes and Genomes showed that cathelicidin-BF mainly interferes with metabolic pathways related to amino acid synthesis, metabolism of cofactors and vitamins, metabolism of purine and energy supply, and other processes. Although specific targets of cathelicidin-BF must still be validated, our study offers strong evidence that cathelicidin-BF may act upon intracellular targets to kill superbugs, which may be helpful for further efforts to discover novel antibiotics to fight against them.

  19. MicroRNA-429 induces tumorigenesis of human non-small cell lung cancer cells and targets multiple tumor suppressor genes

    Energy Technology Data Exchange (ETDEWEB)

    Lang, Yaoguo; Xu, Shidong; Ma, Jianqun; Wu, Jun [Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, Heilongjiang 150081 (China); Jin, Shi; Cao, Shoubo [Department of Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, Heilongjiang 150081 (China); Yu, Yan, E-mail: yuyan@hrbmu.edu.cn [Department of Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, Heilongjiang 150081 (China)

    2014-07-18

    Highlights: • MiR-429 expression is upregulated in non-small cell lung cancer (NSCLC). • MiR-429 inhibits PTEN, RASSF8 and TIMP2 expression. • MiR-429 promotes metastasis and proliferation. • We report important regulatory mechanisms involved in NSCLC progression. • MiR-429 is a potential therapeutic target and diagnostic marker. - Abstract: Lung cancer is the major cause of cancer death globally. MicroRNAs are evolutionally conserved small noncoding RNAs that are critical for the regulation of gene expression. Aberrant expression of microRNA (miRNA) has been implicated in cancer initiation and progression. In this study, we demonstrated that the expression of miR-429 are often upregulated in non-small cell lung cancer (NSCLC) compared with normal lung tissues, and its expression level is also increased in NSCLC cell lines compared with normal lung cells. Overexpression of miR-429 in A549 NSCLC cells significantly promoted cell proliferation, migration and invasion, whereas inhibition of miR-429 inhibits these effects. Furthermore, we demonstrated that miR-429 down-regulates PTEN, RASSF8 and TIMP2 expression by directly targeting the 3′-untranslated region of these target genes. Taken together, our results suggest that miR-429 plays an important role in promoting the proliferation and metastasis of NSCLC cells and is a potential target for NSCLC therapy.

  20. The RNA Template Channel of the RNA-Dependent RNA Polymerase as a Target for Development of Antiviral Therapy of Multiple Genera within a Virus Family

    NARCIS (Netherlands)

    van der Linden, Lonneke; Vives-Adrián, Laia; Selisko, Barbara; Ferrer-Orta, Cristina; Liu, Xinran; Lanke, Kjerstin; Ulferts, Rachel; De Palma, Armando M; Tanchis, Federica; Goris, Nesya; Lefebvre, David; De Clercq, Kris; Leyssen, Pieter; Lacroix, Céline; Pürstinger, Gerhard; Coutard, Bruno; Canard, Bruno; Boehr, David D; Arnold, Jamie J; Cameron, Craig E; Verdaguer, Nuria; Neyts, Johan; van Kuppeveld, Frank J M

    2015-01-01

    The genus Enterovirus of the family Picornaviridae contains many important human pathogens (e.g., poliovirus, coxsackievirus, rhinovirus, and enterovirus 71) for which no antiviral drugs are available. The viral RNA-dependent RNA polymerase is an attractive target for antiviral therapy.

  1. Optical Remote Sensing for Fence-Line Monitoring using Open-Path Quantum Cascade Laser (QCL) mono-static system for multiple target compounds in the Mid IR 7-13um (Fingerprint) region.

    Science.gov (United States)

    Zemek, P. G.

    2017-12-01

    Quantum Cascade Lasers (QCLs) are quickly replacing Tunable Diode Lasers (TDL) for multi-target species identification and quantification in both extractive and open-path (OP) Optical Remote Sensing (ORS) fence-line instrumentation. As was seen with TDL incorporation and pricing drops as the adoption by the telecommunications industry and its current scaling has improved robustness and pricing, the QCL is also, albiet more slowly, becoming a mature market. There are several advantages of QCLs over conventional TDLs such as improved brightness and beam density, high resolution, as well as the incorporation of external etalons or internal gratings to scan over wide spectral areas. QCLs typically operate in the Mid infra-red (MIR) as opposed to the Near-Infrared (NIR) region used with TDL. The MidIR is a target rich absorption band area where compounds have high absorbtivity coefficients resulting in better detection limits as compared to TDL instruments. The use of novel chemometrics and more sensitive non-cryo-cooled detectors has allowed some of the first QCL open-path instruments in both active and passive operation. Data and field studies of one of the newest QCL OP systems is presented that allows one system to measure multiple target compounds. Multiple QCL spectral regions may be stitched together to increase the capability of QCLs over TDL OP systems. A comparison of several ORS type systems will be presented.

  2. Charged particle fusion targets

    International Nuclear Information System (INIS)

    Bangerter, R.O.; Meeker, D.J.

    1977-01-01

    The power, voltage, energy and other requirements of electron and ion beam fusion targets are reviewed. Single shell, multiple shell and magnetically insulated target designs are discussed. Questions of stability are also considered. In particular, it is shown that ion beam targets are stabilized by an energy spread in the ion beam

  3. The RNA template channel of the RNA-dependent RNA polymerase as a target for development of antiviral therapy of multiple genera within a virus family.

    Directory of Open Access Journals (Sweden)

    Lonneke van der Linden

    2015-03-01

    Full Text Available The genus Enterovirus of the family Picornaviridae contains many important human pathogens (e.g., poliovirus, coxsackievirus, rhinovirus, and enterovirus 71 for which no antiviral drugs are available. The viral RNA-dependent RNA polymerase is an attractive target for antiviral therapy. Nucleoside-based inhibitors have broad-spectrum activity but often exhibit off-target effects. Most non-nucleoside inhibitors (NNIs target surface cavities, which are structurally more flexible than the nucleotide-binding pocket, and hence have a more narrow spectrum of activity and are more prone to resistance development. Here, we report a novel NNI, GPC-N114 (2,2'-[(4-chloro-1,2-phenylenebis(oxy]bis(5-nitro-benzonitrile with broad-spectrum activity against enteroviruses and cardioviruses (another genus in the picornavirus family. Surprisingly, coxsackievirus B3 (CVB3 and poliovirus displayed a high genetic barrier to resistance against GPC-N114. By contrast, EMCV, a cardiovirus, rapidly acquired resistance due to mutations in 3Dpol. In vitro polymerase activity assays showed that GPC-N114 i inhibited the elongation activity of recombinant CVB3 and EMCV 3Dpol, (ii had reduced activity against EMCV 3Dpol with the resistance mutations, and (iii was most efficient in inhibiting 3Dpol when added before the RNA template-primer duplex. Elucidation of a crystal structure of the inhibitor bound to CVB3 3Dpol confirmed the RNA-binding channel as the target for GPC-N114. Docking studies of the compound into the crystal structures of the compound-resistant EMCV 3Dpol mutants suggested that the resistant phenotype is due to subtle changes that interfere with the binding of GPC-N114 but not of the RNA template-primer. In conclusion, this study presents the first NNI that targets the RNA template channel of the picornavirus polymerase and identifies a new pocket that can be used for the design of broad-spectrum inhibitors. Moreover, this study provides important new insight

  4. Therapeutic strategy with artificially-designed i-lncRNA targeting multiple oncogenic microRNAs exhibits effective antitumor activity in diffuse large B-cell lymphoma.

    Science.gov (United States)

    Su, Yinghan; Sun, Bin; Lin, Xuejing; Zhao, Xinying; Ji, Weidan; He, Miaoxia; Qian, Haihua; Song, Xianmin; Yang, Jianmin; Wang, Jianmin; Chen, Jie

    2016-08-02

    In diffuse large B-cell lymphoma (DLBCL), many oncogenic microRNAs (OncomiRs) are highly expressed to promote disease development and progression by inhibiting the expression and function of certain tumor suppressor genes, and these OncomiRs comprise a promising new class of molecular targets for the treatment of DLBCL. However, most current therapeutic studies have focused on a single miRNA, with limited treatment outcomes. In this study, we generated tandem sequences of 10 copies of the complementary binding sequences to 13 OncomiRs and synthesized an interfering long non-coding RNA (i-lncRNA). The highly-expressed i-lncRNA in DLBCL cells would compete with the corresponding mRNAs of OncomiR target genes for binding OncomiRs, thereby effectively consuming a large amount of OncomiRs and protecting many tumor suppressor genes. The in vitro experiments confirmed that the i-lncRNA expression significantly inhibited cell proliferation, induced cell cycle arrest and apoptosis in DLBCL cell lines, mainly through upregulating the expression of PTEN, p27kip1, TIMP3, RECK and downregulating the expression of p38/MAPK, survivin, CDK4, c-myc. In the established SUDHL-4 xenografts in nude mice, the treatment strategy involving adenovirus-mediated i-lncRNA expression significantly inhibited the growth of DLBCL xenografts. Therefore, this treatment would specifically target the carcinogenic effects of many OncomiRs that are usually expressed in DLBCL and not in normal cells, such a strategy could improve anti-tumor efficacy and safety and may be a good prospect for clinical applications.

  5. Activator Gcn4 Employs Multiple Segments of Med15/Gal11, Including the KIX Domain, to Recruit Mediator to Target Genes in Vivo*♦

    OpenAIRE

    Jedidi, Iness; Zhang, Fan; Qiu, Hongfang; Stahl, Stephen J.; Palmer, Ira; Kaufman, Joshua D.; Nadaud, Philippe S.; Mukherjee, Sujoy; Wingfield, Paul T.; Jaroniec, Christopher P.; Hinnebusch, Alan G.

    2009-01-01

    Mediator is a multisubunit coactivator required for initiation by RNA polymerase II. The Mediator tail subdomain, containing Med15/Gal11, is a target of the activator Gcn4 in vivo, critical for recruitment of native Mediator or the Mediator tail subdomain present in sin4Δ cells. Although several Gal11 segments were previously shown to bind Gcn4 in vitro, the importance of these interactions for recruitment of Mediator and transcriptional activation by Gcn4 in cells was unknown. We show that i...

  6. Canonical A-to-I and C-to-U RNA editing is enriched at 3'UTRs and microRNA target sites in multiple mouse tissues.

    Directory of Open Access Journals (Sweden)

    Tongjun Gu

    Full Text Available RNA editing is a process that modifies RNA nucleotides and changes the efficiency and fidelity of the central dogma. Enzymes that catalyze RNA editing are required for life, and defects in RNA editing are associated with many diseases. Recent advances in sequencing have enabled the genome-wide identification of RNA editing sites in mammalian transcriptomes. Here, we demonstrate that canonical RNA editing (A-to-I and C-to-U occurs in liver, white adipose, and bone tissues of the laboratory mouse, and we show that apparent non-canonical editing (all other possible base substitutions is an artifact of current high-throughput sequencing technology. Further, we report that high-confidence canonical RNA editing sites can cause non-synonymous amino acid changes and are significantly enriched in 3' UTRs, specifically at microRNA target sites, suggesting both regulatory and functional consequences for RNA editing.

  7. Scenario-targeted toxicity assessment through multiple endpoint bioassays in a soil posing unacceptable environmental risk according to regulatory screening values.

    Science.gov (United States)

    Rodriguez-Ruiz, A; Etxebarria, J; Boatti, L; Marigómez, I

    2015-09-01

    Lanestosa is a chronically polluted site (derelict mine) where the soil (Lanestosa (LA) soil) exceeds screening values (SVs) of regulatory policies in force (Basque Country; Europe) for Zn, Pb and Cd. A scenario-targeted toxicity assessment was carried out on the basis of a multi-endpoint bioassay approach. Acute and chronic toxicity bioassays were conducted with selected test species (Vibrio fischeri, Dictyostelium discoideum, Lactuca sativa, Raphanus sativus and Eisenia fetida) in combination with chemical analysis of soils and elutriates and with bioaccumulation studies in earthworms. Besides, the toxicity profile was compared with that of the mine runoff (RO) soil and of a fresh artificially polluted soil (LAAPS) resembling LA soil pollutant profile. Extractability studies in LA soil revealed that Pb, Zn and Cd were highly available for exchange and/or release into the environment. Indeed, Pb and Zn were accumulated in earthworms and LA soil resulted to be toxic. Soil respiration, V. fischeri, vegetative and developmental cycles of D. discoideum and survival and juvenile production of E. fetida were severely affected. These results confirmed that LA soil had unacceptable environmental risk and demanded intervention. In contrast, although Pb and Zn concentrations in RO soil revealed also unacceptable risk, both metal extractability and toxicity were much lower than in LA soil. Thus, within the polluted site, the need for intervention varied between areas that posed dissimilar risk. Besides, since LAAPS, with a high exchangeable metal fraction, was the most toxic, ageing under in situ natural conditions seemingly contributed to attenuate LA soil risk. As a whole, combining multi-endpoint bioassays with scenario-targeted analysis (including leaching and ageing) provides reliable risk assessment in soils posing unacceptable environmental risk according to SVs, which is useful to optimise the required intervention measures.

  8. Luteolin inhibits Cr(VI)-induced malignant cell transformation of human lung epithelial cells by targeting ROS mediated multiple cell signaling pathways

    Energy Technology Data Exchange (ETDEWEB)

    Pratheeshkumar, Poyil; Son, Young-Ok; Divya, Sasidharan Padmaja; Roy, Ram Vinod; Hitron, John Andrew; Wang, Lei [Center for Research on Environmental Disease, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Graduate Center for Toxicology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Kim, Donghern; Dai, Jin [Graduate Center for Toxicology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Asha, Padmaja [National Centre for Aquatic Animal Health, Cochin University of Science and Technology, Cochin (India); Zhang, Zhuo [Graduate Center for Toxicology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Wang, Yitao [State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau (China); Shi, Xianglin, E-mail: xshi5@email.uky.edu [Center for Research on Environmental Disease, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Graduate Center for Toxicology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States)

    2014-12-01

    Hexavalent chromium [Cr(VI)] is a well-known human carcinogen associated with the incidence of lung cancer. Inhibition of metal induced carcinogenesis by a dietary antioxidant is a novel approach. Luteolin, a natural dietary flavonoid found in fruits and vegetables, possesses potent antioxidant and anti-inflammatory activity. We found that short term exposure of human bronchial epithelial cells (BEAS-2B) to Cr(VI) (5 μM) showed a drastic increase in ROS generation, NADPH oxidase (NOX) activation, lipid peroxidation, and glutathione depletion, which were significantly inhibited by the treatment with luteolin in a dose dependent manner. Treatment with luteolin decreased AP-1, HIF-1α, COX-2, and iNOS promoter activity induced by Cr(VI) in BEAS-2B cells. In addition, luteolin protected BEAS-2B cells from malignant transformation induced by chronic Cr(VI) exposure. Moreover, luteolin also inhibited the production of pro-inflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α) and VEGF in chronic Cr(VI) exposed BEAS-2B cells. Western blot analysis showed that luteolin inhibited multiple gene products linked to survival (Akt, Fak, Bcl-2, Bcl-xL), inflammation (MAPK, NF-κB, COX-2, STAT-3, iNOS, TNF-α) and angiogenesis (HIF-1α, VEGF, MMP-9) in chronic Cr(VI) exposed BEAS-2B cells. Nude mice injected with BEAS-2B cells chronically exposed to Cr(VI) in the presence of luteolin showed reduced tumor incidence compared to Cr(VI) alone treated group. Overexpression of catalase (CAT) or SOD2, eliminated Cr(VI)-induced malignant transformation. Overall, our results indicate that luteolin protects BEAS-2B cells from Cr(VI)-induced carcinogenesis by scavenging ROS and modulating multiple cell signaling mechanisms that are linked to ROS. Luteolin, therefore, serves as a potential chemopreventive agent against Cr(VI)-induced carcinogenesis. - Highlights: • Luteolin inhibited Cr(VI)-induced oxidative stress. • Luteolin inhibited chronic Cr(VI)-induced malignant transformation.

  9. Luteolin inhibits Cr(VI)-induced malignant cell transformation of human lung epithelial cells by targeting ROS mediated multiple cell signaling pathways

    International Nuclear Information System (INIS)

    Pratheeshkumar, Poyil; Son, Young-Ok; Divya, Sasidharan Padmaja; Roy, Ram Vinod; Hitron, John Andrew; Wang, Lei; Kim, Donghern; Dai, Jin; Asha, Padmaja; Zhang, Zhuo; Wang, Yitao; Shi, Xianglin

    2014-01-01

    Hexavalent chromium [Cr(VI)] is a well-known human carcinogen associated with the incidence of lung cancer. Inhibition of metal induced carcinogenesis by a dietary antioxidant is a novel approach. Luteolin, a natural dietary flavonoid found in fruits and vegetables, possesses potent antioxidant and anti-inflammatory activity. We found that short term exposure of human bronchial epithelial cells (BEAS-2B) to Cr(VI) (5 μM) showed a drastic increase in ROS generation, NADPH oxidase (NOX) activation, lipid peroxidation, and glutathione depletion, which were significantly inhibited by the treatment with luteolin in a dose dependent manner. Treatment with luteolin decreased AP-1, HIF-1α, COX-2, and iNOS promoter activity induced by Cr(VI) in BEAS-2B cells. In addition, luteolin protected BEAS-2B cells from malignant transformation induced by chronic Cr(VI) exposure. Moreover, luteolin also inhibited the production of pro-inflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α) and VEGF in chronic Cr(VI) exposed BEAS-2B cells. Western blot analysis showed that luteolin inhibited multiple gene products linked to survival (Akt, Fak, Bcl-2, Bcl-xL), inflammation (MAPK, NF-κB, COX-2, STAT-3, iNOS, TNF-α) and angiogenesis (HIF-1α, VEGF, MMP-9) in chronic Cr(VI) exposed BEAS-2B cells. Nude mice injected with BEAS-2B cells chronically exposed to Cr(VI) in the presence of luteolin showed reduced tumor incidence compared to Cr(VI) alone treated group. Overexpression of catalase (CAT) or SOD2, eliminated Cr(VI)-induced malignant transformation. Overall, our results indicate that luteolin protects BEAS-2B cells from Cr(VI)-induced carcinogenesis by scavenging ROS and modulating multiple cell signaling mechanisms that are linked to ROS. Luteolin, therefore, serves as a potential chemopreventive agent against Cr(VI)-induced carcinogenesis. - Highlights: • Luteolin inhibited Cr(VI)-induced oxidative stress. • Luteolin inhibited chronic Cr(VI)-induced malignant transformation.

  10. Anti-inflammatory mechanisms of IFN-γ studied in experimental autoimmune encephalomyelitis reveal neutrophils as a potential target in multiple sclerosis

    Directory of Open Access Journals (Sweden)

    Nichole M Miller

    2015-08-01

    Full Text Available Multiple sclerosis (MS is an autoimmune disease of the central nervous system (CNS mediated by T helper (h1 and/or Th17 CD4 T cells that drive inflammatory lesion development along with demyelination and neuronal damage. Defects in immune regulatory mechanisms are thought to play a role in the pathogenesis of MS. While an early clinical trial indicated that IFN-γ administration was detrimental to MS, studies in the mouse model of MS, experimental autoimmune encephalomyelitis (EAE, indicated that IFN-γ exhibits a number of anti-inflammatory properties within the CNS. These mechanisms include inhibition of IL-17 production, induction of regulatory T cells, T cell apoptosis and regulation of chemokine production. Mice deficient in IFN-γ or its receptor were instrumental in deciphering the anti-inflammatory properties of IFN-γ in the CNS. In particular, they revealed that IFN-γ is a major regulator of neutrophil recruitment into the CNS, which by a variety of mechanisms including disruption of the blood-brain-barrier (BBB and production of reactive oxygen species are thought to contribute to the onset and progression of EAE. Neutrophils were also shown to be instrumental in EAE relapses. To date neutrophils have not been appreciated as a driver of MS, but more recently based largely on the strong EAE data this view is being reevaluated by some investigators in the field.

  11. Multiple Hfq-Crc target sites are required to impose catabolite repression on (methyl)phenol metabolism in Pseudomonas putida CF600.

    Science.gov (United States)

    Wirebrand, Lisa; Madhushani, Anjana W K; Irie, Yasuhiko; Shingler, Victoria

    2018-01-01

    The dmp-system encoded on the IncP-2 pVI150 plasmid of Pseudomonas putida CF600 confers the ability to assimilate (methyl)phenols. Regulation of the dmp-genes is subject to sophisticated control, which includes global regulatory input to subvert expression of the pathway in the presence of preferred carbon sources. Previously we have shown that in P. putida, translational inhibition exerted by the carbon repression control protein Crc operates hand-in-hand with the RNA chaperon protein Hfq to reduce translation of the DmpR regulator of the Dmp-pathway. Here, we show that Crc and Hfq co-target four additional sites to form riboprotein complexes within the proximity of the translational initiation sites of genes encoding the first two steps of the Dmp-pathway to mediate two-layered control in the face of selection of preferred substrates. Furthermore, we present evidence that Crc plays a hitherto unsuspected role in maintaining the pVI150 plasmid within a bacterial population, which has implications for (methyl)phenol degradation and a wide variety of other physiological processes encoded by the IncP-2 group of Pseudomonas-specific mega-plasmids. © 2017 Society for Applied Microbiology and John Wiley & Sons Ltd.

  12. Multiple antibody targets on herpes B glycoproteins B and D identified by screening sera of infected rhesus macaques with peptide microarrays.

    Directory of Open Access Journals (Sweden)

    Sven-Kevin Hotop

    Full Text Available Herpes B virus (or Herpesvirus simiae or Macacine herpesvirus 1 is endemic in many populations of macaques, both in the wild and in captivity. The virus elicits only mild clinical symptoms (if any in monkeys, but can be transmitted by various routes, most commonly via bites, to humans where it causes viral encephalitis with a high mortality rate. Hence, herpes B constitutes a considerable occupational hazard for animal caretakers, veterinarians and laboratory personnel. Efforts are therefore being made to reduce the risk of zoonotic infection and to improve prognosis after accidental exposure. Among the measures envisaged are serological surveillance of monkey colonies and specific diagnosis of herpes B zoonosis against a background of antibodies recognizing the closely related human herpes simplex virus (HSV. 422 pentadecapeptides covering, in an overlapping fashion, the entire amino acid sequences of herpes B proteins gB and gD were synthesized and immobilized on glass slides. Antibodies present in monkey sera that bind to subsets of the peptide collection were detected by microserological techniques. With 42 different rhesus macaque sera, 114 individual responses to 18 different antibody target regions (ATRs were recorded, 17 of which had not been described earlier. This finding may pave the way for a peptide-based, herpes B specific serological diagnostic test.

  13. PEGylation, increasing specific activity and multiple dosing as strategies to improve the risk-benefit profile of targeted radionuclide therapy with 177Lu-DOTA-bombesin analogues

    Science.gov (United States)

    2012-01-01

    Background Radiolabelled bombesin (BN) conjugates are promising radiotracers for imaging and therapy of breast and prostate tumours, in which BN2/gastrin-releasing peptide receptors are overexpressed. We describe the influence of the specific activity of a 177Lu-DOTA-PEG5k-Lys-B analogue on its therapeutic efficacy and compare it with its non-PEGylated counterpart. Methods Derivatisation of a stabilised DOTA-BN(7–14)[Cha13,Nle14] analogue with a linear PEG molecule of 5 kDa (PEG5k) was performed by PEGylation of the ϵ-amino group of a β3hLys-βAla-βAla spacer between the BN sequence and the DOTA chelator. The non-PEGylated and the PEGylated analogues were radiolabelled with 177Lu. In vitro evaluation was performed in human prostate carcinoma PC-3 cells, and in vivo studies were carried out in nude mice bearing PC-3 tumour xenografts. Different specific activities of the PEGylated BN analogue and various dose regimens were evaluated concerning their therapeutic efficacy. Results The specificity and the binding affinity of the BN analogue for BN2/GRP receptors were only slightly reduced by PEGylation. In vitro binding kinetics of the PEGylated analogue was slower since steady-state condition was reached after 4 h. PEGylation improved the stability of BN conjugate in vitro in human plasma by a factor of 5.6. The non-PEGylated BN analogue showed favourable pharmacokinetics already, i.e. fast blood clearance and renal excretion, but PEGylation improved the in vivo behaviour further. One hour after injection, the tumour uptake of the PEG5k-BN derivative was higher compared with that of the non-PEGylated analogue (3.43 ± 0.63% vs. 1.88 ± 0.4% ID/g). Moreover, the increased tumour retention resulted in a twofold higher tumour accumulation at 24 h p.i., and increased tumour-to-non-target ratios (tumour-to-kidney, 0.6 vs. 0.4; tumour-to-liver, 8.8 vs. 5.9, 24 h p.i.). In the therapy study, both 177Lu-labelled BN analogues significantly inhibited tumour

  14. The syndemic of HIV, HIV-related risk and multiple co-morbidities among women who use drugs in Malaysia: Important targets for intervention.

    Science.gov (United States)

    Loeliger, Kelsey B; Marcus, Ruthanne; Wickersham, Jeffrey A; Pillai, Veena; Kamarulzaman, Adeeba; Altice, Frederick L

    2016-02-01

    Substance use and HIV are syndemic public health problems in Malaysia. Harm reduction efforts to reduce HIV transmission have primarily focused on men with substance use disorders. To explore HIV risk behaviors, substance use, and social factors associated with poor health outcomes among women who use drugs in Malaysia. A cross-sectional survey of 103 drug-using women in Kuala Lumpur, Malaysia were recruited to assess their medical, psychiatric and social comorbidity as well as their engagement in nationally recommended HIV testing and monitoring activities. One-third reported having ever injected drugs, with most (68.2%) having recently shared injection paraphernalia. Sex work (44.7%) and infrequent condom use (42.4%) were common as was underlying psychiatric illness and physical and sexual violence during childhood and adulthood. Most women (62.1%) had unstable living situations and suffered from an unmet need for social support and health services. HIV prevalence was high (20%) with only two thirds of women eligible for antiretroviral therapy having received it. Suboptimal HIV testing and/or monitoring was positively associated with interpersonal violence (AOR 2.73; 95% CI 1.04-7.14) and negatively associated with drug injection (AOR 0.28; 95% CI 0.10-0.77). Women who use drugs in Malaysia demonstrate considerable medical, psychiatric and social co-morbidity, which negatively contributes to optimal and crucial engagement in HIV treatment-as-prevention strategies. Mental health and social support may be key targets for future public health interventions aimed at drug-using women in Malaysia. Copyright © 2015 Elsevier Ltd. All rights reserved.

  15. Multiplicity of secondary electrons emitted by carbon thin targets by impact of H0, H2+ and H3+ projectiles at MeV energies

    International Nuclear Information System (INIS)

    Vidovic, Zvonimir

    1997-01-01

    This work focuses on the study of the emission statistics of secondary electrons from thin carbon foils bombarded with H 0 , H 2 + and H 3 + projectiles in the 0.25 - 2.2 MeV energy range. The phenomenon of secondary electron emission from solids under the impact of swift ions is mainly due to inelastic interactions with target electrons. Phenomenological and theoretical descriptions as well as a summary of the main theoretical models are the subjects of the first chapter. The experimental set-up used to measure event by event the electron emission of the two faces of the thin carbon foils crossed by an energetic projectile is described in the chapter two. In this chapter there are also presented the method and the algorithms used to process experimental spectra in order to obtain the statistical distribution of the emitted electrons. Chapter three presents the measurements of secondary electron emission induced by H 0 atoms passing through thin carbon foils. The secondary electron yields are studied in correlation with emergent projectile charge state. We show the peculiar role of the projectile electron, whether it remains or not bound to the incident proton. The fourth chapter is dedicated to the secondary electron emission induced by H 2 + and H 3 + polyatomic ions. The results are interpreted in terms of collective effects in the interactions of the ions with solids. The role of the proximity of the protons, molecular ions fragments, upon the amplitude of these collected effects is evidenced from the study of the statistics of forward emission. The experiments allowed us to shed light on various aspects of atom and polyatomic ion interactions with solid surfaces. (author)

  16. Efficacy of melflufen, a peptidase targeted therapy, and dexamethasone in an ongoing open-label phase 2a study in patients with relapsed and relapsed-refractory multiple myeloma (RRMM) including an initial report on progression free survival

    DEFF Research Database (Denmark)

    Voorhees, P. M.; Magarotto, V.; Sonneveld, P.

    2015-01-01

    to DNA or is readily metabolized by intracellular peptidases into hydrophilic alkylating metabolites. With targeted delivery of alkylating metabolites to tumor cells in vitro (such as multiple myeloma that are rich in activating peptidase), melflufen exerts a 20-100 fold higher anti-tumor potency...... and produces a 20 fold higher intracellular concentration of alkylating moieties compared with melphalan. Methods: Melflufen is evaluated in combination with dexamethasone (dex) 40 mg weekly in an ongoing Phase 1/2a study. RRMM patients with measurable disease and at least 2 prior lines of therapy are eligible......%) and constipation and epistaxis (13%). Treatment-related Grade 3 or 4 AEs were reported in 27 patients (87%). Those occurring in >5% of patients were thrombocytopenia (68%), neutropenia (55%), anemia (42%), leukopenia (32%) and febrile neutropenia, fatigue, pyrexia, asthenia and hyperglycemia each occurred in 6...

  17. Hypermethylation of MIR21 in CD4+ T cells from patients with relapsing-remitting multiple sclerosis associates with lower miRNA-21 levels and concomitant up-regulation of its target genes

    KAUST Repository

    Ruhrmann, Sabrina

    2017-08-02

    Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system caused by genetic and environmental factors. DNA methylation, an epigenetic mechanism that controls genome activity, may provide a link between genetic and environmental risk factors.We sought to identify DNA methylation changes in CD4+ T cells in patients with relapsing-remitting (RR-MS) and secondary-progressive (SP-MS) disease and healthy controls (HC).We performed DNA methylation analysis in CD4+ T cells from RR-MS, SP-MS, and HC and associated identified changes with the nearby risk allele, smoking, age, and gene expression.We observed significant methylation differences in the VMP1/MIR21 locus, with RR-MS displaying higher methylation compared to SP-MS and HC. VMP1/MIR21 methylation did not correlate with a known MS risk variant in VMP1 or smoking but displayed a significant negative correlation with age and the levels of mature miR-21 in CD4+ T cells. Accordingly, RR-MS displayed lower levels of miR-21 compared to SP-MS, which might reflect differences in age between the groups, and healthy individuals and a significant enrichment of up-regulated miR-21 target genes.Disease-related changes in epigenetic marking of MIR21 in RR-MS lead to differences in miR-21 expression with a consequence on miR-21 target genes.

  18. Noninvasive pulsed focused ultrasound allows spatiotemporal control of targeted homing for multiple stem cell types in murine skeletal muscle and the magnitude of cell homing can be increased through repeated applications.

    Science.gov (United States)

    Burks, Scott R; Ziadloo, Ali; Kim, Saejeong J; Nguyen, Ben A; Frank, Joseph A

    2013-11-01

    Stem cells are promising therapeutics for cardiovascular diseases, and i.v. injection is the most desirable route of administration clinically. Subsequent homing of exogenous stem cells to pathological loci is frequently required for therapeutic efficacy and is mediated by chemoattractants (cell adhesion molecules, cytokines, and growth factors). Homing processes are inefficient and depend on short-lived pathological inflammation that limits the window of opportunity for cell injections. Noninvasive pulsed focused ultrasound (pFUS), which emphasizes mechanical ultrasound-tissue interactions, can be precisely targeted in the body and is a promising approach to target and maximize stem cell delivery by stimulating chemoattractant expression in pFUS-treated tissue prior to cell infusions. We demonstrate that pFUS is nondestructive to murine skeletal muscle tissue (no necrosis, hemorrhage, or muscle stem cell activation) and initiates a largely M2-type macrophage response. We also demonstrate that local upregulation of chemoattractants in pFUS-treated skeletal muscle leads to enhance homing, permeability, and retention of human mesenchymal stem cells (MSC) and human endothelial precursor cells (EPC). Furthermore, the magnitude of MSC or EPC homing was increased when pFUS treatments and cell infusions were repeated daily. This study demonstrates that pFUS defines transient "molecular zip codes" of elevated chemoattractants in targeted muscle tissue, which effectively provides spatiotemporal control and tunability of the homing process for multiple stem cell types. pFUS is a clinically translatable modality that may ultimately improve homing efficiency and flexibility of cell therapies for cardiovascular diseases. © AlphaMed Press.

  19. Detection of dim targets in multiple environments

    Science.gov (United States)

    Mirsky, Grace M.; Woods, Matthew; Grasso, Robert J.

    2013-10-01

    The proliferation of a wide variety of weapons including Anti-Aircraft Artillery (AAA), rockets, and small arms presents a substantial threat to both military and civilian aircraft. To address this ever-present threat, Northrop Grumman has assessed unguided threat phenomenology to understand the underlying physical principles for detection. These principles, based upon threat transit through the atmosphere, exploit a simple phenomenon universal to all objects moving through an atmosphere comprised of gaseous media to detect and track the threat in the presence of background and clutter. Threat detection has rapidly become a crucial component of aircraft survivability systems that provide situational awareness to the crew. It is particularly important to platforms which may spend a majority of their time at low altitudes and within the effective range of a large variety of weapons. Detection of these threats presents a unique challenge as this class of threat typically has a dim signature coupled with a short duration. Correct identification of each of the threat components (muzzle flash and projectile) is important to determine trajectory and intent while minimizing false alarms and maintaining a high detection probability in all environments.

  20. Protein kinase FgSch9 serves as a mediator of the target of rapamycin and high osmolarity glycerol pathways and regulates multiple stress responses and secondary metabolism in Fusarium graminearum.

    Science.gov (United States)

    Gu, Qin; Zhang, Chengqi; Yu, Fangwei; Yin, Yanni; Shim, Won-Bo; Ma, Zhonghua

    2015-08-01

    Saccharomyces cerevisiae protein kinase Sch9 is one of the downstream effectors of the target of rapamycin (TOR) complex 1 and plays multiple roles in stress resistance, longevity and nutrient sensing. However, the functions of Sch9 orthologs in filamentous fungi, particularly in pathogenic species, have not been characterized to date. Here, we investigated biological and genetic functions of FgSch9 in Fusarium graminearum. The FgSCH9 deletion mutant (ΔFgSch9) was defective in aerial hyphal growth, hyphal branching and conidial germination. The mutant exhibited increased sensitivity to osmotic and oxidative stresses, cell wall-damaging agents, and to rapamycin, while showing increased thermal tolerance. We identified FgMaf1 as one of the FgSch9-interacting proteins that plays an important role in regulating mycotoxin biosynthesis and virulence of F. graminearum. Co-immunoprecipitation and affinity capture-mass spectrometry assays showed that FgSch9 also interacts with FgTor and FgHog1. More importantly, both ΔFgSch9 and FgHog1 null mutant (ΔFgHog1) exhibited increased sensitivity to osmotic and oxidative stresses. This defect was more severe in the FgSch9/FgHog1 double mutant. Taken together, we propose that FgSch9 serves as a mediator of the TOR and high osmolarity glycerol pathways, and regulates vegetative differentiation, multiple stress responses and secondary metabolism in F. graminearum. © 2014 Society for Applied Microbiology and John Wiley & Sons Ltd.

  1. Multiple Perspectives / Multiple Readings

    Directory of Open Access Journals (Sweden)

    Simon Biggs

    2005-01-01

    Full Text Available People experience things from their own physical point of view. What they see is usually a function of where they are and what physical attitude they adopt relative to the subject. With augmented vision (periscopes, mirrors, remote cameras, etc we are able to see things from places where we are not present. With time-shifting technologies, such as the video recorder, we can also see things from the past; a time and a place we may never have visited.In recent artistic work I have been exploring the implications of digital technology, interactivity and internet connectivity that allow people to not so much space/time-shift their visual experience of things but rather see what happens when everybody is simultaneously able to see what everybody else can see. This is extrapolated through the remote networking of sites that are actual installation spaces; where the physical movements of viewers in the space generate multiple perspectives, linked to other similar sites at remote locations or to other viewers entering the shared data-space through a web based version of the work.This text explores the processes involved in such a practice and reflects on related questions regarding the non-singularity of being and the sense of self as linked to time and place.

  2. CERN: Fixed target targets

    Energy Technology Data Exchange (ETDEWEB)

    Anon.

    1993-03-15

    Full text: While the immediate priority of CERN's research programme is to exploit to the full the world's largest accelerator, the LEP electron-positron collider and its concomitant LEP200 energy upgrade (January, page 1), CERN is also mindful of its long tradition of diversified research. Away from LEP and preparations for the LHC proton-proton collider to be built above LEP in the same 27-kilometre tunnel, CERN is also preparing for a new generation of heavy ion experiments using a new source, providing heavier ions (April 1992, page 8), with first physics expected next year. CERN's smallest accelerator, the LEAR Low Energy Antiproton Ring continues to cover a wide range of research topics, and saw a record number of hours of operation in 1992. The new ISOLDE on-line isotope separator was inaugurated last year (July, page 5) and physics is already underway. The remaining effort concentrates around fixed target experiments at the SPS synchrotron, which formed the main thrust of CERN's research during the late 1970s. With the SPS and LEAR now approaching middle age, their research future was extensively studied last year. Broadly, a vigorous SPS programme looks assured until at least the end of 1995. Decisions for the longer term future of the West Experimental Area of the SPS will have to take into account the heavy demand for test beams from work towards experiments at big colliders, both at CERN and elsewhere. The North Experimental Area is the scene of larger experiments with longer lead times. Several more years of LEAR exploitation are already in the pipeline, but for the longer term, the ambitious Superlear project for a superconducting ring (January 1992, page 7) did not catch on. Neutrino physics has a long tradition at CERN, and this continues with the preparations for two major projects, the Chorus and Nomad experiments (November 1991, page 7), to start next year in the West Area. Delicate neutrino oscillation effects could become visible for the first

  3. CERN: Fixed target targets

    International Nuclear Information System (INIS)

    Anon.

    1993-01-01

    Full text: While the immediate priority of CERN's research programme is to exploit to the full the world's largest accelerator, the LEP electron-positron collider and its concomitant LEP200 energy upgrade (January, page 1), CERN is also mindful of its long tradition of diversified research. Away from LEP and preparations for the LHC proton-proton collider to be built above LEP in the same 27-kilometre tunnel, CERN is also preparing for a new generation of heavy ion experiments using a new source, providing heavier ions (April 1992, page 8), with first physics expected next year. CERN's smallest accelerator, the LEAR Low Energy Antiproton Ring continues to cover a wide range of research topics, and saw a record number of hours of operation in 1992. The new ISOLDE on-line isotope separator was inaugurated last year (July, page 5) and physics is already underway. The remaining effort concentrates around fixed target experiments at the SPS synchrotron, which formed the main thrust of CERN's research during the late 1970s. With the SPS and LEAR now approaching middle age, their research future was extensively studied last year. Broadly, a vigorous SPS programme looks assured until at least the end of 1995. Decisions for the longer term future of the West Experimental Area of the SPS will have to take into account the heavy demand for test beams from work towards experiments at big colliders, both at CERN and elsewhere. The North Experimental Area is the scene of larger experiments with longer lead times. Several more years of LEAR exploitation are already in the pipeline, but for the longer term, the ambitious Superlear project for a superconducting ring (January 1992, page 7) did not catch on. Neutrino physics has a long tradition at CERN, and this continues with the preparations for two major projects, the Chorus and Nomad experiments (November 1991, page 7), to start next year in the West Area. Delicate neutrino oscillation effects could become

  4. Multiple sclerosis

    Science.gov (United States)

    ... indwelling catheter Osteoporosis or thinning of the bones Pressure sores Side effects of medicines used to treat the ... Daily bowel care program Multiple sclerosis - discharge Preventing pressure ulcers Swallowing problems Images Multiple sclerosis MRI of the ...

  5. Auger electron emitter against multiple myeloma - targeted endo-radio-therapy with {sup 125}I-labeled thymidine analogue 5-iodo-4'-thio-2'-deoxyuridine

    Energy Technology Data Exchange (ETDEWEB)

    Morgenroth, Agnieszka, E-mail: amorgenroth@ukaachen.de [Nuclear Medicine Clinic, University Ulm, Albert-Einstein-Allee 23, D-89081 Ulm (Germany); Nuclear Medicine Clinic, University Aachen, RWTH, Pauwelsstrasse 30, D-52074 Aachen (Germany); Dinger, Cornelia; Zlatopolskiy, Boris D.; Al-Momani, Ehab; Glatting, Gerhard [Nuclear Medicine Clinic, University Ulm, Albert-Einstein-Allee 23, D-89081 Ulm (Germany); Mottaghy, Felix M. [Nuclear Medicine Clinic, University Aachen, RWTH, Pauwelsstrasse 30, D-52074 Aachen (Germany); Reske, Sven N. [Nuclear Medicine Clinic, University Ulm, Albert-Einstein-Allee 23, D-89081 Ulm (Germany)

    2011-10-15

    Introduction: Multiple myeloma (MM) is a plasma cell malignancy characterized by accumulation of malignant, terminally differentiated B cells in the bone marrow. Despite advances in therapy, MM remains an incurable disease. Novel therapeutic approaches are, therefore, urgently needed. Auger electron-emitting radiopharmaceuticals are attractive for targeted nano-irradiation therapy, given that DNA of malignant cells is selectively addressed. Here we evaluated the antimyeloma potential of the Auger electron-emitting thymidine analogue {sup 125}I-labeled 5-iodo-4'-thio-2'-deoxyuridine ([{sup 125}I]ITdU). Methods: Cellular uptake and DNA incorporation of [{sup 125}I]ITdU were determined in fluorodeoxyuridine-pretreated KMS12BM, U266, dexamethasone-sensitive MM1.S and -resistant MM1.R cell lines. The effect of stimulation with interleukin 6 (IL6) or insulin-like growth factor 1 (IGF1) on the intracellular incorporation of [{sup 125}I]ITdU was investigated in cytokine-sensitive MM1.S and MM1.R cell lines. Apoptotic cells were identified using Annexin V. Cleavage of caspase 3 and PARP was visualized by Western blot. DNA fragmentation was investigated using laddering assay. Therapeutic efficiency of [{sup 125}I]ITdU was proven by clonogenic assay. Results: [{sup 125}I]ITdU was shown to be efficiently incorporated into DNA of malignant cells, providing a promising mechanism for delivering highly toxic Auger radiation emitters into tumor DNA. [{sup 125}I]ITdU had a potent antimyeloma effect in cell lines representing distinct disease stages and, importantly, in cell lines sensitive or resistant to the conventional therapeutic agent, but was not toxic for normal plasma and bone marrow stromal cells. Furthermore, [{sup 125}I]ITdU abrogated the protective actions of IL6 and IGF1 on MM cells. [{sup 125}I]ITdU induced massive damage in the DNA of malignant plasma cells, which resulted in efficient inhibition of clonogenic growth. Conclusion: These studies may provide a

  6. Mangiferin Reduces the Inhibition of Chondrogenic Differentiation by IL-1β in Mesenchymal Stem Cells from Subchondral Bone and Targets Multiple Aspects of the Smad and SOX9 Pathways

    Directory of Open Access Journals (Sweden)

    Jeong-Eun Huh

    2014-09-01

    Full Text Available Mangiferin is a natural immunomodulator found in plants including mango trees. The effects of mangiferin on chondrogenesis and cartilage repair have not yet been reported. This study was designed to determine the effect of mangiferin on chondrogenic differentiation in IL-1β-stimulated mesenchymal stem cells (MSCs from subchondral bone and to explore the mechanisms underlying these effects. MSCs were isolated from the subchondral bone of rabbit and treated with mangiferin alone and/or interleukin-1β (IL-1β. Mangiferin induced chondrogenic differentiation in MSCs by upregulating transforming growth factor (TGF-β, bone morphogenetic protein (BMP-2, and BMP-4 and several key markers of chondrogenesis, including sex-determining region Y–box (SRY-box containing gene 9 (SOX9, type 2α1 collagen (Col2α1, cartilage link protein, and aggrecan. In IL-1β-stimulated MSCs, mangiferin significantly reversed the production of TGF-β, BMP-2, BMP-4, SOX9, Col2α1, cartilage link protein, and aggrecan, as well as matrix metalloproteinase (MMP-1, MMP-13, and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS5. Mangiferin upregulated the phosphorylation of Smad 2, Smad 3, Smad 1/5/8, and SOX9 in IL-1β-stimulated MSCs. In the presence of mangiferin, SOX9 siRNA suppressed the activation of Smad 2, Smad 3, Smad 1/5/8, aggrecan, and Col2α1 expression. In conclusion, mangiferin exhibits both chondrogenic and chondroprotective effects on damaged MSCs and mediates these effects by targeting multiple aspects of the Smad and SOX9 signaling pathways.

  7. Price regulation to remove EE-DSM disincentives and pressure for increased energy sales in monopoly segments of restructured electricity and gas markets: the multiple drivers target (MDT) tariff scheme

    International Nuclear Information System (INIS)

    Pagliano, L.; Alari, P.; Ruggieri, G.; Irrek, W.; Thomas, S.; Leprich, U.

    2002-01-01

    Even in restructured markets a part of the energy business remains a monopoly and should be correctly regulated. We present an analysis which reveals common structures in schemes enacted in UK, Norway, Portugal and recently (on the basis of this study) in Italy. The identified structure, which we named Multiple Driver Target (MDT) regulation is a performance-based regulation scheme, which provides incentives for greater economic efficiency, without creating biases against environmental efficiency. The method relies on a statistical analysis of the correlation of utility costs and a few 'cost drivers' (e.g. number of customers served, grid length, sold or transported energy). We discuss how MDT can be used to set price levels and price changes in the regulatory period in such a way to correctly match the evolution of costs and avoid awarding unwanted signals to utilities. At the opposite, pure Price Cap regulation provides artificial incentives to utilities to increase energy sales (even if this is not economic for the customers nor for society ) beyond the predicted levels foreseen in the price fixing Rate Cases. We show that Under MDT regulation the reduction in profits due to reduced sales as a consequence of DSM is minimised. In so doing this procedure removes the most important disincentive for utilities to implement DSM programmes since lost profits due to reduced sales can be substantially higher than direct costs of DSM programmes; once MDT regulation is in place, also these direct costs can be recovered through a small part of the tariff. We also discuss how MDT can be implemented with a moderate effort by regulatory authorities. (author)

  8. Mean associated multiplicities in deep inelastic processes

    International Nuclear Information System (INIS)

    Dzhaparidze, G.Sh.; Kiselev, A.V.; Petrov, V.A.

    1982-01-01

    A formula is derived for the mean hadron multiplicity in the target fragmentation range of deep inelastic scattering processes. It is shown that in the high-x region the ratio of the mean multiplicities in the current fragmentation region and in the target fragmentation region tends to unity at high energies. The mean multiplicity for the Drell-Yan process is considered

  9. Target laboratory

    International Nuclear Information System (INIS)

    Ephraim, D.C.; Pednekar, A.R.

    1993-01-01

    A target laboratory to make stripper foils for the accelerator and various targets for use in the experiments is set up in the pelletron accelerator facility. The facilities available in the laboratory are: (1) D.C. glow discharge setup, (2) carbon arc set up, and (3) vacuum evaporation set up (resistance heating), electron beam source, rolling mill - all for target preparation. They are described. Centrifugal deposition technique is used for target preparation. (author). 3 figs

  10. MULTIPLE OBJECTS

    Directory of Open Access Journals (Sweden)

    A. A. Bosov

    2015-04-01

    Full Text Available Purpose. The development of complicated techniques of production and management processes, information systems, computer science, applied objects of systems theory and others requires improvement of mathematical methods, new approaches for researches of application systems. And the variety and diversity of subject systems makes necessary the development of a model that generalizes the classical sets and their development – sets of sets. Multiple objects unlike sets are constructed by multiple structures and represented by the structure and content. The aim of the work is the analysis of multiple structures, generating multiple objects, the further development of operations on these objects in application systems. Methodology. To achieve the objectives of the researches, the structure of multiple objects represents as constructive trio, consisting of media, signatures and axiomatic. Multiple object is determined by the structure and content, as well as represented by hybrid superposition, composed of sets, multi-sets, ordered sets (lists and heterogeneous sets (sequences, corteges. Findings. In this paper we study the properties and characteristics of the components of hybrid multiple objects of complex systems, proposed assessments of their complexity, shown the rules of internal and external operations on objects of implementation. We introduce the relation of arbitrary order over multiple objects, we define the description of functions and display on objects of multiple structures. Originality.In this paper we consider the development of multiple structures, generating multiple objects.Practical value. The transition from the abstract to the subject of multiple structures requires the transformation of the system and multiple objects. Transformation involves three successive stages: specification (binding to the domain, interpretation (multiple sites and particularization (goals. The proposed describe systems approach based on hybrid sets

  11. Ice targets

    International Nuclear Information System (INIS)

    Pacheco, C.; Stark, C.; Tanaka, N.; Hodgkins, D.; Barnhart, J.; Kosty, J.

    1979-12-01

    This report presents a description of ice targets that were constructed for research work at the High Resolution Spectrometer (HRS) and at the Energetic Pion Channel and Spectrometer (EPICS). Reasons for using these ice targets and the instructions for their construction are given. Results of research using ice targets will be published at a later date

  12. Determination of multiple scattering effects

    International Nuclear Information System (INIS)

    Langevin, M.

    1981-01-01

    The integration of Sigmund and Winterbon numerical values is extended to the reduced thickness tau=2000. The diagram obtained allows a simple determination of the multiple scattering effect for different targets and projectiles [fr

  13. Multiple sclerosis

    International Nuclear Information System (INIS)

    Grunwald, I.Q.; Kuehn, A.L.; Backens, M.; Papanagiotou, P.; Shariat, K.; Kostopoulos, P.

    2008-01-01

    Multiple sclerosis is the most common chronic inflammatory disease of myelin with interspersed lesions in the white matter of the central nervous system. Magnetic resonance imaging (MRI) plays a key role in the diagnosis and monitoring of white matter diseases. This article focuses on key findings in multiple sclerosis as detected by MRI. (orig.) [de

  14. Multiple homicides.

    Science.gov (United States)

    Copeland, A R

    1989-09-01

    A study of multiple homicides or multiple deaths involving a solitary incident of violence by another individual was performed on the case files of the Office of the Medical Examiner of Metropolitan Dade County in Miami, Florida, during 1983-1987. A total of 107 multiple homicides were studied: 88 double, 17 triple, one quadruple, and one quintuple. The 236 victims were analyzed regarding age, race, sex, cause of death, toxicologic data, perpetrator, locale of the incident, and reason for the incident. This article compares this type of slaying with other types of homicide including those perpetrated by serial killers. Suggestions for future research in this field are offered.

  15. Burglar Target Selection

    Science.gov (United States)

    Townsley, Michael; Bernasco, Wim; Ruiter, Stijn; Johnson, Shane D.; White, Gentry; Baum, Scott

    2015-01-01

    Objectives: This study builds on research undertaken by Bernasco and Nieuwbeerta and explores the generalizability of a theoretically derived offender target selection model in three cross-national study regions. Methods: Taking a discrete spatial choice approach, we estimate the impact of both environment- and offender-level factors on residential burglary placement in the Netherlands, the United Kingdom, and Australia. Combining cleared burglary data from all study regions in a single statistical model, we make statistical comparisons between environments. Results: In all three study regions, the likelihood an offender selects an area for burglary is positively influenced by proximity to their home, the proportion of easily accessible targets, and the total number of targets available. Furthermore, in two of the three study regions, juvenile offenders under the legal driving age are significantly more influenced by target proximity than adult offenders. Post hoc tests indicate the magnitudes of these impacts vary significantly between study regions. Conclusions: While burglary target selection strategies are consistent with opportunity-based explanations of offending, the impact of environmental context is significant. As such, the approach undertaken in combining observations from multiple study regions may aid criminology scholars in assessing the generalizability of observed findings across multiple environments. PMID:25866418

  16. Multiple Sclerosis

    Science.gov (United States)

    Multiple sclerosis (MS) is a nervous system disease that affects your brain and spinal cord. It damages the myelin sheath, the material that surrounds and protects your nerve cells. This damage slows down ...

  17. Multiple myeloma.

    LENUS (Irish Health Repository)

    Collins, Conor D

    2012-02-01

    Advances in the imaging and treatment of multiple myeloma have occurred over the past decade. This article summarises the current status and highlights how an understanding of both is necessary for optimum management.

  18. Multiple mononeuropathy

    Science.gov (United States)

    ... with multiple mononeuropathy are prone to new nerve injuries at pressure points such as the knees and elbows. They should avoid putting pressure on these areas, for example, by not leaning on the elbows, crossing the knees, ...

  19. Antiproton Target

    CERN Multimedia

    1980-01-01

    Antiproton target used for the AA (antiproton accumulator). The first type of antiproton production target used from 1980 to 1982 comprised a rod of copper 3mm diameter and 120mm long embedded in a graphite cylinder that was itself pressed into a finned aluminium container. This assembly was air-cooled and it was used in conjunction with the Van der Meer magnetic horn. In 1983 Fermilab provided us with lithium lenses to replace the horn with a view to increasing the antiproton yield by about 30%. These lenses needed a much shorter target made of heavy metal - iridium was chosen for this purpose. The 50 mm iridium rod was housed in an extension to the original finned target container so that it could be brought very close to the entrance to the lithium lens. Picture 1 shows this target assembly and Picture 2 shows it mounted together with the lithium lens. These target containers had a short lifetime due to a combination of beam heating and radiation damage. This led to the design of the water-cooled target in...

  20. Hypermethylation of MIR21 in CD4+ T cells from patients with relapsing-remitting multiple sclerosis associates with lower miRNA-21 levels and concomitant up-regulation of its target genes

    KAUST Repository

    Ruhrmann, Sabrina; Ewing, Ewoud; Piket, Eliane; Kular, Lara; Cetrulo Lorenzi, Julio Cesar; Fernandes, Sunjay Jude; Morikawa, Hiromasa; Aeinehband, Shahin; Sayols-Baixeras, Sergi; Aslibekyan, Stella; Absher, Devin M; Arnett, Donna K; Tegner, Jesper; Gomez-Cabrero, David; Piehl, Fredrik; Jagodic, Maja

    2017-01-01

    Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system caused by genetic and environmental factors. DNA methylation, an epigenetic mechanism that controls genome activity, may provide a link between genetic

  1. Hadron multiplicities at COMPASS

    Energy Technology Data Exchange (ETDEWEB)

    Du Fresne von Hohenesche, Nicolas [Institut fuer Kernphysik, Universitaet Mainz, Johann-Joachim-Becher-Weg 45, 55128 Mainz (Germany); Collaboration: COMPASS Collaboration

    2014-07-01

    Quark fragmentation functions (FF) D{sub q}{sup h}(z,Q{sup 2}) describe final-state hadronization of quarks q into hadrons h. The FFs can be extracted from hadron multiplicities produced in semi-inclusive deep inelastic scattering. The COMPASS collaboration has recently measured charged hadron multiplicities for identified pions and kaons using a 160 GeV/c muon beam impinging on an iso-scalar target. The data cover a large kinematical range and provide an important input for global QCD analyses of world data at NLO, aiming at the determination of FFs in particular in the strange quark sector. The newest results from COMPASS on pion and kaon multiplicities will be presented.

  2. [Multiple meningiomas].

    Science.gov (United States)

    Terrier, L-M; François, P

    2016-06-01

    Multiple meningiomas (MMs) or meningiomatosis are defined by the presence of at least 2 lesions that appear simultaneously or not, at different intracranial locations, without the association of neurofibromatosis. They present 1-9 % of meningiomas with a female predominance. The occurrence of multiple meningiomas is not clear. There are 2 main hypotheses for their development, one that supports the independent evolution of these tumors and the other, completely opposite, that suggests the propagation of tumor cells of a unique clone transformation, through cerebrospinal fluid. NF2 gene mutation is an important intrinsic risk factor in the etiology of multiple meningiomas and some exogenous risk factors have been suspected but only ionizing radiation exposure has been proven. These tumors can grow anywhere in the skull but they are more frequently observed in supratentorial locations. Their histologic types are similar to unique meningiomas of psammomatous, fibroblastic, meningothelial or transitional type and in most cases are benign tumors. The prognosis of these tumors is eventually good and does not differ from the unique tumors except for the cases of radiation-induced multiple meningiomas, in the context of NF2 or when diagnosed in children where the outcome is less favorable. Each meningioma lesion should be dealt with individually and their multiple character should not justify their resection at all costs. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  3. Multiple sclerosis

    DEFF Research Database (Denmark)

    Stenager, Egon; Stenager, E N; Knudsen, Lone

    1994-01-01

    In a cross-sectional study of 117 randomly selected patients (52 men, 65 women) with definite multiple sclerosis, it was found that 76 percent were married or cohabitant, 8 percent divorced. Social contacts remained unchanged for 70 percent, but outgoing social contacts were reduced for 45 percent......, need for structural changes in home and need for pension became greater with increasing physical handicap. No significant differences between gender were found. It is concluded that patients and relatives are under increased social strain, when multiple sclerosis progresses to a moderate handicap...

  4. Target for production of X-rays

    Energy Technology Data Exchange (ETDEWEB)

    Korenev, S.A. E-mail: sergey_korenev@steris.com

    2004-10-01

    The patented new type of X-ray target is considered in this report. The main concept of the target consists in developing a sandwich structure depositing a coating of materials with high Z on the substrate with low Z, high thermal conductivity and high thermal stability. The target presents multiple layers system. The thermal conditions for X-ray target are discussed. The experimental results for Ta target on the Al and Cu substrates are presented.

  5. Target for production of X-rays

    International Nuclear Information System (INIS)

    Korenev, S.A.

    2004-01-01

    The patented new type of X-ray target is considered in this report. The main concept of the target consists in developing a sandwich structure depositing a coating of materials with high Z on the substrate with low Z, high thermal conductivity and high thermal stability. The target presents multiple layers system. The thermal conditions for X-ray target are discussed. The experimental results for Ta target on the Al and Cu substrates are presented

  6. Target for production of X-rays

    Science.gov (United States)

    Korenev, S. A.

    2004-09-01

    The patented new type of X-ray target is considered in this report. The main concept of the target consists in developing a sandwich structure depositing a coating of materials with high Z on the substrate with low Z, high thermal conductivity and high thermal stability. The target presents multiple layers system. The thermal conditions for X-ray target are discussed. The experimental results for Ta target on the Al and Cu substrates are presented.

  7. Multiple myeloma

    International Nuclear Information System (INIS)

    Sohn, Jeong Ick; Ha, Choon Ho; Choi, Karp Shik

    1994-01-01

    Multiple myeloma is a malignant plasma cell tumor that is thought to originate proliferation of a single clone of abnormal plasma cell resulting production of a whole monoclonal paraprotein. The authors experienced a case of multiple myeloma with severe mandibular osteolytic lesions in 46-year-old female. As a result of careful analysis of clinical, radiological, histopathological features, and laboratory findings, we diagnosed it as multiple myeloma, and the following results were obtained. 1. Main clinical symptoms were intermittent dull pain on the mandibular body area, abnormal sensation of lip and pain due to the fracture on the right clavicle. 2. Laboratory findings revealed M-spike, reversed serum albumin-globulin ratio, markedly elevated ESR and hypercalcemia. 3. Radiographically, multiple osteolytic punched-out radiolucencies were evident on the skull, zygoma, jaw bones, ribs, clavicle and upper extremities. Enlarged liver and increased uptakes on the lesional sites in RN scan were also observed. 4. Histopathologically, markedly hypercellular marrow with sheets of plasmoblasts and megakaryocytes were also observed.

  8. Multiple sclerosis

    DEFF Research Database (Denmark)

    Stenager, E; Jensen, K

    1988-01-01

    Forty-two (12%) of a total of 366 patients with multiple sclerosis (MS) had psychiatric admissions. Of these, 34 (81%) had their first psychiatric admission in conjunction with or after the onset of MS. Classification by psychiatric diagnosis showed that there was a significant positive correlation...

  9. Multiple sclerosis

    DEFF Research Database (Denmark)

    Stenager, E; Knudsen, L; Jensen, K

    1991-01-01

    In a cross-sectional investigation of 116 patients with multiple sclerosis, the social and sparetime activities of the patient were assessed by both patient and his/her family. The assessments were correlated to physical disability which showed that particularly those who were moderately disabled...

  10. Multiple sclerosis

    DEFF Research Database (Denmark)

    Stenager, E; Jensen, K

    1990-01-01

    An investigation on the correlation between ability to read TV subtitles and the duration of visual evoked potential (VEP) latency in 14 patients with definite multiple sclerosis (MS), indicated that VEP latency in patients unable to read the TV subtitles was significantly delayed in comparison...

  11. Multiple sclerosis

    DEFF Research Database (Denmark)

    Stenager, E; Knudsen, L; Jensen, K

    1994-01-01

    In a cross-sectional study of 94 patients (42 males, 52 females) with definite multiple sclerosis (MS) in the age range 25-55 years, the correlation of neuropsychological tests with the ability to read TV-subtitles and with the use of sedatives is examined. A logistic regression analysis reveals...

  12. Multiple Sclerosis.

    Science.gov (United States)

    Plummer, Nancy; Michael, Nancy, Ed.

    This module on multiple sclerosis is intended for use in inservice or continuing education programs for persons who administer medications in long-term care facilities. Instructor information, including teaching suggestions, and a listing of recommended audiovisual materials and their sources appear first. The module goal and objectives are then…

  13. Parenting Multiples

    Science.gov (United States)

    ... when your babies do. Though it can be hard to let go of the thousand other things you need to do, remember that your well-being is key to your ability to take care of your babies. What Problems Can Happen? It may be hard to tell multiple babies apart when they first ...

  14. Targeted Learning

    CERN Document Server

    van der Laan, Mark J

    2011-01-01

    The statistics profession is at a unique point in history. The need for valid statistical tools is greater than ever; data sets are massive, often measuring hundreds of thousands of measurements for a single subject. The field is ready to move towards clear objective benchmarks under which tools can be evaluated. Targeted learning allows (1) the full generalization and utilization of cross-validation as an estimator selection tool so that the subjective choices made by humans are now made by the machine, and (2) targeting the fitting of the probability distribution of the data toward the targe

  15. Using the Dual-Target Cost to Explore the Nature of Search Target Representations

    Science.gov (United States)

    Stroud, Michael J.; Menneer, Tamaryn; Cave, Kyle R.; Donnelly, Nick

    2012-01-01

    Eye movements were monitored to examine search efficiency and infer how color is mentally represented to guide search for multiple targets. Observers located a single color target very efficiently by fixating colors similar to the target. However, simultaneous search for 2 colors produced a dual-target cost. In addition, as the similarity between…

  16. Mean associated multiplicities in deep inelastic processes

    International Nuclear Information System (INIS)

    Dzhaparidze, G.S.; Kiselev, A.V.; Petrov, V.A.

    1982-01-01

    A formula is derived for the mean multiplicity of hadrons in the target-fragmentation region in the process of deep inelastic scattering. It is shown that in the region of large x the ratio of the mean multiplicities in the current- and target-fragmentation regions tends to unity at high energies. The mean multiplicity in the Drell-Yan process is also discussed

  17. Multiple sclerosis

    International Nuclear Information System (INIS)

    Sadashima, Hiromichi; Kusaka, Hirofumi; Imai, Terukuni; Takahashi, Ryosuke; Matsumoto, Sadayuki; Yamamoto, Toru; Yamasaki, Masahiro; Maya, Kiyomi

    1986-01-01

    Eleven patients with a definite diagnosis of multiple sclerosis were examined in terms of correlations between the clinical features and the results of cranial computed tomography (CT), and magnetic resonance imaging (MRI). Results: In 5 of the 11 patients, both CT and MRI demonstrated lesions consistent with a finding of multiple sclerosis. In 3 patients, only MRI demonstrated lesions. In the remaining 3 patients, neither CT nor MRI revealed any lesion in the brain. All 5 patients who showed abnormal findings on both CT and MRI had clinical signs either of cerebral or brainstem - cerebellar lesions. On the other hand, two of the 3 patients with normal CT and MRI findings had optic-nerve and spinal-cord signs. Therefore, our results suggested relatively good correlations between the clinical features, CT, and MRI. MRI revealed cerebral lesions in two of the four patients with clinical signs of only optic-nerve and spinal-cord lesions. MRI demonstrated sclerotic lesions in 3 of the 6 patients whose plaques were not detected by CT. In conclusion, MRI proved to be more helpful in the demonstration of lesions attributable to chronic multiple sclerosis. (author)

  18. Inter- and intra-specific competition of duckweed under multiple heavy metal contaminated water.

    Science.gov (United States)

    Zhao, Zhao; Shi, Huijuan; Kang, Xianjiang; Liu, Cunqi; Chen, Lingci; Liang, Xiaofei; Jin, Lei

    2017-11-01

    The influences of intra- and inter-species competition on ecosystems are poorly understood. Lemna aequinoctialis and Spirodela polyrhiza were used to assess the effects of exposure to different concentrations of multiple heavy metals (copper-cadmium-zinc), when the plants were grown in mixed- or mono-culture. Parameters assessed included relative growth rate (RGR), content of chlorophyll, glutathione (GSH), malondialdehyde (MDA), as well as the activity of catalase (CAT), superoxide dismutase (SOD) and peroxidase (POD). Inter-specific competition was affected by metal concentration, with results indicating that inter-specific competition significantly affected duckweed growth and metal uptake in different heavy metal exposure conditions. Inter-specific competition increased growth rate of duckweed under high metal concentrations, although when compared with intra-specific competition, it caused no obvious differences under low metal concentrations. The growth of L. aequinoctialis was further increased in mixed culture when exposed to high metal concentrations, with inter-specific competition increasing the content of cadmium and zinc, while decreasing copper content of L. aequinoctialis compared with under intra-specific conditions. Conversely, inter-specific competition increased the content of copper and cadmium of S. polyrhiza, without causing obvious differences in zinc accumulation under high ambient concentrations. Under high metal conditions, inter-specific competition increased antioxidant enzyme activities in duckweed species, increasing resistance to heavy metals. Results show that inter-specific competition makes duckweed develop mechanisms to increase fitness and survival, such as enhancement of antioxidant enzyme activities, rather than limiting metal uptake when exposed to high concentrations of multiple metals. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Implementing Target Value Design.

    Science.gov (United States)

    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.

  20. Multiple time scale dynamics

    CERN Document Server

    Kuehn, Christian

    2015-01-01

    This book provides an introduction to dynamical systems with multiple time scales. The approach it takes is to provide an overview of key areas, particularly topics that are less available in the introductory form.  The broad range of topics included makes it accessible for students and researchers new to the field to gain a quick and thorough overview. The first of its kind, this book merges a wide variety of different mathematical techniques into a more unified framework. The book is highly illustrated with many examples and exercises and an extensive bibliography. The target audience of this  book are senior undergraduates, graduate students as well as researchers interested in using the multiple time scale dynamics theory in nonlinear science, either from a theoretical or a mathematical modeling perspective. 

  1. Multiple inflation

    International Nuclear Information System (INIS)

    Murphy, P.J.

    1987-01-01

    The Theory of Inflation, namely, that at some point the entropy content of the universe was greatly increased, has much promise. It may solve the puzzles of homogeneity and the creation of structure. However, no particle physics model has yet been found that can successfully drive inflation. The difficulty in satisfying the constraint that the isotropy of the microwave background places on the effective potential of prospective models is immense. In this work we have codified the requirements of such models in a most general form. We have carefully calculated the amounts of inflation the various problems of the Standard Model need for their solution. We have derived a completely model independent upper bond on the inflationary Hubble parameter. We have developed a general notation with which to probe the possibilities of Multiple Inflation. We have shown that only in very unlikely circumstances will any evidence of an earlier inflation, survive the de Sitter period of its successor. In particular, it is demonstrated that it is most unlikely that two bouts of inflation will yield high amplitudes of density perturbations on small scales and low amplitudes on large. We conclude that, while multiple inflation will be of great theoretical interest, it is unlikely to have any observational impact

  2. Multiple Entity Reconciliation

    OpenAIRE

    Samoila, Lavinia Andreea

    2015-01-01

    Living in the age of "Big Data" is both a blessing and a curse. On he one hand, the raw data can be analysed and then used for weather redictions, user recommendations, targeted advertising and more. On he other hand, when data is aggregated from multiple sources, there is no guarantee that each source has stored the data in a standardized or even compatible format to what is required by the application. So there is a need to parse the available data and convert it to the desired form. Here i...

  3. Targets of curcumin

    Science.gov (United States)

    Zhou, Hongyu; Beevers, Christopher S.; Huang, Shile

    2010-01-01

    Curcumin (diferuloylmethane), an orange-yellow component of turmeric or curry powder, is a polyphenol natural product isolated from the rhizome of the plant Curcuma longa. For centuries, curcumin has been used in some medicinal preparation or used as a food-coloring agent. In recent years, extensive in vitro and in vivo studies suggested curcumin has anticancer, antiviral, antiarthritic, anti-amyloid, antioxidant, and anti-inflammatory properties. The underlying mechanisms of these effects are diverse and appear to involve the regulation of various molecular targets, including transcription factors (such as nuclear factor-κB), growth factors (such as vascular endothelial cell growth factor), inflammatory cytokines (such as tumor necrosis factor, interleukin 1 and interleukin 6), protein kinases (such as mammalian target of rapamycin, mitogen-activated protein kinases, and Akt) and other enzymes (such as cyclooxygenase 2 and 5 lipoxygenase). Thus, due to its efficacy and regulation of multiple targets, as well as its safety for human use, curcumin has received considerable interest as a potential therapeutic agent for the prevention and/or treatment of various malignant diseases, arthritis, allergies, Alzheimer’s disease, and other inflammatory illnesses. This review summarizes various in vitro and in vivo pharmacological aspects of curcumin as well as the underlying action mechanisms. The recently identified molecular targets and signaling pathways modulated by curcumin are also discussed here. PMID:20955148

  4. The targets of curcumin.

    Science.gov (United States)

    Zhou, Hongyu; Beevers, Christopher S; Huang, Shile

    2011-03-01

    Curcumin (diferuloylmethane), an orange-yellow component of turmeric or curry powder, is a polyphenol natural product isolated from the rhizome of the plant Curcuma longa. For centuries, curcumin has been used in some medicinal preparation or used as a food-coloring agent. In recent years, extensive in vitro and in vivo studies suggested curcumin has anticancer, antiviral, antiarthritic, anti-amyloid, antioxidant, and anti-inflammatory properties. The underlying mechanisms of these effects are diverse and appear to involve the regulation of various molecular targets, including transcription factors (such as nuclear factor-kB), growth factors (such as vascular endothelial cell growth factor), inflammatory cytokines (such as tumor necrosis factor, interleukin 1 and interleukin 6), protein kinases (such as mammalian target of rapamycin, mitogen-activated protein kinases, and Akt) and other enzymes (such as cyclooxygenase 2 and 5 lipoxygenase). Thus, due to its efficacy and regulation of multiple targets, as well as its safety for human use, curcumin has received considerable interest as a potential therapeutic agent for the prevention and/or treatment of various malignant diseases, arthritis, allergies, Alzheimer's disease, and other inflammatory illnesses. This review summarizes various in vitro and in vivo pharmacological aspects of curcumin as well as the underlying action mechanisms. The recently identified molecular targets and signaling pathways modulated by curcumin are also discussed here.

  5. A Study of Multiplicities in Hadronic Interactions

    Energy Technology Data Exchange (ETDEWEB)

    Estrada Tristan, Nora Patricia; /San Luis Potosi U.

    2006-02-01

    Using data from the SELEX (Fermilab E781) experiment obtained with a minimum-bias trigger, we study multiplicity and angular distributions of secondary particles produced in interactions in the experimental targets. We observe interactions of {Sigma}{sup -}, proton, {pi}{sup -}, and {pi}{sup +}, at beam momenta between 250 GeV/c and 650 GeV/c, in copper, polyethylene, graphite, and beryllium targets. We show that the multiplicity and angular distributions for meson and baryon beams at the same momentum are identical. We also show that the mean multiplicity increases with beam momentum, and presents only small variations with the target material.

  6. Development of targeted radiotherapy systems

    International Nuclear Information System (INIS)

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

    2001-01-01

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

  7. A pH and solvent optimized reverse-phase ion-paring-LC–MS/MS method that leverages multiple scan-types for targeted absolute quantification of intracellular metabolites

    DEFF Research Database (Denmark)

    McCloskey, Douglas; Gangoiti, Jon A.; Palsson, Bernhard O.

    2015-01-01

    Comprehensive knowledge of intracellular biochemistry is needed to accurately understand, model, and manipulate metabolism for industrial and therapeutic applications. Quantitative metabolomics has been driven by advances in analytical instrumentation and can add valuable knowledge to the underst......Comprehensive knowledge of intracellular biochemistry is needed to accurately understand, model, and manipulate metabolism for industrial and therapeutic applications. Quantitative metabolomics has been driven by advances in analytical instrumentation and can add valuable knowledge...... existing reverse phase ion-paring liquid chromatography methods for separation and detection of polar and anionic compounds that comprise key nodes of intracellular metabolism by optimizing pH and solvent composition. In addition, the presented method utilizes multiple scan types provided by hybrid...

  8. A smart pH-responsive nano-carrier as a drug delivery system for the targeted delivery of ursolic acid: suppresses cancer growth and metastasis by modulating P53/MMP-9/PTEN/CD44 mediated multiple signaling pathways.

    Science.gov (United States)

    Jiang, Kai; Chi, Ting; Li, Tao; Zheng, Guirong; Fan, Lulu; Liu, Yajun; Chen, Xiufen; Chen, Sijia; Jia, Lee; Shao, Jingwei

    2017-07-13

    Ursolic acid (UA) has been recently used as a promising anti-tumor and cancer metastatic chemo-preventive agent due to its low toxicity and liver-protecting property. However, the low bioavailability and nonspecific tumor targeting restrict its further clinical application. To address the problem, a silica-based mesoporous nanosphere (MSN) controlled-release drug delivery system (denoted UA@M-CS-FA) was designed and successfully synthesized, and was functionalized with folic acid (FA) and pH-sensitive chitosan (CS) for the targeted delivery of UA to folate receptor (FR) positive tumor cells. UA@M-CS-FA were spherical with mean diameter below 150 nm, and showed about -20 mV potential. Meanwhile, UA@M-CS-FA exhibited a pH-sensitive release manner and high cellular uptake in FR over-expressing HeLa cancer cells. Also, in vitro cellular assays suggested that UA@M-CS-FA inhibited cancer cell growth, invasion and migration. Mechanistically, UA@M-CS-FA induced cancer cell apoptosis and inhibited migration via cell cycle arrest in the G0/G1 stage, regulating the PARP/Bcl-2/MMP-9/CD44/PTEN/P53. Importantly, in vivo experiments further confirmed that UA@M-CS-FA significantly suppressed the tumor progression and lung metastasis in tumor-bearing nude mice. Immunohistochemical analysis revealed that UA@M-CS-FA treatment regulated CD44, a biomarker of cancer metastasis. Overall, our data demonstrated that a CS and FA modified MSN controlled-release drug delivery system could help broaden the usage of UA and reflect the great application potential of the UA as an anticancer or cancer metastatic chemopreventive agent.

  9. Neuromyelitis optica and multiple sclerosis

    DEFF Research Database (Denmark)

    Bennett, J. L.; de Seze, J.; Lana-Peixoto, M.

    2015-01-01

    Neuromyelitis optica (NMO) is an inflammatory autoimmune disease of the central nervous system that preferentially targets the optic nerves and spinal cord. The clinical presentation may suggest multiple sclerosis (MS), but a highly specific serum autoantibody against the astrocytic water channel...

  10. Low Complexity Parameter Estimation For Off-the-Grid Targets

    KAUST Repository

    Jardak, Seifallah; Ahmed, Sajid; Alouini, Mohamed-Slim

    2015-01-01

    In multiple-input multiple-output radar, to estimate the reflection coefficient, spatial location, and Doppler shift of a target, a derived cost function is usually evaluated and optimized over a grid of points. The performance of such algorithms

  11. Multiple scattering of ions in polyatomic materials

    International Nuclear Information System (INIS)

    Eastham, D.A.

    1980-01-01

    The equations which determine small angle multiple scattering in the thin polyatomic layers are evaluated numerically for certain cases. A simple approximate method for calculating the scattering in terms of an average target charge which is a function of the target thickness is given and compared with the exact numerical value. The results agree to better than 5% over a wide range of target composition and thickness. (orig.)

  12. Albumin and multiple sclerosis.

    Science.gov (United States)

    LeVine, Steven M

    2016-04-12

    Leakage of the blood-brain barrier (BBB) is a common pathological feature in multiple sclerosis (MS). Following a breach of the BBB, albumin, the most abundant protein in plasma, gains access to CNS tissue where it is exposed to an inflammatory milieu and tissue damage, e.g., demyelination. Once in the CNS, albumin can participate in protective mechanisms. For example, due to its high concentration and molecular properties, albumin becomes a target for oxidation and nitration reactions. Furthermore, albumin binds metals and heme thereby limiting their ability to produce reactive oxygen and reactive nitrogen species. Albumin also has the potential to worsen disease. Similar to pathogenic processes that occur during epilepsy, extravasated albumin could induce the expression of proinflammatory cytokines and affect the ability of astrocytes to maintain potassium homeostasis thereby possibly making neurons more vulnerable to glutamate exicitotoxicity, which is thought to be a pathogenic mechanism in MS. The albumin quotient, albumin in cerebrospinal fluid (CSF)/albumin in serum, is used as a measure of blood-CSF barrier dysfunction in MS, but it may be inaccurate since albumin levels in the CSF can be influenced by multiple factors including: 1) albumin becomes proteolytically cleaved during disease, 2) extravasated albumin is taken up by macrophages, microglia, and astrocytes, and 3) the location of BBB damage affects the entry of extravasated albumin into ventricular CSF. A discussion of the roles that albumin performs during MS is put forth.

  13. Estrogen Treatment in Multiple Sclerosis

    OpenAIRE

    Gold, Stefan M; Voskuhl, Rhonda R

    2009-01-01

    Currently available treatments for multiple sclerosis reduce inflammatory lesions on MRI and decrease clinical relapses but have limited effects on disability. Novel treatment options that target both the inflammatory as well as the neurodegenerative component of the disease are therefore needed. A growing body of evidence from basic science and clinical studies supports the therapeutic potential of estrogens in MS. Mechanisms of action include both immunomodulatory and directly neuroprotecti...

  14. Multiple Input - Multiple Output (MIMO) SAR

    Data.gov (United States)

    National Aeronautics and Space Administration — This effort will research and implement advanced Multiple-Input Multiple-Output (MIMO) Synthetic Aperture Radar (SAR) techniques which have the potential to improve...

  15. Targeting ECM Disrupts Cancer Progression

    DEFF Research Database (Denmark)

    Venning, Freja A; Wullkopf, Lena; Erler, Janine T

    2015-01-01

    , the extracellular matrix (ECM). Many ECM proteins are significantly deregulated during the progression of cancer, causing both biochemical and biomechanical changes that together promote the metastatic cascade. In this review, the influence of several ECM proteins on these multiple steps of cancer spread...... is summarized. In addition, we highlight the promising (pre-)clinical data showing benefits of targeting these ECM macromolecules to prevent cancer progression....

  16. RNAblueprint: flexible multiple target nucleic acid sequence design.

    Science.gov (United States)

    Hammer, Stefan; Tschiatschek, Birgit; Flamm, Christoph; Hofacker, Ivo L; Findeiß, Sven

    2017-09-15

    Realizing the value of synthetic biology in biotechnology and medicine requires the design of molecules with specialized functions. Due to its close structure to function relationship, and the availability of good structure prediction methods and energy models, RNA is perfectly suited to be synthetically engineered with predefined properties. However, currently available RNA design tools cannot be easily adapted to accommodate new design specifications. Furthermore, complicated sampling and optimization methods are often developed to suit a specific RNA design goal, adding to their inflexibility. We developed a C ++  library implementing a graph coloring approach to stochastically sample sequences compatible with structural and sequence constraints from the typically very large solution space. The approach allows to specify and explore the solution space in a well defined way. Our library also guarantees uniform sampling, which makes optimization runs performant by not only avoiding re-evaluation of already found solutions, but also by raising the probability of finding better solutions for long optimization runs. We show that our software can be combined with any other software package to allow diverse RNA design applications. Scripting interfaces allow the easy adaption of existing code to accommodate new scenarios, making the whole design process very flexible. We implemented example design approaches written in Python to demonstrate these advantages. RNAblueprint , Python implementations and benchmark datasets are available at github: https://github.com/ViennaRNA . s.hammer@univie.ac.at, ivo@tbi.univie.ac.at or sven@tbi.univie.ac.at. Supplementary data are available at Bioinformatics online. © The Author(s) 2017. Published by Oxford University Press.

  17. Multiplicity distributions of shower particles and target fragments in 7

    Indian Academy of Sciences (India)

    Author Affiliations. N N Abd Allah1 Fu-Hu Liu2 E A Sultan1 M Hassan1. Physics Department, Faculty of Science, Sohag University, Sohag, Egypt; Institute of Theoretical Physics, Shanxi University, Taiyuan, Shanxi 030006, China ...

  18. Simultaneous detection of multiple targets for ultrastructural immunocytochemistry

    Czech Academy of Sciences Publication Activity Database

    Philimonenko, Vlada; Filimonenko, Anatolij; Šloufová, I.; Hrubý, Martin; Novotný, F.; Halbhuber, Z.; Krivjanská, M.; Nebesářová, Jana; Šlouf, Miroslav; Hozák, Pavel

    2014-01-01

    Roč. 141, č. 3 (2014), s. 229-239 ISSN 0948-6143 R&D Projects: GA AV ČR KAN200520704; GA TA ČR TE01020118; GA ČR GAP305/11/2232; GA MŠk LD12063 Grant - others:Human Frontier Science Program(FR) RGP0017/2013 Institutional research plan: CEZ:AV0Z50520514 Institutional support: RVO:61389013 ; RVO:60077344 ; RVO:68378050 Keywords : Immunolabeling * Metal nanoparticles * Electron microscopy * Cell nucleus * Ultrastructure * Phosphatidylinositol-4,5-Bisphosphate (PIP2) Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.927, year: 2013

  19. Multiple Targeting Approaches on Histamine H3 Receptor Antagonists

    Directory of Open Access Journals (Sweden)

    Mohammad eKhanfar

    2016-05-01

    Full Text Available With the very recent market approval of pitolisant (Wakix®, the interest in clinical applications of novel multifunctional histamine H3 receptor antagonists has clearly increased. Since histamine H3 receptor antagonists in clinical development have been tested for a variety of different indications, the combination of pharmacological properties in one molecule for improved pharmacological effects and reduced unwanted side-effects is rationally based on the increasing knowledge on the complex neurotransmitter regulations. The polypharmacological approaches on histamine H3 receptor antagonists on different G-protein coupled receptors, transporters, enzymes as well as on NO-signaling mechanism are described, supported with some lead structures.

  20. Multiplicity distributions of shower particles and target fragments in ...

    Indian Academy of Sciences (India)

    2Institute of Theoretical Physics, Shanxi University, Taiyuan, Shanxi 030006, China. *Corresponding ... describes the probability distributions of different quantities [17–19]. ... In the Monte Carlo method, let Rij denote random numbers in [0,1].

  1. Targeting Chemerin Receptor CMKLR1 in Multiple Sclerosis

    Science.gov (United States)

    2012-09-01

    polycaprylactone. Oral delivery systems include tablets and capsules. These can contain excipients such as binders (e.g...Transmucosal delivery systems include patches, tablets , suppositories, pessaries, gels and creams, and can contain excipients such as solubilizers and...with no further testing. Magnetic resonance imaging ( MRI ) of the brain and spine is often used during the diagnostic process. MRI shows areas of

  2. Multiple ionization of atoms by ion impact

    International Nuclear Information System (INIS)

    DuBois, R.D.

    1988-01-01

    In order to model the energy deposition of fast ions as they slow down in gaseous media, information about the ionization occurring in collisions between ions and target atoms/molecules is required. Our measurements of doubly differential electron emission cross sections provide detailed information about the ionization process but do not provide any information about the final states of the target. They also do not distinguish between the emission of one or more target electrons in a single collision. It is important to know the relative importance of multiple-, with respect to single-, target ionization in order to accurately model the energy deposition. To date, multiple ionization of He, Ne, Ar, Kr, and Xe targets has been studied. Primarily, H and He ions were used, although some data for heavier ions (C,N and O) have also been obtained

  3. Heavy-ion targets

    International Nuclear Information System (INIS)

    Adair, H.L.; Kobisk, E.H.

    1985-01-01

    This chapter examines the characteristics of targets required in heavy-ion accelerator physics experiments. The effects of target parameters on heavy-ion experimental results are reviewed. The target fabrication and characterization techniques used to minimize experimental problems during heavy-ion bombardment are described. Topics considered include target thickness and uniformity, target lifetime, target purity, substrate materials, Doppler shift effects, metal preparations, and target preparation methods

  4. The INEL beryllium multiplication experiment

    International Nuclear Information System (INIS)

    Smith, J.R.; King, J.J.

    1991-03-01

    The experiment to measure the multiplication of 14-MeV neutrons in bulk beryllium has been completed. The experiment consists of determining the ratio of 56 Mn activities induced in a large manganese bath by a central 14-MeV neutron source, with and without a beryllium sample surrounding the source. In the manganese bath method a neutron source is placed at the center of a totally-absorbing aqueous solution of MnSo 4 . The capture of neutrons by Mn produces a 56 Mn activity proportional to the emission rate of the source. As applied to the measurement of the multiplication of 14- MeV neutrons in bulk beryllium, the neutron source is a tritium target placed at the end of the drift tube of a small deuteron accelerator. Surrounding the source is a sample chamber. When the sample chamber is empty, the neutrons go directly to the surrounding MnSO 4 solution, and produce a 56 Mn activity proportional to the neutron emission rate. When the chamber contains a beryllium sample, the neutrons first enter the beryllium and multiply through the (n,2n) process. Neutrons escaping from the beryllium enter the bath and produce a 56 Mn activity proportional to the neutron emission rate multiplied by the effective value of the multiplication in bulk beryllium. The ratio of the activities with and without the sample present is proportional to the multiplication value. Detailed calculations of the multiplication and all the systematic effects were made with the Monte Carlo program MCNP, utilizing both the Young and Stewart and the ENDF/B-VI evaluations for beryllium. Both data sets produce multiplication values that are in excellent agreement with the measurements for both raw and corrected values of the multiplication. We conclude that there is not real discrepancy between experimental and calculated values for the multiplication of neutrons in bulk beryllium. 12 figs., 11 tabs., 18 refs

  5. Common pitfalls in preclinical cancer target validation.

    Science.gov (United States)

    Kaelin, William G

    2017-07-01

    An alarming number of papers from laboratories nominating new cancer drug targets contain findings that cannot be reproduced by others or are simply not robust enough to justify drug discovery efforts. This problem probably has many causes, including an underappreciation of the danger of being misled by off-target effects when using pharmacological or genetic perturbants in complex biological assays. This danger is particularly acute when, as is often the case in cancer pharmacology, the biological phenotype being measured is a 'down' readout (such as decreased proliferation, decreased viability or decreased tumour growth) that could simply reflect a nonspecific loss of cellular fitness. These problems are compounded by multiple hypothesis testing, such as when candidate targets emerge from high-throughput screens that interrogate multiple targets in parallel, and by a publication and promotion system that preferentially rewards positive findings. In this Perspective, I outline some of the common pitfalls in preclinical cancer target identification and some potential approaches to mitigate them.

  6. Target assignment for security officers to K targets (TASK)

    International Nuclear Information System (INIS)

    Rowland, J.R.; Shelton, K.W.; Stunkel, C.B.

    1983-02-01

    A probabilistic algorithm is developed to provide an optimal Target Assignment for Security officers to K targets (TASK) using a maximin criterion. Under the assumption of only a limited number (N) of security officers, the TASK computer model determines deployment assignments which maximize the system protection against sabotage by an adversary who may select any link in the system, including the weakest, for the point of attack. Applying the TASK model to a hypothetical nuclear facility containing a nine-level building reveals that aggregate targets covering multiple vital areas should be utilized to reduce the number of possible target assignments to a value equal to or only slightly larger than N. The increased probability that a given aggregate target is covered by one or more security officers offsets the slight decrease in interruption probability due to its occurring earlier in the adversary's path. In brief, the TASK model determines the optimal maximin deployment strategy for limited numbers of security officers and calculates a quantitative measure of the resulting system protection

  7. Multiple model cardinalized probability hypothesis density filter

    Science.gov (United States)

    Georgescu, Ramona; Willett, Peter

    2011-09-01

    The Probability Hypothesis Density (PHD) filter propagates the first-moment approximation to the multi-target Bayesian posterior distribution while the Cardinalized PHD (CPHD) filter propagates both the posterior likelihood of (an unlabeled) target state and the posterior probability mass function of the number of targets. Extensions of the PHD filter to the multiple model (MM) framework have been published and were implemented either with a Sequential Monte Carlo or a Gaussian Mixture approach. In this work, we introduce the multiple model version of the more elaborate CPHD filter. We present the derivation of the prediction and update steps of the MMCPHD particularized for the case of two target motion models and proceed to show that in the case of a single model, the new MMCPHD equations reduce to the original CPHD equations.

  8. A multiplicity jump trigger using silicon planes

    International Nuclear Information System (INIS)

    Alexopoulos, T.; Erwin, A.R.

    1993-01-01

    Since silicon tracking planes are already present in a B decay experiment, it is an attractive idea to use these as part of a multiplicity jump detector. Two average B decays would produce a multiplicity jump of around 10 in the final state. Such a trigger has been tried for a fixed target Charm experiment with disappointing success. The failure was attributed to the difficulty in adequately controlling the gains of a large number of microstrip amplifies

  9. Tumor-targeted nanomedicines for cancer theranostics

    Science.gov (United States)

    Lammers, Twan; Shi, Yang

    2017-01-01

    Chemotherapeutic drugs have multiple drawbacks, including severe side effects and suboptimal therapeutic efficacy. Nanomedicines assist in improving the biodistribution and the target accumulation of chemotherapeutic drugs, and are therefore able to enhance the balance between efficacy and toxicity. Multiple different types of nanomedicines have been evaluated over the years, including liposomes, polymer-drug conjugates and polymeric micelles, which rely on strategies such as passive targeting, active targeting and triggered release for improved tumor-directed drug delivery. Based on the notion that tumors and metastases are highly heterogeneous, it is important to integrate imaging properties in nanomedicine formulations in order to enable non-invasive and quantitative assessment of targeting efficiency. By allowing for patient pre-selection, such next generation nanotheranostics are useful for facilitating clinical translation and personalizing nanomedicine treatments. PMID:27865762

  10. Organelle targeting: third level of drug targeting

    Directory of Open Access Journals (Sweden)

    Sakhrani NM

    2013-07-01

    Full Text Available Niraj M Sakhrani, Harish PadhDepartment of Cell and Molecular Biology, BV Patel Pharmaceutical Education and Research Development (PERD Centre, Gujarat, IndiaAbstract: Drug discovery and drug delivery are two main aspects for treatment of a variety of disorders. However, the real bottleneck associated with systemic drug administration is the lack of target-specific affinity toward a pathological site, resulting in systemic toxicity and innumerable other side effects as well as higher dosage requirement for efficacy. An attractive strategy to increase the therapeutic index of a drug is to specifically deliver the therapeutic molecule in its active form, not only into target tissue, nor even to target cells, but more importantly, into the targeted organelle, ie, to its intracellular therapeutic active site. This would ensure improved efficacy and minimize toxicity. Cancer chemotherapy today faces the major challenge of delivering chemotherapeutic drugs exclusively to tumor cells, while sparing normal proliferating cells. Nanoparticles play a crucial role by acting as a vehicle for delivery of drugs to target sites inside tumor cells. In this review, we spotlight active and passive targeting, followed by discussion of the importance of targeting to specific cell organelles and the potential role of cell-penetrating peptides. Finally, the discussion will address the strategies for drug/DNA targeting to lysosomes, mitochondria, nuclei and Golgi/endoplasmic reticulum.Keywords: intracellular drug delivery, cancer chemotherapy, therapeutic index, cell penetrating peptides

  11. Multiple-Ring Digital Communication Network

    Science.gov (United States)

    Kirkham, Harold

    1992-01-01

    Optical-fiber digital communication network to support data-acquisition and control functions of electric-power-distribution networks. Optical-fiber links of communication network follow power-distribution routes. Since fiber crosses open power switches, communication network includes multiple interconnected loops with occasional spurs. At each intersection node is needed. Nodes of communication network include power-distribution substations and power-controlling units. In addition to serving data acquisition and control functions, each node acts as repeater, passing on messages to next node(s). Multiple-ring communication network operates on new AbNET protocol and features fiber-optic communication.

  12. TargetCompare: A web interface to compare simultaneous miRNAs targets.

    Science.gov (United States)

    Moreira, Fabiano Cordeiro; Dustan, Bruno; Hamoy, Igor G; Ribeiro-Dos-Santos, André M; Dos Santos, Andrea Ribeiro

    2014-01-01

    MicroRNAs (miRNAs) are small non-coding nucleotide sequences between 17 and 25 nucleotides in length that primarily function in the regulation of gene expression. A since miRNA has thousand of predict targets in a complex, regulatory cell signaling network. Therefore, it is of interest to study multiple target genes simultaneously. Hence, we describe a web tool (developed using Java programming language and MySQL database server) to analyse multiple targets of pre-selected miRNAs. We cross validated the tool in eight most highly expressed miRNAs in the antrum region of stomach. This helped to identify 43 potential genes that are target of at least six of the referred miRNAs. The developed tool aims to reduce the randomness and increase the chance of selecting strong candidate target genes and miRNAs responsible for playing important roles in the studied tissue. http://lghm.ufpa.br/targetcompare.

  13. TargetMine, an integrated data warehouse for candidate gene prioritisation and target discovery.

    Directory of Open Access Journals (Sweden)

    Yi-An Chen

    Full Text Available Prioritising candidate genes for further experimental characterisation is a non-trivial challenge in drug discovery and biomedical research in general. An integrated approach that combines results from multiple data types is best suited for optimal target selection. We developed TargetMine, a data warehouse for efficient target prioritisation. TargetMine utilises the InterMine framework, with new data models such as protein-DNA interactions integrated in a novel way. It enables complicated searches that are difficult to perform with existing tools and it also offers integration of custom annotations and in-house experimental data. We proposed an objective protocol for target prioritisation using TargetMine and set up a benchmarking procedure to evaluate its performance. The results show that the protocol can identify known disease-associated genes with high precision and coverage. A demonstration version of TargetMine is available at http://targetmine.nibio.go.jp/.

  14. Uranium briquettes for irradiation target

    Energy Technology Data Exchange (ETDEWEB)

    Saliba-Silva, Adonis Marcelo; Garcia, Rafael Henrique Lazzari; Martins, Ilson Carlos; Carvalho, Elita Fontenele Urano de; Durazzo, Michelangelo, E-mail: saliba@ipen.b [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil)

    2011-07-01

    Direct irradiation on targets inside nuclear research or multiple purpose reactors is a common route to produce {sup 99}Mo-{sup 99m}Tc radioisotopes. Nevertheless, since the imposed limits to use LEU uranium to prevent nuclear armament production, the amount of uranium loaded in target meats has physically increased and new processes have been proposed for production. Routes using metallic uranium thin film and UAl{sub x} dispersion have been used for this purpose. Both routes have their own issues, either by bringing difficulties to disassemble the aluminum case inside hot cells or by generating great amount of alkaline radioactive liquid rejects. A potential route might be the dispersion of powders of LEU metallic uranium and nickel, which are pressed as a blend inside a die and followed by pulse electroplating of nickel. The electroplating provides more strength to the briquettes and creates a barrier for gas evolution during neutronic disintegration of {sup 235}U. A target briquette platted with nickel encapsulated in an aluminum case to be irradiated may be an alternative possibility to replace other proposed targets. This work uses pulse Ni-electroplating over iron powder briquette to simulate the covering of uranium by nickel. The following parameters were applied 10 times for each sample: 900Hz, -0.84A/square centimeters with duty cycle of 0.1 in Watts Bath. It also presented the optical microscopy analysis of plated microstructure section. (author)

  15. Uranium briquettes for irradiation target

    International Nuclear Information System (INIS)

    Saliba-Silva, Adonis Marcelo; Garcia, Rafael Henrique Lazzari; Martins, Ilson Carlos; Carvalho, Elita Fontenele Urano de; Durazzo, Michelangelo

    2011-01-01

    Direct irradiation on targets inside nuclear research or multiple purpose reactors is a common route to produce 99 Mo- 99m Tc radioisotopes. Nevertheless, since the imposed limits to use LEU uranium to prevent nuclear armament production, the amount of uranium loaded in target meats has physically increased and new processes have been proposed for production. Routes using metallic uranium thin film and UAl x dispersion have been used for this purpose. Both routes have their own issues, either by bringing difficulties to disassemble the aluminum case inside hot cells or by generating great amount of alkaline radioactive liquid rejects. A potential route might be the dispersion of powders of LEU metallic uranium and nickel, which are pressed as a blend inside a die and followed by pulse electroplating of nickel. The electroplating provides more strength to the briquettes and creates a barrier for gas evolution during neutronic disintegration of 235 U. A target briquette platted with nickel encapsulated in an aluminum case to be irradiated may be an alternative possibility to replace other proposed targets. This work uses pulse Ni-electroplating over iron powder briquette to simulate the covering of uranium by nickel. The following parameters were applied 10 times for each sample: 900Hz, -0.84A/square centimeters with duty cycle of 0.1 in Watts Bath. It also presented the optical microscopy analysis of plated microstructure section. (author)

  16. Deuterium pass through target

    International Nuclear Information System (INIS)

    Alger, D.L.

    1975-01-01

    A neutron emitting target is described for use in neutron generating apparatus including a deuteron source and an accelerator vacuum chamber. The target consists of a tritium-containing target layer, a deuteron accumulation layer, and a target support containing passages providing communication between the accumulation layer and portions of the surface of the support exposed to the accelerator vacuum chamber. With this arrangement, deuterons passing through the target layer and implanting in and diffusing through the accumulation layer, diffuse into the communicating passages and are returned to the accelerator vacuum chamber. The invention allows the continuous removal of deuterons from the target in conventional water cooled neutron generating apparatus. Preferably, the target is provided with thin barrier layers to prevent undesirable tritium diffusion out of the target layer, as well as deuteron diffusion into the target layer

  17. Generalized internal multiple imaging

    KAUST Repository

    Zuberi, Mohammad Akbar Hosain

    2014-12-04

    Various examples are provided for generalized internal multiple imaging (GIMI). In one example, among others, a method includes generating a higher order internal multiple image using a background Green\\'s function and rendering the higher order internal multiple image for presentation. In another example, a system includes a computing device and a generalized internal multiple imaging (GIMI) application executable in the computing device. The GIMI application includes logic that generates a higher order internal multiple image using a background Green\\'s function and logic that renders the higher order internal multiple image for display on a display device. In another example, a non-transitory computer readable medium has a program executable by processing circuitry that generates a higher order internal multiple image using a background Green\\'s function and renders the higher order internal multiple image for display on a display device.

  18. MultipleColposcopyJCO

    Science.gov (United States)

    Performing multiple biopsies during a procedure known as colposcopy—visual inspection of the cervix—is more effective than performing only a single biopsy of the worst-appearing area for detecting cervical cancer precursors. This multiple biopsy approach

  19. Salmonella Infections - Multiple Languages

    Science.gov (United States)

    ... Are Here: Home → Multiple Languages → All Health Topics → Salmonella Infections URL of this page: https://medlineplus.gov/ ... V W XYZ List of All Topics All Salmonella Infections - Multiple Languages To use the sharing features ...

  20. Health Literacy - Multiple Languages

    Science.gov (United States)

    ... Here: Home → Multiple Languages → All Health Topics → Health Literacy URL of this page: https://medlineplus.gov/languages/ ... W XYZ List of All Topics All Health Literacy - Multiple Languages To use the sharing features on ...

  1. Cosmetic Dentistry - Multiple Languages

    Science.gov (United States)

    ... Here: Home → Multiple Languages → All Health Topics → Cosmetic Dentistry URL of this page: https://medlineplus.gov/languages/ ... W XYZ List of All Topics All Cosmetic Dentistry - Multiple Languages To use the sharing features on ...

  2. Atrial Fibrillation - Multiple Languages

    Science.gov (United States)

    ... Are Here: Home → Multiple Languages → All Health Topics → Atrial Fibrillation URL of this page: https://medlineplus.gov/languages/ ... V W XYZ List of All Topics All Atrial Fibrillation - Multiple Languages To use the sharing features on ...

  3. Zika Virus - Multiple Languages

    Science.gov (United States)

    ... Are Here: Home → Multiple Languages → All Health Topics → Zika Virus URL of this page: https://medlineplus.gov/languages/ ... V W XYZ List of All Topics All Zika Virus - Multiple Languages To use the sharing features on ...

  4. Elder Abuse - Multiple Languages

    Science.gov (United States)

    ... Are Here: Home → Multiple Languages → All Health Topics → Elder Abuse URL of this page: https://medlineplus.gov/languages/ ... V W XYZ List of All Topics All Elder Abuse - Multiple Languages To use the sharing features on ...

  5. Herbal Medicine - Multiple Languages

    Science.gov (United States)

    ... Are Here: Home → Multiple Languages → All Health Topics → Herbal Medicine URL of this page: https://medlineplus.gov/languages/ ... V W XYZ List of All Topics All Herbal Medicine - Multiple Languages To use the sharing features on ...

  6. Generalized internal multiple imaging

    KAUST Repository

    Zuberi, Mohammad Akbar Hosain; Alkhalifah, Tariq

    2014-01-01

    Various examples are provided for generalized internal multiple imaging (GIMI). In one example, among others, a method includes generating a higher order internal multiple image using a background Green's function and rendering the higher order internal multiple image for presentation. In another example, a system includes a computing device and a generalized internal multiple imaging (GIMI) application executable in the computing device. The GIMI application includes logic that generates a higher order internal multiple image using a background Green's function and logic that renders the higher order internal multiple image for display on a display device. In another example, a non-transitory computer readable medium has a program executable by processing circuitry that generates a higher order internal multiple image using a background Green's function and renders the higher order internal multiple image for display on a display device.

  7. Domestic Violence - Multiple Languages

    Science.gov (United States)

    ... Are Here: Home → Multiple Languages → All Health Topics → Domestic Violence URL of this page: https://medlineplus.gov/languages/ ... V W XYZ List of All Topics All Domestic Violence - Multiple Languages To use the sharing features on ...

  8. Multiple Primary Tumors

    African Journals Online (AJOL)

    2017-12-05

    Dec 5, 2017 ... Multiple primary tumors occur in clinical practice causing diagnostic dilemma. It is not very .... was estrogen receptor negative, progesterone receptor negative, and ... cervical, ovarian, and urinary bladder cancers. Multiple.

  9. Diabetic Foot - Multiple Languages

    Science.gov (United States)

    ... Are Here: Home → Multiple Languages → All Health Topics → Diabetic Foot URL of this page: https://medlineplus.gov/languages/ ... V W XYZ List of All Topics All Diabetic Foot - Multiple Languages To use the sharing features on ...

  10. Child Abuse - Multiple Languages

    Science.gov (United States)

    ... Are Here: Home → Multiple Languages → All Health Topics → Child Abuse URL of this page: https://medlineplus.gov/languages/ ... V W XYZ List of All Topics All Child Abuse - Multiple Languages To use the sharing features on ...

  11. Fatigue and Multiple Sclerosis

    Science.gov (United States)

    ... to navigation Skip to content Menu Navigation National Multiple Sclerosis Society Sign In In Your Area Donate Donate ... of MS What Causes MS? Who Gets MS? Multiple Sclerosis FAQs Types of MS Related Conditions Symptoms & Diagnosis ...

  12. Rotavirus Infections - Multiple Languages

    Science.gov (United States)

    ... Are Here: Home → Multiple Languages → All Health Topics → Rotavirus Infections URL of this page: https://medlineplus.gov/ ... V W XYZ List of All Topics All Rotavirus Infections - Multiple Languages To use the sharing features ...

  13. Molecular Targets for Targeted Radionuclide Therapy

    International Nuclear Information System (INIS)

    Mather, S.J.

    2009-01-01

    Molecular targeted radionuclide cancer therapy is becoming of increasing importance, especially for disseminated diseases. Systemic chemotherapies often lack selectivity while targeted radionuclide therapy has important advantages as the radioactive cytotoxic unit of the targeting vector is specifically directed to the cancer, sparing normal tissues. The principle strategy to improve cancer selectivity is to couple therapeutic agents to tumour-targeting vectors. In targeted radionuclide therapy (TRT), the cytotoxic portion of the conjugates normally contains a therapeutic radiometal immobilised by a bifunctional chelator. The aim is therefore to use as ligand-targeted therapeutics vectors coupled to Auger-, alpha- and/or beta-emitting radionuclides. An advantage of using radiation instead of chemotherapeutics as the cytotoxic agent is the so called 'crossfire effect'. This allows sterilisation of tumour cells that are not directly targeted due to heterogeneity in target molecule expression or inhomogeneous vector delivery. However, before the targeting ligands can be selected, the target molecule on the tumour has to be selected. It should be uniquely expressed, or at least highly overexpressed, on or in the target cells relative to normal tissues. The target should be easily accessible for ligand delivery and should not be shed or down- regulated after ligand binding. An important property of a receptor (or antigen) is its potential to be internalized upon binding of the ligand. This provides an active uptake mechanism and allows the therapeutic agent to be trapped within the tumour cells. Molecular targets of current interest include: Receptors: G-protein coupled receptors are overexpressed on many major human tumours. The prototype of these receptors are somatostatin receptors which show very high density in neuroendocrine tumours, but there are many other most interesting receptors to be applied for TRT. The targeting ligands for these receptors are

  14. 29 mm Diameter Target Test Report

    Energy Technology Data Exchange (ETDEWEB)

    Woloshun, Keith Albert [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Olivas, Eric Richard [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Dale, Gregory E. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Naranjo, Angela Carol [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Romero, Frank Patrick [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Chemerisov, Sergey [Argonne National Lab. (ANL), Argonne, IL (United States); Gromov, Roman [Argonne National Lab. (ANL), Argonne, IL (United States)

    2017-10-23

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

  15. Neutron Multiplicity Analysis

    Energy Technology Data Exchange (ETDEWEB)

    Frame, Katherine Chiyoko [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2017-06-28

    Neutron multiplicity measurements are widely used for nondestructive assay (NDA) of special nuclear material (SNM). When combined with isotopic composition information, neutron multiplicity analysis can be used to estimate the spontaneous fission rate and leakage multiplication of SNM. When combined with isotopic information, the total mass of fissile material can also be determined. This presentation provides an overview of this technique.

  16. Introduction: multiple myeloma.

    Science.gov (United States)

    Cook, Richard

    2008-09-01

    Multiple myeloma (MM) is the most common type of primary bone tumor, affecting approximately 50,000 patients in the United States. Although it is currently not curable, recent advancements in treatment are bringing myeloma closer to becoming a chronic disease instead of a terminal illness. To better understand the prevalence of MM as well as provide an overview of the costs associated with treatment. The goals of treatment in MM include eradicating all evidence of disease, controlling disease to prevent damage to target organs, preserving normal function and quality of life, relieving pain, and managing myeloma that is in remission. To achieve these goals, treatment must be individually tailored for each patient based on the patient's age, overall health status, symptoms, and laboratory test results. Advancements in the understanding of the pathogenesis of myeloma and the role of genetic mutations are leading to a new standard of treatment. Advancements in diagnostic technology, such as cytogenetic testing, are also being used to tailor treatment for each individual to work toward achieving better response rates, longer periods of remission, and improved quality of life. Increased costs associated with the improved therapies being used to treat MM, and the comorbid conditions associated with the disease, present a challenge to managed care. Health plans and formulary decision makers need to better understand the complexity of therapy to best use resources. The economic burden to the patient must also be considered when developing treatment strategies. Better understanding of the pathophysiology of MM, including the role of cytogenetics, is leading to the development and use of novel agents and treatment options. Head-to-head studies comparing treatments must be performed to best balance the costs associated with treatment and the benefits of improved survival rates and maintaining quality of life.

  17. Monoclonal Antibodies for Relapsing Multiple Sclerosis

    DEFF Research Database (Denmark)

    Blinkenberg, Morten; Soelberg Sørensen, Per

    2017-01-01

    Treatment of multiple sclerosis (MS) has improved considerably over the last decade because of new insights into MS pathology and biotechnological advances. This has led to the development of new potent pharmaceutical compounds targeting different processes in the complex autoimmune pathology...... the context of different treatment strategies. Finally, we consider the most important future developments....

  18. Neutron multiplication measurement instrument

    International Nuclear Information System (INIS)

    Nixon, K.V.; Dowdy, E.J.; France, S.W.; Millegan, D.R.; Robba, A.A.

    1983-01-01

    The Advanced Nuclear Technology Group of the Los Alamos National Laboratory is now using intelligent data-acquisition and analysis instrumentation for determining the multiplication of nuclear material. Earlier instrumentation, such as the large NIM-crate systems, depended on house power and required additional computation to determine multiplication or to estimate error. The portable, battery-powered multiplication measurement unit, with advanced computational power, acquires data, calculates multiplication, and completes error analysis automatically. Thus, the multiplication is determined easily and an available error estimate enables the user to judge the significance of results

  19. Monitoring production target thickness

    International Nuclear Information System (INIS)

    Oothoudt, M.A.

    1993-01-01

    Pion and muon production targets at the Clinton P. Anderson Meson Physics Facility consist of rotating graphite wheels. The previous target thickness monitoring Procedure scanned the target across a reduced intensity beam to determine beam center. The fractional loss in current across the centered target gave a measure of target thickness. This procedure, however, required interruption of beam delivery to experiments and frequently indicated a different fractional loss than at normal beam currents. The new monitoring Procedure compares integrated ups and downs toroid current monitor readings. The current monitors are read once per minute and the integral of readings are logged once per eight-hour shift. Changes in the upstream to downstream fractional difference provide a nonintrusive continuous measurement of target thickness under nominal operational conditions. Target scans are now done only when new targets are installed or when unexplained changes in the current monitor data are observed

  20. Visualizing Energy on Target: Molecular Dynamics Simulations

    Science.gov (United States)

    2017-12-01

    to be construed as an official Department of the Army position unless so designated by other authorized documents. Citation of manufacturer’s or...all atoms to the interior of the cell. After equilibration, N2 was driven into the target at multiple impact velocities, vimp. Momentum of N2 toward

  1. Is it wise to protect false targets?

    International Nuclear Information System (INIS)

    Levitin, Gregory; Hausken, Kjell

    2011-01-01

    The paper considers a system consisting of genuine elements and false targets that cannot be distinguished by the attacker's observation. The false targets can be destroyed with much less effort than the genuine elements. We show that even when an attacker cannot distinguish between the genuine elements and the false targets, in many cases it can enhance the attack efficiency using a double attack strategy in which it tries first to eliminate with minimal effort as many false targets as possible in the first attack and then distributes its entire remaining resource among all surviving targets in the second attack. The model for evaluating the system vulnerability in the double attack is suggested for a single genuine element, and multiple genuine elements configured in parallel or in series. This model assumes that in both attacks the attacking resource is distributed evenly among the attacked targets. The defender can optimize its limited resource distribution between deploying more false targets and protecting them better. The attacker can optimize its limited resource distribution between two attacks. The defense strategy is analyzed based on a two period minmax game. A numerical procedure is suggested that allows the defender to find the optimal resource distribution between deploying and protecting the false targets. The methodology of optimal attack and defense strategies analysis is demonstrated. It is shown that protecting the false targets may reduce the efficiency of the double attack strategy and make this strategy ineffective in situations with low contest intensity and few false targets. - Highlights: ► The efficiency of the double attack tactics against using false targets is analyzed. ► The role of the false target protection in system survivability enhancement is shown. ► The resource distribution between deploying more false targets and protecting them better is optimized. ► Both series and parallel systems are considered.

  2. Liquid helium target

    International Nuclear Information System (INIS)

    Fujii, Y.; Kitami, T.; Torikoshi, M.

    1984-12-01

    A liquid helium target system has been built and used for the experiment on the reaction 4 He(γ, p). The target system has worked satisfactorily; the consumption rate of liquid helium is 360 ml/h and the cryogenic system retains liquid helium for about ten hours. The structure, operation and performance of the target system are reported. (author)

  3. Graphite targets at LAMPF

    International Nuclear Information System (INIS)

    Brown, R.D.; Grisham, D.L.

    1983-01-01

    Rotating polycrystalline and stationary pyrolytic graphite target designs for the LAMPF experimental area are described. Examples of finite element calculations of temperatures and stresses are presented. Some results of a metallographic investigation of irradiated pyrolytic graphite target plates are included, together with a brief description of high temperature bearings for the rotating targets

  4. Cooperative Robots to Observe Moving Targets: Review.

    Science.gov (United States)

    Khan, Asif; Rinner, Bernhard; Cavallaro, Andrea

    2018-01-01

    The deployment of multiple robots for achieving a common goal helps to improve the performance, efficiency, and/or robustness in a variety of tasks. In particular, the observation of moving targets is an important multirobot application that still exhibits numerous open challenges, including the effective coordination of the robots. This paper reviews control techniques for cooperative mobile robots monitoring multiple targets. The simultaneous movement of robots and targets makes this problem particularly interesting, and our review systematically addresses this cooperative multirobot problem for the first time. We classify and critically discuss the control techniques: cooperative multirobot observation of multiple moving targets, cooperative search, acquisition, and track, cooperative tracking, and multirobot pursuit evasion. We also identify the five major elements that characterize this problem, namely, the coordination method, the environment, the target, the robot and its sensor(s). These elements are used to systematically analyze the control techniques. The majority of the studied work is based on simulation and laboratory studies, which may not accurately reflect real-world operational conditions. Importantly, while our systematic analysis is focused on multitarget observation, our proposed classification is useful also for related multirobot applications.

  5. Tyrosine kinase inhibitors: Multi-targeted or single-targeted?

    Science.gov (United States)

    Broekman, Fleur; Giovannetti, Elisa; Peters, Godefridus J

    2011-02-10

    Since in most tumors multiple signaling pathways are involved, many of the inhibitors in clinical development are designed to affect a wide range of targeted kinases. The most important tyrosine kinase families in the development of tyrosine kinase inhibitors are the ABL, SCR, platelet derived growth factor, vascular endothelial growth factor receptor and epidermal growth factor receptor families. Both multi-kinase inhibitors and single-kinase inhibitors have advantages and disadvantages, which are related to potential resistance mechanisms, pharmacokinetics, selectivity and tumor environment. In different malignancies various tyrosine kinases are mutated or overexpressed and several resistance mechanisms exist. Pharmacokinetics is influenced by interindividual differences and differs for two single targeted inhibitors or between patients treated by the same tyrosine kinase inhibitor. Different tyrosine kinase inhibitors have various mechanisms to achieve selectivity, while differences in gene expression exist between tumor and stromal cells. Considering these aspects, one type of inhibitor can generally not be preferred above the other, but will depend on the specific genetic constitution of the patient and the tumor, allowing personalized therapy. The most effective way of cancer treatment by using tyrosine kinase inhibitors is to consider each patient/tumor individually and to determine the strategy that specifically targets the consequences of altered (epi)genetics of the tumor. This strategy might result in treatment by a single multi kinase inhibitor for one patient, but in treatment by a couple of single kinase inhibitors for other patients.

  6. Multiple sclerosis: current immunological aspects

    Directory of Open Access Journals (Sweden)

    Carlos Cuevas-García

    2017-02-01

    Full Text Available Multiple sclerosis is the most common inflammatory, chronic and degenerative condition of the central nervous system, and represents the first cause of disability in young adults. In Mexico, 11 to 20 out of every 100 000 people suffer from this disease. The causes of multiple sclerosis remain unknown, but several theories have been proposed on its origin: the interaction of environmental factors, viral infectious factors and genetic and immune susceptibility of each individual patient, which induce an autoimmune response and promote neuronal/axonal degeneration. In this review, the immune reaction main components and neurodegeneration present in multiple sclerosis are analyzed, as well as the inflammatory cascade associated with demyelination. Available treatments’ main purpose is to modulate aspects related to the adaptive immune response (B and T cells. The therapeutic challenge will be antigen-specific immune-tolerance induction, for example, with the use of tolerance protocols with peptides or DNA or nanoparticles vaccines. Future therapies should aim to control innate components (microglia, macrophages, astrocytes and to promote remyelination. To optimize the treatment, a combined therapeutic approach targeting the control of inflammatory and neurodegenerative components of the disease and monitoring of biomarkers will be necessary.

  7. Wake Shield Target Protection

    International Nuclear Information System (INIS)

    Valmianski, Emanuil I.; Petzoldt, Ronald W.; Alexander, Neil B.

    2003-01-01

    The heat flux from both gas convection and chamber radiation on a direct drive target must be limited to avoid target damage from excessive D-T temperature increase. One of the possibilities of protecting the target is a wake shield flying in front of the target. A shield will also reduce drag force on the target, thereby facilitating target tracking and position prediction. A Direct Simulation Monte Carlo (DSMC) code was used to calculate convection heat loads as boundary conditions input into ANSYS thermal calculations. These were used for studying the quality of target protection depending on various shapes of shields, target-shield distance, and protective properties of the shield moving relative to the target. The results show that the shield can reduce the convective heat flux by a factor of 2 to 5 depending on pressure, temperature, and velocity. The protective effect of a shield moving relative to the target is greater than the protective properties of a fixed shield. However, the protective effect of a shield moving under the drag force is not sufficient for bringing the heat load on the target down to the necessary limit. Some other ways of diminishing heat flux using a protective shield are discussed

  8. Generalised two target localisation using passive monopulse radar

    KAUST Repository

    Jardak, Seifallah

    2017-04-07

    The simultaneous lobing technique, also known as monopulse technique, has been widely used for fast target localisation and tracking purposes. Many works focused on accurately localising one or two targets lying within a narrow beam centred around the monopulse antenna boresight. In this study, a new approach is proposed, which uses the outputs of four antennas to rapidly localise two point targets present in the hemisphere. If both targets have the same elevation angle, the proposed scheme cannot detect them. To detect such targets, a second set of antennas is required. In this study, to detect two targets at generalised locations, the antenna array is divided into multiple overlapping sets each of four antennas. Two algorithms are proposed to combine the outputs from multiple sets and improve the detection performance. Simulation results show that the algorithm is able to localise both targets with <;2° mean square error in azimuth and elevation.

  9. Development of distributed target

    CERN Document Server

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

    2002-01-01

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

  10. Polarized targets and beams

    International Nuclear Information System (INIS)

    Meyer, W.

    1985-01-01

    First the experimental situation of the single-pion photoproduction and the photodisintegration of the deuteron is briefly discussed. Then a description of the Bonn polarization facilities is given. The point of main effort is put on the polarized target which plays a vital role in the program. A facility for photon induced double polarization experiments at ELSA will be presented in section 4. Properties of a tensor polarized deuteron target are discussed in section 5. The development in the field of polarized targets, especially on new target materials, enables a new generation of polarized target experiments with (polarized) electrons. Some comments on the use of a polarized target in combination with electron beams will be discussed in section 6. Electron deuteron scattering from a tensor polarized deuteron target is considered and compared with other experimental possibilities. (orig./HSI)

  11. Improving your target-template alignment with MODalign.

    KAUST Repository

    Barbato, Alessandro; Benkert, Pascal; Schwede, Torsten; Tramontano, Anna; Kosinski, Jan

    2012-01-01

    , upon modification of the target-template alignment, updates the multiple sequence alignments of the two protein families, their conservation score, secondary structure and solvent accessibility values, and local quality scores of the implied three

  12. Accurate scaling on multiplicity

    International Nuclear Information System (INIS)

    Golokhvastov, A.I.

    1989-01-01

    The commonly used formula of KNO scaling P n =Ψ(n/ ) for descrete distributions (multiplicity distributions) is shown to contradict mathematically the condition ΣP n =1. The effect is essential even at ISR energies. A consistent generalization of the concept of similarity for multiplicity distributions is obtained. The multiplicity distributions of negative particles in PP and also e + e - inelastic interactions are similar over the whole studied energy range. Collider data are discussed. 14 refs.; 8 figs

  13. Nova target experiments

    International Nuclear Information System (INIS)

    Drake, R.P.

    1985-11-01

    The Nova laser, at the Lawrence Livermore National Laboratory, provides unique opportunities for target experiments. It has unprecedented energy on target and significant flexibility. The paper presented by John Hunt described the capabilities and the status of Nova. This paper discusses plans for future experiments using Nova, and the present status of target experiments. We plan to perform high-quality physics experiments that exploit the unique capabilities of Nova. Because this is our goal, we are fielding an extensive array of well-characterized target diagnostics to measure the emissions from the target. The first section of this paper discusses the basic target diagnostics. We are also taking care to quantify the performance of the laser

  14. Targeting and Persuasive Advertising

    OpenAIRE

    Egli, Alain (Autor/in)

    2015-01-01

    Firms face a prisoner's dilemma when advertising in a competitive environment. In a Hotelling framework with persuasive advertisingfirms counteract this prisoner's dilemma with targeting. The firms even solve the prisoner's problem if targeted advertising is effective enough. Advertising turns from wasteful competition into profits. This is in contrast to wasteful competition as argument for regulations. A further result is maximum advertising differentiation: thefirms target their advertisin...

  15. The ISOLDE target robots

    CERN Multimedia

    Maximilein Brice

    2002-01-01

    ISOLDE targets need to be changed frequently, around 80 times per year. The high radiation levels do not permit this to be done by human hands and the target changes are effected by 2 industrial robots (picture _01). On the left, in the distance, the front-end of the GPS (General Purpose Separator) is seen, while the HRS (High Resolution Separator) is at the right. Also seen are the doors to the irradiated-target storage.

  16. Deuterium high pressure target

    International Nuclear Information System (INIS)

    Perevozchikov, V.V.; Yukhimchuk, A.A.; Vinogradov, Yu.I.

    2001-01-01

    The design of the deuterium high-pressure target is presented. The target having volume of 76 cm 3 serves to provide the experimental research of muon catalyzed fusion reactions in ultra-pure deuterium in the temperature range 80-800 K under pressures of up to 150 MPa. The operation of the main systems of the target is described: generation and purification of deuterium gas, refrigeration, heating, evacuation, automated control system and data collection system

  17. Targeted Radionuclide Therapy

    Directory of Open Access Journals (Sweden)

    David Cheng

    2011-10-01

    Full Text Available Targeted radiotherapy is an evolving and promising modality of cancer treatment. The killing of cancer cells is achieved with the use of biological vectors and appropriate radionuclides. Among the many advantages of this approach are its selectiveness in delivering the radiation to the target, relatively less severe and infrequent side effects, and the possibility of assessing the uptake by the tumor prior to the therapy. Several different radiopharmaceuticals are currently being used by various administration routes and targeting mechanisms. This article aims to briefly review the current status of targeted radiotherapy as well as to outline the advantages and disadvantages of radionuclides used for this purpose.

  18. Targeted Radionuclide Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Ersahin, Devrim, E-mail: devrimersahin@yahoo.com; Doddamane, Indukala; Cheng, David [Department of Diagnostic Radiology, School of Medicine, Yale University, 333 Cedar St., New Haven, CT 06520 (United States)

    2011-10-11

    Targeted radiotherapy is an evolving and promising modality of cancer treatment. The killing of cancer cells is achieved with the use of biological vectors and appropriate radionuclides. Among the many advantages of this approach are its selectiveness in delivering the radiation to the target, relatively less severe and infrequent side effects, and the possibility of assessing the uptake by the tumor prior to the therapy. Several different radiopharmaceuticals are currently being used by various administration routes and targeting mechanisms. This article aims to briefly review the current status of targeted radiotherapy as well as to outline the advantages and disadvantages of radionuclides used for this purpose.

  19. Target Assembly Facility

    Data.gov (United States)

    Federal Laboratory Consortium — The Target Assembly Facility integrates new armor concepts into actual armored vehicles. Featuring the capability ofmachining and cutting radioactive materials, it...

  20. Targeted Radionuclide Therapy

    International Nuclear Information System (INIS)

    Ersahin, Devrim; Doddamane, Indukala; Cheng, David

    2011-01-01

    Targeted radiotherapy is an evolving and promising modality of cancer treatment. The killing of cancer cells is achieved with the use of biological vectors and appropriate radionuclides. Among the many advantages of this approach are its selectiveness in delivering the radiation to the target, relatively less severe and infrequent side effects, and the possibility of assessing the uptake by the tumor prior to the therapy. Several different radiopharmaceuticals are currently being used by various administration routes and targeting mechanisms. This article aims to briefly review the current status of targeted radiotherapy as well as to outline the advantages and disadvantages of radionuclides used for this purpose

  1. Targeting the tumor microenvironment

    Energy Technology Data Exchange (ETDEWEB)

    Kenny, P.A.; Lee, G.Y.; Bissell, M.J.

    2006-11-07

    Despite some notable successes cancer remains, for the most part, a seemingly intractable problem. There is, however, a growing appreciation that targeting the tumor epithelium in isolation is not sufficient as there is an intricate mutually sustaining synergy between the tumor epithelial cells and their surrounding stroma. As the details of this dialogue emerge, new therapeutic targets have been proposed. The FDA has already approved drugs targeting microenvironmental components such as VEGF and aromatase and many more agents are in the pipeline. In this article, we describe some of the 'druggable' targets and processes within the tumor microenvironment and review the approaches being taken to disrupt these interactions.

  2. ALICE Photon Multiplicity Detector

    CERN Multimedia

    Nayak, T

    2013-01-01

    Photon Multiplicity Detector (PMD) measures the multiplicity and spatial distribution of photons in the forward region of ALICE on a event-by-event basis. PMD is a pre-shower detector having fine granularity and full azimuthal coverage in the pseudo-rapidity region 2.3 < η < 3.9.

  3. Body Weight - Multiple Languages

    Science.gov (United States)

    ... Supplements Videos & Tools You Are Here: Home → Multiple Languages → All Health Topics → Body Weight URL of this page: https://medlineplus.gov/ ... V W XYZ List of All Topics All Body Weight - Multiple Languages To use the sharing features on this page, ...

  4. Multiplicity in difference geometry

    OpenAIRE

    Tomasic, Ivan

    2011-01-01

    We prove a first principle of preservation of multiplicity in difference geometry, paving the way for the development of a more general intersection theory. In particular, the fibres of a \\sigma-finite morphism between difference curves are all of the same size, when counted with correct multiplicities.

  5. Applying Multiple Intelligences

    Science.gov (United States)

    Christodoulou, Joanna A.

    2009-01-01

    The ideas of multiple intelligences introduced by Howard Gardner of Harvard University more than 25 years ago have taken form in many ways, both in schools and in other sometimes-surprising settings. The silver anniversary of Gardner's learning theory provides an opportunity to reflect on the ways multiple intelligences theory has taken form and…

  6. Formation of multiple networks

    DEFF Research Database (Denmark)

    Magnani, Matteo; Rossi, Luca

    2013-01-01

    we introduce the first network formation model for multiple networks. Network formation models are among the most popular tools in traditional network studies, because of both their practical and theoretical impact. However, existing models are not sufficient to describe the generation of multiple...

  7. Orchestrating Multiple Intelligences

    Science.gov (United States)

    Moran, Seana; Kornhaber, Mindy; Gardner, Howard

    2006-01-01

    Education policymakers often go astray when they attempt to integrate multiple intelligences theory into schools, according to the originator of the theory, Howard Gardner, and his colleagues. The greatest potential of a multiple intelligences approach to education grows from the concept of a profile of intelligences. Each learner's intelligence…

  8. Assessing Children's Multiplicative Thinking

    Science.gov (United States)

    Hurst, Chris; Hurrell, Derek

    2016-01-01

    Multiplicative thinking is a "big idea" of mathematics that underpins much of the mathematics learned beyond the early primary school years. This paper reports on a current study that utilises an interview tool and a written quiz to gather data about children's multiplicative thinking. The development of the tools and some of the…

  9. Extended Target Recognition in Cognitive Radar Networks

    Directory of Open Access Journals (Sweden)

    Xiqin Wang

    2010-11-01

    Full Text Available We address the problem of adaptive waveform design for extended target recognition in cognitive radar networks. A closed-loop active target recognition radar system is extended to the case of a centralized cognitive radar network, in which a generalized likelihood ratio (GLR based sequential hypothesis testing (SHT framework is employed. Using Doppler velocities measured by multiple radars, the target aspect angle for each radar is calculated. The joint probability of each target hypothesis is then updated using observations from different radar line of sights (LOS. Based on these probabilities, a minimum correlation algorithm is proposed to adaptively design the transmit waveform for each radar in an amplitude fluctuation situation. Simulation results demonstrate performance improvements due to the cognitive radar network and adaptive waveform design. Our minimum correlation algorithm outperforms the eigen-waveform solution and other non-cognitive waveform design approaches.

  10. Power and the objectification of social targets.

    Science.gov (United States)

    Gruenfeld, Deborah H; Inesi, M Ena; Magee, Joe C; Galinsky, Adam D

    2008-07-01

    Objectification has been defined historically as a process of subjugation whereby people, like objects, are treated as means to an end. The authors hypothesized that objectification is a response to social power that involves approaching useful social targets regardless of the value of their other human qualities. Six studies found that under conditions of power, approach toward a social target was driven more by the target's usefulness, defined in terms of the perceiver's goals, than in low-power and baseline conditions. This instrumental response to power, which was linked to the presence of an active goal, was observed using multiple instantiations of power, different measures of approach, a variety of goals, and several types of instrumental and noninstrumental target attributes. Implications for research on the psychology of power, automatic goal pursuit, and self-objectification theory are discussed.

  11. Nuclear Targeting Terms for Engineers and Scientists

    Energy Technology Data Exchange (ETDEWEB)

    St Ledger, John W. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2017-02-01

    The Department of Defense has a methodology for targeting nuclear weapons, and a jargon that is used to communicate between the analysts, planners, aircrews, and missile crews. The typical engineer or scientist in the Department of Energy may not have been exposed to the nuclear weapons targeting terms and methods. This report provides an introduction to the terms and methodologies used for nuclear targeting. Its purpose is to prepare engineers and scientists to participate in wargames, exercises, and discussions with the Department of Defense. Terms such as Circular Error Probable, probability of hit and damage, damage expectancy, and the physical vulnerability system are discussed. Methods for compounding damage from multiple weapons applied to one target are presented.

  12. Target Visualization at the National Ignition Facility

    Energy Technology Data Exchange (ETDEWEB)

    Potter, Daniel Abraham [Univ. of California, Davis, CA (United States)

    2011-01-01

    As the National Ignition Facility continues its campaign to achieve ignition, new methods and tools will be required to measure the quality of the targets used to achieve this goal. Techniques have been developed to measure target surface features using a phase-shifting diffraction interferometer and Leica Microsystems confocal microscope. Using these techniques we are able to produce a detailed view of the shell surface, which in turn allows us to refine target manufacturing and cleaning processes. However, the volume of data produced limits the methods by which this data can be effectively viewed by a user. This paper introduces an image-based visualization system for data exploration of target shells at the National Ignition Facility (NIF) at Lawrence Livermore National Laboratory. It aims to combine multiple image sets into a single visualization to provide a method of navigating the data in ways that are not possible with existing tools.

  13. Dual Target Search is Neither Purely Simultaneous nor Purely Successive.

    Science.gov (United States)

    Cave, Kyle R; Menneer, Tamaryn; Nomani, Mohammad S; Stroud, Michael J; Donnelly, Nick

    2017-08-31

    Previous research shows that visual search for two different targets is less efficient than search for a single target. Stroud, Menneer, Cave and Donnelly (2012) concluded that two target colours are represented separately based on modeling the fixation patterns. Although those analyses provide evidence for two separate target representations, they do not show whether participants search simultaneously for both targets, or first search for one target and then the other. Some studies suggest that multiple target representations are simultaneously active, while others indicate that search can be voluntarily simultaneous, or switching, or a mixture of both. Stroud et al.'s participants were not explicitly instructed to use any particular strategy. These data were revisited to determine which strategy was employed. Each fixated item was categorised according to whether its colour was more similar to one target or the other. Once an item similar to one target is fixated, the next fixated item is more likely to be similar to that target than the other, showing that at a given moment during search, one target is generally favoured. However, the search for one target is not completed before search for the other begins. Instead, there are often short runs of one or two fixations to distractors similar to one target, with each run followed by a switch to the other target. Thus, the results suggest that one target is more highly weighted than the other at any given time, but not to the extent that search is purely successive.

  14. SPANDY: a Monte Carlo program for gas target scattering geometry

    International Nuclear Information System (INIS)

    Jarmie, N.; Jett, J.H.; Niethammer, A.C.

    1977-02-01

    A Monte Carlo computer program is presented that simulates a two-slit gas target scattering geometry. The program is useful in estimating effects due to finite geometry and multiple scattering in the target foil. Details of the program are presented and experience with a specific example is discussed

  15. Target reactor development problems

    International Nuclear Information System (INIS)

    Lathrop, K.D.; Vigil, J.C.

    1977-01-01

    Target-blanket design studies are discussed for an accelerator-breeder concept employing a linear accelerator in conjunction with a modified conventional power reactor to produce both fissile fuel and power. The following problems in target and blanket system design are discussed: radiation damage, heat removal, neutronic design, and economics

  16. The CNGS target

    CERN Multimedia

    Patrice Loïez

    2005-01-01

    The CERN Neutrinos to Gran Sasso (CNGS) target ‘magazine’ of five target units. Each unit contains a series of 10-cm long graphite rods distributed over a length of 2 m. It is designed to maximize the number of secondary particles produced and hence the number of neutrinos. One unit is used at a time to prevent over heating.

  17. Targeted radionuclide therapy

    African Journals Online (AJOL)

    target for which a speci c treatment/drug is intended (Fig. 1). eranostics .... Using an anti-CD20 antibody as a delivery device to target the follicular ... systems combine diagnostic imaging (Ga-68-DOTATATE PET/CT) .... Intra-articular injected ...

  18. Modelling Recycling Targets

    DEFF Research Database (Denmark)

    hill, amanda; Leinikka Dall, Ole; Andersen, Frits Møller

    2014-01-01

    % for household waste, and sets an ambitious goal of a 50% recycling rate by 2020. This study integrates the recycling target into the FRIDA model to project how much waste and from which streams should be diverted from incineration to recycling in order to achieve the target. Furthermore, it discusses how...

  19. Strategic Targeted Advertising

    NARCIS (Netherlands)

    A. Galeotti; J.L. Moraga-Gonzalez (José Luis)

    2003-01-01

    textabstractWe present a strategic game of pricing and targeted-advertising. Firms can simultaneously target price advertisements to different groups of customers, or to the entire market. Pure strategy equilibria do not exist and thus market segmentation cannot occur surely. Equilibria exhibit

  20. Seedling root targets

    Science.gov (United States)

    Diane L. Haase

    2011-01-01

    Roots are critical to seedling performance after outplanting. Although root quality is not as quick and simple to measure as shoot quality, target root characteristics should be included in any seedling quality assessment program. This paper provides a brief review of root characteristics most commonly targeted for operational seedling production. These are: root mass...

  1. Internal targets for LEAR

    International Nuclear Information System (INIS)

    Kilian, K.; Gspann, J.; Mohl, D.; Poth, H.

    1984-01-01

    This chapter considers the use of thin internal targets in conjunction with phase-space cooling at the Low-Energy Antiproton Ring (LEAR). Topics considered include the merits of internal target operation; the most efficient use of antiprotons and of proton synchrotron (PS) protons, highest center-of-mass (c.m.) energy resolution; highest angular resolution and access to extreme angles; the transparent environment for all reaction products; a windowless source and pure targets; highest luminosity and count rates; access to lowest energies with increasing resolution; internal target thickness and vacuum requirements; required cooling performance; and modes of operation. It is demonstrated that an internal target in conjunction with phase-space cooling has the potential of better performance in terms of the economic use of antiprotons and consequently of PS protons; energy resolution; angular resolution; maximum reaction rate capability (statistical precision); efficient parasitic operation; transparency of the target for reaction products; access to low energies; and the ease of polarized target experiments. It is concluded that all p - experiments which need high statistics and high p - flux, such as studies of rare channels or broad, weak resonance structures, would profit from internal targets

  2. Fusion target design

    International Nuclear Information System (INIS)

    Bangerter, R.O.

    1978-01-01

    Most detailed fusion target design is done by numerical simulation using large computers. Although numerical simulation is briefly discussed, this lecture deals primarily with the way in which basic physical arguments, driver technology considerations and economical power production requirements are used to guide and augment the simulations. Physics topics discussed include target energetics, preheat, stability and symmetry. A specific design example is discussed

  3. Distributed video coding with multiple side information

    DEFF Research Database (Denmark)

    Huang, Xin; Brites, C.; Ascenso, J.

    2009-01-01

    Distributed Video Coding (DVC) is a new video coding paradigm which mainly exploits the source statistics at the decoder based on the availability of some decoder side information. The quality of the side information has a major impact on the DVC rate-distortion (RD) performance in the same way...... the quality of the predictions had a major impact in predictive video coding. In this paper, a DVC solution exploiting multiple side information is proposed; the multiple side information is generated by frame interpolation and frame extrapolation targeting to improve the side information of a single...

  4. Electron beam fusion targets

    International Nuclear Information System (INIS)

    Clauser, M.J.; Sweeney, M.A.

    1975-01-01

    R The behavior of the DT filled gold shells when irradiated by a variety of pulse shapes was studied. In these pulses the power (and beam current) was varied, but the voltage was kept constant at 1 MeV. In general the performance of the target, for a given peak power, was not significantly affected by the pulse shape. Pulses with rise times of up to half the implosion time do not significantly degrade the target performance. The use of the ''optimal pulse'' of laser fusion with a fixed peak power does not appear to improve the performance of these targets. The main function of the ''optimal pulse'' is to produce a large rho r of the target during the thermonuclear burn. In e-beam targets a total rho r of 5--10 g/cm 2 can be obtained without pulse shaping; the problem here is one of achieving high enough temperatures to ignite the DT. (U.S.)

  5. Duration judgements over multiple elements

    Directory of Open Access Journals (Sweden)

    Inci eAyhan

    2012-11-01

    Full Text Available We investigated the limits of the number of events observers can simultaneously time. For single targets occurring in one of eight positions sensitivity to duration was improved for spatially pre-cued items as compared to post-cued items indicating that exogenous driven attention can improve duration discrimination. Sensitivity to duration for pre-cued items was also marginally better for single items as compared to eight items indicating that even after the allocation of focal attention, distracter items can interfere with the encoding of duration. For an eight item array discrimination was worse for post-cued locations as compared to pre-cued locations indicating both that attention can improve duration discrimination performance and that it was not possible to access a perfect memory trace of the duration of eight elements. The interference from the distracters in the pre-cued eight item array may reflect some mandatory averaging of target and distracter events. To further explore duration averaging we asked subjects to explicitly compare average durations of multiple item arrays against a single item standard duration. Duration discrimination thresholds were significantly lower for single elements as compared to multiple elements, showing that averaging, either automatically or intentionally, impairs duration discrimination. There was no set size effect. Performance was the same for averages of two and eight items, but performance with even an average of two items was worse than for one item. This was also true for sequential presentation indicating poor performance was not due to limits on the division of attention across items. Rather performance appears to be limited by an inability to remember or aggregate duration information from two or more items. Although it is possible to manipulate perceived duration locally, there appears to be no perceptual mechanisms for aggregating local durations across space.

  6. Safe Dynamic Multiple Inheritance

    DEFF Research Database (Denmark)

    Ernst, Erik

    2002-01-01

    Multiple inheritance and similar mechanisms are usually only supported at compile time in statically typed languages. Nevertheless, dynamic multiple inheritance would be very useful in the development of complex systems, because it allows the creation of many related classes without an explosion...... in the size and level of redundancy in the source code. In fact, dynamic multiple inheritance is already available. The language gbeta is statically typed and has supported run-time combination of classes and methods since 1997, by means of the combination operator '&'. However, with certain combinations...

  7. A multiplicity logic unit

    International Nuclear Information System (INIS)

    Bialkowski, J.; Moszynski, M.; Zagorski, A.

    1981-01-01

    The logic diagram principle of operation and some details of the design of the multiplicity logic unit are presented. This unit was specially designed to fulfil the requirements of a multidetector arrangement for gamma-ray multiplicity measurements. The unit is equipped with 16 inputs controlled by a common coincidence gate. It delivers a linear output pulse with the height proportional to the multiplicity of coincidences and logic pulses corresponding to 0, 1, ... up to >= 5-fold coincidences. These last outputs are used to steer the routing unit working with the multichannel analyser. (orig.)

  8. Fission neutron multiplicity calculations

    International Nuclear Information System (INIS)

    Maerten, H.; Ruben, A.; Seeliger, D.

    1991-01-01

    A model for calculating neutron multiplicities in nuclear fission is presented. It is based on the solution of the energy partition problem as function of mass asymmetry within a phenomenological approach including temperature-dependent microscopic energies. Nuclear structure effects on fragment de-excitation, which influence neutron multiplicities, are discussed. Temperature effects on microscopic energy play an important role in induced fission reactions. Calculated results are presented for various fission reactions induced by neutrons. Data cover the incident energy range 0-20 MeV, i.e. multiple chance fission is considered. (author). 28 refs, 13 figs

  9. [Thalidomide teratogenicity and its direct target identification].

    Science.gov (United States)

    Ito, Takumi; Ando, Hideki; Handa, Hiroshi

    2015-01-01

    Half a century ago, thalidomide was developed as a sedative drug and was wildly used over 40 countries. However the drug has serious birth defects such as amelia and phocomelia. Now thalidomide is regarded as a clinically effective drug and used for the treatment of multiple myeloma under strict controls. The direct target of thalidomide had been a long-standing question. We identified cereblon as a primary direct target protein for thalidomide teratogenicity using new affinity bead technology in 2010. In this review, we introduce an overview of thalidomide teratogenicity, a story about how we identified cereblon, and recent advances in cereblon studies.

  10. Targeting IAP proteins in combination with radiotherapy

    International Nuclear Information System (INIS)

    Fulda, Simone

    2015-01-01

    The efficacy of radiotherapy critically depends on the activation of intrinsic cell death programs in cancer cells. This implies that evasion of cell death, a hallmark of human cancers, can contribute to radioresistance. Therefore, novel strategies to reactivate cell death programs in cancer cells are required in order to overcome resistance to radiotherapy. Since Inhibitor of Apoptosis (IAP) proteins are expressed at high levels in multiple cancers and block cell death induction at a central point, therapeutic targeting of IAP proteins represents a promising approach to potentiate the efficacy of radiotherapy. The current review discusses the concept of targeting IAP proteins in combination with radiotherapy

  11. Multiple sclerosis research

    International Nuclear Information System (INIS)

    Battaglia, M.A.

    1990-01-01

    This volume proceedings contains four contributions which are in INIS scope, dealing with MRI and SPECT in the diagnosis of multiple sclerosis and assessment of disease activity. (H.W.). refs.; figs.; tabs

  12. Generalized internal multiple imaging

    KAUST Repository

    Zuberi, M. A. H.; Alkhalifah, Tariq Ali

    2014-01-01

    Internal multiples deteriorate the image when the imaging procedure assumes only single scattering, especially if the velocity model does not have sharp contrasts to reproduce such scattering in the Green’s function through forward modeling

  13. Connecting the Production Multiple

    DEFF Research Database (Denmark)

    Lichen, Alex Yu; Mouritsen, Jan

    &OP process itself is a fluid object, but there is still possibility to organise the messy Production. There are connections between the Production multiple and the managerial technology fluid. The fluid enacted the multiplicity of Production thus making it more difficult to be organised because there were...... in opposite directions. They are all part of the fluid object. There is no single chain of circulating references that makes the object a matter of fact. Accounting fluidity means that references drift back and forth and enact new realities also connected to the chain. In this setting future research may......This paper is about objects. It follows post ANT trajectories and finds that objects are multiple and fluid. Extant classic ANT inspired accounting research largely sees accounting inscriptions as immutable mobiles. Although multiplicity of objects upon which accounting acts has been explored...

  14. Multiple sex partner

    African Journals Online (AJOL)

    User

    intercourse, about 60% reported having a single sexual partner and 40% reported having multiple ... masturbation, start having sex at a younger age, have sex with married people and/or .... sex were considered unacceptable by 89 vs.

  15. Multiple Stages 2

    DEFF Research Database (Denmark)

    Andreasen, John

    Multiple stages 2: theatrical futures, set design, community plays, cultural capitals, democracy & drama, WWII dramas, performance on adoption, promenade about emigration, qualities in political theatre, performance analysis, dramaturgical education, Toulmin Variations...

  16. Rehabilitation and multiple sclerosis

    DEFF Research Database (Denmark)

    Dalgas, Ulrik

    2011-01-01

    In a chronic and disabling disease like multiple sclerosis, rehabilitation becomes of major importance in the preservation of physical, psychological and social functioning. Approximately 80% of patients have multiple sclerosis for more than 35 years and most will develop disability at some point......, a paradigm shift is taking place and it is now increasingly acknowledged that exercise therapy is both safe and beneficial. Robot-assisted training is also attracting attention in multiple sclerosis rehabilitation. Several sophisticated commercial robots exist, but so far the number of scientific studies...... promising. This drug has been shown to improve walking ability in some patients with multiple sclerosis, associated with a reduction of patients' self-reported ambulatory disability. Rehabilitation strategies involving these different approaches, or combinations of them, may be of great use in improving...

  17. Generalized internal multiple imaging

    KAUST Repository

    Zuberi, M. A. H.

    2014-08-05

    Internal multiples deteriorate the image when the imaging procedure assumes only single scattering, especially if the velocity model does not have sharp contrasts to reproduce such scattering in the Green’s function through forward modeling. If properly imaged, internal multiples (internally scattered energy) can enhance the seismic image. Conventionally, to image internal multiples, accurate, sharp contrasts in the velocity model are required to construct a Green’s function with all the scattered energy. As an alternative, we have developed a generalized internal multiple imaging procedure that images any order internal scattering using the background Green’s function (from the surface to each image point), constructed from a smooth velocity model, usually used for conventional imaging. For the first-order internal multiples, the approach consisted of three steps, in which we first back propagated the recorded surface seismic data using the background Green’s function, then crosscorrelated the back-propagated data with the recorded data, and finally crosscorrelated the result with the original background Green’s function. This procedure images the contribution of the recorded first-order internal multiples, and it is almost free of the single-scattering recorded energy. The cost includes one additional crosscorrelation over the conventional single-scattering imaging application. We generalized this method to image internal multiples of any order separately. The resulting images can be added to the conventional single-scattering image, obtained, e.g., from Kirchhoff or reverse-time migration, to enhance the image. Application to synthetic data with reflectors illuminated by multiple scattering (double scattering) demonstrated the effectiveness of the approach.

  18. Neutron source multiplication method

    International Nuclear Information System (INIS)

    Clayton, E.D.

    1985-01-01

    Extensive use has been made of neutron source multiplication in thousands of measurements of critical masses and configurations and in subcritical neutron-multiplication measurements in situ that provide data for criticality prevention and control in nuclear materials operations. There is continuing interest in developing reliable methods for monitoring the reactivity, or k/sub eff/, of plant operations, but the required measurements are difficult to carry out and interpret on the far subcritical configurations usually encountered. The relationship between neutron multiplication and reactivity is briefly discussed and data presented to illustrate problems associated with the absolute measurement of neutron multiplication and reactivity in subcritical systems. A number of curves of inverse multiplication have been selected from a variety of experiments showing variations observed in multiplication during the course of critical and subcritical experiments where different methods of reactivity addition were used, with different neutron source detector position locations. Concern is raised regarding the meaning and interpretation of k/sub eff/ as might be measured in a far subcritical system because of the modal effects and spectrum differences that exist between the subcritical and critical systems. Because of this, the calculation of k/sub eff/ identical with unity for the critical assembly, although necessary, may not be sufficient to assure safety margins in calculations pertaining to far subcritical systems. Further study is needed on the interpretation and meaning of k/sub eff/ in the far subcritical system

  19. AA antiproton production target

    CERN Multimedia

    CERN PhotoLab

    1979-01-01

    The first version of the antiproton production target was a tungsten rod, 11 cm long and 3 mm in diameter. The rod was embedded in graphite, pressure-seated into an outer casing of stainless steel. At the entrance to the target assembly was a scintillator screen, imprinted with circles every 5 mm in radius, which allowed to precisely aim the 26 GeV high-intensity proton beam from the PS onto the centre of the target rod. The scintillator screen was a 1 mm thick plate of Cr-doped alumina. See also 7903034 and 7905091.

  20. Shiva target irradiation facility

    International Nuclear Information System (INIS)

    Manes, K.R.; Ahlstrom, H.G.; Coleman, L.W.; Storm, E.K.; Glaze, J.A.; Hurley, C.A.; Rienecker, F.; O'Neal, W.C.

    1977-01-01

    The first laser/plasma studies performed with the Shiva laser system will be two sided irradiations extending the data obtained by other LLL lasers to higher powers. The twenty approximately 1 TW laser pulses will reach the target simultaneously from above and below in nested pentagonal clusters. The upper and lower clusters of ten beams each are radially polarized so that they strike the target in p-polarization and maximize absorption. This geometry introduces laser system isolation problems which will be briefly discussed. The layout and types of target diagnostics will be described and a brief status report on the facility given

  1. STANFORD: Internal targets

    Energy Technology Data Exchange (ETDEWEB)

    Riordan, Michael

    1989-05-15

    Of burgeoning interest to many nuclear and particle physicists is a storage ring technique for fixed target experiments. It hinges on the use of gas-jet targets, shooting a narrow stream of atoms through a circulating beam of electrons or protons. Pioneered at CERN and the Soviet Novosibirsk Laboratory, more such 'internal targets' are being built or contemplated for storage rings in Europe, the Soviet Union, and the United States. From 9-12 January, physicists from around the world met at the Stanford Linear Accelerator Center (SLAC) to discuss prospects and problems in this expanding field.

  2. TARGET Research Goals

    Science.gov (United States)

    TARGET researchers use various sequencing and array-based methods to examine the genomes, transcriptomes, and for some diseases epigenomes of select childhood cancers. This “multi-omic” approach generates a comprehensive profile of molecular alterations for each cancer type. Alterations are changes in DNA or RNA, such as rearrangements in chromosome structure or variations in gene expression, respectively. Through computational analyses and assays to validate biological function, TARGET researchers predict which alterations disrupt the function of a gene or pathway and promote cancer growth, progression, and/or survival. Researchers identify candidate therapeutic targets and/or prognostic markers from the cancer-associated alterations.

  3. Multiple marker abundance profiling

    DEFF Research Database (Denmark)

    Hooper, Cornelia M.; Stevens, Tim J.; Saukkonen, Anna

    2017-01-01

    proteins and the scoring accuracy of lower-abundance proteins in Arabidopsis. NPAS was combined with subcellular protein localization data, facilitating quantitative estimations of organelle abundance during routine experimental procedures. A suite of targeted proteomics markers for subcellular compartment...

  4. Designing multiple ligands - medicinal chemistry strategies and challenges.

    Science.gov (United States)

    Morphy, Richard; Rankovic, Zoran

    2009-01-01

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

  5. Extinction with multiple excitors

    OpenAIRE

    McConnell, Bridget L.; Miguez, Gonzalo; Miller, Ralph R.

    2013-01-01

    Four conditioned suppression experiments with rats, using an ABC renewal design, investigated the effects of compounding the target conditioned excitor with additional, nontarget conditioned excitors during extinction. Experiment 1 showed stronger extinction, as evidenced by less renewal, when the target excitor was extinguished in compound with a second excitor, relative to when it was extinguished with associatively neutral stimuli. Critically, this deepened extinction effect was attenuated...

  6. MULTIPLE SPINAL CANAL MENINGIOMAS

    Directory of Open Access Journals (Sweden)

    Nandigama Pratap Kumar

    2016-10-01

    Full Text Available BACKGROUND Meningiomas of the spinal canal are common tumours with the incidence of 25 percent of all spinal cord tumours. But multiple spinal canal meningiomas are rare in compare to solitary lesions and account for 2 to 3.5% of all spinal meningiomas. Most of the reported cases are both intra cranial and spinal. Exclusive involvement of the spinal canal by multiple meningiomas are very rare. We could find only sixteen cases in the literature to the best of our knowledge. Exclusive multiple spinal canal meningiomas occurring in the first two decades of life are seldom reported in the literature. We are presenting a case of multiple spinal canal meningiomas in a young patient of 17 years, who was earlier operated for single lesion. We analysed the literature, with illustration of our case. MATERIALS AND METHODS In September 2016, we performed a literature search for multiple spinal canal meningiomas involving exclusively the spinal canal with no limitation for language and publication date. The search was conducted through http://pubmed.com, a wellknown worldwide internet medical address. To the best of our knowledge, we could find only sixteen cases of multiple meningiomas exclusively confined to the spinal canal. Exclusive multiple spinal canal meningiomas occurring in the first two decades of life are seldom reported in the literature. We are presenting a case of multiple spinal canal meningiomas in a young patient of 17 years, who was earlier operated for solitary intradural extra medullary spinal canal meningioma at D4-D6 level, again presented with spastic quadriparesis of two years duration and MRI whole spine demonstrated multiple intradural extra medullary lesions, which were excised completely and the histopathological diagnosis was transitional meningioma. RESULTS Patient recovered from his weakness and sensory symptoms gradually and bladder and bowel symptoms improved gradually over a period of two to three weeks. CONCLUSION Multiple

  7. Multi-Robot, Multi-Target Particle Swarm Optimization Search in Noisy Wireless Environments

    Energy Technology Data Exchange (ETDEWEB)

    Kurt Derr; Milos Manic

    2009-05-01

    Multiple small robots (swarms) can work together using Particle Swarm Optimization (PSO) to perform tasks that are difficult or impossible for a single robot to accomplish. The problem considered in this paper is exploration of an unknown environment with the goal of finding a target(s) at an unknown location(s) using multiple small mobile robots. This work demonstrates the use of a distributed PSO algorithm with a novel adaptive RSS weighting factor to guide robots for locating target(s) in high risk environments. The approach was developed and analyzed on multiple robot single and multiple target search. The approach was further enhanced by the multi-robot-multi-target search in noisy environments. The experimental results demonstrated how the availability of radio frequency signal can significantly affect robot search time to reach a target.

  8. Structured cylindrical targets

    International Nuclear Information System (INIS)

    Arnold, R.

    1986-01-01

    A variety of experimental concepts using high-energy heavy-ion beams in cylindrical targets have been studied through numerical simulation. With an accelerator planned for GSl, plasma temperatures of 100 eV can be reached by cylindrical compression, using inhomogeneous hollow-shell targets. Magnetic insulation, using external fields, has been explored as an aid in reaching high core temperatures. Experiments on collision-pumped x-ray laser physics are also discussed. (ii) Two-dimensional PlC code simulations of homogeneous solid targets show hydrodynamic effects not found in previous 1-D calculations. (iii) Preliminary ideas for an experiment on non-equilibrium heavy-ion charge-states using an existing accelerator and a pre-formed plasma target are outlined. (author)

  9. Structured cylindrical targets

    International Nuclear Information System (INIS)

    Arnold, R.; Lackner-Russo, D.; Meyer-ter-Vehn, J.; Hoffmann, I.

    1986-01-01

    A variety of experimental concepts using high-energy heavy-ion beams in cylindrical targets have been studied through numerical simulation. With an accelerator planned for GSl, plasma temperatures of 100 eV can be reached by cylindrical compression, using inhomogenous hollow-shell targets. Magnetic insulation, using external fields, has been explored as an aid in reaching high core temperatures. Experiments on collision-pumped x-ray laser physics are also discussed. (ii) Two-dimensional PlC code simulations of homogeneous solid targets show hydrodynamic effects not found in previous l-D calculations. (iii) Preliminary ideas for an experiment on non-equilibrium heavy-ion charge-states using an existing accelerator and a pre-formed plasma target are outlined. (author)

  10. Target Price Accuracy

    Directory of Open Access Journals (Sweden)

    Alexander G. Kerl

    2011-04-01

    Full Text Available This study analyzes the accuracy of forecasted target prices within analysts’ reports. We compute a measure for target price forecast accuracy that evaluates the ability of analysts to exactly forecast the ex-ante (unknown 12-month stock price. Furthermore, we determine factors that explain this accuracy. Target price accuracy is negatively related to analyst-specific optimism and stock-specific risk (measured by volatility and price-to-book ratio. However, target price accuracy is positively related to the level of detail of each report, company size and the reputation of the investment bank. The potential conflicts of interests between an analyst and a covered company do not bias forecast accuracy.

  11. Autonomous Target Ranging Techniques

    DEFF Research Database (Denmark)

    Jørgensen, Peter Siegbjørn; Jørgensen, John Leif; Denver, Troelz

    2003-01-01

    of this telescope, a fast determination of the range to and the motion of the detected targets are important. This is needed in order to prepare the future observation strategy for each target, i.e. when is the closest approach where imaging will be optimal. In order to quickly obtain such a determination two...... ranging strategies are presented. One is an improved laser ranger with an effective range with non-cooperative targets of at least 10,000 km, demonstrated in ground tests. The accuracy of the laser ranging will be approximately 1 m. The laser ranger may furthermore be used for trajectory determination...... of nano-gravity probes, which will perform direct mass measurements of selected targets. The other is triangulation from two spacecraft. For this method it is important to distinguish between detection and tracking range, which will be different for Bering since different instruments are used...

  12. Targeted Cancer Therapies

    Science.gov (United States)

    ... are sometimes referred to as the product of "rational" drug design.) One approach to identify potential targets ... molecules that stimulate new blood vessel growth. Immunotherapies trigger the immune system to destroy cancer cells. Some ...

  13. Targeting radiation to tumours

    International Nuclear Information System (INIS)

    Wheldon, T.E.; Greater Glasgow Health Board, Glasgow

    1994-01-01

    Biologically targeted radiotherapy entails the preferential delivery of radiation to solid tumours or individual tumour cells by means of tumour-seeking delivery vehicles to which radionuclides can be conjugated. Monoclonal antibodies have attracted attention for some years as potentially selective targeting agents, but advances in tumour and molecular biology are now providing a much wider choice of molecular species. General radiobiological principles may be derived which are applicable to most forms of targeted radiotherapy. These principles provide guidelines for the appropriate choice of radionuclide in specific treatment situations and its optimal combination with other treatment modalities. In future, the availability of gene targeting agents will focus attention on the use of Auger electron emitters whose high potency and short range selectivity makes them attractive choices for specific killing of cancer cells whose genetic peculiarities are known. (author)

  14. Targeting TMPRSS2 ERG in Prostate Cancer

    Science.gov (United States)

    2016-09-01

    kinome library, using physiologic cell based assays of ERG activity. We made lentivirus expressing multiple shRNAs targeting each candidate 9...MDV3100 reverses the effect of R1881 (compare columns 2 and 3). Interestingly, PKCi inhibited a subset of androgen induced genes ( column 4...expenditures Nothing to report. Significant changes in use or care of human subjects, vertebrate animals, biohazards, and/or select agents Nothing to

  15. Strategic Targeted Advertising

    OpenAIRE

    Andrea Galeotti; Jose Luis Moraga

    2003-01-01

    textabstractWe present a strategic game of pricing and targeted-advertising. Firms can simultaneously target price advertisements to different groups of customers, or to the entire market. Pure strategy equilibria do not exist and thus market segmentation cannot occur surely. Equilibria exhibit random advertising --to induce an unequal distribution of information in the market-- and random pricing --to obtain profits from badly informed buyers--. We characterize a positive profits equilibrium...

  16. Targets and teamwork

    DEFF Research Database (Denmark)

    Skinner, Timothy C.; Lange, Karin S.; Hoey, Hilary

    2017-01-01

    differences in mean HbA1c between centers ranging from 7.3±0.8% (53mmol/mol±8.7) to 8.9±1.1% (74mmol/mol±12.0). Centers with lower mean HbA1c had (1) parents who reported lower targets for their children, (2) health-care professionals that reported lower targets and more frequent testing, and (3) teams...

  17. Targets and special materials

    International Nuclear Information System (INIS)

    Blanc, R.; Bouriant, M.; Richaud, J.P.

    1997-01-01

    The target preparation group supplied a large number of samples to nuclear physicists for experiments using SARA and also other accelerators throughout the world. Particular preparation and projects include: 208 Pb, 116 Cd, 6 LiF, 123 Sb, In and Ta targets, strippers for SARA and GANIL, optical silicone disks for POLDER and GRAAL experiments, active participations for the AMS project and finally filament preparation for the GENEPI project. (authors)

  18. The ISIS target

    International Nuclear Information System (INIS)

    Carne, A.; Broome, T.A.; Hogston, J.R.; Holding, M.

    1989-01-01

    This presentation discusses the two target failures that have occurred, gives the understanding of the causes and indicates the steps being taken to alleviate the problems. At the outset of the design it was understood that the target would have a finite lifetime, due to radiation damage effects, exacerbated by mechanical damage due to thermal cycling and fatigue. Estimates of target lifetime at full intensity are about 2 years for radiation damage swelling and about 10E4 gross thermal excursions. The latter number is the one which gives uncertainty in defining the life of the target, since it is dependent on the reliability of the accelerator and quality of the proton beam. The commissioning of an accelerator system and bringing it up to high beam intensities have their own special problems. There must be protection of components against uncontrolled beam loss, which produces thermal damage, prompt radiation and induced activity. Fast beam trips for beam loss protection, or equipment failures, result in quenches from high temperature in the target which get bigger with increasing beam intensity. But the target itself is a difficult device to make, taking about 12 months to manufacture. Further, changing one is a complex and time consuming task, not without its hazards. There is thus something of a balancing act to bring the accelerator towards specification before the target fails due to thermal cycling fatigue. In the early days of ISIS beam loss protection was the dominant consideration and the target was regarded somewhat as a sacrificial lamb to the goddess of machine reliability. 2 refs., 6 figs

  19. Detection of Multiple Stationary Humans Using UWB MIMO Radar

    Directory of Open Access Journals (Sweden)

    Fulai Liang

    2016-11-01

    Full Text Available Remarkable progress has been achieved in the detection of single stationary human. However, restricted by the mutual interference of multiple humans (e.g., strong sidelobes of the torsos and the shadow effect, detection and localization of the multiple stationary humans remains a huge challenge. In this paper, ultra-wideband (UWB multiple-input and multiple-output (MIMO radar is exploited to improve the detection performance of multiple stationary humans for its multiple sight angles and high-resolution two-dimensional imaging capacity. A signal model of the vital sign considering both bi-static angles and attitude angle of the human body is firstly developed, and then a novel detection method is proposed to detect and localize multiple stationary humans. In this method, preprocessing is firstly implemented to improve the signal-to-noise ratio (SNR of the vital signs, and then a vital-sign-enhanced imaging algorithm is presented to suppress the environmental clutters and mutual affection of multiple humans. Finally, an automatic detection algorithm including constant false alarm rate (CFAR, morphological filtering and clustering is implemented to improve the detection performance of weak human targets affected by heavy clutters and shadow effect. The simulation and experimental results show that the proposed method can get a high-quality image of multiple humans and we can use it to discriminate and localize multiple adjacent human targets behind brick walls.

  20. Identifying Drug-Target Interactions with Decision Templates.

    Science.gov (United States)

    Yan, Xiao-Ying; Zhang, Shao-Wu

    2018-01-01

    During the development process of new drugs, identification of the drug-target interactions wins primary concerns. However, the chemical or biological experiments bear the limitation in coverage as well as the huge cost of both time and money. Based on drug similarity and target similarity, chemogenomic methods can be able to predict potential drug-target interactions (DTIs) on a large scale and have no luxurious need about target structures or ligand entries. In order to reflect the cases that the drugs having variant structures interact with common targets and the targets having dissimilar sequences interact with same drugs. In addition, though several other similarity metrics have been developed to predict DTIs, the combination of multiple similarity metrics (especially heterogeneous similarities) is too naïve to sufficiently explore the multiple similarities. In this paper, based on Gene Ontology and pathway annotation, we introduce two novel target similarity metrics to address above issues. More importantly, we propose a more effective strategy via decision template to integrate multiple classifiers designed with multiple similarity metrics. In the scenarios that predict existing targets for new drugs and predict approved drugs for new protein targets, the results on the DTI benchmark datasets show that our target similarity metrics are able to enhance the predictive accuracies in two scenarios. And the elaborate fusion strategy of multiple classifiers has better predictive power than the naïve combination of multiple similarity metrics. Compared with other two state-of-the-art approaches on the four popular benchmark datasets of binary drug-target interactions, our method achieves the best results in terms of AUC and AUPR for predicting available targets for new drugs (S2), and predicting approved drugs for new protein targets (S3).These results demonstrate that our method can effectively predict the drug-target interactions. The software package can

  1. An ISOLDE target unit

    CERN Multimedia

    Maximilien Brice

    2002-01-01

    A good dozen different targets are available for ISOLDE, made of different materials and equipped with different kinds of ion-sources, according to the needs of the experiments. Each separator (GPS: general purpose; HRS: high resolution) has its own target. Because of the high radiation levels, robots effect the target changes, about 80 times per year. In the standard unit shown in picture _01, the target is the cylindrical object in the front. It contains uranium-carbide kept at a temperature of 2200 deg C, necessary for the isotopes to be able to escape. At either end, one sees the heater current leads, carrying 700 A. The Booster beam, some 3E13 protons per pulse, enters the target from left. The evaporated isotope atoms enter a hot-plasma ion source (the black object behind the target). The whole unit sits at 60 kV potential (pulsed in synchronism with the arrival of the Booster beam) which accelerates the ions (away from the viewer) towards one of the 2 separators.

  2. Laser targets: introduction

    International Nuclear Information System (INIS)

    Rosen, M.D.

    1985-01-01

    The laser target design group was engaged in three main tasks in 1984: (1) analyzing Novette implosion and hohlraum-scaling data, (2) planning for the first experiments on Nova, and (3) designing laboratory x-ray laser targets and experiments. The Novette implosion and hohlraum scaling data are mostly classified and are therefore not discussed in detail here. The authors achieved average final/initial pusher pr ratios of about 50, some 3 times higher than the value achieved in the best Shiva shots. These pr values imply a fuel compression to 100 times liquid density, although this figure and other aspects of the experiments are subject to further interpretation because of detailed questions of target symmetry and stability. Their main long-term goal for Nova is to produce a so-called hydrodynamically equivalent target (HET) - that is, a target whose hydrodynamic behavior (implosion velocity, convergence ratio, symmetry and stability requirements, etc.) is very much like that of a high-gain target, but one that is scaled down in size to match the energy available from Nova and is too small to achieve enough hot-spot pr to ignite the cold, near-Fermi-degenerate fuel around it. Their goal for Nova's first year is to do experiments that will teach them how to achieve the symmetry and stability conditions required by an HET

  3. Argus target chamber

    International Nuclear Information System (INIS)

    Rienecker, F. Jr.; Glaros, S.S.; Kobierecki, M.

    1975-01-01

    A target chamber for application in the laser fusion program must satisfy some very basic requirements. (1) Provide a vacuum on the order of 10 -6 torr. (2) Support a microscopically small target in a fixed point in space and verify its location within 5 micrometers. (3) Contain an adjustable beam focusing system capable of delivering a number of laser beams onto the target simultaneously, both in time and space. (4) Provide access for diagnostics to evaluate the results of target irradiation. (5) Have flexibility to allow changes in targets, focusing optics and number of beams. The ARGUS laser which is now under construction at LLL will have a target chamber which meets these requirements in a simple economic manner. The chamber and auxiliary equipment are described, with reference to two double beam focusing systems; namely, lenses and ellipsoidal mirrors. Provision is made for future operation with four beams, using ellipsoidal mirrors for two-sided illumination and lens systems for tetragonal and tetrahedral irradiation

  4. Particle multiplicity distributions in silicon-emulsion collisions at 4.5A GeV/c

    International Nuclear Information System (INIS)

    Liu Fuhu; Abd Allah, Nabil N.; Zhang Donghai; Duan Maiying

    2003-01-01

    The experimental results of particle multiplicity distributions in silicon-emulsion collisions at 4.5A GeV/c (the Dubna synchrophasotron momentum) are reported. The correlations between the multiplicities of target fragments are given. The saturation effect of target black fragment multiplicity in the collisions is observed

  5. COMPASS hadron multiplicity measurements and fragmentation functions

    International Nuclear Information System (INIS)

    Stolarski, M.

    2016-01-01

    COMPASS is an experiment located at CERN SPS accelerator. For the results presented in this paper a 160 GeV positive muon beam was impinging on 6 LiD target. The COMPASS spectrometer was designed to reconstruct scattered muons and charged hadrons in a wide kinematic range. COMPASS preliminary results on hadron, pion and kaon multiplicities are presented. The hadron and pion data show a good agreement with (N)LO QCD expectations and some of these preliminary data have been already successfully incorporated in the global NLO QCD fits to world data. However, the results for kaon multiplicities, are different from the expectations of the DSS fit. There is also a tension between COMPASS and HERMES results, the only other experiment which measured kaon multiplicities in Semi-Inclusive Deep Inelastic scattering

  6. Multiple primary cancer

    International Nuclear Information System (INIS)

    Jung, Gyu Sik; Lee, Ouk; Kim, So Sun; Kim, Ho Joon; Chun, Byung Hee; Joh, Young Duck

    1989-01-01

    It is rare for one human being to be afflicted with more than one cancer. However with further advances in therapeutic regimens, histopathologic observation, diagnostic modalities, and increased curiosity, there are increasing number of case reports of multiple primary cancer. The present study evaluates 25 histologically confirmed cases of multiple primary cancer from 1974 to 1988 at Kosin Medical Center. The most frequent site of the first primary cancer in male was stomach and in female, uterine cervix. The first primary cancer in female occurred in endocrine-related organs (breast, uterus and thyroid) in 63.6 percent. Synchronous cancers are diagnosed simultaneously or within an interval of about six months and synchronous cancers were 16 out of 25 cases. Metachronous cancers are diagnosed at interval of more than six months. There were 9 metachronous cancers and average interval between the first and second primary cancer was 22.8 months. The incidence of multiple primary cancer was 0.11 percent. The average age was 51.9 years at the time of the first primary cancer (53.1 years in male and 50.3 years in female). CT scan was most helpful in early detection of multiple primary cancers facilitating biopsy and surgery. Multiple primary cancers are beyond the medical curiosity. Early diagnosis of the disease and careful follow-up study, based on an awareness of the possibility of second cancers, will substantially increase the survival of these patients

  7. Visual performance on detection tasks with double-targets of the same and different difficulty.

    Science.gov (United States)

    Chan, Alan H S; Courtney, Alan J; Ma, C W

    2002-10-20

    This paper reports a study of measurement of horizontal visual sensitivity limits for 16 subjects in single-target and double-targets detection tasks. Two phases of tests were conducted in the double-targets task; targets of the same difficulty were tested in phase one while targets of different difficulty were tested in phase two. The range of sensitivity for the double-targets test was found to be smaller than that for single-target in both the same and different target difficulty cases. The presence of another target was found to affect performance to a marked degree. Interference effect of the difficult target on detection of the easy one was greater than that of the easy one on the detection of the difficult one. Performance decrement was noted when correct percentage detection was plotted against eccentricity of target in both the single-target and double-targets tests. Nevertheless, the non-significant correlation found between the performance for the two tasks demonstrated that it was impossible to predict quantitatively ability for detection of double targets from the data for single targets. This indicated probable problems in generalizing data for single target visual lobes to those for multiple targets. Also lobe area values obtained from measurements using a single-target task cannot be applied in a mathematical model for situations with multiple occurrences of targets.

  8. The Future Multiple

    DEFF Research Database (Denmark)

    Spaniol, Matthew Jon; Rowland, Nicholas James

    2015-01-01

    /value – The original contribution is in demonstrating how plural futures and the singular future co-exist in practice. Thus, an eclipse of the future by futures can only ever be partial. For “futures” to be conceptually potent, “the future” must be at least provisionally believable and occasionally useful. Otherwise......, if “the future” were so preposterous an idea, then “futures” would cease to be a critical alternative to it. Futures needs the future; they are relationally bound together in a multiplicity. This paper considers what such a logical reality implies for a field that distances itself from the future and self......). Multiplicity, as a post-ANT sensibility, helps one make sense of the empirical materials. This paper examines the possibility that rather than being alternatives to one another, plural futures and the singular future might co-exist in practice, and, thus, constitute a multiplicity. Design...

  9. Target-present guessing as a function of target prevalence and accumulated information in visual search.

    Science.gov (United States)

    Peltier, Chad; Becker, Mark W

    2017-05-01

    Target prevalence influences visual search behavior. At low target prevalence, miss rates are high and false alarms are low, while the opposite is true at high prevalence. Several models of search aim to describe search behavior, one of which has been specifically intended to model search at varying prevalence levels. The multiple decision model (Wolfe & Van Wert, Current Biology, 20(2), 121--124, 2010) posits that all searches that end before the observer detects a target result in a target-absent response. However, researchers have found very high false alarms in high-prevalence searches, suggesting that prevalence rates may be used as a source of information to make "educated guesses" after search termination. Here, we further examine the ability for prevalence level and knowledge gained during visual search to influence guessing rates. We manipulate target prevalence and the amount of information that an observer accumulates about a search display prior to making a response to test if these sources of evidence are used to inform target present guess rates. We find that observers use both information about target prevalence rates and information about the proportion of the array inspected prior to making a response allowing them to make an informed and statistically driven guess about the target's presence.

  10. Targeting the Thioredoxin System for Cancer Therapy.

    Science.gov (United States)

    Zhang, Junmin; Li, Xinming; Han, Xiao; Liu, Ruijuan; Fang, Jianguo

    2017-09-01

    Thioredoxin (Trx) and thioredoxin reductase (TrxR) are essential components of the Trx system which plays pivotal roles in regulating multiple cellular redox signaling pathways. In recent years TrxR/Trx have been increasingly recognized as an important modulator of tumor development, and hence targeting TrxR/Trx is a promising strategy for cancer treatment. In this review we first discuss the structural details of TrxR, the functions of the Trx system, and the rational of targeting TrxR/Trx for cancer treatment. We also highlight small-molecule TrxR/Trx inhibitors that have potential anticancer activity and review their mechanisms of action. Finally, we examine the challenges of developing TrxR/Trx inhibitors as anticancer agents and perspectives for selectively targeting TrxR/Trx. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. Multiplicities and parton dynamics

    International Nuclear Information System (INIS)

    Knuteson, R.O.

    1987-01-01

    The production of strongly interacting particles from the annihilation of electrons and positrons at high energies is studied, with emphasis on the multiplicity, or number, of particles produced. A probabilistic branching model based on the leading log approximation in QCD is formulated to predict the evolution of particle number with the energy of collision. Direct integration of a master equation for the probabilities allows a comparison to the experimentally observed particle distribution. The production of strongly interacting particles from proton-antiproton collisions is also considered. A model for the production of particles from parton-parton collisions is presented and the growth in multiplicity with energy demonstrated

  12. Sentencing Multiple Crimes

    DEFF Research Database (Denmark)

    Most people assume that criminal offenders have only been convicted of a single crime. However, in reality almost half of offenders stand to be sentenced for more than one crime.The high proportion of multiple crime offenders poses a number of practical and theoretical challenges for the criminal......, and psychology offer their perspectives to the volume. A comprehensive examination of the dynamics involved with sentencing multiple offenders has the potential to be a powerful tool for legal scholars and professionals, particularly given the practical importance of the topic and the relative dearth of research...

  13. High-multiplicity processes

    International Nuclear Information System (INIS)

    Shelkov, G.; Sisakyan, A.; Mandzhavidze, I.

    1999-01-01

    We wish to demonstrate that investigation of asymptotically high multiplicity (AHM) hadron reactions may solve, or at least clear up, a number of problems unsolvable by other ways. We would lean upon the idea: (i) the reactions final state entropy is proportional to multiplicity and, by this reason, just in the AHM domain one may expect the equilibrium final state and (ii) the AHM final state is cold because of the energy-momentum conservation laws. This means that the collective phenomena may become important in the AHM domain. The possibility of hard processes dominance is considered also

  14. LANSCE target system performance

    International Nuclear Information System (INIS)

    Russell, G.J.; Gilmore, J.S.; Robinson, H.; Legate, G.L.; Bridge, A.; Sanchez, R.J.; Brewton, R.J.; Woods, R.; Hughes, H.G. III

    1989-01-01

    We measured neutron beam fluxes at LANSCE using gold foil activation techniques. We did an extensive computer simulation of the as-built LANSCE Target/Moderator/Reflector/Shield geometry. We used this mockup in a Monte Carlo calculation to predict LANSCE neutronic performance for comparison with measured results. For neutron beam fluxes at 1 eV, the ratio of measured data to calculated varies from ∼0.6-0.9. The computed 1 eV neutron leakage at the moderator surface is 3.9 x 10 10 n/eV-sr-s-μA for LANSCE high-intensity water moderators. The corresponding values for the LANSCE high-resolution water moderator and the liquid hydrogen moderator are 3.3 and 2.9 x 10 10 , respectively. LANSCE predicted moderator intensities (per proton) for a tungsten target are essentially the same as ISIS predicted moderator intensities for a depleted uranium target. The calculated LANSCE steady state unperturbed thermal (E 13 n/cm 2 -s. The unique LANSCE split-target/flux-trap-moderator system is performing exceedingly well. The system has operated without a target or moderator change for over three years at nominal proton currents of ∼25 μA of 800-MeV protons. (author)

  15. GMTI Direction of Arrival Measurements from Multiple Phase Centers.

    Energy Technology Data Exchange (ETDEWEB)

    Doerry, Armin W. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Bickel, Douglas L. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)

    2015-03-01

    Ground Moving Target Indicator (GMTI) radar attempts to detect and locate targets with unknown motion. Very slow-moving targets are difficult to locate in the presence of surrounding clutter. This necessitates multiple antenna phase centers (or equivalent) to offer independent Direction of Arrival (DOA) measurements. DOA accuracy and precision generally remains dependent on target Signal-to-Noise Ratio (SNR), Clutter-toNoise Ratio (CNR), scene topography, interfering signals, and a number of antenna parameters. This is true even for adaptive techniques like Space-Time-AdaptiveProcessing (STAP) algorithms.

  16. THE RELIABILITY OF IDENTIFICATION EVIDENCE WITH MULTIPLE LINEUPS

    Directory of Open Access Journals (Sweden)

    Nick J. Broers

    2013-01-01

    Full Text Available This study aimed to establish the diagnostic value of multiple lineup decisions made for portrait, body, and profile lineups, including multiple target/suspect choices, rejections, foil choices, and don’t know answers. A total of 192 participants identified a thief and a victim of theft from independent simultaneous target-present or target-absent 6-person portrait, body and profile lineups after watching one of two stimulus films. As hypothesized, multiple target/suspect choices had incriminating value whereas multiple rejections, foil choices, and don’t know answers had mostly exonerating value. For suspect choices, the combination of all three lineup modes consistently elicited high diagnosticities across targets. Combinations of non-suspect choices (rejections, foil choices, or don’t know answers were less successful and the different combinations showed less consistency in terms of diagnosticity. It was concluded that the use of multiple lineups, such as different facial poses and different aspects of a person should be particularly beneficial in three situations: if a witness only saw the perpetrator from a pose different than the frontal view normally used for lineups; if one or more witnesses saw the perpetrator from more than one perspective; and if different witnesses saw the perpetrator from different perspectives.

  17. Modelling Recycling Targets

    DEFF Research Database (Denmark)

    Hill, Amanda Louise; Leinikka Dall, Ole; Andersen, Frits M.

    2014-01-01

    Within the European Union (EU) a paradigm shift is currently occurring in the waste sector, where EU waste directives and national waste strategies are placing emphasis on resource efficiency and recycling targets. The most recent Danish resource strategy calculates a national recycling rate of 22......% for household waste, and sets an ambitious goal of a 50% recycling rate by 2020. This study integrates the recycling target into the FRIDA model to project how much waste and from which streams should be diverted from incineration to recycling in order to achieve the target. Furthermore, it discusses how...... the existing technological, organizational and legislative frameworks may affect recycling activities. The results of the analysis show that with current best practice recycling rates, the 50% recycling rate cannot be reached without recycling of household biowaste. It also shows that all Danish municipalities...

  18. Targeted Phototherapy (newer phototherapy

    Directory of Open Access Journals (Sweden)

    Zonunsanga

    2015-04-01

    Full Text Available Conventional phototherapy uses a whole body cabinet or body part machine such as hand, foot or scalp machines. They have many disadvantages due to which new phototherapy technique was then developed to overcome this situation. This new technique is called targeted phototherapy which includes excimer laser, intense pulse light system (IPL, photodynamic therapy and ultraviolet (UV light source with a sophisticated delivery system which is easy to be operated by hands. The mechanisms of action of targeted phototherapy systems are similar to those in conventional UVB/UVA therapy. They have many advantages like less chances of side effects, avoidance of exposure of unnecessary sites, faster response, shortening of the duration of treatments. But they have disadvantages like high costs and inability to use for extensive areas. This review article discusses targeted phototherapy in considerable to the mechanism of actions and advantages and disadvantages in comparison to the conventional phototherapy.

  19. Setting reference targets

    International Nuclear Information System (INIS)

    Ruland, R.E.

    1997-04-01

    Reference Targets are used to represent virtual quantities like the magnetic axis of a magnet or the definition of a coordinate system. To explain the function of reference targets in the sequence of the alignment process, this paper will first briefly discuss the geometry of the trajectory design space and of the surveying space, then continue with an overview of a typical alignment process. This is followed by a discussion on magnet fiducialization. While the magnetic measurement methods to determine the magnetic centerline are only listed (they will be discussed in detail in a subsequent talk), emphasis is given to the optical/mechanical methods and to the task of transferring the centerline position to reference targets

  20. [Delivery in multiple pregnancies].

    Science.gov (United States)

    Colla, F; D'Addato, F; Grio, R

    2001-04-01

    A knowledge of clinical physiognomy in pathologies related to multiple births is indispensable for improving maternal and feto-neonatal prognosis. This study is a contribution to the solution of this problem. A meta-analysis of data for multiple births at Department B of the Gynecology and Obstetrics Clinic at the University of Turi during the decade 1989-1998 was carried out, focusing on the arrangement and presentation of fetuses, the various types of birth, the gestational age at which birth occurred, the weight of neonates, neonatal mortality and maternal morbidity. Out of 11,523 births, there were a total of 194 (1.68%) multiple births, including 190 sets of twins and 4 triplets. 154 (79.38%) premature births were reported; 20 occurred 1500 g). The perinatal mortality rate was 3.82%. Maternal complications mainly occurred during the placental state, in the immediate postpartum and in puerperio. The authors feel that a more careful medical and social assistance, preventive hospitalisation, early recognition of the risk, constant monitoring for the optimal timing of birth, and lastly, qualified medical assistance during labour (expert gynecologist, trained obstetric staff) with other medical personnel (anesthetist, neonatal specialist) represent winning strategies to solve the problems arising during multiple pregnancies.