WorldWideScience

Sample records for cobalt targets multiple

  1. Cobalt.

    Science.gov (United States)

    Fowler, Joseph F

    2016-01-01

    Cobalt has been a recognized allergen capable of causing contact dermatitis for decades. Why, therefore, has it been named 2016 "Allergen of the Year"? Simply put, new information has come to light in the last few years regarding potential sources of exposure to this metallic substance. In addition to reviewing some background on our previous understanding of cobalt exposures, this article will highlight the recently recognized need to consider leather as a major site of cobalt and the visual cues suggesting the presence of cobalt in jewelry. In addition, a chemical spot test for cobalt now allows us to better identify its presence in suspect materials.

  2. Multiple superficial basal cell carcinomas (basalomatosis) following cobalt irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Wollenberg, A.; Przybilla, B. [Muenchen Univ. (Germany). Dermatologische Klinik und Poliklinik; Peter, R.U. [Federal Armed Forces Medical Academy, Munich (Germany). Inst. of Radiobiology

    1995-10-01

    Basalomatosis is an uncommon skin condition characterized by the occurrence of multiple basal cell carcinomas. Many cases reported in the literature have been attributed to arsenic treatment in psoriasis patients. We report a patient with basalomatosis caused by cobalt-60 ({sup 60}Co) irradiation. A 55-year-old farmer developed 43 basal cell carcinomas 20 years after treatment of an immuno-blastoma with {sup 60}Co irradiation. All the tumours were located within the radiation fields. Other possible causes of basalomatosis, such as arsenic intoxication and basal cell naevus syndrome, were excluded. The patient`s multiple superficial basal cell carcinomas probably represent a late adverse effect of the {sup 60}Co irradiation. (Author).

  3. Advantageous use of metallic cobalt in the target for pulsed laser deposition of cobalt-doped ZnO films

    Science.gov (United States)

    Ying, Minju; Blythe, Harry J.; Dizayee, Wala; Heald, Steve M.; Gerriu, Fatma M.; Fox, A. Mark; Gehring, Gillian A.

    2016-08-01

    We investigate the magnetic properties of ZnCoO thin films grown by pulsed laser deposition (PLD) from targets made containing metallic Co or CoO precursors instead of the usual Co3O4. We find that the films grown from metallic Co precursors in an oxygen rich environment contain negligible amounts of Co metal and have a large magnetization at room temperature. Structural analysis by X-ray diffraction and magneto-optical measurements indicate that the enhanced magnetism is due, in part, from Zn vacancies that partially compensate the naturally occurring n-type defects. We conclude that strongly magnetic films of Zn0.95Co0.05O that do not contain metallic cobalt can be grown by PLD from Co-metal-precursor targets if the films are grown in an oxygen atmosphere.

  4. Targeting autophagy in multiple myeloma.

    Science.gov (United States)

    Yun, Zhuang; Zhichao, Jin; Hao, Yao; Ou, Ji; Ran, Yang; Wen, Dong; Qun, Shen

    2017-08-01

    Autophagy plays an important role in plasma cell ontogeny and in the pathophysiology of multiple myeloma. Autophagy is usually considered a pro-survival mechanism, and cooperates with the ubiquitin proteasome system in maintaining the homeostasis of myeloma cells by degrading excessive and misfolded proteins for energy recycling. Therefore, the inhibition of autophagy could effectively induce death in myeloma cells, and could synergize with proteasome inhibitors. However, the excessive activation of autophagy could also lead to the extreme degradation of the organelles that induce autophagic cell death. Hence, the activation of autophagic cell death might also represent a promising approach for treating myeloma. Recent studies have demonstrated that autophagy also mediates drug resistance in myeloma cells and the complications of myeloma, while the inhibition of autophagy may reverse the response to drugs. In this study, we have mainly reviewed recent research on autophagy in relationship to the therapeutic effect, the reversal of drug resistance, and the mediation of complications. Copyright © 2017. Published by Elsevier Ltd.

  5. Attentional processing of multiple targets and distractors.

    Science.gov (United States)

    Munneke, Jaap; Fait, Elisa; Mazza, Veronica

    2013-11-01

    We assessed the functioning of attention when multiple relevant objects are intermingled with multiple distractors, measuring two electrophysiological subcomponents of the N2pc that have been associated, respectively, with target selection and distractor suppression: the target negativity (Nt) and the distractor positivity (Pd). To this aim, we orthogonally manipulated the number of targets and distractors in an enumeration task. The Nt was modulated by target, but not distractor numerosity, suggesting that an increase in target numerosity leads to an increase in attentional resources needed to form individual representations of the targets. In contrast, the number of distractors did not differentially alter the Pd. We hypothesize that distractors sharing similar visual features can be processed (and possibly suppressed) as a set, without the need for individuation.

  6. Description of Mechanism Function about Dehydration of Cobalt Oxalate Dihydrate by Multiple Rates Isotemperature Method

    Institute of Scientific and Technical Information of China (English)

    Li Li-qing; Chen Dong-hua

    2004-01-01

    A new method of the multiple rates isotemperature is proposed to define the most probable mechanism g(α) of thermal analysis; the iterative isoconversional procedure has been employed to estimate apparent activation energy E; the pre-exponential factor A is obtained on the basis of E and g(α). By this new method, the thermal analysis kinetics triplet of dehydration of cobalt oxalate dihydrate is determined, apparent activation energy E is 99.84 kJ\\5mol-1; pre-exponential factor A is 3.427×109-3.872×109 s-1 and the most probable mechanism belongs to nucleation and growth, Am model, the range of m is from 1.50 to 1.70.

  7. Comparative analysis of multiple target tracking methods

    Directory of Open Access Journals (Sweden)

    Michael Kamaraj Devadoss

    2016-07-01

    Full Text Available Many applications such as intelligent transportation, video surveillance, robotics of computer vision mainly depend on task of multiple object tracking. It includes the process of detection, classifications and tracking. The main focus of the study is to develop an efficient and effective multiple target tracking methods to solve the issues of illumination changes, occlusions and affinity matching. Accordingly, the various multiple target tracking methods are tested and evaluated using the metrics on publicly available datasets from which it is obvious that the outcome of the global energy minimization and optimization techniques is comparatively better than any other existing techniques in all aspects. This comparative study work will also help in better understanding of the problem, knowledge of the methods and experimental evaluation skill for further research works.

  8. 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.

  9. Immunotherapies targeting CD38 in Multiple Myeloma

    Science.gov (United States)

    Atanackovic, Djordje; Steinbach, Mary; Radhakrishnan, Sabarinath Venniyil; Luetkens, Tim

    2016-01-01

    ABSTRACT Recently, the monoclonal antibody daratumumab was approved as a single agent for the treatment of patients with relapsed/refractory Multiple Myeloma (MM). Daratumumab is an antibody targeting surface molecule CD38 on myeloma cells and the agent is already widely being used based on its good tolerability and proven efficacy. We believe, however, that the efficacy of this drug and other anti-CD38 monoclonal antibodies can be further improved by combining it with other types of immunotherapies. Furthermore, surface molecule CD38 can be used as a target for immunotherapies other than just naked monoclonal antibodies. In this report, we review the expression pattern of CD38 among normal tissues and in different types of plasma cell dyscrasias including their progenitor cells, minimal residual disease, and circulating tumor cells. We summarize the physiological role of CD38 as well as its role in the pathophysiology of MM and we present the most recent clinical trials using CD38 as a target. In addition, we highlight possible combination immunotherapies incorporating anti-CD38 monoclonal antibodies and we demonstrate alternative immunotherapeutic approaches targeting the same antigen such as CD38-specific chimeric antigen receptor (CAR) T cells. PMID:27999737

  10. Targeting Toll-like receptor 4 prevents cobalt-mediated inflammation.

    Science.gov (United States)

    Lawrence, Helen; Mawdesley, Amy Elizabeth; Holland, James Patrick; Kirby, John Andrew; Deehan, David John; Tyson-Capper, Alison Jane

    2016-02-16

    Cobalt-chrome alloy is a widely used biomaterial in joint replacements, dental implants and spinal rods. Although it is an effective and biocompatible material, adverse reactions to metal debris (ARMD) have arisen in a minority of patients, particularly in those with metal-on-metal bearing hip replacements. There is currently no treatment for ARMD and once progressive, early revision surgery of the implant is necessary. Therapeutic agents to prevent, halt or reverse ARMD would therefore be advantageous. Cobalt ions activate Toll-like receptor 4 (TLR4), an innate immune receptor responsible for inflammatory responses to bacterial lipopolysaccharide (LPS) resulting in the production of pro-inflammatory cytokines and chemokines. We hypothesised that anti-TLR4 neutralising antibodies, reported to inhibit TLR4-mediated inflammation, could prevent the inflammatory response to cobalt ions in an in vitro macrophage cell culture model. This study shows that a monoclonal anti-TLR4 antibody inhibited cobalt-mediated increases in pro-inflammatory IL8, CCL20 and IL1A expression, as well as IL-8 secretion. In contrast, a polyclonal antibody did not prevent the effect of cobalt ions on either IL-8 or IL1A expression, although it did have a small effect on the CCL20 response. Interestingly, both antibodies inhibited cobalt-mediated neutrophil migration although the greater effect was observed with the monoclonal antibody. In summary our data shows that a monoclonal anti-TLR4 antibody can inhibit cobalt-mediated inflammatory responses while a polyclonal antibody only inhibits the effect of specific cytokines. Anti-TLR4 antibodies have therapeutic potential in ARMD although careful antibody design is required to ensure that the LPS response is preserved.

  11. Active debris removal of multiple priority targets

    Science.gov (United States)

    Braun, Vitali; Lüpken, A.; Flegel, S.; Gelhaus, J.; Möckel, M.; Kebschull, C.; Wiedemann, C.; Vörsmann, P.

    2013-05-01

    Today's space debris environment shows major concentrations of objects within distinct orbital regions for nearly all size regimes. The most critical region is found at orbital altitudes near 800 km with high declinations. Within this region many satellites are operated in so called sun-synchronous orbits (SSO). Among those, there are Earth observation, communication and weather satellites. Due to the orbital geometry in SSO, head-on encounters with relative velocities of about 15 km/s are most probable and would thus result in highly energetic collisions, which are often referred to as catastrophic collisions, leading to the complete fragmentation of the participating objects. So called feedback collisions can then be triggered by the newly generated fragments, thus leading to a further population increase in the affected orbital region. This effect is known as the Kessler syndrome.Current studies show that catastrophic collisions are not a major problem today, but will become the main process for debris generation within the SSO region in the near future, even without any further launches. In order to avoid this effect, objects with a major impact on collisional cascading have to be actively removed from the critical region after their end of life. Not having the capability to perform an end-of-life maneuver in order to transfer to a graveyard orbit or to de-orbit, many satellites and rocket bodies would have to be de-orbited within a dedicated mission. In such a mission, a service satellite would perform a de-orbit maneuver, after having docked to a specific target.In this paper, chemical and electric propulsion systems were analysed with the main focus on removing multiple targets within one single mission. The targets were chosen from a previously defined priority list in order to enhance the mission efficiency. Total mission time, ΔV and system mass were identified as key parameters to allow for an evaluation of the different concepts. It was shown that it

  12. 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.

  13. Separation of no-carrier-added {sup 66,67}Ga produced in heavy ion-induced cobalt target using alginate biopolymers

    Energy Technology Data Exchange (ETDEWEB)

    Nayak, Dalia [Chemical Sciences Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata-700064 (India); Banerjee, Anupam [University of Calcutta, 35 Ballygunge Circular Road, Kolkata-700019 (India); Lahiri, Susanta [Chemical Sciences Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata-700064 (India)]. E-mail: susanta.lahiri@saha.ac.in

    2007-08-15

    Heavy ion activation of natural cobalt foil with 84 MeV {sup 12}C results in the formation of no-carrier-added (nca) {sup 66,67}As radionuclides, along with their corresponding decay products, {sup 66,67}Ge and {sup 66,67}Ga, in the matrix. Because arsenic and germanium radionuclides are short-lived, after a cooling period of 10 h only nca gallium radionuclides remain in the matrix. We attempted to separate the nca gallium radionuclides from the target matrix cobalt by biopolymeric calcium alginate (CA) and Fe-doped calcium alginate (Fe-CA) beads. A complete separation has been achieved by adsorbing {sup 66,67}Ga and a lesser amount of bulk cobalt at pH 3 on Fe-CA beads, followed by desorbing cobalt from the beads with 0.4 M NaNO{sub 2}.

  14. Frnakenstein: multiple target inverse RNA folding

    Directory of Open Access Journals (Sweden)

    Lyngsø Rune B

    2012-10-01

    Full Text Available Abstract Background RNA secondary structure prediction, or folding, is a classic problem in bioinformatics: given a sequence of nucleotides, the aim is to predict the base pairs formed in its three dimensional conformation. The inverse problem of designing a sequence folding into a particular target structure has only more recently received notable interest. With a growing appreciation and understanding of the functional and structural properties of RNA motifs, and a growing interest in utilising biomolecules in nano-scale designs, the interest in the inverse RNA folding problem is bound to increase. However, whereas the RNA folding problem from an algorithmic viewpoint has an elegant and efficient solution, the inverse RNA folding problem appears to be hard. Results In this paper we present a genetic algorithm approach to solve the inverse folding problem. The main aims of the development was to address the hitherto mostly ignored extension of solving the inverse folding problem, the multi-target inverse folding problem, while simultaneously designing a method with superior performance when measured on the quality of designed sequences. The genetic algorithm has been implemented as a Python program called Frnakenstein. It was benchmarked against four existing methods and several data sets totalling 769 real and predicted single structure targets, and on 292 two structure targets. It performed as well as or better at finding sequences which folded in silico into the target structure than all existing methods, without the heavy bias towards CG base pairs that was observed for all other top performing methods. On the two structure targets it also performed well, generating a perfect design for about 80% of the targets. Conclusions Our method illustrates that successful designs for the inverse RNA folding problem does not necessarily have to rely on heavy biases in base pair and unpaired base distributions. The design problem seems to become more

  15. Production of {sup 61}Cu using natural cobalt target and its separation using ascorbic acid and common anion exchange resin

    Energy Technology Data Exchange (ETDEWEB)

    Das, Sujata Saha; Chattopadhyay, Sankha; Barua, Luna [Radiopharmaceuticals Laboratory, Board of Radiation and Isotope Technology (BRIT), Variable Energy Cyclotron Centre (VECC), Kolkata 700064 (India); Das, Malay Kanti, E-mail: mkdas@vecc.gov.in [Radiopharmaceuticals Laboratory, Board of Radiation and Isotope Technology (BRIT), Variable Energy Cyclotron Centre (VECC), Kolkata 700064 (India)

    2012-02-15

    {sup 61}Cu was produced by {sup nat}Co({alpha}, xn){sup 61}Cu reaction. {sup 61}Cu production yield was 89.5 MBq/{mu}Ah (2.42 mCi/{mu}Ah) at the end of irradiation (EOI). A simple radiochemical separation method using anion exchange resin and ascorbic acid has been employed to separate the product radionuclide from inactive target material and co-produced non-isotopic impurities. The radiochemical separation yield was about 90%. Radiochemical purity of {sup 61}Cu was >99% 1 h after EOI. Final product was suitable for making complex with N{sub 2}S{sub 2} type of ligands. - Highlights: Black-Right-Pointing-Pointer High purity, no-carrier added {sup 61}Cu produced from natural cobalt target. Black-Right-Pointing-Pointer {sup 61}Cu separated from impurities using anion exchange resin and ascorbic acid. Black-Right-Pointing-Pointer {sup 61}Cu preparation was successfully used to label N{sub 2}S{sub 2}-type of ligand.

  16. 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.

  17. Sequential stratified sampling belief propagation for multiple targets tracking

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Rather than the difficulties of highly non-linear and non-Gaussian observation process and the state distribution in single target tracking, the presence of a large, varying number of targets and their interactions place more challenge on visual tracking. To overcome these difficulties, we formulate multiple targets tracking problem in a dynamic Markov network which consists of three coupled Markov random fields that model the following: a field for joint state of multi-target, one binary process for existence of individual target, and another binary process for occlusion of dual adjacent targets. By introducing two robust functions, we eliminate the two binary processes, and then apply a novel version of belief propagation called sequential stratified sampling belief propagation algorithm to obtain the maximum a posteriori (MAP) estimation in the dynamic Markov network. By using stratified sampler, we incorporate bottom-up information provided by a learned detector (e.g. SVM classifier) and belief information for the messages updating. Other low-level visual cues (e.g. color and shape) can be easily incorporated in our multi-target tracking model to obtain better tracking results. Experimental results suggest that our method is comparable to the state-of-the-art multiple targets tracking methods in several test cases.

  18. Surface modification of Cobalt ferrite nano-hollowspheres for inherent multiple photoluminescence and enhanced photocatalytic activities

    Science.gov (United States)

    Talukdar, Souvanik; Mandal, Dipika; Mandal, Kalyan

    2017-03-01

    Nano-hollow spheres (NHSs) are the new drift in magnetic nanostructures as they provide more surface area at nano length scale with enhanced magnetic properties compared to their nanoparticle counterpart. Here we reported the synthesis of biocompatible CoFe2O4 NHSs of diameter around 250 nm and emergence of intrinsic multiple photoluminescence from blue, green to red on modifying their surface with small organic ligands like tartrate. The surface modified NHSs also showed notable photocatalytic activity towards the degradation of environmentally malefic dyes like Methylene Blue and Rhodamine B. The surface modified NHSs are found to exhibit superior magnetic properties.

  19. 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

  20. Bayesian tracking of multiple point targets using expectation maximization

    DEFF Research Database (Denmark)

    Selvan, Raghavendra

    The range of applications where target tracking is useful has grown well beyond the classical military and radar-based tracking applications. With the increasing enthusiasm in autonomous solutions for vehicular and robotics navigation, much of the maneuverability can be provided based on solutions...... the measurements from sensors to choose the best data association hypothesis, from which the estimates of target trajectories can be obtained. In an ideal world, we could maintain all possible data association hypotheses from observing all measurements, and pick the best hypothesis. But, it turns out the number...... joint density is maximized over the data association variables, or over the target state variables, two EM-based algorithms for tracking multiple point targets are derived, implemented and evaluated. In the first algorithm, the data association variable is integrated out, and the target states...

  1. Targeting CD38 with daratumumab monotherapy in multiple myeloma

    NARCIS (Netherlands)

    Lokhorst, H. M.; Plesner, T.; Laubach, J. P.; Nahi, H.; Gimsing, P.; Hansson, M.; Minnema, M. C.; Lassen, U.; Krejcik, J.; Palumbo, A.; Van De Donk, N. W C J; Ahmadi, T.; Khan, I.; Uhlar, C. M.; Wang, J.; Sasser, A. K.; Losic, N.; Lisby, S.; Basse, L.; Brun, N.; Richardson, P. G.

    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, t

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

    Science.gov (United States)

    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.

    2015-09-01

    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 239Pu α source and RI beams. A Z resolution (FWHM) of 0.4-0.6 was achieved for nuclear fragments of 18O at 400 AMeV.

  3. Hybrid foraging search: Searching for multiple instances of multiple types of target.

    Science.gov (United States)

    Wolfe, Jeremy M; Aizenman, Avigael M; Boettcher, Sage E P; Cain, Matthew S

    2016-02-01

    This paper introduces the "hybrid foraging" paradigm. In typical visual search tasks, observers search for one instance of one target among distractors. In hybrid search, observers search through visual displays for one instance of any of several types of target held in memory. In foraging search, observers collect multiple instances of a single target type from visual displays. Combining these paradigms, in hybrid foraging tasks observers search visual displays for multiple instances of any of several types of target (as might be the case in searching the kitchen for dinner ingredients or an X-ray for different pathologies). In the present experiment, observers held 8-64 target objects in memory. They viewed displays of 60-105 randomly moving photographs of objects and used the computer mouse to collect multiple targets before choosing to move to the next display. Rather than selecting at random among available targets, observers tended to collect items in runs of one target type. Reaction time (RT) data indicate searching again for the same item is more efficient than searching for any other targets, held in memory. Observers were trying to maximize collection rate. As a result, and consistent with optimal foraging theory, they tended to leave 25-33% of targets uncollected when moving to the next screen/patch. The pattern of RTs shows that while observers were collecting a target item, they had already begun searching memory and the visual display for additional targets, making the hybrid foraging task a useful way to investigate the interaction of visual and memory search.

  4. Overexpression of the neuroglobin gene delivered by ultrasound-targeted microbubble destruction protects SH-SY5Y cells against cobalt chloride induced hypoxia

    Institute of Scientific and Technical Information of China (English)

    Qian Yang; Dianwen Gao; Qingzhu Nie; Zhengang Cai; Jian Du; Lujuan Shan; Yuejian Liu

    2011-01-01

    In this study, we examined the effects of neuroglobin gene (Ngb) transfection into SH-SY5Y cells, using ultrasound-targeted microbubble destruction (UTMD), on cobalt chloride-induced hypoxia. With an ultrasound intensity of 0.8 W/cm2, a 60-second exposure duration, 50% duty cycle, and 20% microbubble concentration, pAcGFP1-C1-Ngb-transfected cells exhibited the highest cell viability and transfection efficiency. The efficiency of plasmid delivery was significantly higher with UTMD than transfection with plasmid alone, transfection with plasmid using microbubbles, or transfection of plasmid by ultrasound. In addition, during cobalt chloride-induced hypoxia, caspase-3 activity in pAcGFP1-C1-Ngb-transfected cells was significantly lower than in untransfected cells. Ngb protein and mRNA expression were significantly higher in cells transfected by UTMD than in cells transfected with the other methods. These results demonstrate that UTMD can very efficiently mediate exogenous gene delivery, and that Ngb overexpression protects cells against cobalt chloride-induced hypoxia.

  5. Multiple extended target tracking algorithm based on Gaussian surface matrix

    Institute of Scientific and Technical Information of China (English)

    Jinlong Yang; Peng Li; Zhihua Li; Le Yang

    2016-01-01

    In this paper, we consider the problem of irregular shapes tracking for multiple extended targets by introducing the Gaussian surface matrix (GSM) into the framework of the random finite set (RFS) theory. The Gaussian surface function is constructed first by the measurements, and it is used to define the GSM via a mapping function. We then integrate the GSM with the probability hypothesis density (PHD) filter, the Bayesian recursion formulas of GSM-PHD are derived and the Gaussian mixture implementation is employed to obtain the closed-form solutions. Moreover, the estimated shapes are designed to guide the measurement set sub-partition, which can cope with the problem of the spatialy close target tracking. Simulation results show that the proposed algorithm can effectively estimate irregular target shapes and exhibit good robustness in cross extended target tracking.

  6. 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.

  7. Novel targets and derived small molecule inhibitors in multiple myeloma.

    Science.gov (United States)

    Podar, Klaus

    2012-09-01

    Recent research advances have defined a key role of the bone marrow (BM) in multiple myeloma (MM) pathogenesis thereby leading to new treatment paradigms, which aim to target both the tumor cell as well as its BM microenvironment. The incorporation of thalidomide, bortezomib, and lenalidomide into conventional cytotoxic and transplantation regimens in relapsed and refractory, but also in newly diagnosed MM has changed treatment options during the last decade. However, MM remains still incurable. Ongoing translational research aims to identify additional therapeutic targets and to design derived agents, predominantly small molecule inhibitors, with higher potency and less toxicity to further improve MM patient outcome and to overcome drug resistance.

  8. Identification of potential glucocorticoid receptor therapeutic targets in multiple myeloma.

    Science.gov (United States)

    Thomas, Alexandra L; Coarfa, Cristian; Qian, Jun; Wilkerson, Joseph J; Rajapakshe, Kimal; Krett, Nancy L; Gunaratne, Preethi H; Rosen, Steven T

    2015-01-01

    Glucocorticoids (GC) are a cornerstone of combination therapies for multiple myeloma. However, patients ultimately develop resistance to GCs frequently based on decreased glucocorticoid receptor (GR) expression. An understanding of the direct targets of GC actions, which induce cell death, is expected to culminate in potential therapeutic strategies for inducing cell death by regulating downstream targets in the absence of a functional GR. The specific goal of our research is to identify primary GR targets that contribute to GC-induced cell death, with the ultimate goal of developing novel therapeutics around these targets that can be used to overcome resistance to GCs in the absence of GR. Using the MM.1S glucocorticoid-sensitive human myeloma cell line, we began with the broad platform of gene expression profiling to identify glucocorticoid-regulated genes further refined by combination treatment with phosphatidylinositol-3'-kinase inhibition (PI3Ki). To further refine the search to distinguish direct and indirect targets of GR that respond to the combination GC and PI3Ki treatment of MM.1S cells, we integrated 1) gene expression profiles of combination GC treatment with PI3Ki, which induces synergistic cell death; 2) negative correlation between genes inhibited by combination treatment in MM.1S cells and genes over-expressed in myeloma patients to establish clinical relevance and 3) GR chromatin immunoprecipitation with massively parallel sequencing (ChIP-Seq) in myeloma cells to identify global chromatin binding for the glucocorticoid receptor (GR). Using established bioinformatics platforms, we have integrated these data sets to identify a subset of candidate genes that may form the basis for a comprehensive picture of glucocorticoid actions in multiple myeloma. As a proof of principle, we have verified two targets, namely RRM2 and BCL2L1, as primary functional targets of GR involved in GC-induced cell death.

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

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, X.H., E-mail: zhxh@impcas.ac.cn [Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000 (China); Tang, S.W.; Ma, P.; Lu, C.G.; Yang, H.R.; Wang, S.T.; Yu, Y.H.; Yue, K.; Fang, F. [Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000 (China); Yan, D.; Zhou, Y.; Wang, Z.M.; Sun, Y. [Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000 (China); University of Chinese Academy of Sciences, Beijing 100049 (China); Sun, Z.Y.; Duan, L.M. [Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000 (China); Sun, B.H. [School of Physics and Nuclear Energy Engineering, Beihang University, Beijing 100191 (China)

    2015-09-21

    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 {sup 239}Pu α source and RI beams. A Z resolution (FWHM) of 0.4–0.6 was achieved for nuclear fragments of {sup 18}O at 400 AMeV.

  10. Metabolic pathways as possible therapeutic targets for progressive multiple sclerosis

    Directory of Open Access Journals (Sweden)

    Rebecca M Heidker

    2017-01-01

    Full Text Available Unlike relapsing remitting multiple sclerosis, there are very few therapeutic options for patients with progressive forms of multiple sclerosis. While immune mechanisms are key participants in the pathogenesis of relapsing remitting multiple sclerosis, the mechanisms underlying the development of progressive multiple sclerosis are less well understood. Putative mechanisms behind progressive multiple sclerosis have been put forth: insufficient energy production via mitochondrial dysfunction, activated microglia, iron accumulation, oxidative stress, activated astrocytes, Wallerian degeneration, apoptosis, etc. Furthermore, repair processes such as remyelination are incomplete. Experimental therapies that strive to improve metabolism within neurons and glia, e.g., oligodendrocytes, could act to counter inadequate energy supplies and/or support remyelination. Most experimental approaches have been examined as standalone interventions; however, it is apparent that the biochemical steps being targeted are part of larger pathways, which are further intertwined with other metabolic pathways. Thus, the potential benefits of a tested intervention, or of an established therapy, e.g., ocrelizumab, could be undermined by constraints on upstream and/or downstream steps. If correct, then this argues for a more comprehensive, multifaceted approach to therapy. Here we review experimental approaches to support neuronal and glial metabolism, and/or promote remyelination, which may have potential to lessen or delay progressive multiple sclerosis.

  11. Cobalt poisoning

    Science.gov (United States)

    ... against the metal cup when you walk. These metal particles (ions) can get released into the hip socket and ... Cobalt may also be found in: Alloys Batteries Chemistry/crystal ... Magnets Some metal-on-metal hip implants Tires Cobalt was once ...

  12. Advanced UXO discrimination: resolving multiple targets and overlapping EMI signals

    Science.gov (United States)

    Shubitidze, Fridon; Barrowes, Benjamin E.; Shamatava, Irma; Fernandez, Juan Pablo; Bijamov, Alex; O'Neill, Kevin

    2011-06-01

    In this paper we employ advanced electromagnetic induction models to resolve multiple targets with overlapping EMI signals-i.e. to discriminate objects of interest, such as unexploded ordnance (UXO), from innocuous items. The models include a) a joint diagonalization (JD) technique that takes data from next-generation EMI sensors and uses the eigenvalues of the multistatic response matrix to estimate the number of potential targets, and b) the orthonormalized volume magnetic source (ONVMS) model, a physically complete, fast, and accurate forward model whose representation of a target's intrinsic EMI response is used to extract classification parameters. In the given approach the overall EMI inversion and classification problem proceeds as follows: first, the JD is applied to the data and the number of targets is estimated; once this is known, the ONVMS is combined with an optimization technique to yield the location and orientation of each buried object, as well as the amplitude of its ONVMS. Finally, a total ONVMS is calculated for each object and used as a discriminant to distinguish between UXO and non-UXO items and between different kinds of UXO. We illustrate the applicability of our multi-target analysis technique by using it on several teststand and live-site datasets collected with the TEMTADS sensor array. We end by demonstrating the superior performance of the ONVMS by applying it to multi-target blind-test data compiled at the Aberdeen Proving Ground test-stand facility.

  13. SMET: systematic multiple enzyme targeting - a method to rationally design optimal strains for target chemical overproduction.

    Science.gov (United States)

    Flowers, David; Thompson, R Adam; Birdwell, Douglas; Wang, Tsewei; Trinh, Cong T

    2013-05-01

    Identifying multiple enzyme targets for metabolic engineering is very critical for redirecting cellular metabolism to achieve desirable phenotypes, e.g., overproduction of a target chemical. The challenge is to determine which enzymes and how much of these enzymes should be manipulated by adding, deleting, under-, and/or over-expressing associated genes. In this study, we report the development of a systematic multiple enzyme targeting method (SMET), to rationally design optimal strains for target chemical overproduction. The SMET method combines both elementary mode analysis and ensemble metabolic modeling to derive SMET metrics including l-values and c-values that can identify rate-limiting reaction steps and suggest which enzymes and how much of these enzymes to manipulate to enhance product yields, titers, and productivities. We illustrated, tested, and validated the SMET method by analyzing two networks, a simple network for concept demonstration and an Escherichia coli metabolic network for aromatic amino acid overproduction. The SMET method could systematically predict simultaneous multiple enzyme targets and their optimized expression levels, consistent with experimental data from the literature, without performing an iterative sequence of single-enzyme perturbation. The SMET method was much more efficient and effective than single-enzyme perturbation in terms of computation time and finding improved solutions.

  14. The cytotoxicity and genotoxicity of soluble and particulate cobalt in human lung epithelial cells.

    Science.gov (United States)

    Xie, Hong; Smith, Leah J; Holmes, Amie L; Zheng, Tongzhang; Pierce Wise, John

    2016-05-01

    Cobalt is a toxic metal used in various industrial applications leading to adverse lung effects by inhalation. Cobalt is considered a possible human carcinogen with the lung being a primary target. However, few studies have considered cobalt-induced toxicity in human lung cells, especially normal lung epithelial cells. Therefore, in this study, we sought to determine the cytotoxicity and genotoxicity of particulate and soluble cobalt in normal primary human lung epithelial cells. Cobalt oxide and cobalt chloride were used as representative particulate and soluble cobalt compounds, respectively. Exposure to both particulate and soluble cobalt induced a concentration-dependent increase in cytotoxicity, genotoxicity, and intracellular cobalt ion levels. Based on intracellular cobalt ion levels, we found that soluble and particulate cobalt induced similar cytotoxicity while soluble cobalt was more genotoxic than particulate cobalt. These data indicate that cobalt compounds are cytotoxic and genotoxic to human lung epithelial cells.

  15. Targeted treatments for multiple myeloma: specific role of carfilzomib

    Directory of Open Access Journals (Sweden)

    Sugumar D

    2015-01-01

    Full Text Available Dhivya Sugumar,1 Jesse Keller,2 Ravi Vij2 1Department of Internal Medicine, St Mary’s Health Center, 2Department of Medicine, Division of Oncology, Washington University in St Louis, St Louis, USA Abstract: Carfilzomib is a selective, irreversible proteasome inhibitor, initially approved in the US in 2012 as single-agent therapy for relapsed and refractory multiple myeloma. Numerous Phase II studies have evaluated carfilzomib in the relapsed and refractory as well as the newly diagnosed setting, and Phase III studies are entering their final analysis. Data continue to grow to support its use as both single-agent therapy and in combination with immunomodulatory and other novel agents. This review discusses the role of carfilzomib in the treatment of multiple myeloma. Its mechanism of action, pharmacokinetics, and role in clinical management will be reviewed. Keywords: relapsed and refractory, targeted therapy, proteasome inhibitor, novel agents

  16. Toward Highly Efficient Electrocatalyst for Li-O{sub 2} Batteries Using Biphasic N-Doping Cobalt@Graphene Multiple-Capsule Heterostructures

    Energy Technology Data Exchange (ETDEWEB)

    Tan, Guoqiang; Chong, Lina; Amine, Rachid; Lu, Jun; Liu, Cong; Yuan, Yifei; Wen, Jianguo; He, Kun; Bi, Xuanxuan; Guo, Yuanyuan; Wang, Hsien-Hau; Miller, Dean J.; Liu, Dijia; Amine, Khalil

    2017-05-01

    For the promotion of lithium oxygen batteries available for :practical applications, the development of advanced cathode catalysts with low-high activity, and stable structural properties is demanded. Such development is rooted on certain intelligent catalyst-electrode design that fundamentally facilitates electronic and ionic transport and improves oxygen diffusivity in a porous environment. Here we design a biphasic nitrogen-doped cobalt@grapbene Multiple-capsule heterostructure, combined with a flexible, stable porous electrode architecture, and apply it as promising cathodes for lithium oxygen cells. 'The biphasic nitrogen-doping feature improves the electric conductivity and catalytic activity; the multiple-nanocapsule configuration makes high/uniform electroactive zones possible; furthermore the colander-like porous electrode facilitates the oxygen diffusion, catalytic reaction,and stable deposition of discharge products. As a result, the electrode exhibits much improved electrocatalytic properties associated with unique morphologies of electrochemically grown lithium peroxides.

  17. Targeting B-cell maturation antigen in multiple myeloma

    Science.gov (United States)

    Tai, Yu-Tzu; Anderson, Kenneth C

    2015-01-01

    Novel effective immunotherapies are needed for patients with multiple myeloma (MM), since disease recurrence remains a major obstacle. B-cell maturation antigen (BCMA), a cell surface protein universally expressed on malignant plasma cells , has emerged as a very selective antigen to be targeted in novel treatments for MM. We here first review BCMA-related biology, and then highlight the recent clinical development of a novel afucosylated anti-BCMA monoclonal antibody conjugated with monomethyl auristatin F via noncleavable linker (GSK2857916). Chimeric antigen receptor-expressing T cells targeting BCMA may also induce specific and durable anti-MM responses by patients’ own effector cells. Clinical trials testing these two approaches (NCT02064387, NCT02215967) are currently ongoing in relapsed and refractory MM patients. PMID:26370838

  18. 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...

  19. Therapeutic strategies targeting B-cells in multiple sclerosis.

    Science.gov (United States)

    Milo, Ron

    2016-07-01

    Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system (CNS) that traditionally has been considered to be mediated primarily by T-cells. Increasing evidence, however, suggests the fundamental role of B-cells in the pathogenesis of the disease. Recent strategies targeting B-cells in MS have demonstrated impressive and sometimes surprising results: B-cell depletion by monoclonal antibodies targeting the B-cell surface antigen CD20 (e.g. rituximab, ocrelizumab, ofatumumab) was shown to exert profound anti-inflammatory effect in MS with favorable risk-benefit ratio, with ocrelizumab demonstrating efficacy in both relapsing-remitting (RR) and primary-progressive (PP) MS in phase III clinical trials. Depletion of CD52 expressing T- and B-cells and monocytes by alemtuzumab resulted in impressive and durable suppression of disease activity in RRMS patients. On the other hand, strategies targeting B-cell cytokines such as atacicept resulted in increased disease activity. As our understanding of the biology of B-cells in MS is increasing, new compounds that target B-cells continue to be developed which promise to further expand the armamentarium of MS therapies and allow for more individualized therapy for patients with this complex disease.

  20. Targeting SDF-1 in multiple myeloma tumor microenvironment.

    Science.gov (United States)

    Bouyssou, Juliette M C; Ghobrial, Irene M; Roccaro, Aldo M

    2016-09-28

    Multiple myeloma (MM) is a type of B-cell malignancy that remains incurable to date. The bone marrow (BM) microenvironment plays a crucial role in MM progression. The chemokine SDF-1 (CXCL12) is an important actor of the BM microenvironment that has the ability to regulate numerous processes related to its malignant transformation during MM development. The activity of SDF-1 is mainly mediated by its specific receptor CXCR4, which is expressed at the surface of MM cells and various other BM cell types. Current treatments available for MM patients mainly target tumor cells but have limited effects on the BM microenvironment. In this context, SDF-1 and CXCR4 represent ideal targets for the normalization of the MM-supportive BM microenvironment. The present review focuses on the activity of SDF-1 in the MM BM microenvironment and the current efforts carried out to target the SDF-1/CXCR4 axis for treatment of MM. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  1. Targeting proteasome ubiquitin receptor Rpn13 in multiple myeloma.

    Science.gov (United States)

    Song, Y; Ray, A; Li, S; Das, D S; Tai, Y T; Carrasco, R D; Chauhan, D; Anderson, K C

    2016-09-01

    Proteasome inhibitor bortezomib is an effective therapy for relapsed and newly diagnosed multiple myeloma (MM); however, dose-limiting toxicities and the development of resistance can limit its long-term utility. Recent research has focused on targeting ubiquitin receptors upstream of 20S proteasome, with the aim of generating less toxic therapies. Here we show that 19S proteasome-associated ubiquitin receptor Rpn13 is more highly expressed in MM cells than in normal plasma cells. Rpn13-siRNA (small interfering RNA) decreases MM cell viability. A novel agent RA190 targets Rpn13 and inhibits proteasome function, without blocking the proteasome activity or the 19S deubiquitylating activity. CRISPR/Cas9 Rpn13-knockout demonstrates that RA190-induced activity is dependent on Rpn13. RA190 decreases viability in MM cell lines and patient MM cells, inhibits proliferation of MM cells even in the presence of bone marrow stroma and overcomes bortezomib resistance. Anti-MM activity of RA190 is associated with induction of caspase-dependent apoptosis and unfolded protein response-related apoptosis. MM xenograft model studies show that RA190 is well tolerated, inhibits tumor growth and prolongs survival. Combining RA190 with bortezomib, lenalidomide or pomalidomide induces synergistic anti-MM activity. Our preclinical data validates targeting Rpn13 to overcome bortezomib resistance, and provides the framework for clinical evaluation of Rpn13 inhibitors, alone or in combination, to improve patient outcome in MM.

  2. The cytotoxicity and genotoxicity of soluble and particulate cobalt in human lung fibroblast cells.

    Science.gov (United States)

    Smith, Leah J; Holmes, Amie L; Kandpal, Sanjeev Kumar; Mason, Michael D; Zheng, Tongzhang; Wise, John Pierce

    2014-08-01

    Cobalt exposure is increasing as cobalt demand rises worldwide due to its use in enhancing rechargeable battery efficiency, super-alloys, and magnetic products. Cobalt is considered a possible human carcinogen with the lung being a primary target. However, few studies have considered cobalt-induced toxicity in human lung cells. Therefore, in this study, we sought to determine the cytotoxicity and genotoxicity of particulate and soluble cobalt in human lung cells. Cobalt oxide and cobalt chloride were used as representative particulate and soluble cobalt compounds, respectively. Exposure to both particulate and soluble cobalt induced a concentration-dependent increase in cytotoxicity, genotoxicity, and intracellular cobalt ion levels. Based on intracellular cobalt ion levels, we found that soluble cobalt was more cytotoxic than particulate cobalt while particulate and soluble cobalt induced similar levels of genotoxicity. However, soluble cobalt induced cell cycle arrest indicated by the lack of metaphases at much lower intracellular cobalt concentrations compared to cobalt oxide. Accordingly, we investigated the role of particle internalization in cobalt oxide-induced toxicity and found that particle-cell contact was necessary to induce cytotoxicity and genotoxicity after cobalt exposure. These data indicate that cobalt compounds are cytotoxic and genotoxic to human lung fibroblasts, and solubility plays a key role in cobalt-induced lung toxicity.

  3. Targeting signalling pathways for the treatment of multiple myeloma.

    Science.gov (United States)

    Podar, Klaus; Hideshima, Teru; Chauhan, Dharminder; Anderson, Kenneth C

    2005-04-01

    Multiple myeloma (MM) is characterised by the expansion of monoclonal immunoglobulin-secreting plasma cells. Despite recent advances in systemic and supportive therapy, it remains incurable, with a median survival of about three years. Development of MM is a multistep process associated with an increasing frequency of chromosomal abnormalities and complex translocations, which induce mutations in several proto-oncogenes and tumour suppressor genes. Furthermore, differentiation, maintenance, expansion and drug resistance of MM cells are dependent on multiple growth factors, cytokines, and chemokines, secreted by tumour cells, bone marrow stromal cells, and non-haematopoietic organs; as well as on direct tumour cell-stromal cell contact. Therefore, signalling pathways initiated by both mutated genes in MM cells as well as signals originating in the bone marrow microenvironment represent potential targets for intervention. Close collaboration between basic researchers and clinicians will be required to further improve our knowledge of MM pathophysiologically in order to translate advances from the bench to the bedside and improve patient outcome.

  4. Targeted Inhibition of Multiple Receptor Tyrosine Kinases in Mesothelioma

    Directory of Open Access Journals (Sweden)

    Wen-Bin Ou

    2011-01-01

    Full Text Available The receptor tyrosine kinases (RTKs epidermal growth factor receptor (EGFR and MET are activated in subsets of mesothelioma, suggesting that these kinases might represent novel therapeutic targets in this notoriously chemotherapy-resistant cancer. However, clinical trials have shown little activity for EGFR inhibitors in mesothelioma. Despite the evidence for RTK activation in mesothelioma pathogenesis, it is unclear whether transforming activity is dependent on an individual kinase oncoprotein or the coordinated activity of multiple kinases. Using phospho-RTK and immunoblot assays, we herein demonstrate activation of multiple RTKs (EGFR, MET, AXL, and ERBB3 in individual mesothelioma cell lines but not in normal mesothelioma cells. Inhibition of mesothelioma multi-RTK signaling was accomplished using combinations of RTK direct inhibitors or by inhibition of the RTK chaperone, heat shock protein 90 (HSP90. Multi-RTK inhibition by the HSP90 inhibitor 17-allyloamino-17demethoxygeldanamycin (17-AAG had a substantially greater effect on mesothelioma proliferation and survival compared with inhibition of individual activated RTKs. HSP90 inhibition also suppressed phosphorylation of down-stream signaling intermediates (AKT, mitogen-activated protein kinase, and S6; upregulated the p53, p21, and p27 cell cycle checkpoints; induced G2 phase arrest; induced caspase 3/7 activity; and led to an increase in the sub-G1 apoptotic population. These compelling proapoptotic and antiproliferative responses indicate that HSP90 inhibition warrants clinical evaluation as a novel therapeutic strategy in mesothelioma.

  5. 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

  6. Polycomb target genes are silenced in multiple myeloma.

    Directory of Open Access Journals (Sweden)

    Antonia Kalushkova

    Full Text Available Multiple myeloma (MM is a genetically heterogeneous disease, which to date remains fatal. Finding a common mechanism for initiation and progression of MM continues to be challenging. By means of integrative genomics, we identified an underexpressed gene signature in MM patient cells compared to normal counterpart plasma cells. This profile was enriched for previously defined H3K27-tri-methylated genes, targets of the Polycomb group (PcG proteins in human embryonic fibroblasts. Additionally, the silenced gene signature was more pronounced in ISS stage III MM compared to stage I and II. Using chromatin immunoprecipitation (ChIP assay on purified CD138+ cells from four MM patients and on two MM cell lines, we found enrichment of H3K27me3 at genes selected from the profile. As the data implied that the Polycomb-targeted gene profile would be highly relevant for pharmacological treatment of MM, we used two compounds to chemically revert the H3K27-tri-methylation mediated gene silencing. The S-adenosylhomocysteine hydrolase inhibitor 3-Deazaneplanocin (DZNep and the histone deacetylase inhibitor LBH589 (Panobinostat, reactivated the expression of genes repressed by H3K27me3, depleted cells from the PRC2 component EZH2 and induced apoptosis in human MM cell lines. In the immunocompetent 5T33MM in vivo model for MM, treatment with LBH589 resulted in gene upregulation, reduced tumor load and increased overall survival. Taken together, our results reveal a common gene signature in MM, mediated by gene silencing via the Polycomb repressor complex. The importance of the underexpressed gene profile in MM tumor initiation and progression should be subjected to further studies.

  7. Multiple-frame best-hypothesis target tracking with multiple sensors

    Science.gov (United States)

    Drummond, Oliver E.

    2004-01-01

    The concept of selecting the best hypothesis in the minimum mean square error (MMSE) sense was introduced in 1999 to provide alternative data association algorithms for data association with hard decisions using data from one or more sensors. The motivations for using the estimate based on the best hypothesis in the MMSE sense are two-fold. First, there are situations where there is a natural preference to make hard decisions rather than soft decisions. Secondly, given that a state estimate is based on a single hypothesis as in a typical hard decision, there is the desire to minimize the mean square of the estimation error, since that is a common metric in evaluating performance. For example, for estimation that involves data association, the traditional MMSE criterion leads to so called soft decisions that may not be appropriate for an interceptor with a small region of lethality while, in contrast, hard decisions might increase the probability of a successful engagement. In addition, in processing features for use in target typing, classification or discrimination, soft decisions may degrade performance more than would a reasonable hard decision. While the best hypothesis method may be preferred for certain applications, the improved performance might be at the expense of increased processing load. Since the capability of available processors is increasing rapidly, emphasis can be expected to lean toward algorithms that take advantage of this enhanced capability to provide improved performance based on the specific needs of a target tracking application. The emphasis of this paper is on the use of data from multiple sensors in multiple-frame methods for data association, such as in multiple hypothesis tracking, using as the criteria the best hypothesis in the MMSE sense rather than the most probable hypothesis or the traditional MMSE that leads to soft decisions.

  8. 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.

  9. 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.

  10. The cytotoxicity and genotoxicity of soluble and particulate cobalt in human lung fibroblast cells

    Energy Technology Data Exchange (ETDEWEB)

    Smith, Leah J.; Holmes, Amie L. [Wise Laboratory of Environmental and Genetic Toxicology, University of Southern Maine, 96 Falmouth St., P.O. Box 9300, Portland, ME 04101-9300 (United States); Maine Center for Environmental Toxicology and Health, University of Southern Maine, 96 Falmouth St., P.O. Box 9300, Portland, ME 04101-9300 (United States); Department of Applied Medical Science, University of Southern Maine, 96 Falmouth St., P.O. Box 9300, Portland, ME 04101-9300 (United States); Kandpal, Sanjeev Kumar; Mason, Michael D. [Department of Chemical and Biological Engineering, University of Maine, Orono, ME (United States); Zheng, Tongzhang [Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT (United States); Wise, John Pierce, E-mail: John.Wise@usm.maine.edu [Wise Laboratory of Environmental and Genetic Toxicology, University of Southern Maine, 96 Falmouth St., P.O. Box 9300, Portland, ME 04101-9300 (United States); Maine Center for Environmental Toxicology and Health, University of Southern Maine, 96 Falmouth St., P.O. Box 9300, Portland, ME 04101-9300 (United States); Department of Applied Medical Science, University of Southern Maine, 96 Falmouth St., P.O. Box 9300, Portland, ME 04101-9300 (United States)

    2014-08-01

    Cobalt exposure is increasing as cobalt demand rises worldwide due to its use in enhancing rechargeable battery efficiency, super-alloys, and magnetic products. Cobalt is considered a possible human carcinogen with the lung being a primary target. However, few studies have considered cobalt-induced toxicity in human lung cells. Therefore, in this study, we sought to determine the cytotoxicity and genotoxicity of particulate and soluble cobalt in human lung cells. Cobalt oxide and cobalt chloride were used as representative particulate and soluble cobalt compounds, respectively. Exposure to both particulate and soluble cobalt induced a concentration-dependent increase in cytotoxicity, genotoxicity, and intracellular cobalt ion levels. Based on intracellular cobalt ion levels, we found that soluble cobalt was more cytotoxic than particulate cobalt while particulate and soluble cobalt induced similar levels of genotoxicity. However, soluble cobalt induced cell cycle arrest indicated by the lack of metaphases at much lower intracellular cobalt concentrations compared to cobalt oxide. Accordingly, we investigated the role of particle internalization in cobalt oxide-induced toxicity and found that particle-cell contact was necessary to induce cytotoxicity and genotoxicity after cobalt exposure. These data indicate that cobalt compounds are cytotoxic and genotoxic to human lung fibroblasts, and solubility plays a key role in cobalt-induced lung toxicity. - Highlights: • Particulate and soluble cobalt are cytotoxic and genotoxic to human lung cells. • Soluble cobalt induces more cytotoxicity compared to particulate cobalt. • Soluble and particulate cobalt induce similar levels of genotoxicity. • Particle-cell contact is required for particulate cobalt-induced toxicity.

  11. Aminated β-Cyclodextrin-Modified-Carboxylated Magnetic Cobalt/Nanocellulose Composite for Tumor-Targeted Gene Delivery

    Directory of Open Access Journals (Sweden)

    Thayyath Sreenivasan Anirudhan

    2014-01-01

    Full Text Available Gene therapy is a new kind of medicine, which uses genes as drugs in order to treat life threatening diseases. In the present work, a nonviral vector, aminated β-cyclodextrin-modified-carboxylated magnetic cobalt/nanocellulose composite (ACDC-Co/NCC, was synthesized for efficient transfection of genes into tumour cells. The synthesized ACDC-Co/NCC was characterized by means of FTIR, XRD, SEM, and ESR techniques. DNA condensing ability of ACDC-Co/NCC was found to be increased with increase in amount of ACDC-Co/NCC and 84.9% of DNA (1.0 μg/mL inclusion was observed with 6.0 μg/mL of ACDC-Co/NCC. The cytotoxicity of ACDC-Co/NCC was observed to be minimal, even at higher concentration, with respect to the model transfecting agent, poly(ethyleneimine (PEI. 88.2% of the gene was transfected at high dose of DNA, as indicated by the highest luciferase expression. These results indicated that ACDC-Co/NCC might be a promising candidate for gene delivery with the characteristics of good biocompatibility, potential biodegradability, minimal cytotoxicity, and relatively high gene transfection efficiency.

  12. Radiochemical separation of Cobalt

    NARCIS (Netherlands)

    Erkelens, P.C. van

    1961-01-01

    A method is described for the radiochemical separation of cobalt based on the extraordinary stability of cobalt diethyldithiocarbamate. Interferences are few; only very small amounts of zinc and iron accompany cobalt, which is important in neutron-activation analysis.

  13. Radiochemical separation of Cobalt

    NARCIS (Netherlands)

    Erkelens, P.C. van

    1961-01-01

    A method is described for the radiochemical separation of cobalt based on the extraordinary stability of cobalt diethyldithiocarbamate. Interferences are few; only very small amounts of zinc and iron accompany cobalt, which is important in neutron-activation analysis.

  14. 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.

  15. 2-Amino-2-deoxy-glucose conjugated cobalt ferrite magnetic nanoparticle (2DG-MNP) as a targeting agent for breast cancer cells.

    Science.gov (United States)

    Aşık, Elif; Aslan, Tuğba Nur; Volkan, Mürvet; Güray, N Tülin

    2016-01-01

    In this study, 2-amino-2-deoxy-glucose (2DG) was conjugated to COOH modified cobalt ferrite magnetic nanoparticles (COOH-MNPs), which were designed to target tumor cells as a potential targetable drug/gene delivery agent for cancer treatment. According to our results, it is apparent that, 2DG labeled MNPs were internalized more efficiently than COOH-MNPs under the same conditions in all cell types (MDA-MB-231 and MCF-7 cancer and MCF-10A normal breast cells) (p<0.001). Moreover, the highest amount of uptake was observed in MDA-MB-231, followed by MCF-7 and normal MCF-10A cells for both MNPs. The apoptotic effects of 2DG-MNPs were further evaluated, and it was found that apoptosis was not induced at low concentrations of 2DG-MNPs in all cell types, whereas dramatic cell death was observed at higher concentrations. In addition, the gene expression levels of four drug-metabolizing enzymes, two Phase I (CYP1A1, CYP1B1) and two Phase II (GSTM3, GSTZ1) were also increased with the high concentrations of 2DG-MNPs. Copyright © 2015 Elsevier B.V. All rights reserved.

  16. Energy-balanced multiple-sensor collaborative scheduling for maneuvering target tracking in wireless sensor networks

    Institute of Scientific and Technical Information of China (English)

    2011-01-01

    An energy-balanced multiple-sensor collaborative scheduling is proposed for maneuvering target tracking in wireless sensor networks (WSNs). According to the position of the maneuvering target, some sensor nodes in WSNs are awakened to form a sensor cluster for target tracking collaboratively. In the cluster, the cluster head node is selected to implement tracking task with changed sampling interval. The distributed interactive multiple model (IMM) filter is employed to estimate the target state. The estimat...

  17. Multiple targets vector miss distance measurement accuracy based on 2-D assignment algorithms

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    An extension of 2-D assignment approach is proposed for measurement-to-target association for improving multiple targets vector miss distance measurement accuracy.When the multiple targets move so closely,the measurements can not be fully resolved due to finite resolution.The proposed method adopts an auction algorithm to compute the feasible measurement-to-target assignment with unresolved measurements for solving this 2-D assignment problem.Computer simulation results demonstrate the effectiveness and feasibility of this method.

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

    Energy Technology Data Exchange (ETDEWEB)

    Kwok, K.S.; Driessen, B.J.; Phillips, C.A. [Sandia National Labs., Albuquerque, NM (United States); Tovey, C.A. [Georgia Inst. of Tech., Atlanta, GA (United States)

    1997-10-01

    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. 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.

  20. Multiple oncogenic mutations related to targeted therapy in nasopharyngeal carcinoma

    Institute of Scientific and Technical Information of China (English)

    Jian-Wei Zhang; Hong-Yuan Zhao; Yu-Xiang Ma; Zhi-Huang Hu; Pei-Yu Huang; Li Zhang; Tao Qin; Shao-Dong Hong; Jing Zhang; Wen-Feng Fang; Yuan-Yuan Zhao; Yun-Peng Yang; Cong Xue; Yan Huang

    2015-01-01

    Introduction:An increasing number of targeted drugs have been tested for the treatment of nasopharyngeal carcinoma (NPC). However, targeted therapy-related oncogenic mutations have not been fully evaluated. This study aimed to detect targeted therapy-related oncogenic mutations in NPC and to determine which targeted therapy might be potentially effective in treating NPC. Methods:By using the SNaPshot assay, a rapid detection method, 19 mutation hotspots in 6 targeted therapy-related oncogenes were examined in 70 NPC patients. The associations between oncogenic mutations and clinicopathologic factors were analyzed. Results:Among 70 patients, 12 (17.1%) had mutations in 5 oncogenes:7 (10.0%) had v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) mutation, 2 (2.8%) had epidermal growth factor receptor (EGFR) mutation, 1 (1.4%) had phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutation, 1 (1.4%) had Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation, and 1 (1.4%) had simultaneous EGFR and v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations. No significant differences were observed between oncogenic mutations and clinicopathologic characteristics. Additionally, these oncogenic mutations were not associated with tumor recurrence and metastasis. Conclusions:Oncogenic mutations are present in NPC patients. The efficacy of targeted drugs on patients with the related oncogenic mutations requires further validation.

  1. Supply and Demand Situation in Domestic Cobalt Industry May Come to a Turning Point

    Institute of Scientific and Technical Information of China (English)

    2016-01-01

    Multiple factors overlapped to bring opportunity to the cobalt business unit:Three factors of"Shrinking Supply"+"Growing Demand"+"Price Bottom"overlap to change market’s future expectation for cobalt products.As a big power of cobalt refining and cobalt consumption,China received obvious impact,relevant enterprises mainly include Huayou Cobalt,China Molybdenum,and GEM.

  2. A novel method to synthesize cobalt oxide (Co3O4) nanowires from cobalt (Co) nanobowls

    DEFF Research Database (Denmark)

    Srivastava, Akhilesh Kumar; Madhavi, S.; Ramanujan, R.V.

    2010-01-01

    A novel method suitable for the synthesis of the cobalt oxide (Co3O4) nanowires at targeted regions is presented in this report. Cobalt (Co) nanobowls synthesized by colloidal crystal directed assembly were transformed into Co3O4 nanowires by a simple heat treatment process. Co nanobowls exhibited...

  3. Asynchronous Visualization of Spatiotemporal Information for Multiple Moving Targets

    Science.gov (United States)

    Wang, Huadong

    2013-01-01

    In the modern information age, the quantity and complexity of spatiotemporal data is increasing both rapidly and continuously. Sensor systems with multiple feeds that gather multidimensional spatiotemporal data will result in information clusters and overload, as well as a high cognitive load for users of these systems. To meet future…

  4. 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...

  5. Swarm Robots Search for Multiple Targets Based on an Improved Grouping Strategy.

    Science.gov (United States)

    Tang, Qirong; Ding, Lu; Yu, Fangchao; Zhang, Yuan; Li, Yinghao; Tu, Haibo

    2017-03-14

    Swarm robots search for multiple targets in collaboration in unknown environments has been addressed in this paper. An improved grouping strategy based on constriction factors Particle Swarm Optimization is proposed. Robots are grouped under this strategy after several iterations of stochastic movements, which considers the influence range of targets and environmental information they have sensed. The group structure may change dynamically and each group focuses on searching one target. All targets are supposed to be found finally. Obstacle avoidance is considered during the search process. Simulation compared with previous method demonstrates the adaptability, accuracy and efficiency of the proposed strategy in multiple targets searching.

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

    CERN Document Server

    Steffen, Jason H; Borucki, William J; Buchhave, Lars A; Caldwell, Douglas A; Cochran, William D; Endl, Michael; Fabrycky, Daniel C; Fressin, François; Ford, Eric B; Fortney, Jonathan J; Haas, Michael J; Holman, Matthew J; Isaacson, Howard; Jenkins, Jon M; Koch, David; Latham, David W; Lissauer, Jack J; Moorhead, Althea V; Morehead, Robert C; Marcy, Geoffrey; MacQueen, Phillip J; Quinn, Samuel N; Ragozzine, Darin; Rowe, Jason F; Sasselov, Dimitar D; Seager, Sara; Torres, Guillermo; Welsh, William F

    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 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 compos...

  7. Production of 61Cu using natural cobalt target and its separation using ascorbic acid and common anion exchange resin.

    Science.gov (United States)

    Das, Sujata Saha; Chattopadhyay, Sankha; Barua, Luna; Das, Malay Kanti

    2012-02-01

    (61)Cu was produced by (nat)Co(α, xn)(61)Cu reaction. (61)Cu production yield was 89.5 MBq/μAh (2.42 mCi/μAh) at the end of irradiation (EOI). A simple radiochemical separation method using anion exchange resin and ascorbic acid has been employed to separate the product radionuclide from inactive target material and co-produced non-isotopic impurities. The radiochemical separation yield was about 90%. Radiochemical purity of (61)Cu was >99% 1 h after EOI. Final product was suitable for making complex with N(2)S(2) type of ligands.

  8. Dose response of multiple parameters for calyculin A-induced premature chromosome condensation in human peripheral blood lymphocytes exposed to high doses of cobalt-60 gamma-rays.

    Science.gov (United States)

    Lu, Xue; Zhao, Hua; Feng, Jiang-Bin; Zhao, Xiao-Tao; Chen, De-Qing; Liu, Qing-Jie

    2016-09-01

    Many studies have investigated exposure biomarkers for high dose radiation. However, no systematic study on which biomarkers can be used in dose estimation through premature chromosome condensation (PCC) analysis has been conducted. The present study aims to screen the high-dose radiation exposure indicator in calyculin A-induced PCC. The dose response of multiple biological endpoints, including G2/A-PCC (G2/M and M/A-PCC) index, PCC ring (PCC-R), ratio of the longest/shortest length (L/L ratio), and length and width ratio of the longest chromosome (L/B ratio), were investigated in calyculin A-induced G2/A-PCC spreads in human peripheral blood lymphocytes exposed to 0-20Gy (dose-rate of 1Gy/min) cobalt-60 gamma-rays. The G2/A-PCC index was decreased with enhanced absorbed doses of 4-20Gy gamma-rays. The G2/A PCC-R at 0-12Gy gamma-rays conformed to Poisson distribution. Three types of PCC-R were scored according to their shape and their solidity or hollowness. The frequencies of hollow PCC-R and PCC-R including or excluding solid ring in G2/A-PCC spreads were enhanced with increased doses. The length and width of the longest chromosome, as well as the length of the shortest chromosome in each G2/M-PCC or M/A-PCC spread, were measured. All L/L or L/B ratios in G2/M-PCC or M/A-PCC spread increased with enhanced doses. A blind test with two new irradiated doses was conducted to validate which biomarker could be used in dose estimation. Results showed that hollow PCC-R and PCC-R including solid ring can be utilized for accurate dose estimation, and that hollow PCC-R was optimal for practical application.

  9. A Combined PMHT and IMM Approach to Multiple-Point Target Tracking in Infrared Image Sequence

    Directory of Open Access Journals (Sweden)

    Mukesh A. Zaveri

    2007-09-01

    Full Text Available Data association and model selection are important factors for tracking multiple targets in a dense clutter environment. In this paper, we provide an effective solution to the tracking of multiple single-pixel maneuvering targets in a sequence of infrared images by developing an algorithm that combines a sequential probabilistic multiple hypothesis tracking (PMHT and interacting multiple model (IMM. We explicitly model maneuver as a change in the target's motion model and demonstrate its effectiveness in our tracking application discussed in this paper. We show that inclusion of IMM enables tracking of any arbitrary trajectory in a sequence of infrared images without any a priori special information about the target dynamics. IMM allows us to incorporate different dynamic models for the targets and PMHT helps to avoid the uncertainty about the observation origin. It operates in an iterative mode using expectation-maximization (EM algorithm. The proposed algorithm uses observation association as missing data.

  10. A Combined PMHT and IMM Approach to Multiple-Point Target Tracking in Infrared Image Sequence

    Directory of Open Access Journals (Sweden)

    Merchant SN

    2007-01-01

    Full Text Available Data association and model selection are important factors for tracking multiple targets in a dense clutter environment. In this paper, we provide an effective solution to the tracking of multiple single-pixel maneuvering targets in a sequence of infrared images by developing an algorithm that combines a sequential probabilistic multiple hypothesis tracking (PMHT and interacting multiple model (IMM. We explicitly model maneuver as a change in the target's motion model and demonstrate its effectiveness in our tracking application discussed in this paper. We show that inclusion of IMM enables tracking of any arbitrary trajectory in a sequence of infrared images without any a priori special information about the target dynamics. IMM allows us to incorporate different dynamic models for the targets and PMHT helps to avoid the uncertainty about the observation origin. It operates in an iterative mode using expectation-maximization (EM algorithm. The proposed algorithm uses observation association as missing data.

  11. Toxicity and bioactivity of cobalt nanoparticles on the monocytes.

    Science.gov (United States)

    Liu, Ya-ke; Ye, Jun; Han, Qing-lin; Tao, Ran; Liu, Fan; Wang, Wei

    2015-05-01

    To explore the toxicity and biological activity of cobalt nanoparticles on the osteoclasts. Analyze the relationship between cobalt nanoparticles and osteolysis. Monocyte-macrophages (RAW 264.7) was cultured in vitro, osteoclast-like cells were induced by lipopolysaccharides (LPS). After RAW 264.7 was induced for 24 h, Methyl Thiazolium Tetrazolium (MTT) biological toxicity test of osteoclast-like cell was preceded using Cobalt nanoparticles (set 4 concentrations: 10, 20, 50, 100 μM) and cobalt chloride (set 4 concentrations: 10, 20, 50, 100 μM) at 2, 4, 8, 24 and 48 h respectively. The relative expression of mRNA of CA II and Cat K after RAW 264.7 induction was determined by Q-PCR. mRNA relative expression of CA II, Cat K were reduced at multiple concentrations both cobalt nanoparticles and cobalt chloride, and was time and concentration dependent, cobalt nanoparticles are more significant than cobalt chloride group. But when the cobalt nanoparticles concentration is in 10-50 μM, the mRNA relative expression of CA II, Cat K increased. Cobalt nanoparticles have biological toxicity. At multiple concentrations, the differentiation and proliferation of osteoclasts was inhibited, but when the concentration of cobalt nanoparticles is in 10-50 μM, it has been strengthened. © 2015 Chinese Orthopaedic Association and Wiley Publishing Asia Pty Ltd.

  12. 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.

  13. Five Kepler Target Stars That Show Multiple Transiting Exoplanet Candidates

    Science.gov (United States)

    Steffen, Jason H.; Batalha, Natalie M.; Borucki, William J.; Buchhave, Lars A.; Caldwell, Douglas A.; Cochran, William D.; Endl, Michael; Fabrycky, Daniel C.; Fressin, François; Ford, Eric B.; Fortney, Jonathan J.; Haas, Michael J.; Holman, Matthew J.; Howell, Steve B.; Isaacson, Howard; Jenkins, Jon M.; Koch, David; Latham, David W.; Lissauer, Jack J.; Moorhead, Althea V.; Morehead, Robert C.; Marcy, Geoffrey; MacQueen, Phillip J.; Quinn, Samuel N.; Ragozzine, Darin; Rowe, Jason F.; Sasselov, Dimitar D.; Seager, Sara; Torres, Guillermo; Welsh, William F.

    2010-12-01

    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 multi-transiting 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 (TTVs) 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.

  14. Coordinate-targeted fluorescence nanoscopy with multiple off states

    Science.gov (United States)

    Danzl, Johann G.; Sidenstein, Sven C.; Gregor, Carola; Urban, Nicolai T.; Ilgen, Peter; Jakobs, Stefan; Hell, Stefan W.

    2016-02-01

    Far-field super-resolution fluorescence microscopy discerns fluorophores residing closer than the diffraction barrier by briefly transferring them in different (typically ON and OFF) states before detection. In coordinate-targeted super-resolution variants, such as stimulated emission depletion (STED) microscopy, this state difference is created by the intensity minima and maxima of an optical pattern, causing all fluorophores to assume the off state, for instance, except at the minima. Although strong spatial confinement of the on state enables high resolution, it also subjects the fluorophores to excess intensities and state cycles at the maxima. Here, we address these issues by driving the fluorophores into a second off state that is inert to the excess light. By using reversibly switchable fluorescent proteins as labels, our approach reduces bleaching and enhances resolution and contrast in live-cell STED microscopy. Using two or more transitions to off states is a useful strategy for augmenting the power of coordinate-targeted super-resolution microscopy.

  15. Sensor management for multiple target tracking with heterogeneous sensor models

    Science.gov (United States)

    Williams, Jason L.; Fisher, John W., III; Willsky, Alan S.

    2006-05-01

    Modern sensors are able to rapidly change mode of operation and steer between physically separated objects. While control of such sensors over a rolling planning horizon can be formulated as a dynamic program, the optimal solution is inevitably intractable. In this paper, we consider the control problem under a restricted family of policies and show that the essential sensor control trade-offs are still captured. The advantage of this approach is that one can obtain the optimal policy within the restricted class in a tractable fashion, in this case by using the auction algorithm. The approach is well-suited for problems in which a single sensor (or group of sensors) is being used to track many targets using a heterogeneous sensor model, i.e., where the quality of observations varies with object state, such as due to obscuration. Our algorithm efficiently weighs the rewards achievable by observing each target at each time to find the best sensor plan within the restricted set. We extend this approach using a roll-out algorithm, to handle additional cases such as when observations take different amounts of time to complete.

  16. 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.

  17. Gray matter is targeted in first-attack multiple sclerosis.

    Directory of Open Access Journals (Sweden)

    Steven E Schutzer

    Full Text Available 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.

  18. Triaziflam and Diaminotriazine derivatives affect enantioselectively multiple herbicide target sites.

    Science.gov (United States)

    Grossmann, K; Tresch, S; Plath, P

    2001-01-01

    Enantiomers of triaziflam and structurally related diaminotriazines were synthesized and their herbicidal mode of action was investigated. The compounds caused light and dark-dependent effects in multiple test systems including heterotrophic cleaver and photoautotrophic algal cell suspensions, the Hill reaction of isolated thylakoids and germinating cress seeds. Dose-response experiments revealed that the (S)-enantiomers of the compounds preferentially inhibited photosystem II electron transport (PET) and algae growth with efficacies similar to that of the herbicide atrazine. In contrast, the (R)-enantiomers of the diaminotriazines were up to 100 times more potent inhibitors of growth in cleaver cell suspensions and cress seedlings in the dark than the (S)-enantiomers. The most active compound, the (R)-enantiomer of triaziflam, inhibited shoot and root elongation of cress and maize seedlings at concentrations below 1 microM. The meristematic root tips swelled into a club shape which is typical for the action of mitotic disrupter herbicides and cellulose biosynthesis inhibitors. Microscopic examination using histochemical techniques revealed that triaziflam (R)-enantiomer blocks cell division in maize root tips 4 h after treatment. The chromosomes proceeded to a condensed state of prometaphase but were unable to progress further in the mitotic cycle. Disruption of mitosis was accompanied by a loss of spindle and phragmoplast micotubule arrays. Concomitantly, cortical microtubules decreased which could lead to isodiametric cell growth and consequently to root swelling. In addition, a decline in cellulose deposition in cell walls was found 24 h after treatment. Compared to the (R)-form, triaziflam (S)-enantiomer was clearly less active. The results suggest that triaziflam and related diaminotriazines affect enantioselectively multiple sites of action which include PET inhibitory activity, mitotic disruption by inhibiting microtubule formation and inhibition of

  19. Multiple personalities: synaptic target cells as introverts and extroverts.

    Science.gov (United States)

    Ritzenthaler, S; Chiba, A

    2001-10-01

    The intricate process of wiring a neuronetwork requires a high degree of accuracy in the communication between pre- and post-synaptic cells. While presynaptic cells have been widely recognized for their dynamic role in synaptic matchmaking, post-synaptic cells have historically been overlooked as passive targets. Recent studies in the Drosophila embryonic neuromuscular system provide compelling evidence that post-synaptic cells participate actively in the synaptogenic process. Endocytosis allows them to quickly modify the array of molecular cues they provide on their surfaces and the extension of dynamic filopodia allows post-synaptic cells to engage in direct long-distance communication. By making use of familiar cellular mechanisms such as endocytosis and filopodia formation, post-synaptic cells may be able to communicate more effectively with potential synaptic partners.

  20. 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.

  1. Target detection and reconstruction for compressive multiple-input, multiple-output ultra-wideband noise radar imaging

    Science.gov (United States)

    Kwon, Yangsoo; Narayanan, Ram M.; Rangaswamy, Muralidhar

    2013-04-01

    We propose a sample selection method for multiple-input, multiple-output ultra-wideband noise radar imaging using compressive sensing. The proposed sample selection is based on comparing the norm values of candidates among the potential received signal and selecting the largest M samples among N per antenna to obtain selection diversity. Moreover, we propose an adaptive weighting allocation that improves reconstruction accuracy of compressive sensing by maximizing the mutual information between target echoes and transmitted signals. This weighting scheme is applicable to both sample selection schemes, a conventional random sampling and the proposed selection. Further, the weighting allocation with the knowledge of recovery error is proposed for more practical scenarios. Simulations show that the proposed selection and weighting allocation enhance multiple target detection probability and reduce normalized mean square error.

  2. Multiple Targets for the Management of Alzheimer's Disease.

    Science.gov (United States)

    Ahmad, Syed Sayeed; Akhtar, Salman; Jamal, Qazi Mohammad Sajid; Rizvi, Syed Mohd Danish; Kamal, Mohammad A; Khan, M Kalim A; Siddiqui, Mohd Haris

    2016-01-01

    AD is a progressive and irreversible neurodegenerative disease and the most common cause of dementia in the elderly population. Βeta- amyloid cascade formation along with several cytoskeleton abnormalities succeeding to the hyperphosphorylation of microtubule-associated tau protein in neurons leads to the elicitation of several neurotoxic incidents. As an outcome of these phenomena, steady growth of dementia in aged population is becoming ubiquitous in both developed and developing countries. Thus, the key aspiration is to endow with stable daily life functionality to the person suffering from dementia and to cut down or slower the symptoms of disease leading to disruptive behavior. In sight of this, the proteins amyloid-beta, BACE-1, RAGE and AChE are being aimed for the treatment of AD successfully. Currently, there are several medicines for the treatment of AD under survey like Galangin, Cymserine, Tolserine, Bisnorcymserine and Huperzine A. The article emphasizes clinical and neurobiological aspects of AD. The purpose of this review article is to provide a brief introduction of AD along with the related concept of beta-secretase, beta amyloid and neurotransmitter in the progression of disease. In the present review, we summarize the available evidence on the new therapeutic approaches that target amyloid and neurotransmitter in the AD.

  3. 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.

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

    Directory of Open Access Journals (Sweden)

    Baoliang Sun

    2016-11-01

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

  5. Translational Motion Compensation for Ballistic Targets Based on Delayed Conjugated Multiplication

    Directory of Open Access Journals (Sweden)

    He Si-san

    2014-10-01

    Full Text Available The micro-motion is combined with the high velocity of translation motion for ballistic targets. The translation motion should be compensated for micro-Doppler information extraction. A new method based on delay conjugate multiplication is proposed to compensate the translation motion of ballistic target. By delay conjugate multiplication of the received signal, the micro-Doppler information are canceled out and the translation motion parameters estimation problem is transformed as an multi-polynomial phase signal parameters estimation problem. Thus, the translation parameters can be estimated. Simulation results suggest that the proposed algorithm can achieve high-precision compensation for ballistic targets under low SNR.

  6. 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.

  7. 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.

  8. MicroRNAs targeting TGFβ signalling underlie the regulatory T cell defect in multiple sclerosis.

    Science.gov (United States)

    Severin, Mary E; Lee, Priscilla W; Liu, Yue; Selhorst, Amanda J; Gormley, Matthew G; Pei, Wei; Yang, Yuhong; Guerau-de-Arellano, Mireia; Racke, Michael K; Lovett-Racke, Amy E

    2016-06-01

    Transforming growth factor beta (TGFβ) signalling is critical for regulatory T cell development and function, and regulatory T cell dysregulation is a common observation in autoimmune diseases, including multiple sclerosis. In a comprehensive miRNA profiling study of patients with multiple sclerosis naïve CD4 T cells, 19 differentially expressed miRNAs predicted to target the TGFβ signalling pathway were identified, leading to the hypothesis that miRNAs may be responsible for the regulatory T cell defect observed in patients with multiple sclerosis. Patients with multiple sclerosis had reduced levels of TGFβ signalling components in their naïve CD4 T cells. The differentially expressed miRNAs negatively regulated the TGFβ pathway, resulting in a reduced capacity of naïve CD4 T cells to differentiate into regulatory T cells. Interestingly, the limited number of regulatory T cells, that did develop when these TGFβ-targeting miRNAs were overexpressed, were capable of suppressing effector T cells. As it has previously been demonstrated that compromising TGFβ signalling results in a reduced regulatory T cell repertoire insufficient to control autoimmunity, and patients with multiple sclerosis have a reduced regulatory T cell repertoire, these data indicate that the elevated expression of multiple TGFβ-targeting miRNAs in naïve CD4 T cells of patients with multiple sclerosis impairs TGFβ signalling, and dampens regulatory T cell development, thereby enhancing susceptibility to developing multiple sclerosis.

  9. 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.

  10. Tracking Multiple Video Targets with an Improved GM-PHD Tracker

    Directory of Open Access Journals (Sweden)

    Xiaolong Zhou

    2015-12-01

    Full Text Available Tracking multiple moving targets from a video plays an important role in many vision-based robotic applications. In this paper, we propose an improved Gaussian mixture probability hypothesis density (GM-PHD tracker with weight penalization to effectively and accurately track multiple moving targets from a video. First, an entropy-based birth intensity estimation method is incorporated to eliminate the false positives caused by noisy video data. Then, a weight-penalized method with multi-feature fusion is proposed to accurately track the targets in close movement. For targets without occlusion, a weight matrix that contains all updated weights between the predicted target states and the measurements is constructed, and a simple, but effective method based on total weight and predicted target state is proposed to search the ambiguous weights in the weight matrix. The ambiguous weights are then penalized according to the fused target features that include spatial-colour appearance, histogram of oriented gradient and target area and further re-normalized to form a new weight matrix. With this new weight matrix, the tracker can correctly track the targets in close movement without occlusion. For targets with occlusion, a robust game-theoretical method is used. Finally, the experiments conducted on various video scenarios validate the effectiveness of the proposed penalization method and show the superior performance of our tracker over the state of the art.

  11. Tracking Multiple Video Targets with an Improved GM-PHD Tracker.

    Science.gov (United States)

    Zhou, Xiaolong; Yu, Hui; Liu, Honghai; Li, Youfu

    2015-12-03

    Tracking multiple moving targets from a video plays an important role in many vision-based robotic applications. In this paper, we propose an improved Gaussian mixture probability hypothesis density (GM-PHD) tracker with weight penalization to effectively and accurately track multiple moving targets from a video. First, an entropy-based birth intensity estimation method is incorporated to eliminate the false positives caused by noisy video data. Then, a weight-penalized method with multi-feature fusion is proposed to accurately track the targets in close movement. For targets without occlusion, a weight matrix that contains all updated weights between the predicted target states and the measurements is constructed, and a simple, but effective method based on total weight and predicted target state is proposed to search the ambiguous weights in the weight matrix. The ambiguous weights are then penalized according to the fused target features that include spatial-colour appearance, histogram of oriented gradient and target area and further re-normalized to form a new weight matrix. With this new weight matrix, the tracker can correctly track the targets in close movement without occlusion. For targets with occlusion, a robust game-theoretical method is used. Finally, the experiments conducted on various video scenarios validate the effectiveness of the proposed penalization method and show the superior performance of our tracker over the state of the art.

  12. Targeting multiple types of tumors using NKG2D-coated iron oxide nanoparticles

    Science.gov (United States)

    Wu, Ming-Ru; Cook, W. James; Zhang, Tong; Sentman, Charles L.

    2014-11-01

    Iron oxide nanoparticles (IONPs) hold great potential for cancer therapy. Actively targeting IONPs to tumor cells can further increase therapeutic efficacy and decrease off-target side effects. To target tumor cells, a natural killer (NK) cell activating receptor, NKG2D, was utilized to develop pan-tumor targeting IONPs. NKG2D ligands are expressed on many tumor types and its ligands are not found on most normal tissues under steady state conditions. The data showed that mouse and human fragment crystallizable (Fc)-fusion NKG2D (Fc-NKG2D) coated IONPs (NKG2D/NPs) can target multiple NKG2D ligand positive tumor types in vitro in a dose dependent manner by magnetic cell sorting. Tumor targeting effect was robust even under a very low tumor cell to normal cell ratio and targeting efficiency correlated with NKG2D ligand expression level on tumor cells. Furthermore, the magnetic separation platform utilized to test NKG2D/NP specificity has the potential to be developed into high throughput screening strategies to identify ideal fusion proteins or antibodies for targeting IONPs. In conclusion, NKG2D/NPs can be used to target multiple tumor types and magnetic separation platform can facilitate the proof-of-concept phase of tumor targeting IONP development.

  13. Targeting proliferating cell nuclear antigen and its protein interactions induces apoptosis in multiple myeloma cells.

    Directory of Open Access Journals (Sweden)

    Rebekka Müller

    Full Text Available Multiple myeloma is a hematological cancer that is considered incurable despite advances in treatment strategy during the last decade. Therapies targeting single pathways are unlikely to succeed due to the heterogeneous nature of the malignancy. Proliferating cell nuclear antigen (PCNA is a multifunctional protein essential for DNA replication and repair that is often overexpressed in cancer cells. Many proteins involved in the cellular stress response interact with PCNA through the five amino acid sequence AlkB homologue 2 PCNA-interacting motif (APIM. Thus inhibiting PCNA's protein interactions may be a good strategy to target multiple pathways simultaneously. We initially found that overexpression of peptides containing the APIM sequence increases the sensitivity of cancer cells to contemporary therapeutics. Here we have designed a cell-penetrating APIM-containing peptide, ATX-101, that targets PCNA and show that it has anti-myeloma activity. We found that ATX-101 induced apoptosis in multiple myeloma cell lines and primary cancer cells, while bone marrow stromal cells and primary healthy lymphocytes were much less sensitive. ATX-101-induced apoptosis was caspase-dependent and cell cycle phase-independent. ATX-101 also increased multiple myeloma cells' sensitivity against melphalan, a DNA damaging agent commonly used for treatment of multiple myeloma. In a xenograft mouse model, ATX-101 was well tolerated and increased the anti-tumor activity of melphalan. Therefore, targeting PCNA by ATX-101 may be a novel strategy in multiple myeloma treatment.

  14. 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.

  15. CUL4A as a marker and potential therapeutic target in multiple myeloma.

    Science.gov (United States)

    Yang, Yougang; Wang, Shanan; Li, Jinghong; Qi, Shipeng; Zhang, Debing

    2017-07-01

    Multiple myeloma is the most common cause of death of hematological malignancy worldwide. Cullin 4A has been proposed as oncogene in several types of human cancer, but the expression and function of cullin 4A in multiple myeloma remain unclear. Here, we demonstrate that cullin 4A plays an oncogenic role in multiple myeloma development. The expression of cullin 4A was detected by quantitative real-time polymerase chain reaction in multiple myeloma patients and multiple myeloma cell lines. In addition, silencing of cullin 4A with small interfering RNA was performed in human multiple myeloma cells, and the impact on proliferation, cell cycle, apoptosis, migration, and invasion of the multiple myeloma cells was analyzed. We found that the level of cullin 4A in serum samples was significantly upregulated in patients with multiple myeloma compared with healthy control subjects. Knockdown of cullin 4A via small interfering RNA inhibited the proliferation of the multiple myeloma cell lines by delaying cell-cycle progression and increasing apoptosis. cullin 4A downregulation inhibited multiple myeloma cell migration and invasion in vitro. Our results suggested that cullin 4A could be a promising therapy target in multiple myeloma patients.

  16. 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.

  17. Direction Tracking of Multiple Moving Targets Using Quantum Particle Swarm Optimization

    Directory of Open Access Journals (Sweden)

    Gao Hongyuan

    2016-01-01

    Full Text Available Based on weighted signal covariance (WSC matrix and maximum likelihood (ML estimation, a directionof-arrival (DOA estimation method of multiple moving targets is designed and named as WSC-ML in the presence of impulse noise. In order to overcome the shortcoming of the multidimensional search cost of maximum likelihood estimation, a novel continuous quantum particle swarm optimization (QPSO is proposed for this continuous optimization problem. And a tracking method of multiple moving targets in impulsive noise environment is proposed and named as QPSO-WSC-ML. Later, we make use of rank-one updating to update the weighted signal covariance matrix of WSC-ML. Simulation results illustrate the proposed QPSO-WSC-ML method is efficient and robust for the direction tracking of multiple moving targets in the presence of impulse noise.

  18. Estimation of detection threshold in multiple ship target situations with HF ground wave radar

    Institute of Scientific and Technical Information of China (English)

    Li Hongbo; Shen Yiying; Liu Yongtan

    2007-01-01

    A credible method of calculating the detection threshold is presented for the multiple target situations,which appear frequently in the lower Doppler velocity region during the surveillance of sea with HF ground wave radar. This method defines a whole-peak-outlier elimination (WPOE) criterion, which is based on in-peak-samples correlation of each target echo spectra, to trim off the target signals and abnormal disturbances with great amplitude from the complex spectra. Therefore, cleaned background noise samples are obtained to improve the accuracy and reliability of noise level estimation. When the background noise is nonhomogeneous, the detection samples are limited and often occupied heavily with outliers. In this case, the problem that the detection threshold is overvalued can be solved. In applications on experimental data, it is verified that this method can reduce the miss alarm rate of signal detection effectively in multiple target situations as well as make the adaptability of the detector better.

  19. MiR-191 Regulates Primary Human Fibroblast Proliferation and Directly Targets Multiple Oncogenes.

    Directory of Open Access Journals (Sweden)

    Damon Polioudakis

    Full Text Available miRNAs play a central role in numerous pathologies including multiple cancer types. miR-191 has predominantly been studied as an oncogene, but the role of miR-191 in the proliferation of primary cells is not well characterized, and the miR-191 targetome has not been experimentally profiled. Here we utilized RNA induced silencing complex immunoprecipitations as well as gene expression profiling to construct a genome wide miR-191 target profile. We show that miR-191 represses proliferation in primary human fibroblasts, identify multiple proto-oncogenes as novel miR-191 targets, including CDK9, NOTCH2, and RPS6KA3, and present evidence that miR-191 extensively mediates target expression through coding sequence (CDS pairing. Our results provide a comprehensive genome wide miR-191 target profile, and demonstrate miR-191's regulation of primary human fibroblast proliferation.

  20. MiR-191 Regulates Primary Human Fibroblast Proliferation and Directly Targets Multiple Oncogenes.

    Science.gov (United States)

    Polioudakis, Damon; Abell, Nathan S; Iyer, Vishwanath R

    2015-01-01

    miRNAs play a central role in numerous pathologies including multiple cancer types. miR-191 has predominantly been studied as an oncogene, but the role of miR-191 in the proliferation of primary cells is not well characterized, and the miR-191 targetome has not been experimentally profiled. Here we utilized RNA induced silencing complex immunoprecipitations as well as gene expression profiling to construct a genome wide miR-191 target profile. We show that miR-191 represses proliferation in primary human fibroblasts, identify multiple proto-oncogenes as novel miR-191 targets, including CDK9, NOTCH2, and RPS6KA3, and present evidence that miR-191 extensively mediates target expression through coding sequence (CDS) pairing. Our results provide a comprehensive genome wide miR-191 target profile, and demonstrate miR-191's regulation of primary human fibroblast proliferation.

  1. 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.

  2. Targeting ASIC1 in primary progressive multiple sclerosis: evidence of neuroprotection with amiloride.

    Science.gov (United States)

    Arun, Tarunya; Tomassini, Valentina; Sbardella, Emilia; de Ruiter, Michiel B; Matthews, Lucy; Leite, Maria Isabel; Gelineau-Morel, Rose; Cavey, Ana; Vergo, Sandra; Craner, Matt; Fugger, Lars; Rovira, Alex; Jenkinson, Mark; Palace, Jacqueline

    2013-01-01

    Neurodegeneration is the main cause for permanent disability in multiple sclerosis. The effect of current immunomodulatory treatments on neurodegeneration is insufficient. Therefore, direct neuroprotection and myeloprotection remain an important therapeutic goal. Targeting acid-sensing ion channel 1 (encoded by the ASIC1 gene), which contributes to the excessive intracellular accumulation of injurious Na(+) and Ca(2+) and is over-expressed in acute multiple sclerosis lesions, appears to be a viable strategy to limit cellular injury that is the substrate of neurodegeneration. While blockade of ASIC1 through amiloride, a potassium sparing diuretic that is currently licensed for hypertension and congestive cardiac failure, showed neuroprotective and myeloprotective effects in experimental models of multiple sclerosis, this strategy remains untested in patients with multiple sclerosis. In this translational study, we tested the neuroprotective effects of amiloride in patients with primary progressive multiple sclerosis. First, we assessed ASIC1 expression in chronic brain lesions from post-mortem of patients with progressive multiple sclerosis to identify the target process for neuroprotection. Second, we tested the neuroprotective effect of amiloride in a cohort of 14 patients with primary progressive multiple sclerosis using magnetic resonance imaging markers of neurodegeneration as outcome measures of neuroprotection. Patients with primary progressive multiple sclerosis underwent serial magnetic resonance imaging scans before (pretreatment phase) and during (treatment phase) amiloride treatment for a period of 3 years. Whole-brain volume and tissue integrity were measured with high-resolution T(1)-weighted and diffusion tensor imaging. In chronic brain lesions of patients with progressive multiple sclerosis, we demonstrate an increased expression of ASIC1 in axons and an association with injury markers within chronic inactive lesions. In patients with primary

  3. How target-lure similarity shapes confidence judgments in multiple-alternative decision tasks.

    Science.gov (United States)

    Horry, Ruth; Brewer, Neil

    2016-12-01

    Confidence judgments in 2-alternative decisions have been the subject of a great deal of research in cognitive psychology. Sequential sampling models have been particularly successful at explaining confidence judgments in such decisions and the relationships between confidence, accuracy, and response latencies. Across 5 experiments, we derived predictions from sequential sampling models and applied them to more complex decisions: multiple-alternative decisions, and compound decisions, such as eyewitness identification tasks, in which a target may be present or absent within the array of items that can be selected. We hypothesized that, when a decision-maker chooses an item, confidence in that decision reflects the relative evidence for the chosen item over all unchosen items. We tested this hypothesis by manipulating the similarity between the target (or target-replacement, for trials in which the target was not present in the array) and the weakest lure(s). As target-lure similarity decreased, confidence in correct target identifications increased, while response latencies decreased. When the decision-maker chose none of the items, the similarity between the target-replacement and the lures was unrelated to confidence. We conclude that similar mechanisms underpin confidence judgments in multiple-alternative and positive compound decisions as in simpler, 2-alternative decisions. A goal of future research should be to formally extend sequential sampling models to more complex decisions, such that it will be possible to establish whether diffusion or accumulator models provide a better fit to the data. (PsycINFO Database Record

  4. MBSTAR: multiple instance learning for predicting specific functional binding sites in microRNA targets

    Science.gov (United States)

    Bandyopadhyay, Sanghamitra; Ghosh, Dip; Mitra, Ramkrishna; Zhao, Zhongming

    2015-01-01

    MicroRNA (miRNA) regulates gene expression by binding to specific sites in the 3'untranslated regions of its target genes. Machine learning based miRNA target prediction algorithms first extract a set of features from potential binding sites (PBSs) in the mRNA and then train a classifier to distinguish targets from non-targets. However, they do not consider whether the PBSs are functional or not, and consequently result in high false positive rates. This substantially affects the follow up functional validation by experiments. We present a novel machine learning based approach, MBSTAR (Multiple instance learning of Binding Sites of miRNA TARgets), for accurate prediction of true or functional miRNA binding sites. Multiple instance learning framework is adopted to handle the lack of information about the actual binding sites in the target mRNAs. Biologically validated 9531 interacting and 973 non-interacting miRNA-mRNA pairs are identified from Tarbase 6.0 and confirmed with PAR-CLIP dataset. It is found that MBSTAR achieves the highest number of binding sites overlapping with PAR-CLIP with maximum F-Score of 0.337. Compared to the other methods, MBSTAR also predicts target mRNAs with highest accuracy. The tool and genome wide predictions are available at http://www.isical.ac.in/~bioinfo_miu/MBStar30.htm.

  5. Cobalt sensitization and dermatitis

    DEFF Research Database (Denmark)

    Thyssen, Jacob P

    2012-01-01

    : This clinical review article presents clinical and scientific data on cobalt sensitization and dermatitis. It is concluded that cobalt despite being a strong sensitizer and a prevalent contact allergen to come up on patch testing should be regarded as a very complex metal to test with. Exposure...... data together with clinical data from metal workers heavily exposed to cobalt suggest that patch-test reactions are sometimes false positive and that patch testers should carefully evaluate their clinical relevance....

  6. Prediction of biological targets for compounds using multiple-category Bayesian models trained on chemogenomics databases.

    Science.gov (United States)

    Nidhi; Glick, Meir; Davies, John W; Jenkins, Jeremy L

    2006-01-01

    Target identification is a critical step following the discovery of small molecules that elicit a biological phenotype. The present work seeks to provide an in silico correlate of experimental target fishing technologies in order to rapidly fish out potential targets for compounds on the basis of chemical structure alone. A multiple-category Laplacian-modified naïve Bayesian model was trained on extended-connectivity fingerprints of compounds from 964 target classes in the WOMBAT (World Of Molecular BioAcTivity) chemogenomics database. The model was employed to predict the top three most likely protein targets for all MDDR (MDL Drug Database Report) database compounds. On average, the correct target was found 77% of the time for compounds from 10 MDDR activity classes with known targets. For MDDR compounds annotated with only therapeutic or generic activities such as "antineoplastic", "kinase inhibitor", or "anti-inflammatory", the model was able to systematically deconvolute the generic activities to specific targets associated with the therapeutic effect. Examples of successful deconvolution are given, demonstrating the usefulness of the tool for improving knowledge in chemogenomics databases and for predicting new targets for orphan compounds.

  7. Cooperative multiple target assignment of submunitions based on Chaos-PSO algorithm

    Science.gov (United States)

    Wu, Xuzhong; Tang, Shengjing; Shi, Jiao

    2011-10-01

    In this paper Multi-Objective particle swarm optimization (MOPSO) algorithm is utilized to solve the problem for cooperative multiple target assignment, which is the optimization problem in the discrete search space. At first a model of multi-objective optimization for Cooperative Multiple Target Assignment is established. Aiming to solve out the local convergence phenomenon, the chaos mutation is introduced into PSO for improving global optimal ability. Another underlying problem is that computing speed of the algorithm must meet the operational requirement, so a new kind of Chaos-MOPSO Algorithm is developed to solve the target assignment problem with less population and iterations. At last an authentication example is given in this paper, compared with basic MOPSO and NSGA-II, the Chaos-MOPSO algorithm obtained a better Pareto solution set with smaller computational burden.

  8. 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

    ESTIMATING SINGLE AND MULTIPLE TARGET LOCATIONS USING K-MEANS CLUSTERING WITH RADIO TOMOGRAPHIC IMAGING IN WIRELESS SENSOR NETWORKS THESIS Jeffrey K...AND MULTIPLE TARGET LOCATIONS USING K-MEANS CLUSTERING WITH RADIO TOMOGRAPHIC IMAGING IN WIRELESS SENSOR NETWORKS THESIS Presented to the Faculty...SINGLE AND MULTIPLE TARGET LOCATIONS USING K-MEANS CLUSTERING WITH RADIO TOMOGRAPHIC IMAGING IN WIRELESS SENSOR NETWORKS Jeffrey K. Nishida, B.S.E.E

  9. 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.

  10. Instance influence estimation for hyperspectral target signature characterization using extended functions of multiple instances

    Science.gov (United States)

    Zou, Sheng; Zare, Alina

    2016-05-01

    The Extended Functions of Multiple Instances (eFUMI) algorithm1 is a generalization of Multiple Instance Learning (MIL). In eFUMI, only bag level (i.e. set level) labels are needed to estimate target signatures from mixed data. The training bags in eFUMI are labeled positive if any data point in a bag contains or represents any proportion of the target signature and are labeled as a negative bag if all data points in the bag do not represent any target. From these imprecise labels, eFUMI has been shown to be effective at estimating target signatures in hyperspectral subpixel target detection problems. One motivating scenario for the use of eFUMI is where an analyst circles objects/regions of interest in a hyperspectral scene such that the target signatures of these objects can be estimated and be used to determine whether other instances of the object appear elsewhere in the image collection. The regions highlighted by the analyst serve as the imprecise labels for eFUMI. Often, an analyst may want to iteratively refine their imprecise labels. In this paper, we present an approach for estimating the influence on the estimated target signature if the label for a particular input data point is modified. This instance influence estimation guides an analyst to focus on (re-)labeling the data points that provide the largest change in the resulting estimated target signature and, thus, reduce the amount of time an analyst needs to spend refining the labels for a hyperspectral scene. Results are shown on real hyperspectral sub-pixel target detection data sets.

  11. Cobalt release from inexpensive jewellery

    DEFF Research Database (Denmark)

    Thyssen, Jacob Pontoppidan; Jellesen, Morten Stendahl; Menné, Torkil

    2010-01-01

    Objectives: The aim was to study 354 consumer items using the cobalt spot test. Cobalt release was assessed to obtain a risk estimate of cobalt allergy and dermatitis in consumers who would wear the jewellery. Methods: The cobalt spot test was used to assess cobalt release from all items....... Microstructural characterization was made using scanning electron microscope (SEM) and energy-dispersive spectroscopy (EDS). Results: Cobalt release was found in 4 (1.1%) of 354 items. All these had a dark appearance. SEM/EDS was performed on the four dark appearing items which showed tin-cobalt plating on these....... Conclusions: This study showed that only a minority of inexpensive jewellery purchased in Denmark released cobalt when analysed with the cobalt spot test. As fashion trends fluctuate and we found cobalt release from dark appearing jewellery, cobalt release from consumer items should be monitored in the future...

  12. The Categorical Distinction Between Targets and Distractors Facilitates Tracking in Multiple Identity Tracking Task.

    Science.gov (United States)

    Wei, Liuqing; Zhang, Xuemin; Lyu, Chuang; Li, Zhen

    2016-01-01

    This study investigates the tracking facilitation effect during categorical distinction between targets and distractors in the Multiple Identity Tracking task. We asked observers to track four targets in a total of eight moving objects, and manipulated categorical distinctions of targets and distractors across four experiments, with different combinations of inter-category and intra-category differences. Results show that tracking performance was significantly better when the targets and distractors were inter-category different, compared to when the targets and distractors were identical or intra-category distinctive. As the inter-category distinction between targets and distractors narrowed, tracking performance improved, but the inter-category facilitation effect decreased. These results may indicate a category-based grouping effect: the observers organized the targets within the same semantic category into one group and made the targets more easily and accurately rediscovered when lost during tracking. Furthermore, the tracking facilitation of categorical distinction diminished when all the objects were inverted. This proved that besides their visual distinctiveness, objects' semantic category information also played an important role during tracking.

  13. Molecular Communication Model for Targeted Drug Delivery in Multiple Disease Sites With Diversely Expressed Enzymes.

    Science.gov (United States)

    Chude-Okonkwo, Uche A K; Malekian, Reza; Maharaj, B T Sunil

    2016-04-01

    Targeted drug delivery (TDD) for disease therapy using liposomes as nanocarriers has received extensive attention in the literature. The liposome's ability to incorporate capabilities such as long circulation, stimuli responsiveness, and targeting characteristics, makes it a versatile nanocarrier. Timely drug release at the targeted site requires that trigger stimuli such as pH, light, and enzymes be uniquely overexpressed at the targeted site. However, in some cases, the targeted sites may not express trigger stimuli significantly, hence, achieving effective TDD at those sites is challenging. In this paper, we present a molecular communication-based TDD model for the delivery of therapeutic drugs to multiple sites that may or may not express trigger stimuli. The nanotransmitter and nanoreceiver models for the molecular communication system are presented. Here, the nanotransmitter and nanoreceiver are injected into the targeted body system's blood network. The compartmental pharmacokinetics model is employed to model the transportation of these therapeutic nanocarriers to the targeted sites where they are meant to anchor before the delivery process commences. We also provide analytical expressions for the delivered drug concentration. The effectiveness of the proposed model is investigated for drug delivery on tissue surfaces. Results show that the effectiveness of the proposed molecular communication-based TDD depends on parameters such as the total transmitter volume capacity, the receiver radius, the diffusion characteristic of the microenvironment of the targeted sites, and the concentration of the enzymes associated with the nanotransmitter and the nanoreceiver designs.

  14. Targeting the vascular endothelial growth factor pathway in the treatment of multiple myeloma.

    Science.gov (United States)

    Podar, Klaus; Richardson, Paul G; Chauhan, Dharminder; Anderson, Kenneth C

    2007-04-01

    Multiple myeloma is a clonal plasma cell malignancy within the bone marrow associated with bone loss, renal disease and immunodeficiency. Despite new insights into the pathogenesis of multiple myeloma and novel targeted therapies, the median survival remains 3-5 years. It is now well established that the intimate relation between the tumor cells and components of the microenvironment plays a key role in multiple myeloma pathogenesis. Specifically, tumor cells impact the bone marrow and thereby cause immune suppression and lytic bone lesions; conversely, components of the bone marrow provide signals that influence the behavior of multiple myeloma cells, including tumor cell growth, survival, migration and drug resistance. Important contributing effectors are tumor cell-stroma cell and cell-extracellular matrix contacts, the bone marrow vasculature, and a variety of cytokines and growth factors in the bone marrow milieu.

  15. 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.

  16. Newtonian Imperialist Competitve Approach to Optimizing Observation of Multiple Target Points in Multisensor Surveillance Systems

    Science.gov (United States)

    Afghan-Toloee, A.; Heidari, A. A.; Joibari, Y.

    2013-09-01

    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. On the estimation of target depth using the single transmit multiple receive metal detector array

    Science.gov (United States)

    Ho, K. C.; Gader, P. D.

    2012-06-01

    This paper investigates the use of the Single Transmit Multiple Receive (STMR) metal detector (MD) array to estimate the depth of metal targets, such as 155mm shells. The depth estimation problem using MD has been investigated by a number of researchers and the processing was performed along the down-track. The proposed method takes a different approach by exploring the MD responses in cross-track to achieve the depth estimation. It is found that the normalized energy spread of the MD output is narrower for shallow targets and wider for deeper targets. Based on this observation, a method is derived to estimate the depth of a target. Experimental results from the data collected at an U.S. Army test site validate the performance of the proposed depth estimator.

  18. 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%.

  19. 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.

  20. 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.

  1. Quantitative Comparison of Tumor Delivery for Multiple Targeted Nanoparticles Simultaneously by Multiplex ICP-MS

    Science.gov (United States)

    Elias, Andrew; Crayton, Samuel H.; Warden-Rothman, Robert; Tsourkas, Andrew

    2014-01-01

    Given the rapidly expanding library of disease biomarkers and targeting agents, the number of unique targeted nanoparticles is growing exponentially. The high variability and expense of animal testing often makes it unfeasible to examine this large number of nanoparticles in vivo. This often leads to the investigation of a single formulation that performed best in vitro. However, nanoparticle performance in vivo depends on many variables, many of which cannot be adequately assessed with cell-based assays. To address this issue, we developed a lanthanide-doped nanoparticle method that allows quantitative comparison of multiple targeted nanoparticles simultaneously. Specifically, superparamagnetic iron oxide (SPIO) nanoparticles with different targeting ligands were created, each with a unique lanthanide dopant. Following the simultaneous injection of the various SPIO compositions into tumor-bearing mice, inductively coupled plasma mass spectroscopy was used to quantitatively and orthogonally assess the concentration of each SPIO composition in serial blood and resected tumor samples. PMID:25068300

  2. Quantitative Comparison of Tumor Delivery for Multiple Targeted Nanoparticles Simultaneously by Multiplex ICP-MS

    Science.gov (United States)

    Elias, Andrew; Crayton, Samuel H.; Warden-Rothman, Robert; Tsourkas, Andrew

    2014-07-01

    Given the rapidly expanding library of disease biomarkers and targeting agents, the number of unique targeted nanoparticles is growing exponentially. The high variability and expense of animal testing often makes it unfeasible to examine this large number of nanoparticles in vivo. This often leads to the investigation of a single formulation that performed best in vitro. However, nanoparticle performance in vivo depends on many variables, many of which cannot be adequately assessed with cell-based assays. To address this issue, we developed a lanthanide-doped nanoparticle method that allows quantitative comparison of multiple targeted nanoparticles simultaneously. Specifically, superparamagnetic iron oxide (SPIO) nanoparticles with different targeting ligands were created, each with a unique lanthanide dopant. Following the simultaneous injection of the various SPIO compositions into tumor-bearing mice, inductively coupled plasma mass spectroscopy was used to quantitatively and orthogonally assess the concentration of each SPIO composition in serial blood and resected tumor samples.

  3. A systematic identification of multiple toxin-target interactions based on chemical, genomic and toxicological data.

    Science.gov (United States)

    Zhou, Wei; Huang, Chao; Li, Yan; Duan, Jinyou; Wang, Yonghua; Yang, Ling

    2013-02-01

    Although the assessment of toxicity of various agents, -omics (genomic, proteomic, metabolomic, etc.) data has been accumulated largely, the acquirement of toxicity information of variety of molecules through experimental methods still remains a difficult task. Presently, a systems toxicology approach that integrates massive diverse chemical, genomic and toxicological information was developed for prediction of the toxin targets and their related networks. The procedures are: (1) by use of two powerful statistical methods, i.e., support vector machine (SVM) and random forest (RF), a systemic model for prediction of multiple toxin-target interactions using the extracted chemical and genomic features has been developed with its reliability and robustness estimated. And the qualitative classification of targets according to the phenotypic diseases has been taken into account to further uncover the biological meaning of the targets, as well as to validate the robustness of the in silico models. (2) Based on the predicted toxin-target interactions, a genome-scale toxin-target-disease network exampled by cardiovascular disease is generated. (3) A topological analysis of the network is carried out to identify those targets that are most susceptible in human to topical agents including the most critical toxins, as well as to uncover both the toxin-specific mechanisms and pathways. The methodologies presented herein for systems toxicology will make drug development, toxin environmental risk assessment more efficient, acceptable and cost-effective.

  4. Performance of passive target tracking using bearing-frequency and bearings of multiple arrays

    Institute of Scientific and Technical Information of China (English)

    DU Xuanmin; YAO Lan

    2002-01-01

    Two target motion analysis (TMA) methods using multi-dimension information are studied, one is TMA with bearing-frequency and the other is TMA with multiple arrays. The optimization algorithm combining Gauss-Newton (G-N) method with Levenberg-Marquardt(LM) method is applied to analyze the performance of target tracking with maximum likelihood estimation(MLE), and Monte Carlo experiments are presented. The results show that although the TMA with multi-dimension information have eliminated the maneuvers needed by conventional bearing-only TMA, but the application are not of universality.

  5. Using interacting multiple model particle filter to track airborne targets hidden in blind Doppler

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    In airborne tracking, the blind Doppler makes the target undetectable, resulting in tracking difficulties. In this paper,we studied most possible blind-Doppler cases and summed them up into two types: targets' intentional tangential flying to radar and unintentional flying with large tangential speed. We proposed an interacting multiple model (IMM) particle filter which combines a constant velocity model and an acceleration model to handle maneuvering motions. We compared the IMM particle filter with a previous particle filter solution. Simulation results showed that the IMM particle filter outperforms the method in previous works in terms of tracking accuracy and continuity.

  6. Optimization neural net for multiple-target data association: real-time optical lab results

    Science.gov (United States)

    Yee, Mark L.; Casasent, David P.

    1991-08-01

    The Hopfield neural network was first used for optimization in solving the famous Traveling Salesman Problem. A similar approach has been applied to the solution of another problem, namely, data association for multiple targets. Simulation data are presented which demonstrate the network''s ability to successfully determine the optimum data association solutions, with target noise present. Simulations also indicate the ability to solve the problem on a low accuracy (analog optical) processor. Optical implementation issues are discussed, and an optical architecture is presented with laboratory results.

  7. Effects of target enhancement and distractor suppression on multiple object tracking capacity.

    Science.gov (United States)

    Bettencourt, Katherine C; Somers, David C

    2009-07-14

    Mounting evidence suggests that visual attention may be simultaneously deployed to multiple distinct object locations, but the constraints upon this multi-object attentional system are still debated. Results from multiple object tracking (MOT) experiments have been interpreted as revealing a fixed attentional capacity limit of 4 objects, while other evidence has suggested that attentional capacity may be more fluid. Here, we investigated the influence of target stimulus factors, such as speed and size, and of distractor filtering factors, such as number of distractors and screen density, on MOT performance. Each factor had significant effects on capacity, producing values that ranged from above 6 objects down to one object, depending on the task demands. Although our results support the view that crowding effects modulate the effective capacity of attention, we also find evidence that central processes related to distractor suppression and target enhancement modulate capacity.

  8. 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.

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

    OpenAIRE

    Palmer, Alan M.

    2013-01-01

    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 leuko...

  10. Implementation of non-local quantum controlled-NOT gate with multiple targets

    Institute of Scientific and Technical Information of China (English)

    Libing Chen(陈立冰); Hong Lu(路洪)

    2004-01-01

    We show how a non-local quantum controlled-NOT (CNOT) gate with multiple targets can be implemented with unit fidelity and unit probability. The explicit quantum circuit for implementing the operation is presented. Two schemes for probabilistic implementing the operation via partially entangled quantum channels with unit fidelity are put forward. The overall physical resources required for accomplishing these schemes are different, and the successful implementation probabilities are also different.

  11. 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.

  12. Caveolin-1 as a potential new therapeutic target in multiple myeloma.

    Science.gov (United States)

    Podar, Klaus; Anderson, Kenneth C

    2006-02-20

    Caveolae are specialized flask-shaped lipid rafts enriched in cholesterol, sphingolipids, and structural marker proteins termed caveolins. Caveolins are highly conserved hairpin loop-shaped, oligomeric proteins of 22-24 kDa. Besides the plasma cell membrane, caveolins are also present in mitochondria, the endoplasmatic reticulum, the Golgi/trans-Golgi network, and secretory vesicles. They play a critical role in normal vesicular transport, cholesterol homeostasis, and signal transduction. Conversely, dysregulation of caveolin-1 has been associated with several human diseases including multiple myeloma, an incurable malignancy characterized by excess monoclonal plasma cells within the bone marrow. In this mini-review, we characterize the functional role of caveolin-1 in multiple myeloma, and present the preclinical rationale for novel potential therapeutic approaches targeting caveolin-1 in multiple myeloma.

  13. 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.

  14. Therapeutic Targeting of miR-29b/HDAC4 Epigenetic Loop in Multiple Myeloma.

    Science.gov (United States)

    Amodio, Nicola; Stamato, Maria Angelica; Gullà, Anna Maria; Morelli, Eugenio; Romeo, Enrica; Raimondi, Lavinia; Pitari, Maria Rita; Ferrandino, Ida; Misso, Gabriella; Caraglia, Michele; Perrotta, Ida; Neri, Antonino; Fulciniti, Mariateresa; Rolfo, Christian; Anderson, Kenneth C; Munshi, Nikhil C; Tagliaferri, Pierosandro; Tassone, Pierfrancesco

    2016-06-01

    Epigenetic abnormalities are common in hematologic malignancies, including multiple myeloma, and their effects can be efficiently counteracted by a class of tumor suppressor miRNAs, named epi-miRNAs. Given the oncogenic role of histone deacetylases (HDAC) in multiple myeloma, we investigated whether their activity could be antagonized by miR-29b, a well-established epi-miRNA. We demonstrated here that miR-29b specifically targets HDAC4 and highlighted that both molecules are involved in a functional loop. In fact, silencing of HDAC4 by shRNAs inhibited multiple myeloma cell survival and migration and triggered apoptosis and autophagy, along with the induction of miR-29b expression by promoter hyperacetylation, leading to the downregulation of prosurvival miR-29b targets (SP1, MCL-1). Moreover, treatment with the pan-HDAC inhibitor SAHA upregulated miR-29b, overcoming the negative control exerted by HDAC4. Importantly, overexpression or inhibition of miR-29b, respectively, potentiated or antagonized SAHA activity on multiple myeloma cells, as also shown in vivo by a strong synergism between miR-29b synthetic mimics and SAHA in a murine xenograft model of human multiple myeloma. Altogether, our results shed light on a novel epigenetic circuitry regulating multiple myeloma cell growth and survival and open new avenues for miR-29b-based epi-therapeutic approaches in the treatment of this malignancy. Mol Cancer Ther; 15(6); 1364-75. ©2016 AACR. ©2016 American Association for Cancer Research.

  15. Temperate marine reserves enhance targeted but not untargeted fishes in multiple no-take MPAs.

    Science.gov (United States)

    Tetreault, Irene; Ambrose, Richard F

    2007-12-01

    Although many papers report the effects of no-take marine protected areas (MPAs or reserves), scientifically rigorous empirical studies are rare, particularly for temperate reef fishes. We evaluated the responses of fish populations to protection from fishing in reserves by comparing densities and sizes inside and outside of five no-take reserves in southern California, USA. Our results are robust because we compared responses across multiple rocky-reef reserves in two different years and controlled for possible site differences by (a) ensuring that habitat characteristics were the same inside and outside reserves, and (b) sampling species that are not targeted, which would not be expected to have a direct response to fishing. We compared fish density and size and calculated biomass and egg production across all five sites. Fishes targeted by recreational and/or commercial fisheries consistently exhibited increases in mean density (150%), size (30%), biomass (440%), and egg production (730%) inside reserves. Reserve effects were greatest for legal-sized targeted fishes: significantly greater densities were found exclusively inside reserves for targeted species (580%), the largest size classes existed only inside reserves, and mean biomass was 1000% higher. These responses were unlikely to have been caused by habitat differences because there were no significant differences in habitat characteristics between reserve and control locations. Densities of non-targeted species did not differ between reserve and non-reserve locations, further supporting the conclusions that differences in targeted species between reserve and control locations were due to harvesting rather than site-specific effects. Although MPAs cannot replace traditional fisheries management, the concentration of increased biomass and egg production is a unique MPA benefit that serves both reserves and fisheries. Scientifically rigorous studies that include multiple reserves, such as this study, are

  16. Electrodeposition of Cobalt Nanowires

    Energy Technology Data Exchange (ETDEWEB)

    Ahn, Sungbok; Hong, Kimin [Chungnam National Univ., Daejeon (Korea, Republic of)

    2013-03-15

    We developed an electroplating process of cobalt nanowires of which line-widths were between 70 and 200 nm. The plating electrolyte was made of CoSO{sub 4} and an organic additive, dimethyldithiocarbamic acid ester sodium salt (DAESA). DAESA in plating electrolytes had an accelerating effect and reduced the surface roughness of plated cobalt thin films. We obtained void-free cobalt nanowires when the plating current density was 6.25 mA/cm{sup 2} and DAESA concentration was 1 mL/L.

  17. Phosphine modified cobalt hydroformylation

    Energy Technology Data Exchange (ETDEWEB)

    Rensburg, H. van; Tooze, R.P.; Foster, D.F. [Sasol Technology UK, St. Andrews (United Kingdom); Janse van Rensburg, W. [Sasol Technology, Sasolburg (South Africa)

    2006-07-01

    An ongoing challenge in phosphine modified cobalt hydroformylation is the fundamental understanding of the electronic and steric properties of phosphine ligands that influence the selectivity and activity of the catalytic reaction. A series of acyclic and cyclic phosphines have been prepared and tested in phosphine modified cobalt hydroformylation of 1-octene. Molecular modelling on a series of phospholanes showed some interesting theoretical and experimental correlations. We also evaluated the use of N-heterocyclic carbenes as an alternative for phosphines in modified cobalt hydroformylation. (orig.)

  18. Planning paths to multiple targets: memory involvement and planning heuristics in spatial problem solving.

    Science.gov (United States)

    Wiener, J M; Ehbauer, N N; Mallot, H A

    2009-09-01

    For large numbers of targets, path planning is a complex and computationally expensive task. Humans, however, usually solve such tasks quickly and efficiently. We present experiments studying human path planning performance and the cognitive processes and heuristics involved. Twenty-five places were arranged on a regular grid in a large room. Participants were repeatedly asked to solve traveling salesman problems (TSP), i.e., to find the shortest closed loop connecting a start location with multiple target locations. In Experiment 1, we tested whether humans employed the nearest neighbor (NN) strategy when solving the TSP. Results showed that subjects outperform the NN-strategy, suggesting that it is not sufficient to explain human route planning behavior. As a second possible strategy we tested a hierarchical planning heuristic in Experiment 2, demonstrating that participants first plan a coarse route on the region level that is refined during navigation. To test for the relevance of spatial working memory (SWM) and spatial long-term memory (LTM) for planning performance and the planning heuristics applied, we varied the memory demands between conditions in Experiment 2. In one condition the target locations were directly marked, such that no memory was required; a second condition required participants to memorize the target locations during path planning (SWM); in a third condition, additionally, the locations of targets had to retrieved from LTM (SWM and LTM). Results showed that navigation performance decreased with increasing memory demands while the dependence on the hierarchical planning heuristic increased.

  19. Discovery of rare mutations in extensively pooled DNA samples using multiple target enrichment.

    Science.gov (United States)

    Chi, Xu; Zhang, Yingchun; Xue, Zheyong; Feng, Laibao; Liu, Huaqing; Wang, Feng; Qi, Xiaoquan

    2014-08-01

    Chemical mutagenesis is routinely used to create large numbers of rare mutations in plant and animal populations, which can be subsequently subjected to selection for beneficial traits and phenotypes that enable the characterization of gene functions. Several next-generation sequencing (NGS)-based target enrichment methods have been developed for the detection of mutations in target DNA regions. However, most of these methods aim to sequence a large number of target regions from a small number of individuals. Here, we demonstrate an effective and affordable strategy for the discovery of rare mutations in a large sodium azide-induced mutant rice population (F2 ). The integration of multiplex, semi-nested PCR combined with NGS library construction allowed for the amplification of multiple target DNA fragments for sequencing. The 8 × 8 × 8 tridimensional DNA sample pooling strategy enabled us to obtain DNA sequences of 512 individuals while only sequencing 24 samples. A stepwise filtering procedure was then elaborated to eliminate most of the false positives expected to arise through sequencing error, and the application of a simple Student's t-test against position-prone error allowed for the discovery of 16 mutations from 36 enriched targeted DNA fragments of 1024 mutagenized rice plants, all without any false calls.

  20. One for All? Hitting Multiple Alzheimer's Disease Targets with One Drug.

    Science.gov (United States)

    Hughes, Rebecca E; Nikolic, Katarina; Ramsay, Rona R

    2016-01-01

    HIGHLIGHTS Many AD target combinations are being explored for multi-target drug design.New databases and models increase the potential of computational drug designLiraglutide and other antidiabetics are strong candidates for repurposing to AD.Donecopride a dual 5-HT/AChE inhibitor shows promise in pre-clinical studies 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 (MTDs). Intended as an introduction for non-experts, this review describes the key MTD 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 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.

  1. Pathways targeted by antidiabetes drugs are enriched for multiple genes associated with type 2 diabetes risk.

    Science.gov (United States)

    Segrè, Ayellet V; Wei, Nancy; Altshuler, David; Florez, Jose C

    2015-04-01

    Genome-wide association studies (GWAS) have uncovered >65 common variants associated with type 2 diabetes (T2D); however, their relevance for drug development is not yet clear. Of note, the first two T2D-associated loci (PPARG and KCNJ11/ABCC8) encode known targets of antidiabetes medications. We therefore tested whether other genes/pathways targeted by antidiabetes drugs are associated with T2D. We compiled a list of 102 genes in pathways targeted by marketed antidiabetic medications and applied Gene Set Enrichment Analysis (MAGENTA [Meta-Analysis Gene-set Enrichment of variaNT Associations]) to this gene set, using available GWAS meta-analyses for T2D and seven quantitative glycemic traits. We detected a strong enrichment of drug target genes associated with T2D (P = 2 × 10(-5); 14 potential new associations), primarily driven by insulin and thiazolidinedione (TZD) targets, which was replicated in an independent meta-analysis (Metabochip). The glycemic traits yielded no enrichment. The T2D enrichment signal was largely due to multiple genes of modest effects (P = 4 × 10(-4), after removing known loci), highlighting new associations for follow-up (ACSL1, NFKB1, SLC2A2, incretin targets). Furthermore, we found that TZD targets were enriched for LDL cholesterol associations, illustrating the utility of this approach in identifying potential side effects. These results highlight the potential biomedical relevance of genes revealed by GWAS and may provide new avenues for tailored therapy and T2D treatment design. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  2. Cluster-based centralized data fusion for tracking maneuvering targets using interacting multiple model algorithm

    Indian Academy of Sciences (India)

    V Vaidehi; K Kalavidya; S Indira Gandhi

    2004-04-01

    The interacting multiple model (IMM) algorithm has proved to be useful in tracking maneuvering targets. Tracking accuracy can be further improved using data fusion. Tracking of multiple targets using multiple sensors and fusing them at a central site using centralized architecture involves communication of large volumes of measurements to a common site. This results in heavy processing requirement at the central site. Moreover, track updates have to be obtained in the fusion centre before the next measurement arrives. For solving this computational complexity, a cluster-based parallel processing solution is presented in this paper. In this scheme, measurements are sent to the data fusion centre where the measurements are partitioned and given to the slave processors in the cluster. The slave processors use the IMM algorithm to get accurate updates of the tracks. The master processor collects the updated tracks and performs data fusion using ‘weight decision approach’. The improvement in the computation time using clusters in the data fusion centre is presented in this paper.

  3. A Multiple Impact Hypothesis for Moon Formation: Target Spin and Disk Properties

    Science.gov (United States)

    Rufu, R.; Aharonson, O.

    2015-12-01

    We investigate aspects of the multiple impact hypothesis for Moon's formation, whereby the proto-Earth suffers successive collisions, each forming a debris disk that accretes to form a moonlet. The moonlets tidally advance outward, and potentially coalesce to form the Moon. In addressing the fundamental problem of the Moon's formation, we consider smaller impactors than previously studied, and investigate the effect of new geometries using a Smoothed Particles Hydrodynamics (SPH) code. For impacts within the equatorial plane, we find multiple impactors are effective in draining angular momentum from the target's initial spin due to the often-neglected angular momentum carried by escaping mass. Our simulations reveal new consequences of non-equatorial inclination of the impactor, also previously neglected. We note relationships with the resulting disks of corresponding equatorial cases, but find that the target's axis of rotation can now be tilted by a significant amount (10's of degrees) with sub-Mars size impactors. Importantly for distinguishing among competing Moon formation hypotheses, our results imply that (i) the rotational acceleration of the proto-Earth by successive impacts may be limited by angular momentum drain if the impacting population contains multiple members of medium size, and (ii) impacts onto such a non-rapidly rotation proto-Earth (well below break-up speed) can produce disks compatible with sub-Moon fragments in mass, momentum, and composition.

  4. Multiple Target Localization with Bistatic Radar Using Heuristic Computational Intelligence Techniques

    Directory of Open Access Journals (Sweden)

    Fawad Zaman

    2015-01-01

    Full Text Available We assume Bistatic Phase Multiple Input Multiple Output radar having passive Centrosymmetric Cross Shape Sensor Array (CSCA on its receiver. Let the transmitter of this Bistatic radar send coherent signals using a subarray that gives a fairly wide beam with a large solid angle so as to cover up any potential relevant target in the near field. We developed Heuristic Computational Intelligence (HCI based techniques to jointly estimate the range, amplitude, and elevation and azimuth angles of these multiple targets impinging on the CSCA. In this connection, first the global search optimizers, that is,are developed separately Particle Swarm Optimization (PSO and Differential Evolution (DE are developed separately, and, to enhance the performances further, both of them are hybridized with a local search optimizer called Active Set Algorithm (ASA. Initially, the performance of PSO, DE, PSO hybridized with ASA, and DE hybridized with ASA are compared with each other and then with some traditional techniques available in literature using root mean square error (RMSE as figure of merit.

  5. A distributed automatic target recognition system using multiple low resolution sensors

    Science.gov (United States)

    Yue, Zhanfeng; Lakshmi Narasimha, Pramod; Topiwala, Pankaj

    2008-04-01

    In this paper, we propose a multi-agent system which uses swarming techniques to perform high accuracy Automatic Target Recognition (ATR) in a distributed manner. The proposed system can co-operatively share the information from low-resolution images of different looks and use this information to perform high accuracy ATR. An advanced, multiple-agent Unmanned Aerial Vehicle (UAV) systems-based approach is proposed which integrates the processing capabilities, combines detection reporting with live video exchange, and swarm behavior modalities that dramatically surpass individual sensor system performance levels. We employ real-time block-based motion analysis and compensation scheme for efficient estimation and correction of camera jitter, global motion of the camera/scene and the effects of atmospheric turbulence. Our optimized Partition Weighted Sum (PWS) approach requires only bitshifts and additions, yet achieves a stunning 16X pixel resolution enhancement, which is moreover parallizable. We develop advanced, adaptive particle-filtering based algorithms to robustly track multiple mobile targets by adaptively changing the appearance model of the selected targets. The collaborative ATR system utilizes the homographies between the sensors induced by the ground plane to overlap the local observation with the received images from other UAVs. The motion of the UAVs distorts estimated homography frame to frame. A robust dynamic homography estimation algorithm is proposed to address this, by using the homography decomposition and the ground plane surface estimation.

  6. In silico multiple-targets identification for heme detoxification in the human malaria parasite Plasmodium falciparum.

    Science.gov (United States)

    Phaiphinit, Suthat; Pattaradilokrat, Sittiporn; Lursinsap, Chidchanok; Plaimas, Kitiporn

    2016-01-01

    Detoxification of hemoglobin byproducts or free heme is an essential step and considered potential targets for anti-malaria drug development. However, most of anti-malaria drugs are no longer effective due to the emergence and spread of the drug resistant malaria parasites. Therefore, it is an urgent need to identify potential new targets and even for target combinations for effective malaria drug design. In this work, we reconstructed the metabolic networks of Plasmodium falciparum and human red blood cells for the simulation of steady mass and flux flows of the parasite's metabolites under the blood environment by flux balance analysis (FBA). The integrated model, namely iPF-RBC-713, was then adjusted into two stage-specific metabolic models, which first was for the pathological stage metabolic model of the parasite when invaded the red blood cell without any treatment and second was for the treatment stage of the parasite when a drug acted by inhibiting the hemozoin formation and caused high production rate of heme toxicity. The process of identifying target combinations consisted of two main steps. Firstly, the optimal fluxes of reactions in both the pathological and treatment stages were computed and compared to determine the change of fluxes. Corresponding enzymes of the reactions with zero fluxes in the treatment stage but non-zero fluxes in the pathological stage were predicted as a preliminary list of potential targets in inhibiting heme detoxification. Secondly, the combinations of all possible targets listed in the first step were examined to search for the best promising target combinations resulting in more effective inhibition of the detoxification to kill the malaria parasites. Finally, twenty-three enzymes were identified as a preliminary list of candidate targets which mostly were in pyruvate metabolism and citrate cycle. The optimal set of multiple targets for blocking the detoxification was a set of heme ligase, adenosine transporter, myo

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

    Science.gov (United States)

    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. D. R.; Badełek, B.; Balestra, F.; Ball, M.; Barth, J.; Beck, R.; Bedfer, Y.; Bernhard, J.; Bicker, K.; Bielert, E. R.; Birsa, R.; Bodlak, 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. L.; Curiel, Q.; Dalla Torre, S.; Dasgupta, S. S.; Dasgupta, S.; Denisov, O. Yu.; 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, M.; Fischer, H.; Franco, C.; du 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 Perdekamp, 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.-Y.; Huber, S.; Ishimoto, S.; Ivanov, A.; Ivanshin, Yu.; Iwata, T.; Jary, V.; Joosten, R.; Jörg, 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.; Königsmann, K.; Konorov, I.; Konstantinov, V. F.; Kotzinian, A. M.; Kouznetsov, O. M.; 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. K.; Marianski, B.; Martin, A.; Marzec, J.; Matoušek, J.; Matsuda, H.; Matsuda, T.; Meshcheryakov, G. V.; 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. 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.; Schönning, K.; Seder, E.; Selyunin, A.; Silva, L.; Sinha, L.; Sirtl, S.; Slunecka, M.; Smolik, J.; Sozzi, F.; Srnka, A.; 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.; Zavada, P.; Zavertyaev, M.; Zemlyanichkina, E.; Zhuravlev, N.; Ziembicki, M.; Zink, A.

    2017-04-01

    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 / c) 2 5 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.

  8. 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.

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

    CERN Document Server

    Adolph, C.

    2017-01-01

    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.

  10. INTRSECT: single-component targeting of cells using multiple-feature Boolean logic

    Science.gov (United States)

    Fenno, Lief E.; Mattis, Joanna; Ramakrishnan, Charu; Hyun, Minsuk; Lee, Soo Yeun; He, Miao; Tucciarone, Jason; Selimbeyoglu, Aslihan; Berndt, Andre; Grosenick, Logan; Zalocusky, Kelly A.; Bernstein, Hannah; Swanson, Haley; Perry, Chelsey; Diester, Ilka; Boyce, Frederick M.; Bass, Caroline E.; Neve, Rachael; Huang, Z. Josh; Deisseroth, Karl

    2014-01-01

    Precisely defining the roles of specific cell types is an intriguing and challenging frontier in the study of intact biological systems, and has stimulated the rapid development of genetically-encoded observation and control tools. However, targeting these tools with adequate specificity remains challenging: most cell types are best defined by the intersection of two or more features such as active promoter elements, location, and connectivity. Here we have combined recombinase tools with engineered introns to achieve expression of genetically-encoded payloads conditional upon multiple cell-type features, using Boolean logical operations all governed by a single versatile vector. We use this approach to target intersectionally-specified populations of inhibitory interneurons in mammalian hippocampus and neurons of the ventral tegmental area defined by both genetic and wiring properties. This flexible and modular approach may expand the application of genetically-encoded interventional and observational tools for intact-systems biology. PMID:24908100

  11. The sphingosine-1-phosphate receptor: A novel therapeutic target for multiple sclerosis and other autoimmune diseases.

    Science.gov (United States)

    Mao-Draayer, Yang; Sarazin, Jeffrey; Fox, David; Schiopu, Elena

    2017-02-01

    Multiple sclerosis (MS) is a prototype autoimmune disease of the central nervous system (CNS). Currently, there is no drug that provides a cure for MS. To date, all immunotherapeutic drugs target relapsing remitting MS (RR-MS); it remains a daunting medical challenge in MS to develop therapy for secondary progressive MS (SP-MS). Since the approval of the non-selective sphingosine-1-phosphate (S1P) receptor modulator FTY720 (fingolimod [Gilenya®]) for RR-MS in 2010, there have been many emerging studies with various selective S1P receptor modulators in other autoimmune conditions. In this article, we will review how S1P receptor may be a promising therapeutic target for SP-MS and other autoimmune diseases such as psoriasis, polymyositis and lupus.

  12. In vivo lymphatic targeting of methylene blue with microemulsion and multiple microemulsion.

    Science.gov (United States)

    Wang, Shujun; Yang, Rui; Yao, Huimin; Zhou, Guoqin; Zhang, Yinghui; Yang, Boyang; Ng, Lawrence; Yan, Macheng

    2009-10-01

    Three formulations including methylene blue solution (MB-S), MB water-in-oil microemulsion (MB-ME), and MB multiple microemulsion (MB-MME) were prepared with the aim to evaluate whether the three formulations can carry MB target to regional lymph nodes and show lymphatic tropism after subcutaneous administration. The pseudo-ternary phase diagrams were also studied. The morphology of MB-ME and MB-MME was examined by transmission electron microscopy to characterize the microstructure. The particle size and viscosity were also measured. MB concentrations in plasma, lymph nodes, and limb soles were quantitatively analyzed using HPLC. Results show that MME can target MB to regional lymph nodes, and can be employed as a potential lymph tracer in sentinel lymph node biopsy.

  13. Momentum measurement by the Multiple Coulomb Scattering method in the OPERA lead emulsion target

    CERN Document Server

    Agafonova, N.; Altinok, O.; Anokhina, A.; Aoki, S.; Ariga, A.; Ariga, T.; Autiero, D.; Badertscher, A.; Bagulya, A.; Ben Dhahbi, A.; Bertolin, A.; Besnier, M.; Bozza, C.; Brugiere, T.; Brugnera, R.; Brunet, F.; Brunetti, G.; Buontempo, S.; Cazes, A.; Chaussard, L.; Chernyavskiy, M.; Chiarella, V.; Chukanov, A.; D'Ambrosio, N.; Dal Corso, F.; De Lellis, G.; del Amo Sanchez, P.; Declais, Y.; De Serio, M.; Di Capua, F.; Di Crescenzo, A.; Di Ferdinando, D.; Di Marco, N.; Dmitrievski, S.; Dracos, M.; Duchesneau, D.; Dusini, S.; Dzhatdoev, T.; Ebert, J.; Egorov, O.; Enikeev, R.; Ereditato, A.; Esposito, L.S.; Favier, J.; Ferber, T.; Fini, R.A.; Frekers, D.; Fukuda, T.; Garfagnini, A.; Giacomelli, G.; Giorgini, M.; Gollnitz, C.; Goldberg, J.; Golubkov, D.; Goncharova, L.; Gornushkin, Y.; Grella, G.; Grianti, F.; Guler, A.M.; Gustavino, C.; Hagner, C.; Hamada, K.; Hara, T.; Hierholzer, M.; Hollnagel, A.; Hoshino, K.; Ieva, M.; Ishida, H.; Jakovcic, K.; Jollet, C.; Juget, F.; Kamiscioglu, M.; Kazuyama, K.; Kim, S.H.; Kimura, M.; Kitagawa, N.; Klicek, B.; Knuesel, J.; Kodama, K.; Komatsu, M.; Kose, U.; Kreslo, I.; Kubota, H.; Lazzaro, C.; Lenkeit, J.; Lippi, I.; Ljubicic, A.; Longhin, A.; Loverre, P.; Lutter, G.; Malgin, A.; Mandrioli, G.; Manai, K.; Marteau, J.; Matsuo, T.; Matveev, V.; Mauri, N.; Medinaceli, E.; Meisel, F.; Meregaglia, A.; Migliozzi, P.; Mikado, S.; Miyamoto, S.; Monacelli, P.; Morishima, K.; Moser, U.; Muciaccia, M.T.; Naganawa, N.; Naka, T.; Nakamura, M.; Nakano, T.; Naumov, D.; Nikitina, V.; Niwa, K.; Nonoyama, Y.; Ogawa, S.; Okateva, N.; Olshevskiy, A.; Paniccia, M.; Paoloni, A.; Park, B.D.; Park, I.G.; Pastore, A.; Patrizii, L.; Pennacchio, E.; Pessard, H.; Pretzl, K.; Pilipenko, V.; Pistillo, C.; Polukhina, N.; Pozzato, M.; Pupilli, F.; Rescigno, R.; Roganova, T.; Rokujo, H.; Romano, G.; Rosa, G.; Rostovtseva, I.; Rubbia, A.; Russo, A.; Ryasny, V.; Ryazhskaya, O.; Sato, O.; Sato, Y.; Schembri, A.; Schmidt-Parzefall, W.; Schroeder, H.; Scotto Lavina, L.; Sheshukov, A.; Shibuya, H.; Shoziyoev, G.; Simone, S.; Sioli, M.; Sirignano, C.; Sirri, G.; Song, J.S.; Spinetti, M.; Stanco, L.; Starkov, N.; Stipcevic, M.; Strauss, T.; Strolin, P.; Takahashi, S.; Tenti, M.; Terranova, F.; Tezuka, I.; Tioukov, V.; Tolun, P.; Trabelsi, A.; Tran, T.; Tufanli, S.; Vilain, P.; Vladimirov, M.; Votano, L.; Vuilleumier, J.L.; Wilquet, G.; Wonsak, B.; Yakushev, V.; Yoon, C.S.; Yoshioka, T.; Yoshida, J.; Zaitsev, Y.; Zemskova, S.; Zghiche, A.; Zimmermann, R.

    2012-01-01

    A new method of momentum measurement of charged particles through Multiple Coulomb Scattering (MCS) in the OPERA lead emulsion target is presented. It is based on precise measurements of track angular deviations performed thanks to the very high resolution of nuclear emulsions. The algorithm has been tested with Monte Carlo (MC) pions. The results are found to describe within the expected uncertainties the data obtained from test beams. We also report a comparison of muon momenta evaluated through MCS in the OPERA lead emulsion target with those determined by the electronic detectors for neutrino charged current interaction events. The two independent measurements agree within the experimental uncertainties, and the results validate the algorithm developed for the emulsion detector of OPERA.

  14. Modeling and simulation of torpedo acoustic homing trajectory with multiple targets

    Institute of Scientific and Technical Information of China (English)

    GU Hao; KANG Feng-ju; NIE Wei-dong

    2006-01-01

    The characteristics of a torpedo' s acoustic homing trajectory with multiple targets were studied. The differential equations of torpedo motion were presented based on hydrodynamics. The Fourth order Runge-Kutta method was used to solve these equations. Derived from sonar equations and Snell's law, a simple virtual underwater acoustic environment was established for simulating the torpedo homing process. The Newton iteration method was used to calculate homing range and ray tracing was approximated by piecewise line, which takes into consideration distortions cause by temperature, pressure, and salinity in a given sea area. The influence of some acoustic warfare equipment disturb the torpedo homing process in certain circumstances, including decoys and jammers, was alsotaken into account in simulations. Relative target identification logic and homing control laws were presented. Equal consideration during research was given to the requirements of real-timeactivity as well as accuracy. Finally, a practical torpedo homing trajectory simulation program was developed and applied to certain projects.

  15. 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.

  16. Targeting Multiple-Myeloma-Induced Immune Dysfunction to Improve Immunotherapy Outcomes

    Directory of Open Access Journals (Sweden)

    Sergio Rutella

    2012-01-01

    Full Text Available Multiple myeloma (MM is a plasma cell malignancy associated with high levels of monoclonal (M protein in the blood and/or serum. MM can occur de novo or evolve from benign monoclonal gammopathy of undetermined significance (MGUS. Current translational research into MM focuses on the development of combination therapies directed against molecularly defined targets and that are aimed at achieving durable clinical responses. MM cells have a unique ability to evade immunosurveillance through several mechanisms including, among others, expansion of regulatory T cells (Treg, reduced T-cell cytotoxic activity and responsiveness to IL-2, defects in B-cell immunity, and induction of dendritic cell (DC dysfunction. Immune defects could be a major cause of failure of the recent immunotherapy trials in MM. This article summarizes our current knowledge on the molecular determinants of immune evasion in patients with MM and highlights how these pathways can be targeted to improve patients’ clinical outcome.

  17. MultiAlign: a multiple LC-MS analysis tool for targeted omics analysis

    Energy Technology Data Exchange (ETDEWEB)

    Lamarche, Brian L.; Crowell, Kevin L.; Jaitly, Navdeep; Petyuk, Vladislav A.; Shah, Anuj R.; Polpitiya, Ashoka D.; Sandoval, John D.; Kiebel, Gary R.; Monroe, Matthew E.; Callister, Stephen J.; Metz, Thomas O.; Anderson, Gordon A.; Smith, Richard D.

    2013-02-12

    MultiAlign is a free software tool that aligns multiple liquid chromatography-mass spectrometry datasets to one another by clustering mass and LC elution features across datasets. Applicable to both label-free proteomics and metabolomics comparative analyses, the software can be operated in several modes. Clustered features can be matched to a reference database to identify analytes, used to generate abundance profiles, linked to tandem mass spectra based on parent precursor masses, and culled for targeted liquid chromatography-tandem mass spectrometric analysis. MultiAlign is also capable of tandem mass spectral clustering to describe proteome structure and find similarity in subsequent sample runs.

  18. 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.

  19. Increased fatty acid synthase as a potential therapeutic target in multiple myeloma

    Institute of Scientific and Technical Information of China (English)

    Wei-qin WANG; Xiao-ying ZHAO; Hai-yan WANG; Yun LIANG

    2008-01-01

    Objective: To determine fatty acid synthase (FAS) expression in human multiple myeloma and verify its potential as a therapeutic target in multiple myeloma. Methods: FAS expression was determined by immunohistochemistry, reverse-transcription polymerase chain reaction (RT-PCR) and immunoblot analysis in bone marrow samples obtained from 27 patients with multiple myeloma (MM patients) and peripheral blood mononuclear cells (PBMCs) obtained from 12 healthy donors. In parallel, additional analyses were performed on 2 human multiple myeloma cell lines, U266 and RPMI8226. U266 cells were treated with cerulenin at various concentrations (5 to 320μg/ml) for 24 h, and metabolic activity was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Apoptosis was evaluated by dual Annexin V/PI (propidium iodide) labeling and flow cytometry (FCM) in U266 cells treated with 20μg/ml cerulenin for 12 h or 24 h. Results: By immunohistochemistry, we found that 19 of 27 bone marrow samples obtained from MM patients expressed significantly high levels of FAS. Similarly, by RT-PCR, 22 of 27 bone marrow samples obtained from MM patients, U266 and RPMI8226 showed FAS expression, whereas PBMC samples from 12 healthy donors did not express detectable level of FAS. FAS protein expression was confirmed by immunoblot analysis in 16 of 27 bone marrow samples obtained from MM patients, U266 and RPMI8226 cell lines, and no FAS protein expression was detected in PBMC samples from 12 healthy donors. U266 cells were highly sensitive to cerulenin treatment, with a dosage-related effect on metabolic activity, as a measure for cell proliferation. U266 cells treated with20 μg/ml cerulenin for 12 and 24h also showed early sign of apoptosis with 56.9% and 69.3% Annexin V+/PI+ cells, and late apoptotic and necrotic cells with 3.2% and 17.6% Annexin V+/PI+ cells. Conclusion: Increased FAS expression existed in multiple myeloma samples and human myeloma cell lines

  20. 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.

  1. Radio Frequency Identification Sensor Chips with Anticollision Algorithm for Simultaneous Detection of Multiple DNA Targets

    Science.gov (United States)

    Yazawa, Yoshiaki; Oonishi, Tadashi; Watanabe, Kazuki; Nemoto, Ryo; Shiratori, Akiko

    2010-04-01

    A newly developed DNA measurement method for multiple single nucleotide polymorphism (SNP) typing using a radio-frequency identification (RFID) sensor chip was demonstrated. The RFID sensor chip monolithically integrates a sensor, amplifier, analog-to-digital converter (ADC), and a passive wireless communication interface for receiving commands and transmitting data on a 2.5×2.5 mm2 silicon chip. For the simultaneous multitarget measurement, anticollision control and peak-power suppression are essential. To assign a unique identification number (UID) for the identification of multiple sensor chips, a reproducible random number generator circuit (RRG) was designed and installed on the chip. Peak-power consumption was reduced to 1018 µW by a clock gating of functional circuit blocks. Multiple SNP typing was carried out by simultaneously operating five RFID sensor chips (four with photosensors and one with a temperature sensor). The target DNA was captured on the sensor chips, and SNPs were detected by observing bioluminescence. Finally, the observed data were wirelessly transmitted to the reader.

  2. Multiple Targets of Salicylic Acid and Its Derivatives in Plants and Animals

    Science.gov (United States)

    Klessig, Daniel F.; Tian, Miaoying; Choi, Hyong Woo

    2016-01-01

    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 of 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 and glyceraldehyde 3-phosphate dehydrogenase, are critical proteins that not only serve key structural or metabolic functions but also play prominent roles in disease responses in both kingdoms. PMID:27303403

  3. Preclinical validation of interleukin 6 as a therapeutic target in multiple myeloma

    Science.gov (United States)

    Rosean, Timothy R.; Tompkins, Van S.; Tricot, Guido; Holman, Carol J.; Olivier, Alicia K.; Zhan, Fenghuang; Janz, Siegfried

    2014-01-01

    Studies on the biologic and molecular genetic underpinnings of multiple myeloma (MM) have identified the pleiotropic, pro-inflammatory cytokine, interleukin-6 (IL-6), as a factor crucial to the growth, proliferation and survival of myeloma cells. IL-6 is also a potent stimulator of osteoclastogenesis and a sculptor of the tumor microenvironment in the bone marrow of patients with myeloma. This knowledge has engendered considerable interest in targeting IL-6 for therapeutic purposes, using a variety of antibody- and small-molecule-based therapies. However, despite the early recognition of the importance of IL-6 for myeloma and the steady progress in our knowledge of IL-6 in normal and malignant development of plasma cells, additional efforts will be required to translate the promise of IL-6 as a target for new myeloma therapies into significant clinical benefits for patients with myeloma. This review summarizes published research on the role of IL-6 in myeloma development and describes ongoing efforts by the University of Iowa Myeloma Multidisciplinary Oncology Group to develop new approaches to the design and testing of IL-6-targeted therapies and preventions of MM. PMID:24845460

  4. Different predictors of multiple-target search accuracy between nonprofessional and professional visual searchers.

    Science.gov (United States)

    Biggs, Adam T; Mitroff, Stephen R

    2014-01-01

    Visual search, locating target items among distractors, underlies daily activities ranging from critical tasks (e.g., looking for dangerous objects during security screening) to commonplace ones (e.g., finding your friends in a crowded bar). Both professional and nonprofessional individuals conduct visual searches, and the present investigation is aimed at understanding how they perform similarly and differently. We administered a multiple-target visual search task to both professional (airport security officers) and nonprofessional participants (members of the Duke University community) to determine how search abilities differ between these populations and what factors might predict accuracy. There were minimal overall accuracy differences, although the professionals were generally slower to respond. However, the factors that predicted accuracy varied drastically between groups; variability in search consistency-how similarly an individual searched from trial to trial in terms of speed-best explained accuracy for professional searchers (more consistent professionals were more accurate), whereas search speed-how long an individual took to complete a search when no targets were present-best explained accuracy for nonprofessional searchers (slower nonprofessionals were more accurate). These findings suggest that professional searchers may utilize different search strategies from those of nonprofessionals, and that search consistency, in particular, may provide a valuable tool for enhancing professional search accuracy.

  5. 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.

  6. 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.

  7. Neural network data association with application to multiple-target tracking

    Science.gov (United States)

    Leung, Henry

    1996-03-01

    Data association is the process of relating sensor measurements in a data fusion system. It can be structured in a basic framework very similar to that of the classic traveling salesman problem. The derivation of the energy function is presented, and the solution is based on a modified Hopfield network which uses the Runge-Kutta method and Aiyer's network structure. The neural data association is then applied to the problem of multiple-target tracking (MTT). The proposed neural MTT system consists of a modified Hough transform track initiator, a Kalman filter state estimator and the Hopfield probabilistic data association. Real- life air surveillance data are used to evaluate the practicality of the neural MTT system, and the results show that the neural system works efficiently in real-life tracking environments.

  8. Dynamic multiple-target tracing to probe spatiotemporal cartography of cell membranes.

    Science.gov (United States)

    Sergé, Arnauld; Bertaux, Nicolas; Rigneault, Hervé; Marguet, Didier

    2008-08-01

    Although the highly dynamic and mosaic organization of the plasma membrane is well-recognized, depicting a resolved, global view of this organization remains challenging. We present an analytical single-particle tracking (SPT) method and tool, multiple-target tracing (MTT), that takes advantage of the high spatial resolution provided by single-fluorophore sensitivity. MTT can be used to generate dynamic maps at high densities of tracked particles, thereby providing global representation of molecular dynamics in cell membranes. Deflation by subtracting detected peaks allows detection of lower-intensity peaks. We exhaustively detected particles using MTT, with performance reaching theoretical limits, and then reconnected trajectories integrating the statistical information from past trajectories. We demonstrate the potential of this method by applying it to the epidermal growth factor receptor (EGFR) labeled with quantum dots (Qdots), in the plasma membrane of live cells. We anticipate the use of MTT to explore molecular dynamics and interactions at the cell membrane.

  9. Hierarchal Variable Switching Sets of Interacting Multiple Model for Tracking Maneuvering Targets in Sensor Network

    Directory of Open Access Journals (Sweden)

    Seham Moawoud Ay Ebrahim

    2013-01-01

    Full Text Available Tracking maneuvering targets introduce two major directions to improve the Multiple Model (MM approach: Develop a better MM algorithm and design a better model set. The Interacting Multiple Model (IMM estimator is a suboptimal hybrid filter that has been shown to be one of the most cost-effective hybrid state estimation schemes. The main feature of this algorithm is the ability to estimate the state of a dynamic system with several behavior modes which can "switch" from one to another. In particular, the use of too many models is performance-wise as bad as that of too few models. In this paper we show that the use of too many models is performance-wise as bad as that of too few models. To overcome this we divide the models into a small number of sets, tuning these sets during operation at the right operating set. We proposed Hierarchal Switching sets of IMM (HSIMM. The state space of the nonlinear variable is divided into sets each set has its own IMM. The connection between them is the switching algorithm which manages the activation and termination of sets. Also the re-initialization process overcomes the error accumulation due to the targets changes from one model to another. This switching can introduce a number of different models while no restriction on their number. The activation of sets depends on the threshold value of set likely hood. As the likely hood of the set is higher than threshold it is active otherwise it is minimized. The result is the weighted sum of the output of active sets. The computational time is minimum than introduced by IMM and VIMM. HSIMM introduces less error as the noise increase and there is no need for re adjustment to the Covariance as the noise increase so it is more robust against noise and introduces minimum computational time.

  10. 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.

  11. Multiple-target tracking and track management for an FMCW radar network

    Science.gov (United States)

    Kim, Dae-Bong; Hong, Sun-Mog

    2013-12-01

    A multiple-target tracking problem for a frequency-modulated continuous-wave (FMCW) radar network is formulated and an integrated track management system is presented to solve the tracking problem in the presence of clutter. The FMCW radar network obtains beat frequency measurements with multiple collocated radars, each transmitting a sequence of chirps. The beat frequency measurements are associated to tracks directly in the beat frequency measurement space. The direct association eliminates range/range-rate calculations and multilateration processing, and it allows to process beat frequency measurements sequentially on a chirp by chirp basis. The sequential processing effectively decomposes the measurement-to-track association problem into a series of two-dimensional assignment problems that can be solved with much less computational effort. The solution to the measurement-to-track association problem is utilized to initiate and form new tracks and to update or delete existing tracks. Monte Carlo simulations were performed to evaluate the performance of the track management system.

  12. Development of an automated multiple-target mask CD disposition system to enable new sampling strategy

    Science.gov (United States)

    Ma, Jian; Farnsworth, Jeff; Bassist, Larry; Cui, Ying; Mammen, Bobby; Padmanaban, Ramaswamy; Nadamuni, Venkatesh; Kamath, Muralidhar; Buckmann, Ken; Neff, Julie; Freiberger, Phil

    2006-03-01

    Traditional mask critical dimension (CD) disposition systems with only one or two targets is being challenged by the new requirements from mask-users as the wafer process control becomes more complicated in the newer generation of technologies. Historically, the mask shop does not necessarily measure and disposition off the same kind of CD structures that wafer fabs do. Mask disposition specifications and structures come from the frame-design and the tapeout, while wafer-level CD dispositions are mainly based on the historical process window established per CD-skew experiments and EOL (end of line) yield. In the current high volume manufacturing environment, the mask CDs are mainly dispositioned off their mean-to-target (MTT) and uniformity (6sigma) on one or two types of pre-determined structures. The disposition specification is set to ensure the printed mask will meet the design requirements and to ensure minimum deviation from them. The CD data are also used to adjust the dose of the mask exposure tools to control CD MTT. As a result, the mask CD disposition automation system was built to allow only one or two kinds of targets at most. In contrast, wafer-fabs measure a fairly wide range of different structures to ensure their process is on target and in control. The number of such structures that are considered critical is increasing due the growing complexity of the technology. To fully comprehend the wafer-level requirements, it is highly desirable to align the mask CD sample site and disposition to be the same as that of the wafer-fabs, to measure the OPC (optical proximity correction) structures or equivalent whenever possible, and to establish the true correlation between mask CD measurements vs. wafer CD measurement. In this paper, the development of an automated multiple-target mask CD disposition system with the goal of enabling new sampling strategy is presented. The pros and cons of its implementation are discussed. The new system has been inserted in

  13. 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.

  14. Cantilever-based mass sensor for immunodetection of multiple bioactive targets

    Science.gov (United States)

    Tang, Tang; Xu, Bai; Welch, John; Castracane, James

    2004-01-01

    We are investigating the development of a rapid and highly sensitive detection method for immunoreactive substances combining MEMS (Micro Electro Mechanical Systems) technology and the appropriate immune stimulant or response factors. Cantilevers of micrometer scale can be used for trace detection of mass change. When a layer of an antigenic substance is covalently deposited, the cantilever is capable of capturing antibodies from samples with high affinity and specificity. The antigen/antibody binding causes multiple physical changes in the cantilever device, including a shift of effective mass and a change in surface tension. The change of effective mass consequently induces a shift in the cantilever"s natural resonant frequency. By monitoring these changes with an optical readout mechanism, the presence of immunoreactive targets in the sample can be detected. This detection method can be used for various types of targets with immunoreactivity and therefore is potentially applicable in hazardous substance monitoring and disease diagnosis. In our effort, phoS1, an antigen shed by Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), is utilized for rapid and economic TB detection.

  15. A low molecular weight artificial RNA of unique size with multiple probe target regions

    Science.gov (United States)

    Pitulle, C.; Dsouza, L.; Fox, G. E.

    1997-01-01

    Artificial RNAs (aRNAs) containing novel sequence segments embedded in a deletion mutant of Vibrio proteolyticus 5S rRNA have previously been shown to be expressed from a plasmid borne growth rate regulated promoter in E. coli. These aRNAs accumulate to high levels and their detection is a promising tool for studies in molecular microbial ecology and in environmental monitoring. Herein a new construct is described which illustrates the versatility of detection that is possible with aRNAs. This 3xPen aRNA construct carries a 72 nucleotide insert with three copies of a unique 17 base probe target sequence. This aRNA is 160 nucleotides in length and again accumulates to high levels in the E. coli cytoplasm without incorporating into ribosomes. The 3xPen aRNA illustrates two improvements in detection. First, by appropriate selection of insert size, we obtained an aRNA which provides a unique and hence, easily quantifiable peak, on a high resolution gel profile of low molecular weight RNAs. Second, the existence of multiple probe targets results in a nearly commensurate increase in signal when detection is by hybridization. These aRNAs are naturally amplified and carry sequence segments that are not found in known rRNA sequences. It thus may be possible to detect them directly. An experimental step involving RT-PCR or PCR amplification of the gene could therefore be avoided.

  16. Intrathecal IgG Synthesis: A Resistant and Valuable Target for Future Multiple Sclerosis Treatments

    Directory of Open Access Journals (Sweden)

    Mickael Bonnan

    2015-01-01

    Full Text Available Intrathecal IgG synthesis is a key biological feature of multiple sclerosis (MS. When acquired early, it persists over time. A growing body of evidence suggests that intrathecal Ig-secreting cells may be pathogenic either by a direct action of toxic IgG or by locally secreting bystander toxic products. Intrathecal IgG synthesis depends on the presence of CNS lymphoid organs, which are strongly linked at anatomical level to cortical subpial lesions and at clinical level to the impairment slope in progressive MS. As a consequence, targeting CNS lymphoid lesions could be a valuable new target in MS, especially during the progressive phase. As intrathecal IgGs are end-products of these lymphoid lesions, intrathecal IgG synthesis may be considered as a specific marker of the persistence of these inflammatory lesions. Here we review the effect upon intrathecal IgG synthesis of all drugs ever used in MS. Except for steroids, all these therapeutic strategies, including rituximab, failed to decrease intrathecal IgG synthesis, with the exception of a questionable incomplete action of natalizumab. Thus, IgG synthesis is a robust marker of persistent intrathecal inflammation and its complete normalization should be one of the goals in future therapeutic strategies.

  17. Surface molecule CD229 as a novel target for the diagnosis and treatment of multiple myeloma.

    Science.gov (United States)

    Atanackovic, Djordje; Panse, Jens; Hildebrandt, York; Jadczak, Adam; Kobold, Sebastian; Cao, Yanran; Templin, Julia; Meyer, Sabrina; Reinhard, Henrike; Bartels, Katrin; Lajmi, Nesrine; Zander, Axel R; Marx, Andreas H; Bokemeyer, Carsten; Kröger, Nicolaus

    2011-10-01

    To date, multiple myeloma remains an incurable malignancy due to the persistence of minimal residual disease in the bone marrow. In this setting, monoclonal antibodies against myeloma-specific cell surface antigens represent a promising therapeutic approach, which is however hampered by a lack of appropriate target structures expressed across all pathogenic myeloma cell populations. We, therefore, investigated functionally relevant immunoreceptors specifically associated with myeloma cells as well as their clonogenic precursors. Potential target proteins were identified using antibody arrays against phosphorylated immunoreceptors with lysates from myeloma cell lines. CD229 expression was confirmed in primary myeloma cells by reverse transcriptase polymerase chain reaction, western blot, fluorescence-activated cell sorting, and immunohistochemistry. Apoptosis, clonogenic growth, and sensitivity to chemotherapy were determined following short-interfering RNA-mediated downregulation of CD229. Antibody-dependent cellular and complement-dependent cytotoxicity were analyzed using a monoclonal antibody against CD229 to demonstrate the antigen's immunotherapeutic potential. Our screening assay identified CD229 as the most strongly over-expressed/phosphorylated immunoreceptor in myeloma cell lines. Over-expression was further demonstrated in the CD138-negative population, which has been suggested to represent myeloma precursors, as well as on primary tumor cells from myeloma patients. Accordingly, CD229 staining of patients' bone marrow samples enabled the identification of myeloma cells by flow cytometry and immunohistochemistry. Down-regulation of CD229 led to a decreased number of viable myeloma cells and clonal myeloma colonies, and enhanced the anti-tumor activity of conventional chemotherapeutics. Targeting CD229 with a monoclonal antibody resulted in complement- and cell-mediated lysis of myeloma cells. Our results demonstrate that the immunoreceptor CD229 is

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

    Directory of Open Access Journals (Sweden)

    Wei Zhu

    2016-06-01

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

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

    Science.gov (United States)

    Zhu, Wei; Wang, Wei; Yuan, Gannan

    2016-06-01

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

  20. Halogenation of cobalt dicarbollide

    Science.gov (United States)

    Hurlburt, Paul K.; Abney, Kent D.; Kinkead, Scott A.

    1997-01-01

    A method for selectively adding chlorine, bromine, or iodine to cobalt dicarbollide anions by means of electrophilic substitution reactions. Halogens are added only to the B10 and B10' positions of the anion. The process involves use of hypohalous acid or N-halosuccinimide or gaseous chlorine in the presence of iron.

  1. cobalt (ii), nickel (ii)

    African Journals Online (AJOL)

    DR. AMINU

    ABSTRACT. The manganese (II), cobalt (II), nickel (II) and copper (II) complexes of N, N' – ... temperature and coordinated water were determined ... indicating fairly stable complex compounds (Table 1). The complex compounds are insoluble [Table 2] in water and common organic solvents, but are readily soluble in ...

  2. Targeting multiple signaling pathways as a strategy for managing prostate cancer: multifocal signal modulation therapy.

    Science.gov (United States)

    McCarty, Mark F

    2004-12-01

    The aberrant behavior of cancer reflects upregulation of certain oncogenic signaling pathways that promote proliferation, inhibit apoptosis, and enable the cancer to spread and evoke angiogenesis. Theoretically, it should be feasible to decrease the activity of these pathways-or increase the activity of pathways that oppose them-with noncytotoxic agents. Since multiple pathways are dysfunctional in most cancers, and cancers accumulate new oncogenic mutations as they progress, the greatest and most durable therapeutic benefit will likely be achieved with combination regimens that address several targets. Thus, a multifocal signal modulation therapy (MSMT) of cancer is proposed. This concept has already been documented by researchers who have shown that certain combinations of signal modulators-of limited utility when administered individually-can achieve dramatic suppression of tumor growth in rodent xenograft models. The present essay attempts to guide development of MSMTs for prostate cancer. Androgen ablation is a signal-modulating measure already in standard use in the management of delocalized prostate cancer. The additional molecular targets considered here include the type 1 insulin-like growth factor receptor, the epidermal growth factor receptor, mammalian target of rapamycin, NF-kappaB, hypoxia-inducible factor-1alpha, hsp90, cyclooxygenase-2, protein kinase A type I, vascular endothelial growth factor, 5-lipoxygenase, 12-lipoxygenase, angiotensin II receptor type 1, bradykinin receptor type 1, c-Src, interleukin-6, ras, MDM2, bcl-2/bclxL, vitamin D receptor, estrogen receptor-beta, and PPAR-. Various nutrients and phytochemicals suspected to have potential utility in prostate cancer prevention and therapy, but whose key molecular targets are still unknown, might reasonably be incorporated into MSMTs for prostate cancer; these include lycopene, selenium, green tea polyphenols, genistein, and silibinin. MSMTs can be developed systematically by testing

  3. 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

  4. The quality and effectiveness of interventions that target multiple risk factors among young people: a systematic review.

    Science.gov (United States)

    Knight, Alice; Shakeshaft, Anthony; Havard, Alys; Maple, Myfanwy; Foley, Catherine; Shakeshaft, Bernie

    2017-02-01

    To identify evaluations of interventions that target multiple risk factors in high-risk young people, describe their characteristics, critique their methodological quality and summarise their effectiveness. A search of the literature published between 2009 and 2014 identified 13 evaluations of interventions that targeted multiple risk factors, compared to 95 evaluations that targeted single risk factors. The methodological adequacy of the 13 evaluation studies was analysed using the Quality Assessment Tool for Quantitative Studies and information regarding characteristics and intervention effectiveness was extracted and summarised. There were very few outcome evaluation studies of interventions that targeted multiple risk factors, relative to single risk factors, among high-risk young people. Of the identified studies, half were methodologically weak. Interventions delivered in community settings targeted a greater number of risk factors, while those delivered in a school or health setting reported a higher proportion of statistically significant outcomes. No economic analyses were conducted. Conclusions and Implications for Public Health: More methodologically rigorous evaluations of interventions targeting multiple risk factors among high-risk young people are required, especially for those delivered in community settings. Four key areas for improvement are: i) more precisely defining the risk factors experienced by high-risk young people; ii) achieving greater consistency across interventions; iii) standardising outcome measures; and iv) conducting economic analyses. © 2016 The Authors.

  5. Fractal characteristics of resource quantity of cobalt crusts and seamount topography, the West Pacific

    Institute of Scientific and Technical Information of China (English)

    ZHANG Weiyan; ZHANG Fuyuan; YANG Kehong; HU Guangdao; YANG Shengxiong; CHENG Yongshou; ZHAO Guojun

    2007-01-01

    This paper presents the fractal distribution of topography of seamounts from the West Pacific and the resource quantity of cobalt crust therein. The cobalt resource quantity has three to four variable fractal dimensions, corre- sponding to the distinct slopes and water depths of the sea- mount. The multiple fractal property of resource quantity may have resulted from various factors, such as types and components of cobalt crusts and ages of oceanic crusts host- ing the seamounts. Individual seamounts display complex topography and quantity of cobalt crust, both in the same and different regions.

  6. 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.

  7. Mitochondria-targeted Antioxidants as a Prospective Therapeutic Strategy for Multiple Sclerosis.

    Science.gov (United States)

    Fetisova, Elena; Chernyak, Boris; Korshunova, Galina; Muntyan, Maria; Skulachev, Vladimir

    2017-01-01

    Multiple sclerosis (MS) is one of the most widespread chronic neurological diseases that manifests itself by progressive demyelination in the central nervous system. The study of MS pathogenesis begins with the onset of the relapsing-remitting phase of the disease, which becomes apparent due to microglia activation, neuroinflammation and demyelination/ remyelination in the white matter. The following progressive phase is accompanied by severe neurological symptoms when demyelination and neurodegeneration are spread to both gray and white matter. In this review, we discuss a possible role of mitochondrial reactive oxygen species (mtROS) in MS pathogenesis, mechanisms of mtROS generation and effects of some mitochondria-targeted antioxidants as potential components of MS therapy. In the early phase of MS, mtROS stimulate NLRP3 inflammasomes, which is critical for the formation of local inflammatory lesions. Later, mtROS contribute to blood-brain barrier disruption induced by mediators of inflammation, followed by infiltration of leukocytes. ROS generated by leukocytes and activated microglia promote mitochondrial dysfunction and oligodendrocyte cell death. In the progressive phase, neurodegeneration also depends on excessive mtROS generation. Currently, only a few immunomodulatory drugs are approved for treatment of MS. These drugs mainly reduce the number of relapses but do not stop MS progression. Certain dietary and synthetic antioxidants have demonstrated encouraging results in animal models of MS but were ineffective in the completed clinical trials. Novel mitochondria-targeted antioxidants could be promising components of combined programs for MS therapy considering that they can be applied at extremely low doses and concurrently demonstrate anti-inflammatory and neuroprotective activities. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  8. Multiple Ion Cluster Source for the Generation of Magnetic Nanoparticles: Investigation of the Efficiency as a Function of the Working Parameters for the Case of Cobalt

    Directory of Open Access Journals (Sweden)

    Daniel Llamosa Perez

    2014-01-01

    Full Text Available We present dataset of Co nanoparticles production using a Multiple Ion Cluster Source (MICS. We study the evolution of the mean size and deposition rate of Co nanoparticles as a function of the power and argon flux applied to the Co magnetron, the aggregation length of the Co magnetron and the total argon flux. The results show the strong influence of these parameters on the mean size of the nanoparticles and the efficiency of the process as well as on the atomic deposition rate. In particular, it is shown that nanoparticles of mean size ranging from 4 to 14 nm can be produced and that the influence of the working parameters on the production of magnetic nanoparticles is more complex than for the case of noble metal presented previously.

  9. 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).

  10. Engineering novel targeted nanoparticle formulations to increase the therapeutic efficacy of conventional chemotherapeutics against multiple myeloma

    Science.gov (United States)

    Ashley, Jonathan D.

    Multiple myeloma (MM) is a hematological malignancy which results from the uncontrolled clonal expansion of plasma cells within the body. Despite recent medical advances, this disease remains largely incurable, with a median survival of ˜7 years, owing to the development of drug resistance. This dissertation will explore new advances in nanotechnology that will combine the cytotoxic effects of small molecule chemotherapeutics with the tumor targeting capabilities of nanoparticles to create novel nanoparticle formulations that exhibit enhanced therapeutic indices in the treatment of MM. First, doxorubicin was surfaced conjugated onto micellar nanoparticles via an acid labile hydrazone bond to increase the drug accumulation at the tumor. The cell surface receptor Very Late Antigen-4 (VLA-4; alpha4beta1) is expressed on cancers of hematopoietic origin and plays a vital role in the cell adhesion mediated drug resistance (CAM-DR) in MM. Therefore, VLA-4 antagonist peptides were conjugated onto the nanoparticles via a multifaceted procedure to actively target MM cells and simultaneously inhibit CAM-DR. The micellar doxorubicin nanoparticles were able to overcome CAM-DR and demonstrated improved therapeutic index relative to free doxorubicin. In addition to doxorubicin, other classes of therapeutic agents, such as proteasome inhibitors, can be incorporated in nanoparticles for improved therapeutic outcomes. Utilizing boronic acid chemistry, bortezomib prodrugs were synthesized using a reversible boronic ester bond and then incorporated into liposomes. The different boronic ester bonds that could be potentially used in the synthesis of bortezomib prodrugs were screened based on stability using isobutylboronic acid. The liposomal bortezomib nanoparticles demonstrated significant proteasome inhibition and cytotoxicity in MM cells in vitro, and dramatically reduced the non-specific toxicities associated with free bortezomib while maintaining significant tumor growth

  11. Targeting multiple pathogenic mechanisms with polyphenols for the treatment of Alzheimer's disease-experimental approach and therapeutic implications

    OpenAIRE

    Jun eWang; Weina eBi; Alice eCheng; Daniel eFreire; Prashant eVempati; Wei eZhao; Bing eGong; Elsa eJanle; Tzu-Ying eChen; Mario eFerruzzi; James eSchmeidler; Lap eHo; Giulio Maria Pasinetti

    2014-01-01

    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 ju...

  12. G protein-coupled receptors as therapeutic targets for multiple sclerosis

    Institute of Scientific and Technical Information of China (English)

    Changsheng Du; Xin Xie

    2012-01-01

    G protein-coupled receptors (GPCRs) mediate most of our physiological responses to hormones,neurotransmitters and environmental stimulants.They are considered as the most successful therapeutic targets for a broad spectrum of diseases.Multiple sclerosis (MS) is an inflammatory disease that is characterized by immune-mediated demyelination and degeneration of the central nervous system (CNS).It is the leading cause of non-traumatic disability in young adults.Great progress has been made over the past few decades in understanding the pathogenesis of MS.Numerous data from animal and clinical studies indicate that many GPCRs are critically involved in various aspects of MS pathogenesis,including antigen presentation,cytokine production,T-cell differentiation,T-cell proliferation,T-cell invasion,etc.In this review,we summarize the recent findings regarding the expression or functional changes of GPCRs in MS patients or animal models,and the influences of GPCRs on disease severity upon genetic or pharmacological manipulations.Hopefully some of these findings will lead to the development of novel therapies for MS in the near future.

  13. 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.

  14. Comparative proteomic analysis to discover potential therapeutic targets in human multiple myeloma.

    Science.gov (United States)

    Xiao, Chuan-Le; Zhang, Zhi-Ping; Xiong, Sheng; Lu, Chun-Hua; Wei, Hong-Ping; Zeng, Hui-Lan; Liu, Zhi; Zhang, Xian-En; Ge, Feng

    2009-11-01

    To clarify the molecular mechanisms that participate in the formation of multiple myeloma (MM) and to detect any tumor-related biomarkers, we performed proteomic analysis of cellular protein extracts from MM cells and normal plasma cells. Plasma cells from nine patients with newly diagnosed MM and nine healthy donors were purified by using anti-CD138 based immunomagnetic bead-positive selection. The protein profiles of purified MM and normal plasma cells were compared using 2-DE. We identified a total of 43 differentially expressed proteins, and confirmed with Western blotting six proteins. The altered proteins were analyzed using the software program Pathway Studio and the biological network can be accessed via (http://life-health.jnu.edu.cn/pathway/pathway.html). Further functional studies showed that annexin A1 knock down modestly induces lethality alone and potentiates the effects of dexamethasone on both dexamethasone-sensitive and dexamethasone-resistant MM cells. By correlating the proteomic data with these functional studies, the current results provide not only new insights into the pathogenesis of MM but also direct implications for the development of novel anti-MM therapeutic strategies and could lead to the discovery of potential therapeutic targets. Future molecular and functional studies would provide novel insights into the roles of these dysregulated proteins in the molecular etiology of MM.

  15. Curbing Inflammation in Multiple Sclerosis and Endometriosis: Should Mast Cells Be Targeted?

    Directory of Open Access Journals (Sweden)

    David A. Hart

    2015-01-01

    Full Text Available Inflammatory diseases and conditions can arise due to responses to a variety of external and internal stimuli. They can occur acutely in response to some stimuli and then become chronic leading to tissue damage and loss of function. While a number of cell types can be involved, mast cells are often present and can be involved in the acute and chronic processes. Recent studies in porcine and rabbit models have supported the concept of a central role for mast cells in a “nerve-mast cell-myofibroblast axis” in some inflammatory processes leading to fibrogenic outcomes. The current review is focused on the potential of extending aspects of this paradigm into treatments for multiple sclerosis and endometriosis, diseases not usually thought of as having common features, but both are reported to have activation of mast cells involved in their respective disease processes. Based on the discussion, it is proposed that targeting mast cells in these diseases, particularly the early phases, may be a fruitful avenue to control the recurring inflammatory exacerbations of the conditions.

  16. 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.

  17. Targeting MEK1/2 blocks osteoclast differentiation, function and cytokine secretion in multiple myeloma.

    Science.gov (United States)

    Breitkreutz, Iris; Raab, Marc S; Vallet, Sonia; Hideshima, Teru; Raje, Noopur; Chauhan, Dharminder; Munshi, Nikhil C; Richardson, Paul G; Anderson, Kenneth C

    2007-10-01

    Osteolytic bone disease in multiple myeloma (MM) is associated with upregulation of osteoclast (OCL) activity and constitutive inhibition of osteoblast function. The extracellular signal-regulated kinase 1/2 (ERK1/2) pathway mediates OCL differentiation and maturation. We hypothesized that inhibition of ERK1/2 could prevent OCL differentiation and downregulate OCL function. It was found that AZD6244, a mitogen-activated or extracellular signal-regulated protein kinase (MEK) inhibitor, blocked OCL differentiation and formation in a dose-dependent manner, evidenced by decreased alphaVbeta3-integrin expression and tartrate-resistant acid phosphatase positive (TRAP+) cells. Functional dentine disc cultures showed inhibition of OCL-induced bone resorption by AZD6244. Major MM growth and survival factors produced by OCLs including B-cell activation factor (BAFF) and a proliferation-inducing ligand (APRIL), as well as macrophage inflammatory protein (MIP-1alpha), which mediates OCL differentiation and MM, were also significantly inhibited by AZD6244. In addition to ERK inhibition, NFATc1 (nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1) and c-fos were both downregulated, suggesting that AZD6244 targets a later stage of OCL differentiation. These results indicate that AZD6244 inhibits OCL differentiation, formation and bone resorption, thereby abrogating paracrine MM cell survival in the bone marrow microenvironment. The present study therefore provides a preclinical rationale for the evaluation of AZD6244 as a potential new therapy for patients with MM.

  18. Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma

    Science.gov (United States)

    Müller, Judith; Krijgsman, Oscar; Tsoi, Jennifer; Robert, Lidia; Hugo, Willy; Song, Chunying; Kong, Xiangju; Possik, Patricia A.; Cornelissen-Steijger, Paulien D.M.; Foppen, Marnix H. Geukes; Kemper, Kristel; Goding, Colin R.; McDermott, Ultan; Blank, Christian; Haanen, John; Graeber, Thomas G.; Ribas, Antoni; Lo, Roger S.; Peeper, Daniel S.

    2015-01-01

    Increased expression of the Microphthalmia-associated transcription factor (MITF) contributes to melanoma progression and resistance to BRAF pathway inhibition. Here we show that the lack of MITF is associated with more severe resistance to a range of inhibitors, while its presence is required for robust drug responses. Both in primary and acquired resistance, MITF levels inversely correlate with the expression of several activated receptor tyrosine kinases, most frequently AXL. The MITF-low/AXL-high/drug-resistance phenotype is common among mutant BRAF and NRAS melanoma cell lines. The dichotomous behaviour of MITF in drug response is corroborated in vemurafenib-resistant biopsies, including MITF-high and -low clones in a relapsed patient. Furthermore, drug cocktails containing AXL inhibitor enhance melanoma cell elimination by BRAF or ERK inhibition. Our results demonstrate that a low MITF/AXL ratio predicts early resistance to multiple targeted drugs, and warrant clinical validation of AXL inhibitors to combat resistance of BRAF and NRAS mutant MITF-low melanomas. PMID:25502142

  19. Cancer/Testis Antigen MAGE-C1/CT7: New Target for Multiple Myeloma Therapy

    Directory of Open Access Journals (Sweden)

    Fabricio de Carvalho

    2012-01-01

    Full Text Available Cancer/Testis Antigens (CTAs are a promising class of tumor antigens that have a limited expression in somatic tissues (testis, ovary, fetal, and placental cells. Aberrant expression of CTAs in cancer cells may lead to abnormal chromosome segregation and aneuploidy. CTAs are regulated by epigenetic mechanisms (DNA methylation and acetylation of histones and are attractive targets for immunotherapy in cancer because the gonads are immune privileged organs and anti-CTA immune response can be tumor-specific. Multiple myeloma (MM is an incurable hematological malignancy, and several CTAs have been detected in many MM cell lines and patients. Among CTAs expressed in MM we must highlight the MAGE-C1/CT7 located on the X chromosome and expressed specificity in the malignant plasma cells. MAGE-C1/CT7 seems to be related to disease progression and functional studies suggests that this CTA might play a role in cell cycle and mainly in survival of malignant plasma cells, protecting myeloma cells against spontaneous as well as drug-induced apoptosis.

  20. Elicitation threshold of cobalt chloride

    DEFF Research Database (Denmark)

    Fischer, Louise A; Johansen, Jeanne D; Voelund, Aage

    2016-01-01

    BACKGROUND: Cobalt is a strong skin sensitizer (grade 5 of 5 in the guinea-pig maximization test) that is used in various industrial and consumer applications. To prevent sensitization to cobalt and elicitation of allergic cobalt dermatitis, information about the elicitation threshold level...... of cobalt is important. OBJECTIVE: To identify the dermatitis elicitation threshold levels in cobalt-allergic individuals. MATERIALS AND METHODS: Published patch test dose-response studies were reviewed to determine the elicitation dose (ED) levels in dermatitis patients with a previous positive patch test...... reaction to cobalt. A logistic dose-response model was applied to data collected from the published literature to estimate ED values. The 95% confidence interval (CI) for the ratio of mean doses that can elicit a reaction in 10% (ED(10)) of a population was calculated with Fieller's method. RESULTS...

  1. Cobalt sorption in silica-pillared clays.

    Science.gov (United States)

    Sampieri, A; Fetter, G; Bosch, P; Bulbulian, S

    2006-01-03

    Silicon pillared samples were prepared following conventional and microwave irradiation methods. The samples were characterized and tested in cobalt sorption. Ethylenediammine was added before cobalt addition to improve the amount of cobalt retained. The amount of cobalt introduced in the original clay in the presence of ethylenediammine was the highest. In calcined pillared clays the cobalt retention with ethylenediammine was lower (ca. 40%). In all cases the presence of ethylenediammine increased twice the amount of cobalt sorption measured for aqueous solutions.

  2. Bioaccessibility testing of cobalt compounds.

    Science.gov (United States)

    Stopford, Woodhall; Turner, John; Cappellini, Danielle; Brock, Tom

    2003-08-01

    Testing of metal compounds for solubility in artificial fluids has been used for many years to assist determining human health risk from exposure to specific compounds of concern. In lieu of obtaining bioavailability data from samples of urine, blood, or other tissues, these studies measured solubility of compounds in various artificial fluids as a surrogate for bioavailability. In this context, the measurement of metal "bioaccessibility" can be used as an in vitro substitute for measuring metal bioavailability. Bioaccessibility can be defined as a value representing the availability of metal for absorption when dissolved in in vitro surrogates of body fluids or juices. The aim of this study was to measure and compare the bioaccessibility of selected cobalt compounds in artificial human tissue fluids and human serum. A second aim was to initiate studies to experimentally validate an in vitro methodology that would provide a conservative estimate of cobalt bioavailability in the assessment of dose from human exposure to various species of cobalt compounds. This study evaluated the bioaccessibility of cobalt(II) from 11 selected cobalt compounds and an alloy in 2 physical forms in 5 surrogate human tissue fluids and human serum. Four (4) separate extraction times were used up to 72 hours. The effect of variables such as pH, dissolution time, and mass-ion effect on cobalt bioaccessibility were assessed as well. We found that the species of cobalt compound as well as the physico-chemical properties of the surrogate fluids, especially pH, had a major impact on cobalt solubility. Cobalt salts such as cobalt(II) sulfate heptahydrate were highly soluble, whereas cobalt alloys used in medical implants and cobalt aluminate spinels used as pigments, showed minimal dissolution over the period of the assay.

  3. Cobalt ion-containing epoxies

    Science.gov (United States)

    Stoakley, D. M.; St.clair, A. K.

    1983-01-01

    Varying concentrations of an organometallic cobalt complex were added to an epoxy system currently used by the aerospace industry as a composite matrix resin. Methods for combining cobalt (III) acetylacetonate with a tetraglycidyl 4,4 prime - diaminodiphenylmethane-based epoxy were investigated. The effects of increasing cobalt ion concentration on the epoxy cure were demonstrated by epoxy gel times and differential scanning calorimetry cure exotherms. Analysis on cured cobalt-containing epoxy castings included determination of glass transition temperatures by thermomechanical analysis, thermooxidative stabilities by thermogravimetric analysis, and densities in a density gradient column. Flexural strength and stiffness were also measured on the neat resin castings.

  4. Scientific Opinion on safety and efficacy of coated granulated cobaltous carbonate monohydrate as feed additive for all species

    Directory of Open Access Journals (Sweden)

    EFSA Panel on Additives and Products or Substances used in Animal Feed

    2012-07-01

    Full Text Available

    Cobalt(III is a component of cobalamin. Its essentiality as trace element results from the capacity of certain animal species to synthesise cobalamin by the gastrointestinal microbiota. Feeding cobalt(II carbonate hydroxide (2:3 monohydrate up to the maximum authorised total cobalt in feed is safe for the target animals. Cobalt is predominantly excreted via the faecal route. Absorbed cobalt follows aqueous excretion routes. About 43 % of body cobalt is stored in muscle; however, kidney and liver are the edible tissues containing the highest cobalt concentrations and are most susceptible to reflect dietary cobalt concentrations. In animals with the capacity to synthesise cobalamin, cobalt is also deposited in tissues as vitamin B12. Cobalt(II cations are genotoxic under in vitro and in vivo conditions. Cobalt(II carbonate has carcinogen, mutagen and reproduction toxicant (CMR properties. No data are available on the potential carcinogenicity of cobalt(II following oral exposure. However, oral exposure may potentially entail adverse threshold-related effects in humans. The estimated population intake of cobalt most likely includes the contribution of foodstuffs from animals fed cobalt-supplemented feedingstuffs. An increase in cobalt exposure by the use of cobalt-containing feed additives is therefore not expected. Considering the population exposure to cobalt, about 4–10 times lower than the health-based guidance value, no safety concern for the consumer is expected for threshold effects of oral cobalt. Cobalt(II carbonate is a skin and eye irritant, and a dermal and respiratory sensitiser. Its dust is a hazard to persons handling the substance. Exposure by inhalation must be avoided. The use of cobalt from any source at the authorised maximum content in feed does not provide a risk to the environment. The coated granulated cobalt(II carbonate hydroxide (2:3 monohydrate is available for cobalamin synthesis in

  5. Targeting of the Virulence Factor Acetohydroxyacid Synthase by Sulfonylureas Results in Inhibition of Intramacrophagic Multiplication of Brucella suis

    OpenAIRE

    Boigegrain, Rose-Anne; Liautard, Jean-Pierre; Köhler, Stephan

    2005-01-01

    The acetohydroxyacid synthase (AHAS) of Brucella suis can be effectively targeted by the sulfonylureas chlorimuron ethyl and metsulfuron methyl. Growth in minimal medium was inhibited, and multiplication in human macrophages was totally abolished with 100 μM of sulfonylureas. Metsulfuron methyl-resistant mutants showed reduced viability in macrophages and reduced AHAS activity.

  6. Cancer testis antigens in newly diagnosed and relapse multiple myeloma: Prognostic markers and potential targets for immunotherapy

    NARCIS (Netherlands)

    M. van Duin (Mark); A. Broyl (Annemiek); Y. de Knegt (Yvonne); H. Goldschmidt (Hartmut); P.G. Richardson (Paul); B. van der Holt (Bronno); W.C.J. Hop (Wim); D. Joseph-Pietras (Debora); G. Mulligan (George); R. Neuwirth (Rachel); S.S. Sahota (Surinder); P. Sonneveld (Pieter)

    2011-01-01

    textabstractBackground In multiple myeloma, expression of cancer testis antigens may provide prognostic markers and potential targets for immunotherapy. Expression at relapse has not yet been evaluated for a large panel of cancer testis antigens which can be classified by varying expression in norma

  7. Blood doping by cobalt. Should we measure cobalt in athletes?

    Directory of Open Access Journals (Sweden)

    Guidi Gian

    2006-07-01

    Full Text Available Abstract Background Blood doping is commonplace in competitive athletes who seek to enhance their aerobic performances through illicit techniques. Presentation of the hypothesis Cobalt, a naturally-occurring element with properties similar to those of iron and nickel, induces a marked and stable polycythemic response through a more efficient transcription of the erythropoietin gene. Testing the hypothesis Although little information is available so far on cobalt metabolism, reference value ranges or supplementation in athletes, there is emerging evidence that cobalt is used as a supplement and increased serum concentrations are occasionally observed in athletes. Therefore, given the athlete's connatural inclination to experiment with innovative, unfair and potentially unhealthy doping techniques, cobalt administration might soon become the most suited complement or surrogate for erythropoiesis-stimulating substances. Nevertheless, cobalt administration is not free from unsafe consequences, which involve toxic effects on heart, liver, kidney, thyroid and cancer promotion. Implications of the hypothesis Cobalt is easily purchasable, inexpensive and not currently comprehended within the World Anti-Doping Agency prohibited list. Moreover, available techniques for measuring whole blood, serum, plasma or urinary cobalt involve analytic approaches which are currently not practical for antidoping laboratories. Thus more research on cobalt metabolism in athletes is compelling, along with implementation of effective strategies to unmask this potentially deleterious doping practice

  8. Role of Immunotherapy in Targeting the Bone Marrow Microenvironment in Multiple Myeloma: An Evolving Therapeutic Strategy.

    Science.gov (United States)

    Chung, Clement

    2017-01-01

    Multiple myeloma (referred to henceforth as myeloma) is a B-cell malignancy characterized by unregulated growth of plasma cells in the bone marrow. The treatment paradigm for myeloma underwent significant evolution in the last decade, with an improved understanding of the pathogenesis of the disease as well as the development of therapeutic agents that target not only the tumor cells but also their microenvironment. Despite these therapeutic advances, the prognosis of patients with relapsed or refractory myeloma remains poor. Accordingly, a need exists for new therapeutic avenues that can overcome resistance to current therapies and improve survival outcomes. In addition, myeloma is associated with progressive immune dysregulation, with defects in T-cell immunity, natural killer cell function, and the antigen-presenting capacity of dendritic cells, resulting in a tumor microenvironment that promotes disease tolerance and progression. Together, the immunosuppressive microenvironment and oncogenic mutations activate signaling networks that promote myeloma cell survival. Immunotherapy incorporates novel treatment options (e.g., monoclonal antibodies, antibody-drug conjugates, chimeric antigen receptor T-cell therapy, immune checkpoint inhibitors, bispecific antibodies, and tumor vaccines) either alone or in combination with existing lines of therapies (e.g., immunomodulatory agents, proteasome inhibitors, and histone deacetylase inhibitors) to enhance the host anti myeloma immunity within the bone marrow microenvironment and improve clinical response. Following the U.S. Food and Drug Administration approval of daratumumab and elotuzumab in 2015, more immunotherapeutic agents are expected to be become available as valuable treatment options in the near future. This review provides a basic understanding of the role of immunotherapy in modulating the bone marrow tumor microenvironment and its role in the treatment of myeloma. Clinical efficacy and safety of recently

  9. Late multiple organ surge in interferon-regulated target genes characterizes staphylococcal enterotoxin B lethality.

    Directory of Open Access Journals (Sweden)

    Gabriela A Ferreyra

    Full Text Available BACKGROUND: Bacterial superantigens are virulence factors that cause toxic shock syndrome. Here, the genome-wide, temporal response of mice to lethal intranasal staphylococcal enterotoxin B (SEB challenge was investigated in six tissues. RESULTS: The earliest responses and largest number of affected genes occurred in peripheral blood mononuclear cells (PBMC, spleen, and lung tissues with the highest content of both T-cells and monocyte/macrophages, the direct cellular targets of SEB. In contrast, the response of liver, kidney, and heart was delayed and involved fewer genes, but revealed a dominant genetic program that was seen in all 6 tissues. Many of the 85 uniquely annotated transcripts participating in this shared genomic response have not been previously linked to SEB. Nine of the 85 genes were subsequently confirmed by RT-PCR in every tissue/organ at 24 h. These 85 transcripts, up-regulated in all tissues, annotated to the interferon (IFN/antiviral-response and included genes belonging to the DNA/RNA sensing system, DNA damage repair, the immunoproteasome, and the ER/metabolic stress-response and apoptosis pathways. Overall, this shared program was identified as a type I and II interferon (IFN-response and the promoters of these genes were highly enriched for IFN regulatory matrices. Several genes whose secreted products induce the IFN pathway were up-regulated at early time points in PBMCs, spleen, and/or lung. Furthermore, IFN regulatory factors including Irf1, Irf7 and Irf8, and Zbp1, a DNA sensor/transcription factor that can directly elicit an IFN innate immune response, participated in this host-wide SEB signature. CONCLUSION: Global gene-expression changes across multiple organs implicated a host-wide IFN-response in SEB-induced death. Therapies aimed at IFN-associated innate immunity may improve outcome in toxic shock syndromes.

  10. Telomerase inhibition targets clonogenic multiple myeloma cells through telomere length-dependent and independent mechanisms.

    Directory of Open Access Journals (Sweden)

    Sarah K Brennan

    Full Text Available BACKGROUND: Plasma cells constitute the majority of tumor cells in multiple myeloma (MM but lack the potential for sustained clonogenic growth. In contrast, clonotypic B cells can engraft and recapitulate disease in immunodeficient mice suggesting they serve as the MM cancer stem cell (CSC. These tumor initiating B cells also share functional features with normal stem cells such as drug resistance and self-renewal potential. Therefore, the cellular processes that regulate normal stem cells may serve as therapeutic targets in MM. Telomerase activity is required for the maintenance of normal adult stem cells, and we examined the activity of the telomerase inhibitor imetelstat against MM CSC. Moreover, we carried out both long and short-term inhibition studies to examine telomere length-dependent and independent activities. METHODOLOGY/PRINCIPAL FINDINGS: Human MM CSC were isolated from cell lines and primary clinical specimens and treated with imetelstat, a specific inhibitor of the reverse transcriptase activity of telomerase. Two weeks of exposure to imetelstat resulted in a significant reduction in telomere length and the inhibition of clonogenic MM growth both in vitro and in vivo. In addition to these relatively long-term effects, 72 hours of imetelstat treatment inhibited clonogenic growth that was associated with MM CSC differentiation based on expression of the plasma cell antigen CD138 and the stem cell marker aldehyde dehydrogenase. Short-term treatment of MM CSC also decreased the expression of genes typically expressed by stem cells (OCT3/4, SOX2, NANOG, and BMI1 as revealed by quantitative real-time PCR. CONCLUSIONS: Telomerase activity regulates the clonogenic growth of MM CSC. Moreover, reductions in MM growth following both long and short-term telomerase inhibition suggest that it impacts CSC through telomere length-dependent and independent mechanisms.

  11. Targeting multiple signal pathways by chemopreventive agents for cancer prevention and therapy

    Institute of Scientific and Technical Information of China (English)

    Fazlul H SARKAR; Yi-wei LI

    2007-01-01

    In recent years, growing interest has been focused on the field of cancer prevention.Cancer prevention by chemopreventive agents offers significant promise for re-ducing the incidence and mortality of cancer. Chemopreventive agents may exert their effects either by blocking or metabolizing carcinogens or by inhibiting tumor cell growth. Another important benefit of chemopreventive agents is their non-toxic nature. Therefore, chemopreventive agents have recently been used for cancer treatment in combination with chemotherapeutics or radiotherapy, uncov-ering a novel strategy for cancer therapy. This strategy opens a new avenue fromcancer prevention to cancer treatment. In vitro and in vivo studies have demon-strated that chemopreventive agents could enhance the antitumor activity of chemotherapeutics, improving the treatment outcome. Growing evidence has shown that chemopreventive agents potentiate the efficacy of chemotherapy and radiotherapy through the regulation of multiple signaling pathways, including Akt, NF-κB, c-Myc, cyclooxygenase-2, apoptosis, and others, suggesting a multitargeted nature of chemopreventive agents. However, further in-depth mecha-nistic studies, in vivo animal experiments, and clinical trials are needed to investi-gate the effects of chemopreventive agents in combination treatment of cancer with conventional cancer therapies. More potent natural and synthetic chemo-preventive agents are also needed to improve the efficacy of mechanism-based and targeted therapeutic strategies against cancer, which are likely to make a significant impact on saving lives. Here, we have briefly reviewed the role of chemopreventive agents in cancer prevention, but most importantly, we have reviewed how they could be useful for cancer therapy in combination with con-ventional therapies.

  12. Caveolin-1 is required for vascular endothelial growth factor-triggered multiple myeloma cell migration and is targeted by bortezomib.

    Science.gov (United States)

    Podar, Klaus; Shringarpure, Reshma; Tai, Yu-Tzu; Simoncini, Melissa; Sattler, Martin; Ishitsuka, Kenji; Richardson, Paul G; Hideshima, Teru; Chauhan, Dharminder; Anderson, Kenneth C

    2004-10-15

    We recently demonstrated that caveolae, vesicular flask-shaped invaginations of the plasma membrane, represent novel therapeutic targets in multiple myeloma. In the present study, we demonstrate that vascular endothelial growth factor (VEGF) triggers Src-dependent phosphorylation of caveolin-1, which is required for p130(Cas) phosphorylation and multiple myeloma cell migration. Conversely, depletion of caveolin-1 by antisense methodology abrogates p130(Cas) phosphorylation and VEGF-triggered multiple myeloma cell migration. The proteasome inhibitor bortezomib both inhibited VEGF-triggered caveolin-1 phosphorylation and markedly decreased caveolin-1 expression. Consequently, bortezomib inhibited VEGF-induced multiple myeloma cell migration. Bortezomib also decreased VEGF secretion in the bone marrow microenvironment and inhibited VEGF-triggered tyrosine phosphorylation of caveolin-1, migration, and survival in human umbilical vascular endothelial cells. Taken together, these studies demonstrate the requirement of caveolae for VEGF-triggered multiple myeloma cell migration and identify caveolin-1 in multiple myeloma cells and human umbilical vascular endothelial cells as a molecular target of bortezomib.

  13. Association Study between Cervical Lesions and Single or Multiple Vaccine-Target and Non-Vaccine Target Human Papillomavirus (HPV Types in Women from Northeastern Brazil.

    Directory of Open Access Journals (Sweden)

    Bárbara Simas Chagas

    Full Text Available We performed an association between high-grade squamous intraepithelial lesions (HSIL, low-grade squamous intraepithelial lesions (LSIL and single or multiple vaccine-target as well as non-vaccine target Human papillomavirus (HPV types. Using bead-based HPV genotyping, 594 gynecological samples were genotyped. An association between squamous intraepithelial lesion (SIL and presence of HPV16, 18, 31, 58 and 56 types were calculated. The risk was estimated by using odds ratio (OR and 95% of confidence intervals (CI. A total of 370 (62.3% women were HPV positive. Among these, 157 (42.7% presented a single HPV infection, and 212 (57.3% were infected by more than one HPV type. HPV31 was the most prevalent genotype, regardless single and multiple HPV infections. Single infection with HPV31 was associated with LSIL (OR=2.32; 95%CI: 1.01 to 5.32; p=0.04; HPV31 was also associated with LSIL (OR=3.28; 95%CI: 1.74 to 6.19; p= 0.0002 and HSIL (OR=3.82; 95%CI: 2.10 to 6.97; p<0.001 in multiple HPV infections. Risk to harbor cervical lesions was observed in multiple HPV infections with regard to the HPV56 (OR=5.39; 95%CI: 2.44 to 11.90; p<0.001for LSIL; OR=5.37; 95%CI: 2.71 to 10.69; p<0.001 and HPV58 (OR=3.29; 95%CI: 1.34 to 8.09; p=0.0091 for LSIL; OR=3.55; 95%CI: 1.56 to 8.11; p=0.0026 genotypes. In addition, women coinfected with HPV16/31/56 types had 6 and 5-fold increased risk of HSIL (OR=6.46; 95%CI: 1.89 to 22.09; p=0.002 and LSIL (OR=5.22; 95%CI: 1.10 to 24.70; p=0.03, respectively. Multiple HPV infections without HPV16/18 has 2-fold increased risk of HSIL (OR=2.57; 95%CI: 1.41 to 4.70; p=0.002 and LSIL OR=2.03; 95%CI: 1.08 to 3.79; p=0.02. The results of this study suggest that single and multiple vaccine target as well as non-vaccine target HPV types are associated with LSIL and HSIL. These finding should be taken into consideration in the design of HPV vaccination strategies.

  14. Nickel, cobalt, and their alloys

    CERN Document Server

    2000-01-01

    This book is a comprehensive guide to the compositions, properties, processing, performance, and applications of nickel, cobalt, and their alloys. It includes all of the essential information contained in the ASM Handbook series, as well as new or updated coverage in many areas in the nickel, cobalt, and related industries.

  15. Targeting CD38 Suppresses Induction and Function of T Regulatory Cells to Mitigate Immunosuppression in Multiple Myeloma.

    Science.gov (United States)

    Feng, Xiaoyan; Zhang, Li; Acharya, Chirag; An, Gang; Wen, Kenneth; Qiu, Lugui; Munshi, Nikhil C; Tai, Yu-Tzu; Anderson, Kenneth C

    2017-08-01

    Purpose: We study CD38 levels in immunosuppressive CD4(+)CD25(high)Foxp3(+) regulatory T cells (Treg) and further define immunomodulating effects of a therapeutic CD38 mAb isatuximab/SAR650984 in multiple myeloma.Experimental Design: We evaluated percentages of CD38-expressing subsets in Tregs from normal donors and multiple myeloma patients. Peripheral blood mononuclear cells (PBMC) were then treated with isatuximab with or without lenalidomide or pomalidomide to identify their impact on the percentage and immunosuppressive activity of Tregs on CD4(+)CD25(-) T cells (Tcons). We investigated the mechanism of increased Tregs in multiple myeloma patients in ex vivo cocultures of multiple myeloma cells with PBMCs or Tcons.Results: CD38 expression is higher on Tregs than Tcons from multiple myeloma patients versus normal donors. CD38 levels and the percentages of CD38(high) Tregs are increased by lenalidomide and pomalidomide. Isatuximab preferentially decreases Treg and increases Tcon frequencies, which is enhanced by pomalidomide/lenalidomide. Isatuximab reduces Foxp3 and IL10 in Tregs and restores proliferation and function of Tcons. It augments multiple myeloma cell lysis by CD8(+) T and natural killer cells. Coculture of multiple myeloma cells with Tcons significantly induces Tregs (iTregs), which express even higher CD38, CD25, and FoxP3 than natural Tregs. This is associated with elevated circulating CD38(+) Tregs in multiple myeloma patients versus normal donors. Conversely, isatuximab decreases multiple myeloma cell- and bone marrow stromal cell-induced iTreg by inhibiting both cell-cell contact and TGFβ/IL10. Finally, CD38 levels correlate with differential inhibition by isatuximab of Tregs from multiple myeloma versus normal donors.Conclusions: Targeting CD38 by isatuximab can preferentially block immunosuppressive Tregs and thereby restore immune effector function against multiple myeloma. Clin Cancer Res; 23(15); 4290-300. ©2017 AACR. ©2017 American

  16. Preclinical and clinical evaluation of elotuzumab, a SLAMF7-targeted humanized monoclonal antibody in development for multiple myeloma.

    Science.gov (United States)

    Palumbo, Antonio; Sonneveld, Pieter

    2015-08-01

    Although multiple myeloma has historically been treated with chemotherapy, prolonged survival has only been possible since the introduction of thalidomide, lenalidomide and bortezomib. However, multiple myeloma remains largely incurable, and new treatments are needed to improve long-term outcome. Elotuzumab is a humanized IgG1 monoclonal antibody that targets Signaling Lymphocyte Activation Molecule Family member 7 (SLAMF7) to activate NK cells, enabling selective killing of myeloma cells with minimal effects on normal tissue. The combination of elotuzumab with antimyeloma therapies that stimulate host immunity may be an attractive treatment option for patients with newly diagnosed or relapsed/refractory multiple myeloma. Here, we review the role of SLAMF7 in the pathogenesis of multiple myeloma and the preclinical and clinical development of elotuzumab.

  17. 基于WSN的多声源目标定位算法%Acoustic Multiple-Target Location in WSN

    Institute of Scientific and Technical Information of China (English)

    吕方旭; 张金成; 刘立阳

    2012-01-01

    目标定位技术是无线传感器网络应用研究的一个重要领域,如何在传感器节点随机分布下,利用无源探测技术,对同时进入探测区域的多个目标进行实时的精确定位是目标定位的一个难点.基于声源能量衰减模型在最大似然算法的基础上,利用高斯-牛顿迭代算法解决了这个问题.通过对多个声源目标的仿真试验,结果表明,该算法实现了对多目标的精确定位,具有一定的实用价值.%The technology of target location is an important research field in WSN's application study. Under the condition of randomly distributed sensor notes, it is difficult to make a quick and accurate locating for multiple-target entered into the detection field by adopting the technology of passive detection. Based on source energy attenuation model and maximum likelihood, the article uses the Gauss-Newton Iteration Algorithm and solves the problem of multiple-target localization. The emulation result shows that the algorithm realized the accurate location of multiple-target and possesses practical application value.

  18. Hydrogen sulfide slows down progression of experimental Alzheimer's disease by targeting multiple pathophysiological mechanisms.

    Science.gov (United States)

    Giuliani, Daniela; Ottani, Alessandra; Zaffe, Davide; Galantucci, Maria; Strinati, Flavio; Lodi, Renzo; Guarini, Salvatore

    2013-09-01

    inflammation and apoptosis. Our findings indicate that appropriate treatments with H2S donors and Tabiano's spa-waters, and may be other spa-waters rich in H2S content, might represent an innovative approach to slow down AD progression in humans by targeting multiple pathophysiological mechanisms.

  19. 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

  20. Cooperative enclosing control for multiple moving targets by a group of agents

    Science.gov (United States)

    Shi, Y. J.; Li, R.; Teo, K. L.

    2015-01-01

    In this paper, the enclosing control problem of second-order multi-agent systems is considered, where the targets can be either stationary or moving. The objective is to achieve an equidistant circular formation for a group of agents to enclose a team of targets. In order to do so, we first introduce a formal definition explaining certain basic properties of the exploring relation between the agents and the targets. We then construct the estimator of the centre of the targets, which is used to build the control protocol to achieve equidistant circular enclosing. Using a Lyapunov function and Lasalle's Invariance Principle, the convergency of the estimator and control protocol are, respectively, established. We then construct a smooth function to approximate the discontinuous term in the estimator. Finally, the simulations for stationary targets and moving targets are given to verify the validity of the results obtained.

  1. Targeting the binding interface on a shared receptor subunit of a cytokine family enables the inhibition of multiple member cytokines with selectable target spectrum.

    Science.gov (United States)

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

    2015-09-11

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

  2. Cobalt source calibration

    Energy Technology Data Exchange (ETDEWEB)

    Rizvi, H.M.

    1999-12-03

    The data obtained from these tests determine the dose rate of the two cobalt sources in SRTC. Building 774-A houses one of these sources while the other resides in room C-067 of Building 773-A. The data from this experiment shows the following: (1) The dose rate of the No.2 cobalt source in Building 774-A measured 1.073 x 10{sup 5} rad/h (June 17, 1999). The dose rate of the Shepherd Model 109 Gamma cobalt source in Building 773-A measured 9.27 x 10{sup 5} rad/h (June 25, 1999). These rates come from placing the graduated cylinder containing the dosimeter solution in the center of the irradiation chamber. (2) Two calibration tests in the 774-A source placed the graduated cylinder with the dosimeter solution approximately 1.5 inches off center in the axial direction. This movement of the sample reduced the measured dose rate 0.92% from 1.083 x 10{sup 5} rad/h to 1.073 x 10{sup 5} rad/h. and (3) A similar test in the cobalt source in 773-A placed the graduated cylinder approximately 2.0 inches off center in the axial direction. This change in position reduced the measured dose rate by 10.34% from 1.036 x 10{sup 6} to 9.27 x 10{sup 5}. This testing used chemical dosimetry to measure the dose rate of a radioactive source. In this method, one determines the dose by the chemical change that takes place in the dosimeter. For this calibration experiment, the author used a Fricke (ferrous ammonium sulfate) dosimeter. This solution works well for dose rates to 10{sup 7} rad/h. During irradiation of the Fricke dosimeter solution the Fe{sup 2+} ions ionize to Fe{sup 3+}. When this occurs, the solution acquires a slightly darker tint (not visible to the human eye). To determine the magnitude of the change in Fe ions, one places the solution in an UV-VIS Spectrophotometer. The UV-VIS Spectrophotometer measures the absorbency of the solution. Dividing the absorbency by the total time (in minutes) of exposure yields the dose rate.

  3. Split-Inteins for Simultaneous, site-specific conjugation of Quantum Dots to multiple protein targets In vivo

    Directory of Open Access Journals (Sweden)

    Christodoulou Neophytos

    2011-09-01

    Full Text Available Abstract Background Proteins labelled with Quantum Dots (QDs can be imaged over long periods of time with ultrahigh spatial and temporal resolution, yielding important information on the spatiotemporal dynamics of proteins within live cells or in vivo. However one of the major problems regarding the use of QDs for biological imaging is the difficulty of targeting QDs onto proteins. We have recently developed a DnaE split intein-based method to conjugate Quantum Dots (QDs to the C-terminus of target proteins in vivo. In this study, we expand this approach to achieve site-specific conjugation of QDs to two or more proteins simultaneously with spectrally distinguishable QDs for multiparameter imaging of cellular functions. Results Using the DnaE split intein we target QDs to the C-terminus of paxillin and show that paxillin-QD conjugates become localized at focal adhesions allowing imaging of the formation and dissolution of these complexes. We go on to utilize a different split intein, namely Ssp DnaB mini-intein, to demonstrate N-terminal protein tagging with QDs. Combination of these two intein systems allowed us to simultaneously target two distinct proteins with spectrally distinguishable QDs, in vivo, without any cross talk between the two intein systems. Conclusions Multiple target labeling is a unique feature of the intein based methodology which sets it apart from existing tagging methodologies in that, given the large number of characterized split inteins, the number of individual targets that can be simultaneously tagged is only limited by the number of QDs that can be spectrally distinguished within the cell. Therefore, the intein-mediated approach for simultaneous, in vivo, site-specific (N- and C-terminus conjugation of Quantum Dots to multiple protein targets opens up new possibilities for bioimaging applications and offers an effective system to target QDs and other nanostructures to intracellular compartments as well as specific

  4. Recycling cobalt from spent lithium ion battery

    Institute of Scientific and Technical Information of China (English)

    Zhi-dong XIA; Xiao-qian XIE; Yao-wu SHI; Yong-ping LEI; Fu GUO

    2008-01-01

    Spent lithium ion battery is a useful resource of cobalt. In this paper, cobalt was recovered by a chemical process based upon the analysis of the structure and com-position of the lithium ion battery. X-ray diffraction results show that cobalt oxalate and cobaltous sulfate have been obtained in two different processes. Compared with the cobaltous oxalate process, the cobaltous sulfate process was characterized by less chemical substance input and a cobalt recovery rate of as much as 88%. A combination of these two processes in the recycling industry may win in the aspects of compact process and high recovery rate.

  5. CD44v6-targeted T cells mediate potent antitumor effects against acute myeloid leukemia and multiple myeloma.

    Science.gov (United States)

    Casucci, Monica; Nicolis di Robilant, Benedetta; Falcone, Laura; Camisa, Barbara; Norelli, Margherita; Genovese, Pietro; Gentner, Bernhard; Gullotta, Fabiana; Ponzoni, Maurilio; Bernardi, Massimo; Marcatti, Magda; Saudemont, Aurore; Bordignon, Claudio; Savoldo, Barbara; Ciceri, Fabio; Naldini, Luigi; Dotti, Gianpietro; Bonini, Chiara; Bondanza, Attilio

    2013-11-14

    Genetically targeted T cells promise to solve the feasibility and efficacy hurdles of adoptive T-cell therapy for cancer. Selecting a target expressed in multiple-tumor types and that is required for tumor growth would widen disease indications and prevent immune escape caused by the emergence of antigen-loss variants. The adhesive receptor CD44 is broadly expressed in hematologic and epithelial tumors, where it contributes to the cancer stem/initiating phenotype. In this study, silencing of its isoform variant 6 (CD44v6) prevented engraftment of human acute myeloid leukemia (AML) and multiple myeloma (MM) cells in immunocompromised mice. Accordingly, T cells targeted to CD44v6 by means of a chimeric antigen receptor containing a CD28 signaling domain mediated potent antitumor effects against primary AML and MM while sparing normal hematopoietic stem cells and CD44v6-expressing keratinocytes. Importantly, in vitro activation with CD3/CD28 beads and interleukin (IL)-7/IL-15 was required for antitumor efficacy in vivo. Finally, coexpressing a suicide gene enabled fast and efficient pharmacologic ablation of CD44v6-targeted T cells and complete rescue from hyperacute xenogeneic graft-versus-host disease modeling early and generalized toxicity. These results warrant the clinical investigation of suicidal CD44v6-targeted T cells in AML and MM.

  6. 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.

  7. A systematic prediction of multiple drug-target interactions from chemical, genomic, and pharmacological data.

    Directory of Open Access Journals (Sweden)

    Hua Yu

    Full Text Available In silico prediction of drug-target interactions from heterogeneous biological data can advance our system-level search for drug molecules and therapeutic targets, which efforts have not yet reached full fruition. In this work, we report a systematic approach that efficiently integrates the chemical, genomic, and pharmacological information for drug targeting and discovery on a large scale, based on two powerful methods of Random Forest (RF and Support Vector Machine (SVM. The performance of the derived models was evaluated and verified with internally five-fold cross-validation and four external independent validations. The optimal models show impressive performance of prediction for drug-target interactions, with a concordance of 82.83%, a sensitivity of 81.33%, and a specificity of 93.62%, respectively. The consistence of the performances of the RF and SVM models demonstrates the reliability and robustness of the obtained models. In addition, the validated models were employed to systematically predict known/unknown drugs and targets involving the enzymes, ion channels, GPCRs, and nuclear receptors, which can be further mapped to functional ontologies such as target-disease associations and target-target interaction networks. This approach is expected to help fill the existing gap between chemical genomics and network pharmacology and thus accelerate the drug discovery processes.

  8. Multiple target ionization in collisions between highly charged ions and Ar

    NARCIS (Netherlands)

    deNijs, G; Hoekstra, R; Morgenstern, R

    1996-01-01

    We have performed measurements on charge-state distributions of target ions produced in collisions of C6+, N6+, O6+, Ne6+, Ar6+ and Kr6+ on Ar. Charge states of Ar target ions higher than the initial projectile charge state are observed for C6+, N6+ and O6+. This intriguing observation seems to

  9. Nrf2: A Novel Biomarker of Disease Severity and Target for Therapeutic Intervention in Multiple Sclerosis

    Science.gov (United States)

    2014-10-01

    suppression of disease symptoms in EAE (Experimental Autoimmune Encephalomyelitis). In the current report we: 1) characterize the Nrf2-targeted antioxidant ...including their potential to suppress disease symptoms in EAE. In current report we first characterized the Nrf2 targeted antioxidant properties of...sclerosis, rheumatoid arthritis4 and skin inflammation.5 Further it has been reported that Celastrol can inhibit inflammatory reactions between

  10. Identification of “Multiple Components-Multiple Targets-Multiple Pathways” Associated with Naoxintong Capsule in the Treatment of Heart Diseases Using UPLC/Q-TOF-MS and Network Pharmacology

    Science.gov (United States)

    Ma, Xianghui; Lv, Bin; Li, Pan; Jiang, Xiaoqing; Zhou, Qian; Wang, Xiaoying; Gao, Xiumei

    2016-01-01

    Naoxintong capsule (NXT) is a commercial medicinal product approved by the China Food and Drug Administration which is used in the treatment of stroke and coronary heart disease. However, the research on the composition and mechanism of NXT is still lacking. Our research aimed to identify the absorbable components, potential targets, and associated pathways of NXT with network pharmacology method. We explored the chemical compositions of NXT based on UPLC/Q-TOF-MS. Then, we used the five principles of drug absorption to identify absorbable ingredients. The databases of PharmMapper, Universal Protein, and the Molecule Annotation System were used to predict the main targets and related pathways. By the five principles of drug absorption as a judgment rule, we identified 63 compositions that could be absorbed in the blood in all 81 chemical compositions. Based on the constructed networks by the significant regulated 123 targets and 77 pathways, the main components that mediated the efficacy of NXT were organic acids, saponins, and tanshinones. Radix Astragali was the critical herbal medicine in NXT, which contained more active components than other herbs and regulated more targets and pathways. Our results showed that NXT had a therapeutic effect on heart diseases through the pattern “multiple components-multiple targets-multiple pathways.” PMID:27123036

  11. 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.

  12. Fatty acid synthase is a key target in multiple essential tumor functions of prostate cancer: uptake of radiolabeled acetate as a predictor of the targeted therapy outcome.

    Directory of Open Access Journals (Sweden)

    Yukie Yoshii

    -invasive visualization of tumor acetate uptake and selection of responsive tumors. FASN-targeted therapy could be an effective treatment to suppress multiple steps related to tumor progression in prostate cancers selected by [1-(11C]acetate PET.

  13. Targeting Epstein-Barr virus infection as an intervention against multiple sclerosis.

    Science.gov (United States)

    Jons, D; Sundström, P; Andersen, O

    2015-02-01

    We here review contemporary data on genetic and environmental risk factors, particularly Epstein-Barr virus infection, for multiple sclerosis. There is an important immunogenetic etiological factor for multiple sclerosis. However, a general assumption is that immune defense genes are activated by the environment, basically by infections. We contend that the relationship between infectious mononucleosis and multiple sclerosis cannot be completely explained by genetics and inverse causality. Epstein-Barr infection as indicated by positive serology is an obligatory precondition for multiple sclerosis, which is a stronger attribute than a risk factor only. Data on events in the early pathogenesis of multiple sclerosis are cumulating from bio-banks with presymptomatic specimens, but there is only little information from the critical age when Epstein-Barr infection including infectious mononucleosis is acquired, nor on the detailed immunological consequences of this infection in individuals with and without multiple sclerosis. We discuss how focused bio-banking may elaborate a rationale for the development of treatment or vaccination against Epstein-Barr virus infection. A cohort in which intervention against Epstein-Barr infections was performed should be the object of neurological follow-up.

  14. Effective Pincer Cobalt Precatalysts for Lewis Acid Assisted CO2 Hydrogenation.

    Science.gov (United States)

    Spentzos, Ariana Z; Barnes, Charles L; Bernskoetter, Wesley H

    2016-08-15

    The pincer ligand MeN[CH2CH2(P(i)Pr2)]2 ((iPr)PNP) was employed to support a series of cobalt(I) complexes, which were crystallographically characterized. A cobalt monochloride species, ((iPr)PNP)CoCl, served as a precursor for the preparation of several cobalt precatalysts for CO2 hydrogenation, including a cationic dicarbonyl cobalt complex, [((iPr)PNP)Co(CO)2](+). When paired with the Lewis acid lithium triflate, [((iPr)PNP)Co(CO)2](+) affords turnover numbers near 30 000 (at 1000 psi, 45 °C) for CO2-to-formate hydrogenation, which is a notable increase in activity from previously reported homogeneous cobalt catalysts. Though mechanistic information regarding the function of the precatalysts remains limited, multiple experiments suggest the active species is a molecular, homogeneous [((iPr)PNP)Co] complex.

  15. A note on the global properties of an age-structured viral dynamic model with multiple target cell populations.

    Science.gov (United States)

    Wang, Shaoli; Wu, Jianhong; Rong, Libin

    2017-06-01

    Some viruses can infect different classes of cells. The age of infection can affect the dynamics of infected cells and viral production. Here we develop a viral dynamic model with the age of infection and multiple target cell populations. Using the methods of semigroup and Lyapunov function, we study the global asymptotic property of the steady states of the model. The results show that when the basic reproductive number falls below 1, the infection is predicted to die out. When the basic reproductive number exceeds 1, there exists a unique infected steady state which is globally asymptotically stable. The model can be extended to study virus dynamics with multiple compartments or coinfection by multiple types of viruses. We also show that under some scenarios the age-structured model can be reduced to an ordinary differential equation system with or without time delays.

  16. Target enhancement and distractor inhibition affect transitory surround suppression in dual tasks using multiple rapid serial visual presentation streams.

    Science.gov (United States)

    Wu, Xia; Greenwood, Pamela; Fu, Shimin

    2016-01-01

    Few studies have investigated the interaction between temporal and spatial dimensions on selective attention using dual tasks in the multiple rapid serial visual presentation (RSVP) paradigm. A phenomenon that the surround suppression in space changes over time (termed transitory surround suppression, TSS, in the present study) has been observed, suggesting the existence of this time-space interaction. However, it is still unclear whether target enhancement or distractor inhibition modulates TSS. Four behavioural experiments were conducted to investigate the mechanism of TSS by manipulating the temporal lag and spatial distance factors between two targets embedded in six RSVP streams. The TSS effect was replicated in a study that eliminated confounds of perceptual effects and attentional switch (Experiment 1). However, the TSS disappeared when two targets shared the same colour in a between-subjects design (Experiment 2a) and a within-subject design (Experiment 2b), suggesting the impact of target enhancement on TSS. Moreover, the TSS was larger for within-category than for between-category distractors (Experiment 3), indicating the impact of distractor inhibition on TSS. These two influences on TSS under different processing demands of target and distractor processing were further confirmed in a skeletal design (Experiment 4). Overall, combinative effects of target enhancement and distractor suppression contribute to the mechanisms of time-space interaction in selective attention during visual search.

  17. A memetic algorithm for path planning of curvature-constrained UAVs performing surveillance of multiple ground targets

    Institute of Scientific and Technical Information of China (English)

    Zhang Xing; Chen Jie; Xin Bin; Peng Zhihong

    2014-01-01

    The problem of generating optimal paths for curvature-constrained unmanned aerial vehicles (UAVs) performing surveillance of multiple ground targets is addressed in this paper. UAVs are modeled as Dubins vehicles so that the constraints of UAVs’ minimal turning radius can be taken into account. In view of the effective surveillance range of the sensors equipped on UAVs, the problem is formulated as a Dubins traveling salesman problem with neighborhood (DTSPN). Considering its prohibitively high computational complexity, the Dubins paths in the sense of terminal heading relaxation are introduced to simplify the calculation of the Dubins distance, and a boundary-based encoding scheme is proposed to determine the visiting point of every target neighborhood. Then, an evolutionary algorithm is used to derive the optimal Dubins tour. To further enhance the quality of the solutions, a local search strategy based on approximate gradient is employed to improve the visiting points of target neighborhoods. Finally, by a minor modification to the individual encoding, the algorithm is easily extended to deal with other two more sophisticated DTSPN variants (multi-UAV scenario and multiple groups of targets scenario). The performance of the algorithm is demonstrated through comparative experiments with other two state-of-the-art DTSPN algorithms identified in literature. Numerical simulations exhibit that the algorithm proposed in this paper can find high-quality solutions to the DTSPN with lower computational cost and produce significantly improved performance over the other algorithms.

  18. A memetic algorithm for path planning of curvature-constrained UAVs performing surveillance of multiple ground targets

    Directory of Open Access Journals (Sweden)

    Zhang Xing

    2014-06-01

    Full Text Available The problem of generating optimal paths for curvature-constrained unmanned aerial vehicles (UAVs performing surveillance of multiple ground targets is addressed in this paper. UAVs are modeled as Dubins vehicles so that the constraints of UAVs’ minimal turning radius can be taken into account. In view of the effective surveillance range of the sensors equipped on UAVs, the problem is formulated as a Dubins traveling salesman problem with neighborhood (DTSPN. Considering its prohibitively high computational complexity, the Dubins paths in the sense of terminal heading relaxation are introduced to simplify the calculation of the Dubins distance, and a boundary-based encoding scheme is proposed to determine the visiting point of every target neighborhood. Then, an evolutionary algorithm is used to derive the optimal Dubins tour. To further enhance the quality of the solutions, a local search strategy based on approximate gradient is employed to improve the visiting points of target neighborhoods. Finally, by a minor modification to the individual encoding, the algorithm is easily extended to deal with other two more sophisticated DTSPN variants (multi-UAV scenario and multiple groups of targets scenario. The performance of the algorithm is demonstrated through comparative experiments with other two state-of-the-art DTSPN algorithms identified in literature. Numerical simulations exhibit that the algorithm proposed in this paper can find high-quality solutions to the DTSPN with lower computational cost and produce significantly improved performance over the other algorithms.

  19. System simulation method for fiber-based homodyne multiple target interferometers using short coherence length laser sources

    Science.gov (United States)

    Fox, Maik; Beuth, Thorsten; Streck, Andreas; Stork, Wilhelm

    2015-09-01

    Homodyne laser interferometers for velocimetry are well-known optical systems used in many applications. While the detector power output signal of such a system, using a long coherence length laser and a single target, is easily modelled using the Doppler shift, scenarios with a short coherence length source, e.g. an unstabilized semiconductor laser, and multiple weak targets demand a more elaborated approach for simulation. Especially when using fiber components, the actual setup is an important factor for system performance as effects like return losses and multiple way propagation have to be taken into account. If the power received from the targets is in the same region as stray light created in the fiber setup, a complete system simulation becomes a necessity. In previous work, a phasor based signal simulation approach for interferometers based on short coherence length laser sources has been evaluated. To facilitate the use of the signal simulation, a fiber component ray tracer has since been developed that allows the creation of input files for the signal simulation environment. The software uses object oriented MATLAB code, simplifying the entry of different fiber setups and the extension of the ray tracer. Thus, a seamless way from a system description based on arbitrarily interconnected fiber components to a signal simulation for different target scenarios has been established. The ray tracer and signal simulation are being used for the evaluation of interferometer concepts incorporating delay lines to compensate for short coherence length.

  20. Targeted mutagenesis of multiple and paralogous genes in Xenopus laevis using two pairs of transcription activator-like effector nucleases.

    Science.gov (United States)

    Sakane, Yuto; Sakuma, Tetsushi; Kashiwagi, Keiko; Kashiwagi, Akihiko; Yamamoto, Takashi; Suzuki, Ken-Ichi T

    2014-01-01

    Transcription activator-like effector nucleases (TALENs) have been extensively used in genome editing in various organisms. In some cases, however, it is difficult to efficiently disrupt both paralogous genes using a single pair of TALENs in Xenopus laevis because of its polyploidy. Here, we report targeted mutagenesis of multiple and paralogous genes using two pairs of TALENs in X. laevis. First, we show simultaneous targeted mutagenesis of three genes, tyrosinase paralogues (tyra and tyrb) and enhanced green fluorescent protein (egfp) by injection of two TALENs pairs in transgenic embryos carrying egfp. Consistent with the high frequency of both severe phenotypic traits, albinism and loss of GFP fluorescence, frameshift mutation rates of tyr paralogues and egfp reached 40-80%. Next, we show early introduction of TALEN-mediated mutagenesis of these target loci during embryogenesis. Finally, we also demonstrate that two different pairs of TALENs can simultaneously introduce mutations to both paralogues encoding histone chaperone with high efficiency. Our results suggest that targeted mutagenesis of multiple genes using TALENs can be applied to analyze the functions of paralogous genes with redundancy in X. laevis.

  1. Signal-on electrochemical detection of antibiotics at zeptomole level based on target-aptamer binding triggered multiple recycling amplification.

    Science.gov (United States)

    Wang, Hongzhi; Wang, Yu; Liu, Su; Yu, Jinghua; Guo, Yuna; Xu, Ying; Huang, Jiadong

    2016-06-15

    In the work, a signal-on electrochemical DNA sensor based on multiple amplification for ultrasensitive detection of antibiotics has been reported. In the presence of target, the ingeniously designed hairpin probe (HP1) is opened and the polymerase-assisted target recycling amplification is triggered, resulting in autonomous generation of secondary target. It is worth noting that the produced secondary target could not only hybridize with other HP1, but also displace the Helper from the electrode. Consequently, methylene blue labeled HP2 forms a "close" probe structure, and the increase of signal is monitored. The increasing current provides an ultrasensitive electrochemical detection for antibiotics down to 1.3 fM. To our best knowledge, such work is the first report about multiple recycling amplification combing with signal-on sensing strategy, which has been utilized for quantitative determination of antibiotics. It would be further used as a general strategy associated with more analytical techniques toward the detection of a wide spectrum of analytes. Thus, it holds great potential for the development of ultrasensitive biosensing platform for the applications in bioanalysis, disease diagnostics, and clinical biomedicine.

  2. 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.

  3. Target spectrum matrix definition for multiple-input- multiple-output control strategies applied on direct-field- acoustic-excitation tests

    Science.gov (United States)

    Alvarez Blanco, M.; Janssens, K.; Bianciardi, F.

    2016-09-01

    During the last two decades there have been several improvements on environmental acoustic qualification testing for launch and space vehicles. Direct field excitation (DFAX) tests using Multiple-Input-Multiple-Output (MIMO) control strategies seems to become the most cost-efficient way for component and subsystem acoustic testing. However there are still some concerns about the uniformity and diffusivity of the acoustic field produced by direct field testing. Lately, much of the documented progresses aimed to solve the non-uniformity of the field by altering the sound pressure level requirement, limiting responses and adding or modifying control microphones positions. However, the first two solutions imply modifying the qualification criteria, which could lead to under-testing, potentially risking the mission. Furthermore, adding or moving control microphones prematurely changes the system configuration, even if it is an optimal geometric layout in terms of wave interference patterns control. This research investigates the target definition as an initial condition for the acoustic MIMO control. Through experiments it is shown that for a given system configuration the performance of a DFAX test strongly depends on the target definition procedure. As output of this research a set of descriptors are presented describing a phenomenon defined as “Energy- sink”.

  4. Graphene/cobalt nanocarrier for hyperthermia therapy and MRI diagnosis.

    Science.gov (United States)

    Hatamie, Shadie; Ahadian, Mohammad Mahdi; Ghiass, Mohammad Adel; Iraji Zad, Azam; Saber, Reza; Parseh, Benyamin; Oghabian, Mohammad Ali; Shanehsazzadeh, Saeed

    2016-10-01

    Graphene/cobalt nanocomposites are promising materials for theranostic nanomedicine applications, which are defined as the ability to diagnose, provide targeted therapy and monitor the response to the therapy. In this study, the composites were synthesized via chemical method, using graphene oxide as the source material and assembling cobalt nanoparticles of 15nm over the surface of graphene sheets. Various characterization techniques were then employed to reveal the morphology, size and structure of the nanocomposites, such as X-ray diffraction analysis, X-ray photoelectron spectroscopy, Fourier transform infrared spectroscopy, high resolution transmission electron microscopy and ultraviolet visible spectroscopy. Using ion-coupled plasma optical emission spectroscopy, cobalt concentration in the nanocomposites was found to be 80%. In addition, cytotoxicity of graphene/cobalt nanocomposites were evaluated using 3-[4,5-dimethylthiazol-2yl]-2,5-diphenyltetrazolium bromide or MTT assay. MTT viability assay exhibited biocompatibility to L929 mouse fibroblasts cells, under a high dose of 100μg/mL over 24h. Hyperthermia results showed the superior conversion of electromagnetic energy into heat at 350kHz frequency for 0.01 and 0.005g/L of the nanocomposites solution. The measured heat generation and energy transfer results were anticipated by the finite element analysis, conducted for the 3D structure. Magnetic resonance imaging characteristics also showed that negatively charge graphene/cobalt nanocomposites are suitable for T1-weighted imaging. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. TARGET:?

    National Research Council Canada - National Science Library

    James M Acton

    2014-01-01

      By 2003. as military planners had become worried that the country's long-range conventional weapons, such as cruise missiles, might be too slow to reach hypothetical distant targets that needed to be struck urgently...

  6. Cost estimation for the active debris removal of multiple priority targets

    Science.gov (United States)

    Braun, Vitali; Wiedemann, Carsten; Schulz, Eugen

    The increasing number of space debris objects, especially in distinct low Earth orbit (LEO) altitudes between 600 and 1000 km, leads to an increase in the potential collision risk between the objects and threatens active satellites in that region. Several recent studies show that active debris removal (ADR) has to be performed in order to prevent a collisional cascading effect, also known as the Kessler syndrome. In order to stabilize the population growth in the critical LEO region, a removal of five prioritized objects per year has been recognized as a significant figure. Various proposals are addressing the technical issues for ADR missions, including the de-orbiting of objects by means of a service satellite using a chemical or an electric propulsion system. The servicer would rendezvous with a preselected target, perform a docking maneuver and then provide a de-orbit burn to transfer the target on a trajectory where it re-enters the Earth’s atmosphere within a given time frame. In this paper the technical aspects are complemented by a cost estimation model, focusing on multi target missions, which are based on a service satellite capable of de-orbiting more than one target within a single mission. The cost model for ADR includes initial development cost, production cost, launch cost and operation cost as well as the modelling of the propulsion system of the servicer. Therefore, different scenarios are defined for chemical and electric propulsion systems as applied to multi target missions, based on a literature review of concepts currently being under discussion. The costs of multi target missions are compared to a scenario where only one target is removed. Also, the results allow to determine an optimum number of objects to be removed per mission and provide numbers which can be used in future studies, e.g. those related to ADR cost and benefit analyses.

  7. An information potential approach for tracking and surveilling multiple moving targets using mobile sensor agents

    Science.gov (United States)

    Lu, W.; Zhang, G.; Ferrari, S.; Fierro, R.; Palunko, I.

    2011-05-01

    The problem of surveilling moving targets using mobile sensor agents (MSAs) is applicable to a variety of fields, including environmental monitoring, security, and manufacturing. Several authors have shown that the performance of a mobile sensor can be greatly improved by planning its motion and control strategies based on its sensing objectives. This paper presents an information potential approach for computing the MSAs' motion plans and control inputs based on the feedback from a modified particle filter used for tracking moving targets. The modified particle filter, as presented in this paper implements a new sampling method (based on supporting intervals of density functions), which accounts for the latest sensor measurements and adapts, accordingly, a mixture representation of the probability density functions (PDFs) for the target motion. It is assumed that the target motion can be modeled as a semi-Markov jump process, and that the PDFs of the Markov parameters can be updated based on real-time sensor measurements by a centralized processing unit or MSAs supervisor. Subsequently, the MSAs supervisor computes an information potential function that is communicated to the sensors, and used to determine their individual feedback control inputs, such that sensors with bounded field-of-view (FOV) can follow and surveil the target over time.

  8. Multiplicity distributions of shower particles and target fragments in 7Li–Em collisions at 3 A GeV/c

    Indian Academy of Sciences (India)

    N N Abd Allah; Fu-Hu Liu; E A Sultan; M Hassan

    2013-08-01

    Multiplicity distributions of shower particles and target fragments in 7Li–Em (emulsion) collisions at 3 A GeV/c are experimentally studied. In the framework of the multisource thermal model, the multicomponent Erlang distribution is used to describe the experimental multiplicity distributions of shower particles, grey fragments, black fragments, and heavily ionized fragments. The correlations between these multiplicities are experimentally reported. With the increase of impacting centrality (or the target fragment multiplicity), a saturation phenomenon for shower particle multiplicity is observed in the experiment.

  9. 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.

  10. Multiple adaptive losses of alanine-glyoxylate aminotransferase mitochondrial targeting in fruit-eating bats.

    Science.gov (United States)

    Liu, Yang; Xu, Huihui; Yuan, Xinpu; Rossiter, Stephen J; Zhang, Shuyi

    2012-06-01

    The enzyme alanine-glyoxylate aminotransferase 1 (AGT) functions to detoxify glyoxylate before it is converted into harmful oxalate. In mammals, mitochondrial targeting of AGT in carnivorous species versus peroxisomal targeting in herbivores is controlled by two signal peptides that correspond to these respective organelles. Differential expression of the mitochondrial targeting sequence (MTS) is considered an adaptation to diet-specific subcellular localization of glyoxylate precursors. Bats are an excellent group in which to study adaptive changes in dietary enzymes; they show unparalleled mammalian dietary diversification as well as independent origins of carnivory, frugivory, and nectarivory. We studied the AGT gene in bats and other mammals with diverse diets and found that the MTS has been lost in unrelated lineages of frugivorous bats. Conversely, species exhibiting piscivory, carnivory, insectivory, and sanguinivory possessed intact MTSs. Detected positive selection in the AGT of ancestral fruit bats further supports adaptations related to evolutionary changes in diet.

  11. Discovery of the Cobalt Isotopes

    OpenAIRE

    Szymanski, T.; Thoennessen, M.

    2009-01-01

    Twenty-six cobalt isotopes have so far been observed; the discovery of these isotopes is discussed. For each isotope a brief summary of the first refereed publication, including the production and identification method, is presented.

  12. Cobalt: for strength and color

    Science.gov (United States)

    Boland, Maeve A.; Kropschot, S.J.

    2011-01-01

    Cobalt is a shiny, gray, brittle metal that is best known for creating an intense blue color in glass and paints. It is frequently used in the manufacture of rechargeable batteries and to create alloys that maintain their strength at high temperatures. It is also one of the essential trace elements (or "micronutrients") that humans and many other living creatures require for good health. Cobalt is an important component in many aerospace, defense, and medical applications and is a key element in many clean energy technologies. The name cobalt comes from the German word kobold, meaning goblin. It was given this name by medieval miners who believed that troublesome goblins replaced the valuable metals in their ore with a substance that emitted poisonous fumes when smelted. The Swedish chemist Georg Brandt isolated metallic cobalt-the first new metal to be discovered since ancient times-in about 1735 and identified some of its valuable properties.

  13. 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.

  14. 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 implementatio

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

    NARCIS (Netherlands)

    Verhoeven, Aukje A. C.; Adriaanse, Marieke A.; de Ridder, Denise T. D.; de Vet, Emely; Fennis, Bob 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 implementatio

  16. Economic Evaluations of Targeted Therapy and Risk-Stratified Treatment Approaches in Multiple Myeloma

    NARCIS (Netherlands)

    J.G. Gaultney (Jennifer G.)

    2014-01-01

    markdownabstract__Abstract__ Multiple myeloma (MM) is a malignant plasma cell disorder accounting for 1% of all cancer diagnoses worldwide and 13% of all hematologic malignancies [1]. Worldwide, the incidence of MM is 0.4 to 5 per 100,000 people per year [2]. Incidence rates are higher among males

  17. Myriad Functions of Stanniocalcin-1 (STC1 Cover Multiple Therapeutic Targets in the Complicated Pathogenesis of Idiopathic Pulmonary Fibrosis (IPF

    Directory of Open Access Journals (Sweden)

    Shinya Ohkouchi

    2015-01-01

    Full Text Available Idiopathic pulmonary fibrosis (IPF is an intractable disease for which the pathological findings are characterized by temporal and spatial heterogeneity. The pathogenesis is composed of myriad factors, including repetitive injuries to epithelial cells, alterations in immunity, the formation of vascular leakage and coagulation, abnormal wound healing, fibrogenesis, and collagen accumulation. Therefore, the molecular target drugs that are used or attempted for treatment or clinical trials may not cover the myriad therapeutic targets of IPF. In addition, the complicated pathogenesis results in a lack of informative biomarkers to diagnose accurately the status of IPF. These facts point out the necessity of using a combination of drugs, that is, each single drug with molecular targets or a single drug with multiple therapeutic targets. In this review, we introduce a humoral factor, stanniocalcin-1 (STC1, which has myriad functions, including the maintenance of calcium homeostasis, the promotion of early wound healing, uncoupling respiration (aerobic glycolysis, reepithelialization in damaged tissues, the inhibition of vascular leakage, and the regulation of macrophage functions to keep epithelial and endothelial homeostasis, which may adequately cover the myriad therapeutic targets of IPF.

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

    Science.gov (United States)

    She, Ji; Wang, Fei; Zhou, Jianjiang

    2016-12-21

    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.

  19. Pathways Targeted by Antidiabetes Drugs Are Enriched for Multiple Genes Associated With Type 2 Diabetes Risk

    NARCIS (Netherlands)

    Segre, Ayellet V.; Wei, Nancy; Altshuler, David; Florez, Jose C.; Wijmenga, T. N.; Ostaptchouk, J. V.

    2015-01-01

    Genome-wide association studies (GWAS) have uncovered >65 common variants associated with type 2 diabetes (T2D); however, their relevance for drug development is not yet clear. Of note, the first two T2D-associated loci (PPARG and KCNJ11/ABCC8) encode known targets of antidiabetes medications. We th

  20. 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…

  1. Graph theoretic framework based cooperative control and estimation of multiple UAVs for target tracking

    Science.gov (United States)

    Ahmed, Mousumi

    Designing the control technique for nonlinear dynamic systems is a significant challenge. Approaches to designing a nonlinear controller are studied and an extensive study on backstepping based technique is performed in this research with the purpose of tracking a moving target autonomously. Our main motivation is to explore the controller for cooperative and coordinating unmanned vehicles in a target tracking application. To start with, a general theoretical framework for target tracking is studied and a controller in three dimensional environment for a single UAV is designed. This research is primarily focused on finding a generalized method which can be applied to track almost any reference trajectory. The backstepping technique is employed to derive the controller for a simplified UAV kinematic model. This controller can compute three autopilot modes i.e. velocity, ground heading (or course angle), and flight path angle for tracking the unmanned vehicle. Numerical implementation is performed in MATLAB with the assumption of having perfect and full state information of the target to investigate the accuracy of the proposed controller. This controller is then frozen for the multi-vehicle problem. Distributed or decentralized cooperative control is discussed in the context of multi-agent systems. A consensus based cooperative control is studied; such consensus based control problem can be viewed from the algebraic graph theory concepts. The communication structure between the UAVs is represented by the dynamic graph where UAVs are represented by the nodes and the communication links are represented by the edges. The previously designed controller is augmented to account for the group to obtain consensus based on their communication. A theoretical development of the controller for the cooperative group of UAVs is presented and the simulation results for different communication topologies are shown. This research also investigates the cases where the communication

  2. 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.

  3. COBALT SALTS PRODUCTION BY USING SOLVENT EXTRACTION

    Directory of Open Access Journals (Sweden)

    Liudmila V. Dyakova

    2010-06-01

    Full Text Available The paper deals with the extracting cobalt salts by using mixtures on the basis of tertiary amine from multicomponent solutions from the process of hydrochloride leaching of cobalt concentrate. The optimal composition for the extraction mixture, the relationship between the cobalt distribution coefficients and modifier’s nature and concentration, and the saltingout agent type have been determined. A hydrochloride extraction technology of cobalt concentrate yielding a purified concentrated cobalt solution for the production of pure cobalt salts has been developed and introduced at Severonikel combine.

  4. Muscles-Specific MicroRNA-206 Targets Multiple Components in Dystrophic Skeletal Muscle Representing Beneficial Adaptations.

    Science.gov (United States)

    Amirouche, Adel; Jahnke, Vanessa E; Lunde, John A; Koulmann, Nathalie; Freyssenet, Damien G; Jasmin, Bernard J

    2016-12-21

    Over the last several years, converging lines of evidence have indicated that miR-206 plays a pivotal role in promoting muscle differentiation and regeneration, thereby potentially impacting positively on the progression of neuromuscular disorders including Duchenne muscular dystrophy (DMD). Despite several studies showing the regulatory function of miR-206 on target mRNAs in skeletal muscle cells, the effects of overexpression of miR-206 in dystrophic muscles remain to be established. Here, we found that miR-206 overexpression in mdx mouse muscles simultaneously targets multiple mRNAs and proteins implicated in satellite cell differentiation, muscle regeneration, and at the neuromuscular junction. Overexpression of miR-206 also increased the levels of several muscle-specific mRNAs/proteins while enhancing utrophin A expression at the sarcolemma. Finally, we also observed that the increase expression of miR-206 in dystrophin-deficient mouse muscle decreased the production of pro-inflammatory cytokines and infiltration of macrophages. Taken together, our results show that miR-206 acts as a pleiotropic regulator that targets multiple key mRNAs and proteins expected to provide beneficial adaptations in dystrophic muscle, thus highlighting its therapeutic potential for DMD.

  5. 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.

  6. Viability of an isocentric cobalt-60 teletherapy unit for stereotactic radiosurgery.

    Science.gov (United States)

    Poffenbarger, B A; Podgorsak, E B

    1998-10-01

    The potential for radiosurgery with an isocentric teletherapy cobalt unit was evaluated in three areas: (1) the physical properties of radiosurgical beams, (2) the quality of radiosurgical dose distributions obtained with four to ten noncoplanar converging arcs, and (3) the accuracy with which the radiosurgical dose can be delivered. In each of these areas the cobalt unit provides a viable alternative to an isocentric linear accelerator (linac) as a radiation source for radiosurgery. A 10 MV x-ray beam from a linac used for radiosurgery served as a standard for comparison. The difference between the 80%-20% penumbras of stationary radiosurgical fields in the nominal diameter range from 10 to 40 mm of the cobalt-60 and 10 MV photon beams is remarkably small, with the cobalt-60 beam penumbras, on average, only about 0.7 mm larger than those of the linac beam. Differences between the cobalt-60 and 10 MV radiosurgical treatment plans in terms of dose homogeneity within the target volume, conformity of the prescribed isodose volume to the target volume, and dose falloffs outside the target volume are also minimal, and therefore of essentially no clinical significance. Moreover, measured isodose distributions for a radiosurgical procedure on our Theratron T-780 cobalt unit agreed with calculated distributions to within the +/- 1 mm spatial and +/- 5% numerical dose tolerances, which are generally specified for radiosurgery. The viability of isocentric cobalt units for radiosurgery will be of particular interest to centers in developing countries where cobalt units, because of their relatively low costs, provide the only megavoltage source of radiation for radiotherapy, and could easily and inexpensively be modified for radiosurgery. Of course, the quality assurance protocols and mechanical condition of a particular teletherapy cobalt unit must meet stringent requirements before the use of the unit for radiosurgery can be advocated.

  7. Treatment of Multiple Myeloma with VLA4-targeted Nanoparticles Delivering Novel c-MYC Inhibitor Prodrug

    Science.gov (United States)

    2012-09-01

    well to chemotherapy and remissions occur in that majority of MM patients, but all patients eventually relapse and die from progressive disease within...6 years. If the residual post- remission cells of their activation to progressive disease could be disrupted with novel targeted therapies. It would...Bagnasco, L., Malacarne, D., Melchiori, A., Valente, P., Millo, E., Bruno, S., Basso, S., and Parodi, S. A retro-inverso peptide homologous to

  8. Targeting cell-impermeable prodrug activation to tumor microenvironment eradicates multiple drug-resistant neoplasms.

    Science.gov (United States)

    Wu, Wenyuan; Luo, Yunping; Sun, Chengzao; Liu, Yuan; Kuo, Paul; Varga, Janos; Xiang, Rong; Reisfeld, Ralph; Janda, Kim D; Edgington, Thomas S; Liu, Cheng

    2006-01-15

    The tumor microenvironment is notably enriched with a broad spectrum of proteases. The proteolytic specificities of peptide substrates provide modular chemical tools for the rational design of cell-impermeable prodrugs that are specifically activated by proteases extracellularly in the tumor microenvironment. Targeting cell-impermeable prodrug activation to tumor microenvironment will significantly reduce drug toxicity to normal tissues. The activated prodrug attacks both tumor and stroma cells through a "bystander effect" without selectively deleting target-producing cells, therefore further minimizing resistance and toxicity. Here, we showed that legumain, the only asparaginyl endopeptidase of the mammalian genome, is highly expressed by neoplastic, stromal, and endothelial cells in solid tumors. Legumain is present extracellularly in the tumor microenvironment, associated with matrix as well as cell surfaces and functional locally in the reduced pH of the tumor microenvironment. A novel legumain-activated, cell-impermeable doxorubicin prodrug LEG-3 was designed to be activated exclusively in the tumor microenvironment. Upon administration, there is a profound increase of the end-product doxorubicin in nuclei of cells in tumors but little in other tissues. This tumor microenvironment-activated prodrug completely arrested growth of a variety of neoplasms, including multidrug-resistant tumor in vivo and significantly extended survival without evidence of myelosuppression or cardiac toxicity. The tumor microenvironment-activated prodrug design can be extended to other proteases and chemotherapeutic compounds and provides new potentials for the rational development of more effective functionally targeted cancer therapeutics.

  9. Feedback strategy on real-time multiple target tracking in cognitive vision system

    Science.gov (United States)

    Shao, Jie; Jia, Zhen; Li, Zhipeng; Liu, Fuqiang; Zhao, Jianwei; Peng, Pei-Yuan

    2011-10-01

    Under pedestrian and vehicle mixed traffic conditions, the potential accident rate is high due to a complex traffic environment. In order to solve this problem, we present a real-time cognitive vision system. In the scene-capture level, foreground objects are extracted based on the combination of spatial and temporal information. Then, a coarse-to-fine algorithm is employed in tracking. After filtering-based normal tracking, problems of the target blob missing, merging, and splitting are resolved by the adaptive tracking modification method in fine tracking. For greater robustness, the key idea of our approach is adaptively adjusting the classification sensibility of each pixel by employing tracking results as feedback cues for target detection in the next frame. On the basis of the target trajectories, behavior models are evaluated according to a decision logic table in the behavior-evaluation level. The decision logic table is set based on rules of real scenes. The resulting system interprets different kinds of traffic behavior and warns in advance. Experiments show robust and accurate results of abnormality detection and forewarning under different conditions. All the experimental results run at real-time frame rates (>=25 fps) on standard hardware. Therefore, the system is suitable for actual Intelligent Traffic System applications.

  10. 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

  11. 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.

  12. 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.

    2017-01-01

    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.

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

    Science.gov (United States)

    Adolph, C.; Aghasyan, M.; Akhunzyanov, R.; Alexeev, G. D.; Alexeev, M. G.; Amoroso, A.; Andrieux, V.; Anfimov, N. V.; Anosov, V.; Augsten, K.; Augustyniak, W.; Austregesilo, A.; Azevedo, C. D. R.; Badełek, 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.; Büchele, 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.; Dünnweber, W.; Dziewiecki, M.; Efremov, A.; Eversheim, P. D.; Eyrich, W.; Faessler, M.; Ferrero, A.; Finger, M.; Finger, M.; Fischer, H.; Franco, C.; du 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 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.; d'Hose, N.; Hsieh, C.-Y.; Huber, S.; Ishimoto, S.; Ivanov, A.; Ivanshin, Yu.; Iwata, T.; Jahn, R.; Jary, V.; Joosten, R.; Jörg, 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.; Königsmann, K.; Konorov, I.; Konstantinov, V. F.; Kotzinian, A. M.; Kouznetsov, O. M.; 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. V.; 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. 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.; Schönning, K.; Schopferer, S.; Seder, E.; Selyunin, A.; Shevchenko, O. Yu.; Silva, L.; Sinha, L.; Sirtl, S.; Slunecka, M.; Smolik, J.; Sozzi, F.; Srnka, A.; Steffen, D.; 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.; Zhuravlev, N.; Ziembicki, M.; Zink, A.

    2017-01-01

    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 / 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. Automated docking to multiple target structures: incorporation of protein mobility and structural water heterogeneity in AutoDock.

    Science.gov (United States)

    Osterberg, Fredrik; Morris, Garrett M; Sanner, Michel F; Olson, Arthur J; Goodsell, David S

    2002-01-01

    Protein motion and heterogeneity of structural waters are approximated in ligand-docking simulations, using an ensemble of protein structures. Four methods of combining multiple target structures within a single grid-based lookup table of interaction energies are tested. The method is evaluated using complexes of 21 peptidomimetic inhibitors with human immunodeficiency virus type 1 (HIV-1) protease. Several of these structures show motion of an arginine residue, which is essential for binding of large inhibitors. A structural water is also present in 20 of the structures, but it must be absent in the remaining one for proper binding. Mean and minimum methods perform poorly, but two weighted average methods permit consistent and accurate ligand docking, using a single grid representation of the target protein structures. Copyright 2001 Wiley-Liss, Inc.

  15. Experimental Study of High-Range-Resolution Medical Acoustic Imaging for Multiple Target Detection by Frequency Domain Interferometry

    Science.gov (United States)

    Kimura, Tomoki; Taki, Hirofumi; Sakamoto, Takuya; Sato, Toru

    2009-07-01

    We employed frequency domain interferometry (FDI) for use as a medical acoustic imager to detect multiple targets with high range resolution. The phase of each frequency component of an echo varies with the frequency, and target intervals can be estimated from the phase variance. This processing technique is generally used in radar imaging. When the interference within a range gate is coherent, the cross correlation between the desired signal and the coherent interference signal is nonzero. The Capon method works under the guiding principle that output power minimization cancels the desired signal with a coherent interference signal. Therefore, we utilize frequency averaging to suppress the correlation of the coherent interference. The results of computational simulations using a pseudoecho signal show that the Capon method with adaptive frequency averaging (AFA) provides a higher range resolution than a conventional method. These techniques were experimentally investigated and we confirmed the effectiveness of the proposed method of processing by FDI.

  16. Multiple target implementation for a doubly fed induction generator based on direct power control under unbalanced and distorted grid voltage

    Institute of Scientific and Technical Information of China (English)

    Heng NIAN; Yi-peng SONG

    2015-01-01

    This paper presents a multiple target implementation technique for a doubly fed induction generator (DFIG) under unbalanced and distorted grid voltage based on direct power control (DPC). Based on the mathematical model of DFIG under unbalanced and distorted voltage, the proportional and integral (PI) regulator is adopted to regulate the DFIG average active and reactive powers, while the vector PI (VPI) resonant regulator is used to achieve three alternative control targets: (1) balanced and sinusoidal stator current; (2) smooth instantaneous stator active and reactive powers; (3) smooth electromagnetic torque and instantaneous stator reactive power. The major advantage of the proposed control strategy over the conventional method is that neither negative and harmonic sequence decomposition of grid voltage nor complicated control reference calculation is required. The insensitivity of the proposed control strategy to DFIG parameter deviation is analyzed. Finally, the DFIG experimental system is developed to validate the availability of the proposed DPC strategy under unbalanced and distorted grid voltage.

  17. AN ELECTROPLATING METHOD OF FORMING PLATINGS OF NICKEL, COBALT, NICKEL ALLOYS OR COBALT ALLOYS

    DEFF Research Database (Denmark)

    1997-01-01

    An electroplating method of forming platings of nickel, cobalt, nickel alloys or cobalt alloys with reduced stresses in an electrodepositing bath of the type: Watt's bath, chloride bath or a combination thereof, by employing pulse plating with periodic reverse pulse and a sulfonated naphthalene...... additive. This method makes it possible to deposit nickel, cobalt, nickel or cobalt platings without internal stresses....

  18. A method for simultaneously delineating multiple targets in 3D-FISH using limited channels, lasers, and fluorochromes.

    Science.gov (United States)

    Zhao, F Y; Yang, X; Chen, D Y; Ma, W Y; Zheng, J G; Zhang, X M

    2014-01-01

    Many studies have suggested a link between the spatial organization of genomes and fundamental biological processes such as genome reprogramming, gene expression, and differentiation. Multicolor fluorescence in situ hybridization on three-dimensionally preserved nuclei (3D-FISH), in combination with confocal microscopy, has become an effective technique for analyzing 3D genome structure and spatial patterns of defined nucleus targets including entire chromosome territories and single gene loci. This technique usually requires the simultaneous visualization of numerous targets labeled with different colored fluorochromes. Thus, the number of channels and lasers must be sufficient for the commonly used labeling scheme of 3D-FISH, "one probe-one target". However, these channels and lasers are usually restricted by a given microscope system. This paper presents a method for simultaneously delineating multiple targets in 3D-FISH using limited channels, lasers, and fluorochromes. In contrast to other labeling schemes, this method is convenient and simple for multicolor 3D-FISH studies, which may result in widespread adoption of the technique. Lastly, as an application of the method, the nucleus locations of chromosome territory 18/21 and centromere 18/21/13 in normal human lymphocytes were analyzed, which might present evidence of a radial higher order chromatin arrangement.

  19. Silencing of six hydrophobins in Cladosporium fulvum: complexities of simultaneously targeting multiple genes.

    Science.gov (United States)

    Lacroix, Hélène; Spanu, Pietro D

    2009-01-01

    In this study, we have constructed and expressed inverted repeat chimeras from the first exons of the six known hydrophobins of the fungus Cladosporium fulvum, the causal agent of tomato leaf mold. We used quantitative PCR to measure specifically the expression levels of the hydrophobins. The targeted genes are silenced to different degrees, but we also detected clear changes in the expression levels of nontargeted genes. This work highlights the difficulties that are likely to be encountered when attempting to silence more than one gene in a multigene family.

  20. MicroRNA-125b promotes neuronal differentiation in human cells by repressing multiple targets.

    Science.gov (United States)

    Le, Minh T N; Xie, Huangming; Zhou, Beiyan; Chia, Poh Hui; Rizk, Pamela; Um, Moonkyoung; Udolph, Gerald; Yang, Henry; Lim, Bing; Lodish, Harvey F

    2009-10-01

    MicroRNAs (miRNAs) are a class of small noncoding RNAs that regulate gene expression at the posttranscriptional level. Research on miRNAs has highlighted their importance in neural development, but the specific functions of neurally enriched miRNAs remain poorly understood. We report here the expression profile of miRNAs during neuronal differentiation in the human neuroblastoma cell line SH-SY5Y. Six miRNAs were significantly upregulated during differentiation induced by all-trans-retinoic acid and brain-derived neurotrophic factor. We demonstrated that the ectopic expression of either miR-124a or miR-125b increases the percentage of differentiated SH-SY5Y cells with neurite outgrowth. Subsequently, we focused our functional analysis on miR-125b and demonstrated the important role of this miRNA in both the spontaneous and induced differentiations of SH-SH5Y cells. miR-125b is also upregulated during the differentiation of human neural progenitor ReNcell VM cells, and miR-125b ectopic expression significantly promotes the neurite outgrowth of these cells. To identify the targets of miR-125b regulation, we profiled the global changes in gene expression following miR-125b ectopic expression in SH-SY5Y cells. miR-125b represses 164 genes that contain the seed match sequence of the miRNA and/or that are predicted to be direct targets of miR-125b by conventional methods. Pathway analysis suggests that a subset of miR-125b-repressed targets antagonizes neuronal genes in several neurogenic pathways, thereby mediating the positive effect of miR-125b on neuronal differentiation. We have further validated the binding of miR-125b to the miRNA response elements of 10 selected mRNA targets. Together, we report here for the first time the important role of miR-125b in human neuronal differentiation.

  1. Multiple morphologies of gold-magnetite heterostructure nanoparticles are effectively functionalized with protein for cell targeting.

    Science.gov (United States)

    Krystofiak, Evan S; Mattson, Eric C; Voyles, Paul M; Hirschmugl, Carol J; Albrecht, Ralph M; Gajdardziska-Josifovska, Marija; Oliver, Julie A

    2013-08-01

    Nanoparticles composed of a magnetic iron oxide core surrounded by a metal shell have utility in a broad range of biomedical applications. However, the presence of surface energy differences between the two components makes wetting of oxide with metal unfavorable, precluding a "core-shell" structure of an oxide core completely surrounded by a thin metal shell. Three-dimensional island growth followed by island coalescence into thick shells is favored over the two-dimensional layer-by-layer growth of a thin, continuous metal coating of a true core-shell. Aqueous synthesis of gold-coated magnetite nanoparticles with analysis by infrared, energy-dispersive X-ray, and electron energy loss spectroscopies; high-resolution transmission electron microscopy; selected area electron diffraction; and high-angle annular dark-field scanning transmission electron microscopy showed two distinct morphologies that are inconsistent with an idealized core-shell. The majority were isolated ~16-22-nm-diameter nanoparticles consisting of ~7-nm-diameter magnetite and a thick deposition of gold, most often discontinuous, with some potentially "sandwiched" morphologies. A minority were aggregates of agglomerated magnetite decorated with gold but displaying significant bare magnetite. Both populations were successfully conjugated to fibrinogen and targeted to surface-activated platelets, demonstrating that iron oxide-gold nanoparticles produced by aqueous synthesis do not require an ideal core-shell structure for biological activity in cell labeling and targeting applications.

  2. Multiple types of cerebellar target neurons and their circuitry in the vestibulo-ocular reflex.

    Science.gov (United States)

    Shin, Minyoung; Moghadam, Setareh H; Sekirnjak, Chris; Bagnall, Martha W; Kolkman, Kristine E; Jacobs, Richard; Faulstich, Michael; du Lac, Sascha

    2011-07-27

    The cerebellum influences behavior and cognition exclusively via Purkinje cell synapses onto neurons in the deep cerebellar and vestibular nuclei. In contrast with the rich information available about the organization of the cerebellar cortex and its synaptic inputs, relatively little is known about microcircuitry postsynaptic to Purkinje cells. Here we examined the cell types and microcircuits through which Purkinje cells influence an oculomotor behavior controlled by the cerebellum, the horizontal vestibulo-ocular reflex, which involves only two eye muscles. Using a combination of anatomical tracing and electrophysiological recordings in transgenic mouse lines, we identified several classes of neurons in the medial vestibular nucleus that receive Purkinje cell synapses from the cerebellar flocculus. Glycinergic and glutamatergic flocculus target neurons (FTNs) with somata densely surrounded by Purkinje cell terminals projected axons to the ipsilateral abducens and oculomotor nuclei, respectively. Of three additional types of FTNs that were sparsely innervated by Purkinje cells, glutamatergic and glycinergic neurons projected to the contralateral and ipsilateral abducens, respectively, and GABAergic neurons projected to contralateral vestibular nuclei. Densely innervated FTNs had high spontaneous firing rates and pronounced postinhibitory rebound firing, and were physiologically homogeneous, whereas the intrinsic excitability of sparsely innervated FTNs varied widely. Heterogeneity in the molecular expression, physiological properties, and postsynaptic targets of FTNs implies that Purkinje cell activity influences the neural control of eye movements in several distinct ways. These results indicate that the cerebellum regulates a simple reflex behavior via at least five different cell types that are postsynaptic to Purkinje cells.

  3. Emerging therapies targeting tumor vasculature in multiple myeloma and other hematologic and solid malignancies.

    Science.gov (United States)

    Podar, K; Anderson, K C

    2011-11-01

    Research on the formation of new blood vessels (angiogenesis) in general and vascular endothelial growth factor (VEGF) in particular is a major focus in biomedicine and has led to the clinical approval of the monoclonal anti- VEGF antibody bevazicumab; and the second-generation multitargeted receptor kinase inhibitors (RTKIs) sorafenib, sunitinib, and pazopanib. Although these agents show significant preclinical and clinical anti-cancer activity, they prolong overall survival of cancer patients for only months, followed by a restoration of tumor growth and progression. Therefore, there is a clear need to increase our understanding of tumor angiogenesis and the development of resistance. In this review we discuss up-to-date knowledge on mechanisms of tumor angiogenesis, and summarize preclinical and clinical data on existing and potential future anti-angiogenic agents and treatment strategies for Multiple Myeloma (MM) and other hematologic and solid malignancies.

  4. [Cereblon -  a new target of therapy in the treatment of multiple myeloma].

    Science.gov (United States)

    Staňková, M; Bešše, L; Sedlaříková, L; Vrábel, D; Hájek, R; Sevčíková, S

    2014-01-01

    Treatment of multiple myeloma (MM), currently an incurable disease, aims to achieve complete remission. Immunomodulatory drugs (IMiDs), represented by thalidomide, are one class of very effective drugs. However, the mechanism of IMiDs action is not yet completely understood. Recent research suggests that cereblon (CRBN) plays an important role in mediating anti-tumor effects of IMiDs; therefore, our review focuses on this protein. CRBN is a substrate receptor of Cul4- E3 ubiquitin ligase complex, and thus recognizes proteins destined for degradation. Bind-ing of CRBN and IMiDs inhibits function of the entire ubiquitin proteasome complex which partly explains their anti-tumor effects. In addition, a correlation between CRBN gene expression and effectiveness of treatment in MM patients treated with IMiDs was confirmed. These findings suggest that CRBN expression could possibly serve as a bio-marker to predict response to IMiD in MM patients.

  5. COBALT SALTS PRODUCTION BY USING SOLVENT EXTRACTION

    OpenAIRE

    Liudmila V. Dyakova; Aleksander G. Kasikov; Elena S. Kshumaneva; Svetlana V. Drogobuzhskaya

    2010-01-01

    The paper deals with the extracting cobalt salts by using mixtures on the basis of tertiary amine from multicomponent solutions from the process of hydrochloride leaching of cobalt concentrate. The optimal composition for the extraction mixture, the relationship between the cobalt distribution coefficients and modifier’s nature and concentration, and the saltingout agent type have been determined. A hydrochloride extraction technology of cobalt concentrate yielding a purified concentrated cob...

  6. 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

  7. A Versatile Multiple Target Detection System Based on DNA Nano-assembled Linear FRET Arrays.

    Science.gov (United States)

    Li, Yansheng; Du, Hongwu; Wang, Wenqian; Zhang, Peixun; Xu, Liping; Wen, Yongqiang; Zhang, Xueji

    2016-05-27

    DNA molecules have been utilized both as powerful synthetic building blocks to create nanoscale architectures and as inconstant programmable templates for assembly of biosensors. In this paper, a versatile, scalable and multiplex detection system is reported based on an extending fluorescent resonance energy transfer (FRET) cascades on a linear DNA assemblies. Seven combinations of three kinds of targets are successfully detected through the changes of fluorescence spectra because of the three-steps FRET or non-FRET continuity mechanisms. This nano-assembled FRET-based nanowire is extremely significant for the development of rapid, simple and sensitive detection system. The method used here could be extended to a general platform for multiplex detection through more-step FRET process.

  8. 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

  9. Targeting innate receptors with MIS416 reshapes Th responses and suppresses CNS disease in a mouse model of multiple sclerosis.

    Directory of Open Access Journals (Sweden)

    Madeleine White

    Full Text Available Modification of the innate immune cell environment has recently been recognized as a viable treatment strategy for reducing autoimmune disease pathology. MIS416 is a microparticulate immune response modifier that targets myeloid cells, activating cytosolic receptors NOD2 and TLR9, and has completed a phase 1b/2a trial for the treatment of secondary progressive multiple sclerosis. Using a mouse model of multiple sclerosis, we are investigating the pathways by which activation of TLR9 and NOD2 may modify the innate immune environment and the subsequent T cell-mediated autoimmune responses. We have found that MIS416 has profound effects on the Th subset balance by depressing antigen-specific Th1, Th17, and Th2 development. These effects coincided with an expansion of specific myeloid subpopulations and increased levels of MIS416-stimulated IFN-γ by splenocytes. Additionally, systemic IFN-γ serum levels were enhanced and correlated strongly with disease reduction, and the protective effect of MIS416 was abrogated in IFN-γ-deficient animals. Finally, treatment of secondary progressive MS patients with MIS416 similarly elevated the levels of IFN-γ and IFN-γ-associated proteins in the serum. Together, these studies demonstrate that administration of MIS416, which targets innate cells, reshapes autoimmune T cell responses and leads to a significant reduction in CNS inflammation and disease.

  10. MicroRNA-181b suppresses TAG via target IRS2 and regulating multiple genes in the Hippo pathway.

    Science.gov (United States)

    Chen, Zhi; Shi, HuaiPing; Sun, Shuang; Xu, HuiFen; Cao, DuoYao; Luo, Jun

    2016-10-15

    Milk fat metabolism is a complex procedure controlled by several factors. MiRNAs (microRNAs) regulate expression of genes and influence a series of biological procedures, such as fatty acid metabolism. Here we screened expression of goat mammary gland's miRNA during peak-lactation and late-lactation, and found that miR-181b expresses remarkably. Moreover, we illustrated that the over-expression of miR-181b impaired fat metabolism while the knockdown of miR-181b promoted fat metabolism in GMEC. These findings extend the discovery of miR-181b functioning in mediating adipocyte differentiation, by suggesting its role in impairing fat metabolism, which develops our cognition on the importance of miRNAs in milk fat metabolism and synthesis. In this study, we find that over expressed miR-181b impaired adipogenesis and inhibited miR-181b promoted adipogenesis in GMEC. Using Luciferase reporter assay and Western Blot, IRS2 was illustrated to be a miR-181b's potential target gene. What is interesting is that miR-181b regulates multiple key components in the Hippo pathway, such as LATS1 and YAP1 in GMECs. In conclusion, our findings indicated that miR-181b suppress fat metabolism by means of regulating multiple genes in the Hippo pathway and target IRS2, which promotes further study on the function of miRNAs in milk fat metabolism and synthesis.

  11. 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.

  12. 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.

  13. Transport of cobalt-60 industrial radiation sources

    Science.gov (United States)

    Kunstadt, Peter; Gibson, Wayne

    This paper will deal with safety aspects of the handling of Cobalt-60, the most widely used industrial radio-isotope. Cobalt-60 is a man-made radioisotope of Cobalt-59, a naturally occurring non radioactive element, that is made to order for radiation therapy and a wide range of industrial processing applications including sterilization of medical disposables, food irradiation, etc.

  14. Hydrogen evolution catalyzed by cobalt diimine-dioxime complexes.

    Science.gov (United States)

    Kaeffer, Nicolas; Chavarot-Kerlidou, Murielle; Artero, Vincent

    2015-05-19

    Mimicking photosynthesis and producing solar fuels is an appealing way to store the huge amount of renewable energy from the sun in a durable and sustainable way. Hydrogen production through water splitting has been set as a first-ranking target for artificial photosynthesis. Pursuing that goal requires the development of efficient and stable catalytic systems, only based on earth abundant elements, for the reduction of protons from water to molecular hydrogen. Cobalt complexes based on glyoxime ligands, called cobaloximes, emerged 10 years ago as a first generation of such catalysts. They are now widely utilized for the construction of photocatalytic systems for hydrogen evolution. In this Account, we describe our contribution to the development of a second generation of catalysts, cobalt diimine-dioxime complexes. While displaying similar catalytic activities as cobaloximes, these catalysts prove more stable against hydrolysis under strongly acidic conditions thanks to the tetradentate nature of the diimine-dioxime ligand. Importantly, H2 evolution proceeds via proton-coupled electron transfer steps involving the oxime bridge as a protonation site, reproducing the mechanism at play in the active sites of hydrogenase enzymes. This feature allows H2 to be evolved at modest overpotentials, that is, close to the thermodynamic equilibrium over a wide range of acid-base conditions in nonaqueous solutions. Derivatization of the diimine-dioxime ligand at the hydrocarbon chain linking the two imine functions enables the covalent grafting of the complex onto electrode surfaces in a more convenient manner than for the parent bis-bidentate cobaloximes. Accordingly, we attached diimine-dioxime cobalt catalysts onto carbon nanotubes and demonstrated the catalytic activity of the resulting molecular-based electrode for hydrogen evolution from aqueous acetate buffer. The stability of immobilized catalysts was found to be orders of magnitude higher than that of catalysts in the

  15. Myelin Basic Protein Citrullination in Multiple Sclerosis: A Potential Therapeutic Target for the Pathology.

    Science.gov (United States)

    Yang, Lei; Tan, Dewei; Piao, Hua

    2016-08-01

    Multiple sclerosis (MS) is a multifactorial demyelinating disease characterized by neurodegenerative events and autoimmune response against myelin component. Citrullination or deimination, a post-translational modification of protein-bound arginine into citrulline, catalyzed by Ca(2+) dependent peptidylarginine deiminase enzyme (PAD), plays an essential role in physiological processes include gene expression regulation, apoptosis and the plasticity of the central nervous system, while aberrant citrullination can generate new epitopes, thus involving in the initiation and/or progression of autoimmune disorder like MS. Myelin basic protein (MBP) is the major myelin protein and is generally considered to maintain the stability of the myelin sheath. This review describes the MBP citrullination and its consequence, as well as offering further support for the "inside-out" hypothesis that MS is primarily a neurodegenerative disease with secondary inflammatory demyelination. In addition, it discusses the role of MBP citrullination in the immune inflammation and explores the potential of inhibition of PAD enzymes as a therapeutic strategy for the disease.

  16. CtBP1 associates metabolic syndrome and breast carcinogenesis targeting multiple miRNAs

    Science.gov (United States)

    De Luca, Paola; Dalton, Guillermo N.; Scalise, Georgina D.; Moiola, Cristian P.; Porretti, Juliana; Massillo, Cintia; Kordon, Edith; Gardner, Kevin; Zalazar, Florencia; Flumian, Carolina; Todaro, Laura; Vazquez, Elba S.; Meiss, Roberto; De Siervi, Adriana

    2016-01-01

    Metabolic syndrome (MeS) has been identified as a risk factor for breast cancer. C-terminal binding protein 1 (CtBP1) is a co-repressor of tumor suppressor genes that is activated by low NAD+/NADH ratio. High fat diet (HFD) increases intracellular NADH. We investigated the effect of CtBP1 hyperactivation by HFD intake on mouse breast carcinogenesis. We generated a MeS-like disease in female mice by chronically feeding animals with HFD. MeS increased postnatal mammary gland development and generated prominent duct patterns with markedly increased CtBP1 and Cyclin D1 expression. CtBP1 induced breast cancer cells proliferation. Serum from animals with MeS enriched the stem-like/progenitor cell population from breast cancer cells. CtBP1 increased breast tumor growth in MeS mice modulating multiple genes and miRNA expression implicated in cell proliferation, progenitor cells phenotype, epithelial to mesenchymal transition, mammary development and cell communication in the xenografts. These results define a novel function for CtBP1 in breast carcinogenesis. PMID:26933806

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

    Directory of Open Access Journals (Sweden)

    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

  18. Multiple benefits of targeting inflammation in the treatment of type 2 diabetes.

    Science.gov (United States)

    Donath, Marc Y

    2016-04-01

    The association between the metabolic syndrome and a pathological activation of the innate immune system is now well established. Thus, defective insulin secretion and action are due, at least in part, to islet, liver and fat inflammation in type 2 diabetes. Furthermore, an inflammatory process also seems to be involved in the development of cardiovascular, renal and ophthalmological complications of this disease. Interestingly, several other inflammatory diseases are associated with the metabolic syndrome, such as psoriasis, gout and rheumatic arthritis. The aim of this review is to discuss the clinical progress of anti-inflammatory drugs in the treatment of type 2 diabetes and then speculate on the possible further development of these drugs, with the aim of using the drugs in combination in order to combat the multiple manifestations of inflammatory diseases. This review summarises a presentation given at the 'Islet inflammation in type 2 diabetes' symposium at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by Simone Baltrusch, DOI: 10.1007/s00125-016-3891-x , and Jerry Nadler and colleagues, DOI: 10.1007/s00125-016-3890-y ) and a commentary by the Session Chair, Piero Marchetti (DOI: 10.1007/s00125-016-3875-x ).

  19. Structural basis for specific recognition of multiple mRNA targets by a PUF regulatory protein

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Yeming; Opperman, Laura; Wickens, Marvin; Tanaka Hall, Traci M. (NIH); (UW)

    2011-11-02

    Caenorhabditis elegans fem-3 binding factor (FBF) is a founding member of the PUMILIO/FBF (PUF) family of mRNA regulatory proteins. It regulates multiple mRNAs critical for stem cell maintenance and germline development. Here, we report crystal structures of FBF in complex with 6 different 9-nt RNA sequences, including elements from 4 natural mRNAs. These structures reveal that FBF binds to conserved bases at positions 1-3 and 7-8. The key specificity determinant of FBF vs. other PUF proteins lies in positions 4-6. In FBF/RNA complexes, these bases stack directly with one another and turn away from the RNA-binding surface. A short region of FBF is sufficient to impart its unique specificity and lies directly opposite the flipped bases. We suggest that this region imposes a flattened curvature on the protein; hence, the requirement for the additional nucleotide. The principles of FBF/RNA recognition suggest a general mechanism by which PUF proteins recognize distinct families of RNAs yet exploit very nearly identical atomic contacts in doing so.

  20. Structural basis for specific recognition of multiple mRNA targets by a PUF regulatory protein

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Yeming; Opperman, Laura; Wickens, Marvin; Tanaka Hall, Traci M.; (NIH); (UW)

    2010-08-19

    Caenorhabditis elegans fem-3 binding factor (FBF) is a founding member of the PUMILIO/FBF (PUF) family of mRNA regulatory proteins. It regulates multiple mRNAs critical for stem cell maintenance and germline development. Here, we report crystal structures of FBF in complex with 6 different 9-nt RNA sequences, including elements from 4 natural mRNAs. These structures reveal that FBF binds to conserved bases at positions 1-3 and 7-8. The key specificity determinant of FBF vs. other PUF proteins lies in positions 4-6. In FBF/RNA complexes, these bases stack directly with one another and turn away from the RNA-binding surface. A short region of FBF is sufficient to impart its unique specificity and lies directly opposite the flipped bases. We suggest that this region imposes a flattened curvature on the protein; hence, the requirement for the additional nucleotide. The principles of FBF/RNA recognition suggest a general mechanism by which PUF proteins recognize distinct families of RNAs yet exploit very nearly identical atomic contacts in doing so.

  1. Validating Neuro-QoL short forms and targeted scales with people who have multiple sclerosis.

    Science.gov (United States)

    Miller, Deborah M; Bethoux, Francois; Victorson, David; Nowinski, Cindy J; Buono, Sarah; Lai, Jin-Shei; Wortman, Katy; Burns, James L; Moy, Claudia; Cella, David

    2016-05-01

    Multiple sclerosis (MS) is a chronic, progressive, and disabling disease of the central nervous system with dramatic variations in the combination and severity of symptoms it can produce. The lack of reliable disease-specific health-related quality of life (HRQL) measures for use in clinical trials prompted the development of the Neurology Quality of Life (Neuro-QOL) instrument, which includes 13 scales that assess physical, emotional, cognitive, and social domains, for use in a variety of neurological illnesses. The objective of this research paper is to conduct an initial assessment of the reliability and validation of the Neuro-QOL short forms (SFs) in MS. We assessed reliability, concurrent validity, known groups validity, and responsiveness between cross-sectional and longitudinal data in 161 recruited MS patients. Internal consistency was high for all measures (α = 0.81-0.95) and ICCs were within the acceptable range (0.76-0.91); concurrent and known groups validity were highest with the Global HRQL question. Longitudinal assessment was limited by the lack of disease progression in the group. The Neuro-QOL SFs demonstrate good internal consistency, test-re-test reliability, and concurrent and known groups validity in this MS population, supporting the validity of Neuro-QOL in adults with MS. © The Author(s), 2015.

  2. Validating Neuro-QoL Short Forms and Targeted Scales with Persons who have Multiple Sclerosis

    Science.gov (United States)

    Miller, Deborah M.; Bethoux, Francois; Victorson, David; Nowinski, Cindy J.; Buono, Sarah; Lai, Jin-Shei; Wortman, Katy; Burns, James L.; Moy, Claudia; Cella, David

    2015-01-01

    Background Multiple Sclerosis (MS) is a chronic progressive and disabling disease of the central nervous system with dramatic variations in the combination and severity of symptoms it can produce. The lack of reliable disease specific health-related quality of life (HRQL) measures for use in clinical trials prompted the development of the Neurology Quality of Life (Neuro-QOL) instrument, which includes 13 scales that assess physical, emotional, cognitive, and social domains, for use in a variety of neurological illnesses. Objective Initial assessment of the reliability and validation of the Neuro-QOL short forms (SFs) in MS. Methods We assessed reliability, concurrent validity, known groups validity, and responsiveness between cross-sectional and longitudinal data in 161 recruited MS subjects. Results Internal consistency was high for all measures (α = 0.81 - 0.95) and ICCs were within acceptable range (0.76 - 0.91), concurrent and known groups validity were highest with the Global HRQL question. Longitudinal assessment was limited by the lack of disease progression in the group. Conclusions The Neuro-QOL SFs demonstrate good internal consistency, test-re-test reliability, and concurrent and know groups validity in this MS population, supporting the validity of Neuro-QOL in adults with MS PMID:26238464

  3. 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.

  4. An archaeal immune system can detect multiple protospacer adjacent motifs (PAMs) to target invader DNA.

    Science.gov (United States)

    Fischer, Susan; Maier, Lisa-Katharina; Stoll, Britta; Brendel, Jutta; Fischer, Eike; Pfeiffer, Friedhelm; Dyall-Smith, Mike; Marchfelder, Anita

    2012-09-28

    The clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated (Cas) system provides adaptive and heritable immunity against foreign genetic elements in most archaea and many bacteria. Although this system is widespread and diverse with many subtypes, only a few species have been investigated to elucidate the precise mechanisms for the defense of viruses or plasmids. Approximately 90% of all sequenced archaea encode CRISPR/Cas systems, but their molecular details have so far only been examined in three archaeal species: Sulfolobus solfataricus, Sulfolobus islandicus, and Pyrococcus furiosus. Here, we analyzed the CRISPR/Cas system of Haloferax volcanii using a plasmid-based invader assay. Haloferax encodes a type I-B CRISPR/Cas system with eight Cas proteins and three CRISPR loci for which the identity of protospacer adjacent motifs (PAMs) was unknown until now. We identified six different PAM sequences that are required upstream of the protospacer to permit target DNA recognition. This is only the second archaeon for which PAM sequences have been determined, and the first CRISPR group with such a high number of PAM sequences. Cells could survive the plasmid challenge if their CRISPR/Cas system was altered or defective, e.g. by deletion of the cas gene cassette. Experimental PAM data were supplemented with bioinformatics data on Haloferax and Haloquadratum.

  5. A multiple-alignment based primer design algorithm for genetically highly variable DNA targets.

    Science.gov (United States)

    Brodin, Johanna; Krishnamoorthy, Mohan; Athreya, Gayathri; Fischer, Will; Hraber, Peter; Gleasner, Cheryl; Green, Lance; Korber, Bette; Leitner, Thomas

    2013-08-21

    Primer design for highly variable DNA sequences is difficult, and experimental success requires attention to many interacting constraints. The advent of next-generation sequencing methods allows the investigation of rare variants otherwise hidden deep in large populations, but requires attention to population diversity and primer localization in relatively conserved regions, in addition to recognized constraints typically considered in primer design. Design constraints include degenerate sites to maximize population coverage, matching of melting temperatures, optimizing de novo sequence length, finding optimal bio-barcodes to allow efficient downstream analyses, and minimizing risk of dimerization. To facilitate primer design addressing these and other constraints, we created a novel computer program (PrimerDesign) that automates this complex procedure. We show its powers and limitations and give examples of successful designs for the analysis of HIV-1 populations. PrimerDesign is useful for researchers who want to design DNA primers and probes for analyzing highly variable DNA populations. It can be used to design primers for PCR, RT-PCR, Sanger sequencing, next-generation sequencing, and other experimental protocols targeting highly variable DNA samples.

  6. MO-F-CAMPUS-T-02: Optimizing Orientations of Hundreds of Intensity-Modulated Beams to Treat Multiple Brain Targets

    Energy Technology Data Exchange (ETDEWEB)

    Ma, L; Dong, P; Larson, D [University of California San Francisco, San Francisco, CA (United States); Keeling, V; Hossain, S; Ahmad, S [University of Oklahoma Health Science Center, Oklahoma City, OK (United States); Sahgal, A [University of Toronto, Toronto, ON (Canada)

    2015-06-15

    Purpose: To investigate a new modulated beam orientation optimization (MBOO) approach maximizing treatment planning quality for the state-of-the-art flattening filter free (FFF) beam that has enabled rapid treatments of multiple brain targets. Methods: MBOO selects and optimizes a large number of intensity-modulated beams (400 or more) from all accessible beam angles surrounding a patient’s skull. The optimization algorithm was implemented on a standalone system that interfaced with the 3D Dicom images and structure sets. A standard published data set that consisted of 1 to 12 metastatic brain tumor combinations was selected for MBOO planning. The planning results from various coplanar and non-coplanar configurations via MBOO were then compared with the results obtained from a clinical volume modulated arc therapy (VMAT) delivery system (Truebeam RapidArc, Varian Oncology). Results: When planning a few number of targets (n<4), MBOO produced results equivalent to non-coplanar multi-arc VMAT planning in terms of target volume coverage and normal tissue sparing. For example, the 12-Gy and 4-Gy normal brain volumes for the 3-target plans differed by less than 1 mL ( 3.0 mLvs 3.8 mL; and 35.2 mL vs 36.3 mL, respectively) for MBOO versus VMAT. However, when planning a larger number of targets (n≥4), MBOO significantly reduced the dose to the normal brain as compared to VMAT, though the target volume coverage was equivalent. For example, the 12-Gy and 4-Gy normal brain volumes for the 12-target plans were 10.8 mL vs. 18.0 mL and 217.9 mL vs. 390.0 mL, respectively for the non-coplanar MBOO versus the non-coplanar VMAT treatment plans, yielding a reduction in volume of more than 60% for the case. Conclusion: MBOO is a unique approach for maximizing normal tissue sparing when treating a large number (n≥4) of brain tumors with FFF linear accelerators. Dr Ma and Dr Sahgal are currently on the board of international society of stereotactic radiosurgery. Dr Sahgal has

  7. Controlling the misuse of cobalt in horses.

    Science.gov (United States)

    Ho, Emmie N M; Chan, George H M; Wan, Terence S M; Curl, Peter; Riggs, Christopher M; Hurley, Michael J; Sykes, David

    2015-01-01

    Cobalt is a well-established inducer of hypoxia-like responses, which can cause gene modulation at the hypoxia inducible factor pathway to induce erythropoietin transcription. Cobalt salts are orally active, inexpensive, and easily accessible. It is an attractive blood doping agent for enhancing aerobic performance. Indeed, recent intelligence and investigations have confirmed cobalt was being abused in equine sports. In this paper, population surveys of total cobalt in raceday samples were conducted using inductively coupled plasma mass spectrometry (ICP-MS). Urinary threshold of 75 ng/mL and plasma threshold of 2 ng/mL could be proposed for the control of cobalt misuse in raceday or in-competition samples. Results from administration trials with cobalt-containing supplements showed that common supplements could elevate urinary and plasma cobalt levels above the proposed thresholds within 24 h of administration. It would therefore be necessary to ban the use of cobalt-containing supplements on raceday as well as on the day before racing in order to implement and enforce the proposed thresholds. Since the abuse with huge quantities of cobalt salts can be done during training while the use of legitimate cobalt-containing supplements are also allowed, different urinary and plasma cobalt thresholds would be required to control cobalt abuse in non-raceday or out-of-competition samples. This could be achieved by setting the thresholds above the maximum urinary and plasma cobalt concentrations observed or anticipated from the normal use of legitimate cobalt-containing supplements. Urinary threshold of 2000 ng/mL and plasma threshold of 10 ng/mL were thus proposed for the control of cobalt abuse in non-raceday or out-of-competition samples. Copyright © 2014 John Wiley & Sons, Ltd.

  8. Current and future therapies targeting the immune system in multiple sclerosis.

    Science.gov (United States)

    Loleit, Verena; Biberacher, Viola; Hemmer, Bernhard

    2014-01-01

    Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS). The exact pathomechanism is unknown, but an aberrant immune response against CNS antigens, leading to inflammation in brain and spinal cord followed by demyelination, axonal damage and scar formation, seems to play a major role. Later in the disease course, inflammation decreases, while neurodegeneration proceeds. Approximately 80% of the patients initially show a relapsing-remitting disease course (RRMS), but the majority of them later develops a secondary progressive MS (SPMS). A minority suffers from primary progressive MS (PPMS). Primary goals of long-term MS therapy are to prevent relapses and disease progression. Assuming that MS is an autoimmune disease, most therapeutics aim to modulate or suppress the immune system. Until now many drugs have proven efficacy in RRMS, but none in PPMS. Interferon-β (IFN-β) and glatiramer acetate are known in RRMS therapy for years. Based on preclinical research and clinical trials, new treatment strategies have emerged and have been transferred from bench to bedside. The α4β-integrin-antagonist natalizumab was approved in 2005. Fingolimod, dimethyl fumarate and teriflunomide were the first oral drugs introduced in MS therapy. Recently alemtuzuab, another monoclonal antibody, was approved in Europe. Promising future perspectives are alemtuzumab, daclizumab, and laquinimod. Here, we review drug mechanisms in the therapy of MS. The mechanisms of action and the effect of the drugs on the immune system are summarized. We report recent results of clinical trials, highlight special features of different treatment strategies, and discuss future perspectives and ongoing clinical trials.

  9. Multiple roles for mammalian target of rapamycin signaling in both glutamatergic and GABAergic synaptic transmission.

    Science.gov (United States)

    Weston, Matthew C; Chen, Hongmei; Swann, John W

    2012-08-15

    The mammalian target of rapamycin (mTOR) signaling pathway in neurons integrates a variety of extracellular signals to produce appropriate translational responses. mTOR signaling is hyperactive in neurological syndromes in both humans and mouse models that are characterized by epilepsy, autism, and cognitive disturbances. In addition, rapamycin, a clinically important immunosuppressant, is a specific and potent inhibitor of mTOR signaling. While mTOR is known to regulate growth and synaptic plasticity of glutamatergic neurons, its effects on basic parameters of synaptic transmission are less well studied, and its role in regulating GABAergic transmission is unexplored. We therefore performed an electrophysiological and morphological comparison of glutamatergic and GABAergic neurons in which mTOR signaling was either increased by loss of the repressor Pten or decreased by treatment with rapamycin. We found that hyperactive mTOR signaling increased evoked synaptic responses in both glutamatergic and GABAergic neurons by ∼50%, due to an increase in the number of synaptic vesicles available for release, the number of synapses formed, and the miniature event size. Prolonged (72 h) rapamycin treatment prevented these abnormalities and also decreased synaptic transmission in wild-type glutamatergic, but not GABAergic, neurons. Further analyses suggested that hyperactivation of the mTOR pathway also impairs presynaptic function, possibly by interfering with vesicle fusion. Despite this presynaptic impairment, the net effect of Pten loss is enhanced synaptic transmission in both GABAergic and glutamatergic neurons, which has numerous implications, depending on where in the brain mutations of an mTOR suppressor gene occur.

  10. The Sphingosine-1-Phosphate Modulator FTY720 Targets Multiple Myeloma via the CXCR4/CXCL12 Pathway.

    Science.gov (United States)

    Beider, Katia; Rosenberg, Evgenia; Bitner, Hanna; Shimoni, Avichai; Leiba, Merav; Koren-Michowitz, Maya; Ribakovsky, Elena; Klein, Shiri; Olam, Devorah; Weiss, Lola; Wald, Hanna; Abraham, Michal; Galun, Eithan; Peled, Amnon; Nagler, Arnon

    2017-04-01

    Purpose: To explore the functional consequences of possible cross-talk between the CXCR4/CXCL12 and the sphingosine-1-phosphate (S1P) pathways in multiple myeloma (MM) cells and to evaluate the effect of S1P targeting with the FTY720 modulator as a potential anti-MM therapeutic strategy.Experimental Design and Results: S1P targeting with FTY720 induces MM cell apoptosis. The combination of FTY720 with the SPHK1 inhibitor SKI-II results in synergistic inhibition of MM growth. CXCR4/CXCL12-enhanced expression correlates with reduced MM cell sensitivity to both FTY720 and SKI-II inhibitors, and with SPHK1 coexpression in both cell lines and primary MM bone marrow (BM) samples, suggesting regulative cross-talk between the CXCR4/CXCL12 and SPHK1 pathways in MM cells. FTY720 was found to directly target CXCR4. FTY720 profoundly reduces CXCR4 cell-surface levels and abrogates the CXCR4-mediated functions of migration toward CXCL12 and signaling pathway activation. Moreover, FTY720 cooperates with bortezomib, inducing its cytotoxic activity and abrogating the bortezomib-mediated increase in CXCR4 expression. FTY720 effectively targets bortezomib-resistant cells and increases their sensitivity to bortezomib, promoting DNA damage. Finally, in a recently developed novel xenograft model of CXCR4-dependent systemic MM with BM involvement, FTY720 treatment effectively reduces tumor burden in the BM of MM-bearing mice. FTY720 in combination with bortezomib demonstrates superior tumor growth inhibition and abrogates bortezomib-induced CXCR4 increase on MM cells.Conclusions: Altogether, our work identifies a cross-talk between the S1P and CXCR4 pathways in MM cells and provides a preclinical rationale for the therapeutic application of FTY720 in combination with bortezomib in patients with MM. Clin Cancer Res; 23(7); 1733-47. ©2016 AACR. ©2016 American Association for Cancer Research.

  11. Prodrugs Bioactivated to Quinones Target NF-κB and Multiple Protein Networks: Identification of the Quinonome.

    Science.gov (United States)

    Pierce, Emily N; Piyankarage, Sujeewa C; Dunlap, Tareisha; Litosh, Vladislav; Siklos, Marton I; Wang, Yue-Ting; Thatcher, Gregory R J

    2016-07-18

    Electrophilic reactive intermediates resulting from drug metabolism have been associated with toxicity and off-target effects and in some drug discovery programs trigger NO-GO decisions. Many botanicals and dietary supplements are replete with such reactive electrophiles, notably Michael acceptors, which have been demonstrated to elicit chemopreventive mechanisms; and Michael acceptors are gaining regulatory approval as contemporary cancer therapeutics. Identifying protein targets of these electrophiles is central to understanding potential therapeutic benefit and toxicity risk. NO-donating NSAID prodrugs (NO-NSAIDs) have been the focus of extensive clinical and preclinical studies in inflammation and cancer chemoprevention and therapy: a subset exemplified by pNO-ASA, induces chemopreventive mechanisms following bioactivation to an electrophilic quinone methide (QM) Michael acceptor. Having previously shown that these NO-independent, QM-donors activated Nrf2 via covalent modification of Keap-1, we demonstrate that components of canonical NF-κB signaling are also targets, leading to the inhibition of NF-κB signaling. Combining bio-orthogonal probes of QM-donor ASA prodrugs with mass spectrometric proteomics and pathway analysis, we proceeded to characterize the quinonome: the protein cellular targets of QM-modification by pNO-ASA and its ASA pro-drug congeners. Further comparison was made using a biorthogonal probe of the "bare-bones", Michael acceptor, and clinical anti-inflammatory agent, dimethyl fumarate, which we have shown to inhibit NF-κB signaling. Identified quinonome pathways include post-translational protein folding, cell-death regulation, protein transport, and glycolysis; and identified proteins included multiple heat shock elements, the latter functionally confirmed by demonstrating activation of heat shock response.

  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

  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. Cobalt (III) complexes as novel matrix metalloproteinase-9 inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Jiyoun [Sungshin Women' s Univ., Seoul (Korea, Republic of)

    2012-04-15

    We have synthesized a series of novel MMP-9 inhibitors containing cobalt(III) complexes. The synthesized cobalt(III) complexes are effective as enzyme inhibitors and the attachment of a biphenyl group enhanced the efficiency of enzyme inhibition up to 6-fold. When compared to the reported non-hydroxamate MMP inhibitors, the synthesized complexes showed comparable in vitro potency. The enzyme assay showed that the cobalt(III) complex can disrupt the zinc binding active site of MMP-9 and is proposed to work via a ligand exchange mechanism. Since histidine residues are essential for the catalytic activity of a large percentage of enzymes and zinc finger proteins, these cobalt(III) complexes can serve as a prototype inhibitor towards various zinc containing enzymes and proteins. Matrix metalloproteinases (MMPs) are a family of zinc binding endopeptidases that play crucial roles in various physiological processes and diseases such as embryogenic growth, angiogenesis, arthritis, skin ulceration, liver fibrosis and tumor metastasis. Because of their implications in a wide range of diseases, MMPs are considered as intriguing drug targets. The majority of MMP inhibitors are organic small molecules containing a hydroxamate functionality for the zinc binding group. This hydroxamate group binds to a zinc(II) center in a bidentate fashion and creates a distorted trigonal bipyramidal geometry.

  15. Cobalt(II) and Cobalt(III) Coordination Compounds.

    Science.gov (United States)

    Thomas, Nicholas C.; And Others

    1989-01-01

    Presents a laboratory experiment which illustrates the formation of tris(phenanthroline)cobalt complexes in the 2+ and 3+ oxidation states, the effect of coordination on reactions of the ligand, and the use of a ligand displacement reaction in recovering the transformed ligand. Uses IR, UV-VIS, conductivity, and NMR. (MVL)

  16. Pharmacokinetics and dosimetry of cobalt-55 and cobalt-57

    NARCIS (Netherlands)

    Jansen, HML; Knollema, S; vanderDuin, LV; Willemsen, ATM; Wiersma, A; Franssen, EJF; Russel, FGM; Korf, J; Paans, AMJ

    1996-01-01

    The isotopes Co-55 and Co-57 have been evaluated for PET and SPECT imaging in several clinical brain studies. For clinical application of cobalt, it is important to know the delivered radiation dose. The biodistribution of Co-55 in both rat and humans after intravenous (bolus)-administration was

  17. Antibiotics that target mitochondria effectively eradicate cancer stem cells, across multiple tumor types: treating cancer like an infectious disease.

    Science.gov (United States)

    Lamb, Rebecca; Ozsvari, Bela; Lisanti, Camilla L; Tanowitz, Herbert B; Howell, Anthony; Martinez-Outschoorn, Ubaldo E; Sotgia, Federica; Lisanti, Michael P

    2015-03-10

    Here, we propose a new strategy for the treatment of early cancerous lesions and advanced metastatic disease, via the selective targeting of cancer stem cells (CSCs), a.k.a., tumor-initiating cells (TICs). We searched for a global phenotypic characteristic that was highly conserved among cancer stem cells, across multiple tumor types, to provide a mutation-independent approach to cancer therapy. This would allow us to target cancer stem cells, effectively treating cancer as a single disease of "stemness", independently of the tumor tissue type. Using this approach, we identified a conserved phenotypic weak point - a strict dependence on mitochondrial biogenesis for the clonal expansion and survival of cancer stem cells. Interestingly, several classes of FDA-approved antibiotics inhibit mitochondrial biogenesis as a known "side-effect", which could be harnessed instead as a "therapeutic effect". Based on this analysis, we now show that 4-to-5 different classes of FDA-approved drugs can be used to eradicate cancer stem cells, in 12 different cancer cell lines, across 8 different tumor types (breast, DCIS, ovarian, prostate, lung, pancreatic, melanoma, and glioblastoma (brain)). These five classes of mitochondrially-targeted antibiotics include: the erythromycins, the tetracyclines, the glycylcyclines, an anti-parasitic drug, and chloramphenicol. Functional data are presented for one antibiotic in each drug class: azithromycin, doxycycline, tigecycline, pyrvinium pamoate, as well as chloramphenicol, as proof-of-concept. Importantly, many of these drugs are non-toxic for normal cells, likely reducing the side effects of anti-cancer therapy. Thus, we now propose to treat cancer like an infectious disease, by repurposing FDA-approved antibiotics for anti-cancer therapy, across multiple tumor types. These drug classes should also be considered for prevention studies, specifically focused on the prevention of tumor recurrence and distant metastasis. Finally, recent

  18. Targeting angiogenesis via a c-Myc/hypoxia-inducible factor-1alpha-dependent pathway in multiple myeloma.

    Science.gov (United States)

    Zhang, Jing; Sattler, Martin; Tonon, Giovanni; Grabher, Clemens; Lababidi, Samir; Zimmerhackl, Alexander; Raab, Marc S; Vallet, Sonia; Zhou, Yiming; Cartron, Marie-Astrid; Hideshima, Teru; Tai, Yu-Tzu; Chauhan, Dharminder; Anderson, Kenneth C; Podar, Klaus

    2009-06-15

    Bone marrow angiogenesis is associated with multiple myeloma (MM) progression. Here, we report high constitutive hypoxia-inducible factor-1alpha (Hif-1alpha) expression in MM cells, which is associated with oncogenic c-Myc. A drug screen for anti-MM agents that decrease Hif-1alpha and c-Myc levels identified a variety of compounds, including bortezomib, lenalidomide, enzastaurin, and adaphostin. Functionally, based on transient knockdowns and overexpression, our data delineate a c-Myc/Hif-1alpha-dependent pathway mediating vascular endothelial growth factor production and secretion. The antiangiogenic activity of our tool compound, adaphostin, was subsequently shown in a zebrafish model and translated into a preclinical in vitro and in vivo model of MM in the bone marrow milieu. Our data, therefore, identify Hif-1alpha as a novel molecular target in MM and add another facet to anti-MM drug activity.

  19. CS1, a SLAM family receptor involved in immune regulation, is a therapeutic target in multiple myeloma.

    Science.gov (United States)

    Veillette, André; Guo, Huaijian

    2013-10-01

    Signaling lymphocytic activation molecule (SLAM) family receptors have been implicated in normal immunity, immunodeficiencies and autoimmunity. CS1 (also known as CRACC, CD319 and SLAMF7) is a member of the SLAM family expressed on several normal hematopoietic cell types. It is also highly and nearly universally expressed on multiple myeloma (MM) cells. This review focuses on the biology of CS1, both in normal hematopoietic cells and in MM cells. It also discusses the preclinical and clinical data on the use of a humanized anti-CS1 monoclonal antibody, elotuzumab, for the treatment of MM. Based on current knowledge, CS1 is a compelling new target for the treatment of MM.

  20. A Void Reference Sensor-Multiple Signal Classification Algorithm for More Accurate Direction of Arrival Estimation of Low Altitude Target

    Institute of Scientific and Technical Information of China (English)

    XIAO Hui; SUN Jin-cai; YUAN Jun; NIU Yi-long

    2007-01-01

    There exists MUSIC (multiple signal classification) algorithm for direction of arrival (DOA) estimation. This paper is to present a different MUSIC algorithm for more accurate estimation of low altitude target. The possibility of better performance is analyzed using a void reference sensor (VRS) in MUSIC algorithm. The following two topics are discussed: 1) the time delay formula and VRS-MUSIC algorithm with VRS located on the minus of z-axes; 2) the DOA estimation results of VRS-MUSIC and MUSIC algorithms. The simulation results show VRS-MUSIC algorithm has three advantages compared with MUSIC: 1 ) When the signal to noise ratio (SNR) is more than - 5 dB, the direction estimation error is 1/2 as much as that obtained by MUSIC; 2) The side lobe is more lower and the stability is better; 3) The size of array that the algorithm requires is smaller.

  1. Characterization of feline serum-cobalt binding.

    Science.gov (United States)

    Schnelle, Amy N; Barger, Anne M; MacNeill, Amy L; Mitchell, Mark M; Solter, Philip

    2015-06-01

    Oxidative stress inhibits albumin's ability to complex with cobalt. Feline serum-cobalt binding has not been described. The objective was to develop a cobalt binding test for use with feline serum, and correlate the results with other biochemical and cellular constituents in blood, and with clinical diseases of cats. A colorimetric test of cobalt binding, based on the oxidation-reduction reaction of Co(+2) and dithiothreitol, was developed using feline serum. The test was used to measure cobalt binding in stored serum from 176 cats presented to the University of Illinois Veterinary Teaching Hospital for a variety of disease conditions. Time-matched hematology and biochemical data, and clinical information, were obtained from the medical record of each cat and correlated with the serum-cobalt binding results. Serial dilution of feline serum with phosphate-buffered saline resulted in a highly linear decrease in serum-cobalt binding (r(2)  = .9984). Serum-cobalt binding of the clinical samples also correlated with albumin concentrations in a stepwise linear regression model (r(2)  = .425), and both cobalt binding and albumin were significantly decreased in cases of inflammation. Albumin and cobalt binding also shared significant correlations with several erythron variables, and serum concentration of total calcium and bilirubin. The correlation of cobalt binding measured by a colorimetric test with albumin concentration in the clinical samples and with serum dilution is consistent with feline albumin-cobalt complex formation. Hypoalbuminemia is the likely cause of reduced serum-cobalt binding in inflammation and the correlations observed between cobalt binding and other variables. © 2015 American Society for Veterinary Clinical Pathology.

  2. Correlation between crystallographic texture, microstructure and magnetic properties of pulse electrodeposited nanocrystalline Nickel-Cobalt alloys

    Science.gov (United States)

    Sharma, Amit; Chhangani, Sumit; Madhavan, R.; Suwas, Satyam

    2017-07-01

    This paper reports the evolution of microstructure and texture in Nickel-Cobalt electrodeposits fabricated by pulse electrodeposition (PED) technique and the correlation of these attributes with the magnetic properties. The structural and microstructural investigation using X-ray diffraction and transmission electron microscopic studies indicate the presence of nanocrystalline grains and nano-twins in the electrodeposits. Convoluted Multiple Whole profile fitting reveals an increase in dislocation density and twin density with increasing cobalt content in the as-deposited samples. Strengthening of fibre texture and weakening of fibre texture with increasing cobalt concentration has been observed with X-ray texture analysis. A corresponding significant increase in the saturation magnetization and coercivity observed with increasing cobalt content. A significant improvement in the soft magnetic character in the electrodeposits in terms of increase in saturation magnetization and decrease in coercivity has been observed with thermal annealing.

  3. Exploring clustering in alpha-conjugate nuclei using the thick target inverse kinematic technique for multiple alpha emission

    Science.gov (United States)

    Barbui, M.; Hagel, K.; Gauthier, J.; Wuenschel, S.; Goldberg, V. Z.; Zheng, H.; Giuliani, G.; Rapisarda, G.; Kim, E.-J.; Liu, X.; Natowitz, J. B.; Desouza, R. T.; Hudan, S.; Fang, D.

    2015-10-01

    Searching for alpha cluster states analogous to the 12C Hoyle state in heavier alpha-conjugate nuclei can provide tests of the existence of alpha condensates in nuclear matter. Such states are predicted for 16O, 20Ne, 24Mg, etc. at excitation energies slightly above the decay threshold. The Thick Target Inverse Kinematics (TTIK) technique can be successfully used to study the breakup of excited self-conjugate nuclei into many alpha particles. The reaction 20Ne + α at 11 and 13 AMeV was studied at Cyclotron Institute at Texas A&M University. Here the TTIK method was used to study both single α-particle emission and multiple α-particle decays. Due to the limited statistics, only events with alpha multiplicity up to three were analyzed. The analysis of the three α-particle emission data allowed the identification of the Hoyle state and other 12C excited states decaying into three alpha particles. The results will be shown and compared with other data available in the literature. Another experiment is planned in August 2015 to study the system 28Si + α at 15 AMeV. Preliminary results will be shown. Supported by the U.S. DOE and the Robert A. Welch Foundation, Grant No. A0330.

  4. Anisotropy and Magnetostriction in Cobalt-Modified Magnetite: A Crystal Field Approach

    Science.gov (United States)

    Nlebedim, Cajetan; Jiles, David

    2013-03-01

    The anisotropy and magnetostrictive properties of magnetite are altered by the introduction of cobalt ions into the spinel crystal lattice. 4% of Co2+ substituted for Fe2+ changes both the sign and magnitude of magnetocrystalline anisotropy coefficient. Such strong dependence can be useful for tailoring the properties of cobalt-iron oxides for applications. This is especially important, considering that cobalt ferrite materials prepared for magnetostrictive, multiferroic and other related applications often deviate from targeted or stoichiometric compositions. In this study, magnetite has been systematically modified by substitution of cobalt. The changes in anisotropy and magnetostriction have been studied and can be explained using the single ion model. The agreement between the trend observed in this experimental investigation and previous theoretical studies is noteworthy. The variation in anisotropy and magnetostriction will be presented on the basis of two competing factors; the unquenched orbital angular momentum of Co2+ and changes in the crystal field due to Co2+ substitution.

  5. 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.

  6. Fine-tuned h-ferritin nanocage with multiple gold clusters as near-infrared kidney specific targeting nanoprobe.

    Science.gov (United States)

    Sun, Cuiji; Yuan, Yi; Xu, Zhonghe; Ji, Tianjiao; Tian, Yanhua; Wu, Shan; Lei, Jianlin; Li, Jingyuan; Gao, Ning; Nie, Guangjun

    2015-02-18

    When stabilized and functionalized by biomolecules, noble metal (such as gold and silver) cluster-based hybrid nanocomposites have shown great promise for biomedical applications, due to their unique physiochemical properties originating from the inorganic elements and specific functionality and biocompatibility from their biological components. Although certain promise for bioimaging, biosensing, and biomimetic catalysis has been demonstrated, it is still a great challenge to integrate the defined functionality of the biomolecules with enhanced or novel physiochemical properties of the metal clusters, under control at the molecular level. Herein, based on molecular dynamics simulation of a gold (Au) cluster assembly, we designed near-infrared (NIR) fluorescent hybrid nanocomposites with multiple Au clusters within an apo H-ferritin (HFt) nanocage. The fluorescence quantum yield of near-infrared (NIR) Au-HFt is about 63.4% and the emission peak is 810 nm. The NIR Au-HFt is one of the first native protein-guided Au cluster-based nanomaterials for in vivo biowindow imaging. In vivo fluorescent imaging and quantification of Au element confirmed that Au-HFt not only retained the kidney targeting properties of HFt well (about 10 times higher Au concentration in kidney than in liver and spleen, the most common organs for nanoparticle accumulation), but also gained strong NIR imaging capability for live animals. The NIR Au-HFt showed powerful tissue penetrating ability, strong fluorescent efficiency, and excellent kidney targeting specificity. These results thus open new opportunities for kidney disease imaging and theranostic applications.

  7. Bortezomib reduces the tumorigenicity of multiple myeloma via downregulation of upregulated targets in clonogenic side population cells.

    Directory of Open Access Journals (Sweden)

    Miho Nara

    Full Text Available Side population (SP cells in cancers, including multiple myeloma, exhibit tumor-initiating characteristics. In the present study, we isolated SP cells from human myeloma cell lines and primary tumors to detect potential therapeutic targets specifically expressed in SP cells. We found that SP cells from myeloma cell lines (RPMI 8226, AMO1, KMS-12-BM, KMS-11 express CD138 and that non-SP cells include a CD138-negative population. Serial transplantation of SP and non-SP cells into NOD/Shi-scid IL-2γnul mice revealed that clonogenic myeloma SP cells are highly tumorigenic and possess a capacity for self-renewal. Gene expression analysis showed that SP cells from five MM cell lines (RPMI 8226, AMO1, KMS-12-BM, KMS-11, JJN3 express genes involved in the cell cycle and mitosis (e.g., CCNB1, CDC25C, CDC2, BIRC5, CENPE, SKA1, AURKB, KIFs, TOP2A, ASPM, polycomb (e.g., EZH2, EPC1 and ubiquitin-proteasome (e.g., UBE2D3, UBE3C, PSMA5 more strongly than do non-SP cells. Moreover, CCNB1, AURKB, EZH2 and PSMA5 were also upregulated in the SPs from eight primary myeloma samples. On that basis, we used an aurora kinase inhibitor (VX-680 and a proteasome inhibitor (bortezomib with RPMI 8226 and AMO1 cells to determine whether these agents could be used to selectively target the myeloma SP. We found that both these drugs reduced the SP fraction, though bortezomib did so more effectively than VX-680 due to its ability to reduce levels of both phospho-histone H3 (p-hist. H3 and EZH2; VX-680 reduced only p-hist. H3. This is the first report to show that certain oncogenes are specifically expressed in the myeloma SP, and that bortezomib effectively downregulates expression of their products. Our approach may be useful for screening new agents with which to target a cell population possessing strong tumor initiating potential in multiple myeloma.

  8. Biological monitoring of dermal and air exposure to cobalt at a Swedish hard metal production plant: does dermal exposure contribute to uptake?

    Science.gov (United States)

    Klasson, Maria; Lindberg, Magnus; Bryngelsson, Ing-Liss; Arvidsson, Helena; Pettersson, Carin; Husby, Bente; Westberg, Håkan

    2017-10-01

    Occupational exposure to cobalt is well established in hard metal manufacture. Cobalt is known to cause contact allergy, asthma, hard metal lung disease, and lung cancer. The relationship between skin exposure and uptake determined in blood has not been extensively investigated. To examine whether skin and inhalable air exposure to cobalt contributes to uptake, determined as cobalt in blood, in a hard metal manufacturing factory. The amount of cobalt on the skin found with an acid wash technique, the air concentrations of inhalable cobalt and cobalt blood concentrations were determined and correlated in exposed workers. We found a significant rank correlation for cobalt concentrations on the skin, in inhalable air, and in blood (0.376-0.498). Multiple linear regression showed significant regression coefficients for cobalt skin exposure and blood (B = 0.01, p exposure levels at different air concentrations caused a 3-14% increase in blood levels. Our data suggest that skin exposure to cobalt in the hard metal industry could affect the total uptake at the same order of magnitude as air exposure. © 2017 The Authors. Contact Dermatitis published by John Wiley & Sons Ltd.

  9. Cobalt release from inexpensive jewellery: has the use of cobalt replaced nickel following regulatory intervention?

    Science.gov (United States)

    Thyssen, Jacob Pontoppidan; Jellesen, Morten S; Menné, Torkil; Lidén, Carola; Julander, Anneli; Møller, Per; Johansen, Jeanne Duus

    2010-08-01

    Before the introduction of the EU Nickel Directive, concern was raised that manufacturers of jewellery might turn from the use of nickel to cobalt following the regulatory intervention on nickel exposure. The aim was to study 354 consumer items using the cobalt spot test. Cobalt release was assessed to obtain a risk estimate of cobalt allergy and dermatitis in consumers who would wear the jewellery. The cobalt spot test was used to assess cobalt release from all items. Microstructural characterization was made using scanning electron microscope (SEM) and energy-dispersive spectroscopy (EDS). Cobalt release was found in 4 (1.1%) of 354 items. All these had a dark appearance. SEM/EDS was performed on the four dark appearing items which showed tin-cobalt plating on these. This study showed that only a minority of inexpensive jewellery purchased in Denmark released cobalt when analysed with the cobalt spot test. As fashion trends fluctuate and we found cobalt release from dark appearing jewellery, cobalt release from consumer items should be monitored in the future. Industries may not be fully aware of the potential cobalt allergy problem.

  10. 基于交互多模型的水下目标跟踪方法%Method for Underwater Target Tracking Based on an Interacting Multiple Model

    Institute of Scientific and Technical Information of China (English)

    徐卫明; 刘雁春; 殷晓东

    2008-01-01

    According to the requirements of real-time performance and reliability in underwater maneuvering target tracking as well as clarifying motion features of the underwater target, an interacting multiple model algorithm based on fuzzy logic inference (FIMM) is proposed. Maneuvering patterns of the target are represented by model sets, Including the constant velocity model (CA), the Singer model, and the nearly constant speed horizontal-turn model (HT) in FIMM technology. The simulation results show that compared to conventional IMM, the reliability and real-time performance of underwater target tracking can be Improved by FIMM algorithm.

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

    CERN Document Server

    Zhang, Dong-Hai; Wang, Guo-Rong; Li, Wang-Dong; Wang, Qing; Yao, Ji-Jie; Zhou, Jian-Guo; Li, Rong; Li, Jun-Sheng; Li, Hui-Ling

    2014-01-01

    The forward-backward multiplicity and correlations of target evaporated fragment(black track particle) and target recoiled proton(grey track particle) emitted in 150 A MeV He-emulsion, 290 A MeV C-emulsion, 400 A MeV C-emulsion, 400 A MeV Ne-emulsion and 500 A MeV Fe-emulsion interactions are investigated. It is found that the forward and backward averaged multiplicity of grey, black and heavily ionized track particle increase with the increase of target size. Averaged multiplicity of 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 forward grey track particle increases with increase of projectile size and energy. The backward grey track particle multiplicity distribution follows an exponential decay law and the decay constant decreases with increase of target size. The backward-forward multiplicity correlations follow linear law which is independent of the projectile size and energy,...

  12. Cobalt toxicity in anaerobic granular sludge: influence of chemical speciation

    NARCIS (Netherlands)

    Bartacek, J.; Fermoso, F.G.; Baldo-Urrutia, A.M.; Hullebusch, van E.D.; Lens, P.N.L.

    2008-01-01

    The influence of cobalt speciation on the toxicity of cobalt to methylotrophic methanogenesis in anaerobic granular sludge was investigated. The cobalt speciation was studied with three different media that contained varying concentrations of complexing ligands [carbonates, phosphates and ethylenedi

  13. Cobalt toxicity in anaerobic granular sludge: influence of chemical speciation

    NARCIS (Netherlands)

    Bartacek, J.; Fermoso, F.G.; Baldo-Urrutia, A.M.; Hullebusch, van E.D.; Lens, P.N.L.

    2008-01-01

    The influence of cobalt speciation on the toxicity of cobalt to methylotrophic methanogenesis in anaerobic granular sludge was investigated. The cobalt speciation was studied with three different media that contained varying concentrations of complexing ligands [carbonates, phosphates and

  14. Cobalt toxicity in anaerobic granular sludge: influence of chemical speciation

    NARCIS (Netherlands)

    Bartacek, J.; Fermoso, F.G.; Baldo-Urrutia, A.M.; Hullebusch, van E.D.; Lens, P.N.L.

    2008-01-01

    The influence of cobalt speciation on the toxicity of cobalt to methylotrophic methanogenesis in anaerobic granular sludge was investigated. The cobalt speciation was studied with three different media that contained varying concentrations of complexing ligands [carbonates, phosphates and ethylenedi

  15. 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

  16. Therapeutic potential of targeting IRES-dependent c-myc translation in multiple myeloma cells during ER stress.

    Science.gov (United States)

    Shi, Y; Yang, Y; Hoang, B; Bardeleben, C; Holmes, B; Gera, J; Lichtenstein, A

    2016-02-25

    Protein translation is inhibited by the unfolded protein response (UPR)-induced eIF-2α phosphorylation to protect against endoplasmic reticulum (ER) stress. In addition, we found additional inhibition of protein translation owing to diminished mTORC1 (mammalian target of rapamycin complex1) activity in ER-stressed multiple myeloma (MM) cells. However, c-myc protein levels and myc translation was maintained. To ascertain how c-myc was maintained, we studied myc IRES (internal ribosome entry site) function, which does not require mTORC1 activity. Myc IRES activity was upregulated in MM cells during ER stress induced by thapsigargin, tunicamycin or the myeloma therapeutic bortezomib. IRES activity was dependent on upstream MAPK (mitogen-activated protein kinase) and MNK1 (MAPK-interacting serine/threonine kinase 1) signaling. A screen identified hnRNP A1 (A1) and RPS25 as IRES-binding trans-acting factors required for ER stress-activated activity. A1 associated with RPS25 during ER stress and this was prevented by an MNK inhibitor. In a proof of principle, we identified a compound that prevented binding of A1 to the myc IRES and specifically inhibited myc IRES activity in MM cells. This compound, when used alone, was not cytotoxic nor did it inhibit myc translation or protein expression. However, when combined with ER stress inducers, especially bortezomib, a remarkable synergistic cytotoxicity ensued with associated inhibition of myc translation and expression. These results underscore the potential for targeting A1-mediated myc IRES activity in MM cells during ER stress.

  17. Target regulation of PI3K/Akt/mTOR pathway by cannabidiol in treatment of experimental multiple sclerosis.

    Science.gov (United States)

    Giacoppo, Sabrina; Pollastro, Federica; Grassi, Gianpaolo; Bramanti, Placido; Mazzon, Emanuela

    2017-01-01

    This study was aimed to investigate whether treatment with purified cannabidiol (CBD) may counteract the development of experimental multiple sclerosis (MS), by targeting the PI3K/Akt/mTOR pathway. Although the PI3K/Akt/mTOR pathway was found to be activated by cannabinoids in several immune and non-immune cells, currently, there is no data about the effects of CBD in the PI3K/Akt/mTOR activity in MS. Experimental Autoimmune Encephalomyelitis (EAE), the most common model of MS, was induced in C57BL/6 mice by immunization with myelin oligodendroglial glycoprotein peptide (MOG)35-55. After EAE onset, which occurs approximately 14days after disease induction, mice were daily intraperitoneally treated with CBD (10mg/kg mouse) and observed for clinical signs of EAE. At 28days from EAE-induction, mice were euthanized and spinal cord tissues were sampled to perform immunohistochemical evaluations and western blot analysis. Our results showed a clear downregulation of the PI3K/Akt/mTOR pathway following EAE induction. CBD treatment was able to restore it, increasing significantly the phosphorylation of PI3K, Akt and mTOR. Also, an increased level of BNDF in CBD-treated mice seems to be involved in the activation of PI3K/Akt/mTOR pathway. In addition, our data demonstrated that therapeutic efficacy of CBD treatment is due to reduction of pro-inflammatory cytokines, like IFN-γ and IL-17 together with an up-regulation of PPARγ. Finally, CBD was found to promote neuronal survival by inhibiting JNK and p38 MAP kinases. These results provide an interesting discovery about the regulation of the PI3K/Akt/mTOR pathway by cannabidiol administration, that could be a new potential therapeutic target for MS management.

  18. Cobalt release from implants and consumer items and characteristics of cobalt sensitized patients with dermatitis

    DEFF Research Database (Denmark)

    Thyssen, Jacob Pontoppidan; Menne, Torkil; Liden, Carola

    2012-01-01

    -containing dental alloys and revised hip implant components.Results. Six of eight dental alloys and 10 of 98 revised hip implant components released cobalt in the cobalt spot test, whereas none of 50 mobile phones gave positive reactions. The clinical relevance of positive cobalt test reactions was difficult...

  19. Hot Corrosion of Cobalt-Base Alloys

    Science.gov (United States)

    1975-06-01

    scale is similar to that which has already been proposed for cobalt . The oxide ions would react with the Al203 to form aluminate ions in the Na2S04...resistance of cobalt -base and nickel-base alloys. The contract was accomplished under the technical direction of Dr. H. C. Graham of the Aerospace Research...Oxidized Specimens RESULTS AND DISCUSSION 1. INTRODUCfiON 2. SODIUM SULFATE INDUCED HOT CORROSION OF COBALT a. Introduction b. Experimental c

  20. Cobalt-Base Alloy Gun Barrel Study

    Science.gov (United States)

    2014-07-01

    are presented in Section 5. 2. Materials and methods The composition of the cobalt -base alloy (CBA) is presented in Table 1. The production of this... Cobalt -Base Alloy Gun Barrel Study by William S. de Rosset and Jonathan S. Montgomery ARL-RP-0491 July 2014 A reprint...21005-5069 ARL-RP-0491 July 2014 Cobalt -Base Alloy Gun Barrel Study William S. de Rosset and Jonathan S. Montgomery Weapons and Materials

  1. Mineral resource of the month: cobalt

    Science.gov (United States)

    Shedd, Kim B.

    2009-01-01

    Cobalt is a metal used in numerous commercial, industrial and military applications. On a global basis, the leading use of cobalt is in rechargeable lithium-ion, nickel-cadmium and nickel-metal hydride battery electrodes. Cobalt use has grown rapidly since the early 1990s, with the development of new battery technologies and an increase in demand for portable electronics such as cell phones, laptop computers and cordless power tools.

  2. Cobalt and antimony: genotoxicity and carcinogenicity.

    Science.gov (United States)

    De Boeck, Marlies; Kirsch-Volders, Micheline; Lison, Dominique

    2003-12-10

    The purpose of this review is to summarise the data concerning genotoxicity and carcinogenicity of Co and Sb. Both metals have multiple industrial and/or therapeutical applications, depending on the considered species. Cobalt is used for the production of alloys and hard metal (cemented carbide), diamond polishing, drying agents, pigments and catalysts. Occupational exposure to cobalt may result in adverse health effects in different organs or tissues. Antimony trioxide is primarily used as a flame retardant in rubber, plastics, pigments, adhesives, textiles, and paper. Antimony potassium tartrate has been used worldwide as an anti-shistosomal drug. Pentavalent antimony compounds have been used for the treatment of leishmaniasis. Co(II) ions are genotoxic in vitro and in vivo, and carcinogenic in rodents. Co metal is genotoxic in vitro. Hard metal dust, of which occupational exposure is linked to an increased lung cancer risk, is proven to be genotoxic in vitro and in vivo. Possibly, production of active oxygen species and/or DNA repair inhibition are mechanisms involved. Given the recently provided proof for in vitro and in vivo genotoxic potential of hard metal dust, the mechanistic evidence of elevated production of active oxygen species and the epidemiological data on increased cancer risk, it may be advisable to consider the possibility of a new evaluation by IARC. Both trivalent and pentavalent antimony compounds are generally negative in non-mammalian genotoxicity tests, while mammalian test systems usually give positive results for Sb(III) and negative results for Sb(V) compounds. Assessment of the in vivo potential of Sb2O3 to induce chromosome aberrations (CA) gave conflicting results. Animal carcinogenicity data were concluded sufficient for Sb2O3 by IARC. Human carcinogenicity data is difficult to evaluate given the frequent co-exposure to arsenic. Possible mechanisms of action, including potential to produce active oxygen species and to interfere with

  3. Biological synthesis of cobalt ferrite nanoparticles

    Directory of Open Access Journals (Sweden)

    Anal K. Jha

    2012-01-01

    Full Text Available A low-cost green and reproducible yeast (Saccharomyces cerevisiae mediated biosynthesis of cobalt ferrite nanoparticles is reported. The synthesis is performed at close to room temperature in the laboratory. X-ray, Fourier transform infrared spectroscopy and high resolution transmission electron microscopy analyses are performed to ascertain the formation of cobalt ferrite nanoparticles. Individual nanoparticles, as well as a very few aggregate having the size of 3-15 nm, were found. The vibrating sample magnetometer measurement showed superparamagnetic behavior in cobalt ferrite nanoparticles. The mechanism involved in the biosynthesis of cobalt ferrite nanoparticles has also been discussed.

  4. Multiple myeloma cell lines and primary tumors proteoma: protein biosynthesis and immune system as potential therapeutic targets

    Science.gov (United States)

    Mazzotti, Diego Robles; Evangelista, Adriane Feijó; Braga, Walter Moisés Tobias; de Lourdes Chauffaille, Maria; Leme, Adriana Franco Paes; Colleoni, Gisele Wally Braga

    2015-01-01

    Despite great advance in multiple myeloma (MM) treatment since 2000s, it is still an incurable disease and novel therapies are welcome. Therefore, the purpose of this study was to explore MM plasma cells' (MM-PC) proteome, in comparison with their normal counterparts (derived from palatine tonsils of normal donors, ND-PC), in order to find potential therapeutic targets expressed on the surface of these cells. We also aimed to evaluate the proteome of MM cell lines with different genetic alterations, to confirm findings obtained with primary tumor cells. Bone marrow (BM) samples from eight new cases of MM and palatine tonsils from seven unmatched controls were submitted to PC separation and, in addition to two MM cell lines (U266, RPMI-8226), were submitted to protein extraction for mass spectrometry analyses. A total of 81 proteins were differentially expressed between MM-PC and ND-PC - 72 upregulated and nine downregulated; U266 vs. RPMI 8226 cell lines presented 61 differentially expressed proteins - 51 upregulated and 10 downregulated. On primary tumors, bioinformatics analyses highlighted upregulation of protein biosynthesis machinery, as well as downregulation of immune response components, such as MHC class I and II, and complement receptors. We also provided comprehensive information about U266 and RPMI-8226 cell lines' proteome and could confirm some patients' findings. PMID:26807199

  5. Targeting Vascular Endothelial Growth Factor Receptor 2 and Protein Kinase D1 Related Pathways by a Multiple Kinase Inhibitor in Angiogenesis and Inflammation Related Processes In Vitro

    OpenAIRE

    Attila Varga; Pál Gyulavári; Zoltán Greff; Krisztina Futosi; Tamás Németh; Laura Simon-Szabó; Krisztina Kerekes; Csaba Szántai-Kis; Diána Brauswetter; Márton Kokas; Gábor Borbély; Anna Erdei; Attila Mócsai; György Kéri; Tibor Vántus

    2015-01-01

    Emerging evidence suggests that the vascular endothelial growth factor receptor 2 (VEGFR2) and protein kinase D1 (PKD1) signaling axis plays a critical role in normal and pathological angiogenesis and inflammation related processes. Despite all efforts, the currently available therapeutic interventions are limited. Prior studies have also proved that a multiple target inhibitor can be more efficient compared to a single target one. Therefore, development of novel inflammatory pathway-specific...

  6. Oxidation of low cobalt alloys

    Science.gov (United States)

    Barrett, C. A.

    1982-01-01

    Four high temperature alloys: U-700, Mar M-247, Waspaloy and PM/HIP U-700 were modified with various cobalt levels ranging from 0 percent to their nominal commercial levels. The alloys were then tested in cyclic oxidation in static air at temperatures ranging from 1000 to 1150 C at times from 500 to 100 1 hour cycles. Specific weight change with time and X-ray diffraction analyses of the oxidized samples were used to evaluate the alloys. The alloys tend to be either Al2O3/aluminate spinel or Cr2O3/chromite spinel formers depending on the Cr/Al ratio in the alloy. Waspaloy with a ratio of 15:1 is a strong Cr2O3 former while this U-700 with a ratio of 3.33:1 tends to form mostly Cr2O3 while Mar M-247 with a ratio of 1.53:1 is a strong Al2O3 former. The best cyclic oxidation resistance is associated with the Al2O3 formers. The cobalt levels appear to have little effect on the oxidation resistance of the Al2O3/aluminate spinel formers while any tendency to form Cr2O3 is accelerated with increased cobalt levels and leads to increased oxidation attack.

  7. Design of Chemical Conjugate for Targeted Therapy of Multiple Sclerosis Based of Constant Fragment of Human Antibody Heavy Chain and Peptoid Analog of Autoantigen MOG35-55.

    Science.gov (United States)

    Lomakin, Y A; Stepanov, A V; Balabashin, D S; Ponomarenko, N A; Smirnov, I V; Belogurov, A A

    2017-04-01

    Elimination of B cells producing autoantibodies to neuroantigens is considered as beneficial in the treatment of multiple sclerosis. Myelin oligodendrocyte glycoprotein (MOG) is a significant autoantigen in multiple sclerosis. It was shown that MOG-like peptoid AMogP3 can bind autoantibodies produced by pathological lymphocytes. We propose a structure of an innovative drug for targeted elimination of the pool of autoreactive B cells responsible for multiple sclerosis pathogenesis; this compound is a complex of peptoid AMogP3 with Fc fragment of human immunoglobulin. The obtained Fc-PEG-AMogP3 conjugate effectively interact with autoreactive antibodies, which attests to their high therapeutic potential.

  8. The feed forward neural network model for liquid-liquid extraction and separation of cobalt (II) from sodium acetate media using cyanex 272

    Science.gov (United States)

    Sudibyo, Aji, B. B.; Priyanto, S.

    2017-03-01

    Cobalt is one of the precious ferromagnetic metals, which widely used in the preparation of magnetic, wear-resistant and high-strength alloys. This metal was not found naturally in single metal form but is found as impurities in nickel or copper ore. The extraction process is one of the methods to separate cobalt from its impurities. However, this process needs an expensive organic solution. In practice, changing the composition of chemicals composition in extraction process always affect at a high cost. Therefore, the development of the artificial neural network (ANN) model to model the cobalt extraction process can serve as an important tool for predicting and investigating the optimum production for the cobalt extraction without the need to run the actual experiment. Hence, the development of the ANN model of cobalt extraction model is essential to simulate the process, which can lead to high yields of cobalt production. In this work a selected optimum multiple-input-single-output (MISO) model of feed forward neural network (FFNN) was used to predict the percentage of cobalt extraction. MISO FFNN with 20, 30 and 50 hidden nodes were used to simulate cobalt extraction process. The simulation results achieved was compared with data available in the literature. The results show that MISO FFNN with 50 hidden nodes has the best performance. The optimum result of MISO FFNN then exported to Simulink model in Matlab environment, hence make it easy to use in predicting and investigating for the optimum production of the cobalt extraction.

  9. CXCL12 and CXCR7 are relevant targets to reverse cell adhesion-mediated drug resistance in multiple myeloma.

    Science.gov (United States)

    Waldschmidt, Johannes M; Simon, Anna; Wider, Dagmar; Müller, Stefan J; Follo, Marie; Ihorst, Gabriele; Decker, Sarah; Lorenz, Joschka; Chatterjee, Manik; Azab, Abdel K; Duyster, Justus; Wäsch, Ralph; Engelhardt, Monika

    2017-10-01

    Cell adhesion-mediated drug resistance (CAM-DR) by the bone marrow (BM) is fundamental to multiple myeloma (MM) propagation and survival. Targeting BM protection to increase the efficacy of current anti-myeloma treatment has not been extensively pursued. To extend the understanding of CAM-DR, we hypothesized that the cytotoxic effects of novel anti-myeloma agents may be abrogated by the presence of BM stroma cells (BMSCs) and restored by addition of the CXCL12 antagonist NOX-A12 or the CXCR4 inhibitor plerixafor. Following this hypothesis, we evaluated different anti-myeloma agents alone, with BMSCs and when combined with plerixafor or NOX-A12. We verified CXCR4, CD49d (also termed ITGA4) and CD44 as essential mediators of BM adhesion on MM cells. Additionally, we show that CXCR7, the second receptor of stromal-derived-factor-1 (CXCL12), is highly expressed in active MM. Co-culture proved that co-treatment with plerixafor or NOX-A12, the latter inhibiting CXCR4 and CXCR7, functionally interfered with MM chemotaxis to the BM. This led to the resensitization of MM cells to the anti-myeloma agents vorinostat and pomalidomide and both proteasome inhibitors bortezomib and carfilzomib. Within a multicentre phase I/II study, NOX-A12 was tested in combination with bortezomib-dexamethasone, underlining the feasibility of NOX-A12 as an active add-on agent to antagonize myeloma CAM-DR. © 2017 John Wiley & Sons Ltd.

  10. Cochinchina momordica seed suppresses proliferation and metastasis in human lung cancer cells by regulating multiple molecular targets.

    Science.gov (United States)

    Shen, Yang; Meng, Linyi; Sun, Huajun; Zhu, Yizhun; Liu, Hongrui

    2015-01-01

    Cochinchina Momordica Seed, which is the dried ripe seed of Momordica cochinchinensis (Lour.) Spreng, has been used as a mainly anticancer ingredient for many years in China. This study aims at investigating the roles of an ethanol-soluble extract of Cochinchina Momordica Seed (ECMS) in suppressing the proliferation and metastasis of human lung cancer cells, and further elucidating underlying molecular mechanisms. Our researches suggest that ECMS dose-dependently decreased the survival rates of A549 and H1299 cells, and inhibited the migration and invasion in A549 cells. ECMS-induced apoptosis was accompanied by up-regulation of p53, Bax and the down-regulation of Bcl-2, PI-3K/Akt signal pathway, and resulted in the dissipation of mitochondrial membrane potential (ΔΨm) and sequentially activated caspase-3 cascade. Pre-treated with specific inhibitors, LY294002 (PI-3K inhibitor) and BAY11-7082 (NF-κB inhibitor) could enhance the anti-proliferation effects of ECMS on A549 cells. Furthermore, ECMS could increase the level of E-cadherin and decrease of the level of STAT-3 and MMP-2, and scarcely affected the expression of VEGF, and resulted in the inhibition of migration and invasion. Pre-treated with specific inhibitors, WP1066 (STAT-3 inhibitor) and TIMP-2 (MMP-2 inhibitor) could enhance the inhibitory effects of ECMS on migration. In conclusion, the current data demonstrated ECMS inhibited the proliferation of A549 cells by inducing apoptosis, at least partly through the activation of p53 and inactivation of PI-3K/Akt signaling. STAT-3 and MMP-2 pathways may be partly involved in anti-metastasis activities of ECMS. Hence, ECMS might be a promising candidate for the therapy of the non-small cell lung cancer by regulating multiple molecular targets.

  11. Inhalation cancer risk assessment of cobalt metal.

    Science.gov (United States)

    Suh, Mina; Thompson, Chad M; Brorby, Gregory P; Mittal, Liz; Proctor, Deborah M

    2016-08-01

    Cobalt compounds (metal, salts, hard metals, oxides, and alloys) are used widely in various industrial, medical and military applications. Chronic inhalation exposure to cobalt metal and cobalt sulfate has caused lung cancer in rats and mice, as well as systemic tumors in rats. Cobalt compounds are listed as probable or possible human carcinogens by some agencies, and there is a need for quantitative cancer toxicity criteria. The U.S. Environmental Protection Agency has derived a provisional inhalation unit risk (IUR) of 0.009 per μg/m(3) based on a chronic inhalation study of soluble cobalt sulfate heptahydrate; however, a recent 2-year cancer bioassay affords the opportunity to derive IURs specifically for cobalt metal. The mechanistic data support that the carcinogenic mode of action (MOA) is likely to involve oxidative stress, and thus, non-linear/threshold mechanisms. However, the lack of a detailed MOA and use of high, toxic exposure concentrations in the bioassay (≥1.25 mg/m(3)) preclude derivation of a reference concentration (RfC) protective of cancer. Several analyses resulted in an IUR of 0.003 per μg/m(3) for cobalt metal, which is ∼3-fold less potent than the provisional IUR. Future research should focus on establishing the exposure-response for key precursor events to improve cobalt metal risk assessment.

  12. Cobalt particle size effects in catalysis

    NARCIS (Netherlands)

    den Breejen, J.P.

    2010-01-01

    Aim of the work described in this thesis was first to investigate cobalt particle size effects in heterogeneous catalysis. The main focus was to provide a deeper understanding of the origin of the cobalt particle size effects in Fischer-Tropsch (FT) catalysis in which synthesis gas (H2/CO) is conver

  13. Cobalt Complexes as Antiviral and Antibacterial Agents

    Directory of Open Access Journals (Sweden)

    Eddie L. Chang

    2010-05-01

    Full Text Available Metal ion complexes are playing an increasing role in the development of antimicrobials. We review here the antimicrobial properties of cobalt coordination complexes in oxidation state 3+. In addition to reviewing the cobalt complexes containing polydentate donor ligands, we also focus on the antimicrobial activity of the homoleptic [Co(NH36]3+ ion.

  14. Cobalt Complexes as Antiviral and Antibacterial Agents

    OpenAIRE

    Eddie L. Chang; Christa Simmers; D. Andrew Knight

    2010-01-01

    Metal ion complexes are playing an increasing role in the development of antimicrobials. We review here the antimicrobial properties of cobalt coordination complexes in oxidation state 3+. In addition to reviewing the cobalt complexes containing polydentate donor ligands, we also focus on the antimicrobial activity of the homoleptic [Co(NH3)6]3+ ion.

  15. Cobalt particle size effects in catalysis

    NARCIS (Netherlands)

    den Breejen, J.P.

    2010-01-01

    Aim of the work described in this thesis was first to investigate cobalt particle size effects in heterogeneous catalysis. The main focus was to provide a deeper understanding of the origin of the cobalt particle size effects in Fischer-Tropsch (FT) catalysis in which synthesis gas (H2/CO) is

  16. Cobalt Nanocrystals as Starting Materials for Shape Modificationand Assembly Formation

    Energy Technology Data Exchange (ETDEWEB)

    Erdonmez, Can Kerem [Univ. of California, Berkeley, CA (United States)

    2005-01-01

    Surfactant-coated cobalt nanocrystals can be prepared with areasonable degree of control over particle size and shape using athermolytic route. The small crystallite size, enhanced reactivity andtunable interparticle interactions enable use of this material asstarting material for demonstration of achievement of novel structuresusing extremely simple solution-based approaches. In particular,formation of hollow cobalt sulfide nanocrystals upon chemicalmodification and emergence of long-range orientational order upondrying-mediated assembly of cobalt nanocrystals is reportedhere.Colloidal preparation of Co nanocrystals has been well-studied.Here, we emphasize general principles and crystallographic/morphologicalcharacterization of disk-shaped hcp-Co nanocrystals. Use of surfactantmolecules enables achievement of multiple morphologies in one syntheticsystem.Formation of hollow structures upon in-solution sulfidation of Conanocrystals is presented and discussed. A Kirkendall-type effect,involving dominant outward mass transport during formation of the ionicshell material explains the results naturally. It is expected that thisphenomenon will generalize extensively to formation of hollow structuresof an enormous variety of compositions. Detailed study of particlemorphology as a function of reaction conditions suggest phenomena likelyto be generally relevant to use of this approach. A short report ofcrystallographic co-alignment into vortex-like structures is alsoprovided. Our current best picture of this process involves an interplayof packing and magnetic interactions between facetedparticles.

  17. Compliance of a cobalt chromium coronary stent alloy – the COVIS trial

    Directory of Open Access Journals (Sweden)

    Schwinger Robert HG

    2005-10-01

    Full Text Available Abstract Background Cobalt chromium coronary stents are increasingly being used in percutaneous coronary interventions. There are, however, no reliable data about the characteristics of unfolding and visibility of this stent alloy in vivo. The aim of this study is to compare cobalt chromium coronary stents with conventional stainless steel stents using intracoronary ultrasound. Methods Twenty de novo native coronary stenoses ≤ 20 mm in length (target vessel reference diameter ≥ 2.5 and ≤ 4.0 mm received under sequential intracoronary ultrasound either a cobalt chromium stent (Multi-Link Vision®; n = 10 or a stainless steel stent (Multi-Link Zeta®; n = 10. Results For optimal unfolding, the cobalt chromium stent requires a higher balloon deployment pressure (13.90 ± 2.03 atm than the stainless steel stent (11.50 ± 2.12 atm. Furthermore, the achieved target vessel diameter of the cobalt chromium stent (Visibility-Index QCA/IVUS Multi-Link Vision®1.13 / Multi-Link Zeta® 1.04 is more easily overrated by Quantitative Coronary Analysis. Conclusion These data indicate that stent material-specific recommendations for optimal implantation pressure and different stent material with an equal design should both be considered in interpreting QCA-analysis.

  18. SU-E-T-450: Dosimetric Impact of Rotational Error On Multiple-Target Intensity-Modulated Radiosurgery (IMRS) with Single-Isocenter

    Energy Technology Data Exchange (ETDEWEB)

    Jang, S; Huq, M [University of Pittsburgh Medical Center, Pittsburgh, PA (United States)

    2014-06-01

    Purpose: Evaluating the dosimetric-impact on multiple-targets placed away from the isocenter-target with varying rotational-error introduced by initial setup uncertainty and/or intrafractional-movement Methods: CyberKnife-Phantom was scanned with the Intracranial SRS-protocol of 1.25mm slice-thickness and the multiple-targets(GTV) of 1mm and 10mm in diameter were contoured on the Eclipse. PTV for distal-target only was drawn with 1mm expansion around the GTV to find out how much margin is needed to compensate for the rotational-error. The separation between the isocenter-target and distal-target was varied from 3cm to 7cm. RapidArc-based IMRS plans of 16Gy single-fraction were generated with five non-coplanar arcs by using Varian TrueBeam-STx equipped with high resolution MLC leaves of 2.5mm at center and with dose-rate of 1400MU/min at 6MV for flatteringfilter- free(FFF). An identical CT image with intentionally introduced 1° rotational-error was registered with the planning CT image, and the isodose distribution and Dose-Volume-Histogram(DVH) were compared with the original plans. Additionally, the dosimetric-impact of rotational error was evaluated with that of 6X photon energy which was generated with the same target-coverage. Results: For the 1mm-target with 6X-FFF, PTV-coverage(D100) of the distal-target with 1° rotational-error decreased from 1.00 to 0.35 as the separation between isocenter-target and distal-target increased from 3cm to 7cm. However, GTV-coverage(D100) was 1.0 except that of 7cm-separation(0.55), which resulted from the 1mm-margin around the distal-target. For 6X photon, GTV-coverage remained at 1.0 regardless of the separation of targets, showing that the dosimetric-impact of rotational error depends on the degree of rotational-error, separation of targets, and dose distribution around targets. For 10mm-target, PTV-coverage of distaltarget located 3cm-away was better than that of 1mm-target(0.93 versus 0.7) and GTV-coverage was 1

  19. Cobalt Derivatives as Promising Therapeutic Agents

    Science.gov (United States)

    Heffern, Marie C.; Yamamoto, Natsuho; Holbrook, Robert J.; Eckermann, Amanda L.; Meade, Thomas J.

    2013-01-01

    Inorganic complexes are versatile platforms for the development of potent and selective pharmaceutical agents. Cobalt possesses a diverse array of properties that can be manipulated to yield promising drug candidates. Investigations into the mechanism of cobalt therapeutic agents can provide valuable insight into the physicochemical properties that can be harnessed for drug development. This review presents examples of bioactive cobalt complexes with special attention to their mechanisms of action. Specifically, cobalt complexes that elicit biological effects through protein inhibition, modification of drug activity, and bioreductive activation are discussed. Insights gained from these examples reveal features of cobalt that can be rationally tuned to produce therapeutics with high specificity and improved efficacy for the biomolecule or pathway of interest. PMID:23270779

  20. Nickel acts as an adjuvant during cobalt sensitization

    DEFF Research Database (Denmark)

    Bonefeld, Charlotte Menne; Nielsen, Morten Milek; Vennegaard, Marie T.

    2015-01-01

    Metal allergy is the most frequent form of contact allergy with nickel and cobalt being the main culprits. Typically, exposure comes from metal-alloys where nickel and cobalt co-exist. Importantly, very little is known about how co-exposure to nickel and cobalt affects the immune system. We...... investigated these effects by using a recently developed mouse model. Mice were epicutaneously sensitized with i) nickel alone, ii) nickel in the presence of cobalt, iii) cobalt alone, or iv) cobalt in the presence of nickel, and then followed by challenge with either nickel or cobalt alone. We found...... that sensitization with nickel alone induced more local inflammation than cobalt alone as measured by increased ear-swelling. Furthermore, the presence of nickel during sensitization to cobalt led to a stronger challenge response to cobalt as seen by increased ear-swelling and increased B and T cell responses...

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

    Energy Technology Data Exchange (ETDEWEB)

    Krishnan, Kalpagam; Liu, Jeff; Kohli, Kirpal [Department of Physics, BC Cancer Agency, Fraser Valley Centre, 13750 96th Avenue, Surrey, British Columbia V3V 1Z2 (Canada)

    2014-06-15

    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

  2. Development and evaluation of a novel contamination device that targets multiple life-stages of Aedes aegypti

    Science.gov (United States)

    2014-01-01

    Background The increasing global threat of Dengue demands new and easily applicable vector control methods. Ovitraps provide a low-tech and inexpensive means to combat Dengue vectors. Here we describe the development and optimization process of a novel contamination device that targets multiple life-stages of the Aedes aegypti mosquito. Special focus is directed to the diverse array of control agents deployed in this trap, covering adulticidal, larvicidal and autodissemination impacts. Methods Different trap prototypes and their parts are described, including a floater to contaminate alighting gravid mosquitoes. The attractiveness of the trap, different odor lures and floater design were studied using fluorescent powder adhering to mosquito legs and via choice tests. We demonstrate the mosquitocidal impacts of the control agents: a combination of the larvicide pyriproxyfen and the adulticidal fungus Beauveria bassiana. The impact of pyriproxyfen was determined in free-flight dissemination experiments. The effect on larval development inside the trap and in surrounding breeding sites was measured, as well as survival impacts on recaptured adults. Results The developmental process resulted in a design that consists of a black 3 Liter water-filled container with a ring-shaped floater supporting vertically placed gauze dusted with the control agents. On average, 90% of the mosquitoes in the fluorescence experiments made contact with the gauze on the floater. Studies on attractants indicated that a yeast-containing tablet was the most attractive odor lure. Furthermore, the fungus Beauveria bassiana was able to significantly increase mortality of the free-flying adults compared to controls. Dissemination of pyriproxyfen led to >90% larval mortality in alternative breeding sites and 100% larval mortality in the trap itself, against a control mortality of around 5%. Conclusion This ovitrap is a promising new tool in the battle against Dengue. It has proven to be attractive

  3. Direct Laser Cladding of Cobalt on Ti-6Al-4V with a Compositionally Graded Interface

    Directory of Open Access Journals (Sweden)

    Jyotsna Dutta Majumdar

    2011-01-01

    Full Text Available Direct laser cladding of cobalt on Ti-6Al-4V with and without a graded interface has been attempted using a continuous wave CO2 laser. Graded interface is developed by depositing a thin copper layer on Ti-6Al-4V substrate prior to multiple laser cladding of cobalt on it. Presence of copper interlayer was found to suppress the formation of brittle intermetallics of Ti and Co. The effect of process parameters on the microstructures, compositions, and phases of the interface was studied in details. Finally, the mechanical and electrochemical properties of the interface processed under optimum process parameters are reported.

  4. Global gene expression profiling in human lung cells exposed to cobalt

    Directory of Open Access Journals (Sweden)

    Steinmetz Gerard

    2007-06-01

    Full Text Available Abstract Background It has been estimated that more than 1 million workers in the United States are exposed to cobalt. Occupational exposure to 59 Co occurs mainly via inhalation and leads to various lung diseases. Cobalt is classified by the IARC as a possible human carcinogen (group 2B. Although there is evidence for in vivo and in vitro toxicity, the mechanisms of cobalt-induced lung toxicity are not fully known. The purpose of this work was to identify potential signatures of acute cobalt exposure using a toxicogenomic approach. Data analysis focused on some cellular processes and protein targets that are thought to be relevant for carcinogenesis, transport and biomarker research. Results A time course transcriptome analysis was performed on A549 human pulmonary cells, leading to the identification of 85 genes which are repressed or induced in response to soluble 59 Co. A group of 29 of these genes, representing the main biological functions, was assessed by quantitative RT-PCR. The expression profiles of six of them were then tested by quantitative RT-PCR in a time-dependent manner and three modulations were confirmed by Western blotting. The 85 modulated genes include potential cobalt carriers (FBXL2, ZNT1, SLC12A5, tumor suppressors or transcription factors (MAZ, DLG1, MYC, AXL and genes linked to the stress response (UBC, HSPCB, BNIP3L. We also identified nine genes coding for secreted proteins as candidates for biomarker research. Of those, TIMP2 was found to be down-regulated and this modulation was confirmed, in a dose-dependent manner, at protein level in the supernatant of exposed cells. Conclusion Most of these genes have never been described as related to cobalt stress and provide original hypotheses for further study of the effects of this metal ion on human lung epithelial cells. A putative biomarker of cobalt toxicity was identified.

  5. Advances in cobalt complexes as anticancer agents.

    Science.gov (United States)

    Munteanu, Catherine R; Suntharalingam, Kogularamanan

    2015-08-21

    The evolution of resistance to traditional platinum-based anticancer drugs has compelled researchers to investigate the cytostatic properties of alternative transition metal-based compounds. The anticancer potential of cobalt complexes has been extensively studied over the last three decades, and much time has been devoted to understanding their mechanisms of action. This perspective catalogues the development of antiproliferative cobalt complexes, and provides an in depth analysis of their mode of action. Early studies on simple cobalt coordination complexes, Schiff base complexes, and cobalt-carbonyl clusters will be documented. The physiologically relevant redox properties of cobalt will be highlighted and the role this plays in the preparation of hypoxia selective prodrugs and imaging agents will be discussed. The use of cobalt-containing cobalamin as a cancer specific delivery agent for cytotoxins will also be described. The work summarised in this perspective shows that the biochemical and biophysical properties of cobalt-containing compounds can be fine-tuned to produce new generations of anticancer agents with clinically relevant efficacies.

  6. miR-185 plays an anti-hypertrophic role in the heart via multiple targets in the calcium-signaling pathways.

    Directory of Open Access Journals (Sweden)

    Jin Ock Kim

    Full Text Available MicroRNA (miRNA is an endogenous non-coding RNA species that either inhibits RNA translation or promotes degradation of target mRNAs. miRNAs often regulate cellular signaling by targeting multiple genes within the pathways. In the present study, using Gene Set Analysis, a useful bioinformatics tool to identify miRNAs with multiple target genes in the same pathways, we identified miR-185 as a key candidate regulator of cardiac hypertrophy. Using a mouse model, we found that miR-185 was significantly down-regulated in myocardial cells during cardiac hypertrophy induced by transverse aortic constriction. To confirm that miR-185 is an anti-hypertrophic miRNA, genetic manipulation studies such as overexpression and knock-down of miR-185 in neonatal rat ventricular myocytes were conducted. The results showed that up-regulation of miR-185 led to anti-hypertrophic effects, while down-regulation led to pro-hypertrophic effects, suggesting that miR-185 has an anti-hypertrophic role in the heart. Our study further identified Camk2d, Ncx1, and Nfatc3 as direct targets of miR-185. The activity of Nuclear Factor of Activated T-cell (NFAT and calcium/calmodulin-dependent protein kinase II delta (CaMKIIδ was negatively regulated by miR-185 as assessed by NFAT-luciferase activity and western blotting. The expression of phospho-phospholamban (Thr-17, a marker of CaMKIIδ activity, was also significantly reduced by miR-185. In conclusion, miR-185 effectively blocked cardiac hypertrophy signaling through multiple targets, rendering it a potential drug target for diseases such as heart failure.

  7. Evidence of self-affine multiplicity fluctuation of target residues in 84Kr-AgBr interactions at 1.7 AGeV

    Institute of Scientific and Technical Information of China (English)

    ZHANG Dong-Hai; LI Hui-Ling

    2009-01-01

    Self-afline multiplicity scaling is investigated in the framework of a two-dimensional factorial mo-ment methodology using the concept of the Hurst exponent (H). Analyzing the experimental data of target evaporated fragments emitted in84Kr-AgBr interactions at 1.7 AGeV revealed that the best power law behav-ior is exhibited for H = 0.3 indicating a self-affine multiplicity fluctuation pattern. A signal of multifractality is also observed from knowledge of the anomalous fractal dimension dq extracted from the intermittency exponent aq of the anisotropic phase space scenario.

  8. '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

  9. Measurement of multiplicity and momentum spectra in the current and target regions of the Breit frame in Deep Inelastic Scattering at HERA

    CERN Document Server

    Abbiendi, G; Abramowicz, H; Acosta, D; Adamczyk, L; Adamus, M; Ahn, S H; Amelung, C; An Shiz Hong; Anselmo, F; Antonioli, P; Arneodo, M; Bacon, Trevor C; Badgett, W F; Bailey, D C; Bailey, D S; Bamberger, A; Barbagli, G; Bari, G; Barreiro, F; Barret, O; Bashindzhagian, G L; Bashkirov, V; Basile, M; Bauerdick, L A T; Bednarek, B; Behrens, U; Beier, H; Bellagamba, L; Bertolin, A; Bhadra, S; Bienlein, J K; Blaikley, H E; Bohnet, I; Bokel, C; Bornheim, A; Borzemski, P; Boscherini, D; Botje, M; Breitweg, J; Brock, I; Bromley, J T; Brook, N H; Brugnera, R; Brümmer, N; Bruni, A; Bruni, G; Burgard, C; Burow, B D; Bussey, P J; Butterworth, J M; Bylsma, B; Caldwell, A; Capua, M; Cara Romeo, G; Carlin, R; Cartiglia, N; Cashmore, R J; Castellini, G; Catterall, C D; Chapin, D; Chekanov, S; Chwastowski, J; Ciborowski, J; Cifarelli, Luisa; Cindolo, F; Cirio, R; Cloth, P; Coboken, K; Coldewey, C; Cole, J E; Contin, A; Cooper-Sarkar, A M; Coppola, N; Cormack, C; Corradi, M; Corriveau, F; Costa, M; Cottingham, W N; Crittenden, J; Cross, R; D'Agostini, G; Dagan, S; Dal Corso, F; Dardo, M; De Pasquale, S; Deffner, R; Deppe, O; Derrick, M; Deshpande, Abhay A; Desler, K; Devenish, R C E; Dhawan, S; Dolgoshein, B A; Dosselli, U; Doyle, A T; Drews, G; Dulinski, Z; Durkin, L S; Dusini, S; Eckert, M; Edmonds, J K; Eisenberg, Y; Eisenhardt, S; Engelen, J; Epperson, D E; Ermolov, P F; Eskreys, Andrzej; Fagerstroem, C P; Fernández, J P; Ferrero, M I; Figiel, J; Filges, D; Foster, B; Foudas, C; Fox-Murphy, A; Fricke, U; Frisken, W R; Fusayasu, T; Gadaj, T; Galea, R; Gallo, E; García, G; Garfagnini, A; Gendner, N; Gialas, I; Gilmore, J; Ginsburg, C M; Giusti, P; Gladilin, L K; Glasman, C; Göbel, F; Golubkov, Yu A; Göttlicher, P; Grabosch, H J; Graciani, R; Grosse-Knetter, J; Grzelak, G; Haas, T; Hain, W; Hall-Wilton, R; Hamatsu, R; Hanna, D S; Harnew, N; Hart, J C; Hartmann, H; Hartmann, J; Hartner, G F; Hasell, D; Hayes, M E; Heaphy, E A; Heath, G P; Heath, H F; Hebbel, K; Heinloth, K; Heinz, L; Hernández, J M; Heusch, C A; Hilger, E; Hirose, T; Hochman, D; Holm, U; Homma, K; Hong, S J; Howell, G; Hughes, V W; Iacobucci, G; Iannotti, L; Iga, Y; Inuzuka, M; Ishii, T; Jakob, H P; Jelen, K; Jeoung, H Y; Jing, Z; Johnson, K F; Jones, T W; Kananov, S; Kappes, A; Karshon, U; Kasemann, M; Katz, U F; Kcira, D; Kerger, R; Khakzad, M; Khein, L A; Kim, C L; Kim, J Y; Kisielewska, D; Kitamura, S; Klanner, Robert; Klimek, K; Koch, W; Koffeman, E; Kooijman, P; Koop, T; Korotkova, N A; Korzhavina, I A; Kotanski, A; Kötz, U; Kowal, A M; Kowalski, H; Kowalski, T; Krakauer, D; Kreisel, A; Kuze, M; Kuzmin, V A; Labarga, L; Lamberti, L; Lane, J B; Laurenti, G; Lee, J H; Lee, S B; Lee, S W; Levi, G; Levman, G M; Levy, A; Lim, H; Lim, I T; Limentani, S; Lindemann, L; Ling, T Y; Liu, W; Löhr, B; Lohrmann, E; Long, K R; Lopez-Duran Viani, A; Lukina, O Yu; Ma, K J; Maccarrone, G; MacDonald, N; Magill, S; Mallik, U; Margotti, A; Marini, G; Markun, P; Martin, J F; Martínez, M; Maselli, S; Massam, Thomas; Mastroberardino, A; Matsushita, T; Mattingly, M C K; Mattingly, S E K; McCance, G J; McCubbin, N A; McFall, J D; Mellado, B; Menary, S; Meyer, A; Meyer-Larsen, A; Milewski, J; Milite, M; Miller, D B; Monaco, V; Mönig, K; Monteiro, T; Morandin, M; Moritz, M; Murray, W N; Musgrave, B; Nagano, K; Nam, S W; Nania, R; Nigro, A; Nishimura, T; Notz, D; Nowak, R J; Noyes, V A; Nylander, P; Ochs, A; Oh, B Y; Okrasinski, J R; Olkiewicz, K; Orr, R S; Pac, M Y; Padhi, S; Palmonari, F; Park, I H; Park, S K; Parsons, J A; Paul, E; Pavel, N; Pawlak, J M; Pawlak, R; Pelfer, Pier Giovanni; Pellegrino, A; Pelucchi, F; Peroni, C; Pesci, A; Petrucci, M C; Pfeiffer, M; Piccioni, D; Piotrzkowski, K; Poelz, G; Polenz, S; Polini, A; Posocco, M; Prinias, A; Proskuryakov, A S; Przybycien, M B; Puga, J; Quadt, A; Raach, H; Raso, M; Rautenberg, J; Redondo, I; Reeder, D D; Repond, J; Ritz, S; Riveline, M; Rohde, M; Rulikowska-Zarebska, E; Ruske, O; Ruspa, M; Sabetfakhri, A; Sacchi, R; Sadrozinski, H F W; Salehi, H; Sampson, S; Sartorelli, G; Saull, P R B; Savin, A A; Saxon, D H; Schechter, A; Schioppa, M; Schlenstedt, S; Schmidke, W B; Schneekloth, U; Schnurbusch, H; Schwarzer, O; Sciulli, F; Scott, J; Sedgbeer, J K; Seiden, A; Selonke, F; Shah, T P; Shcheglova, L M; Sideris, D; Sievers, M; Simmons, D; Sinclair, L E; Skillicorn, I O; Smalska, B; Smith, W H; Solano, A; Solomin, A N; Son, D; Saint-Laurent, M G; Staiano, A; Stairs, D G; Stanco, L; Stanek, R; Stifutkin, A; Stonjek, S; Straub, P B; Strickland, E; Stroili, R; Susinno, G; Suszycki, L; Sutton, M R; Suzuki, I; Tandler, J; Tapper, A D; Tapper, R J; Tassi, E; Terron, J; Tiecke, H G; Tokushuku, K; Toothacker, W S; Tsurugai, T; Tuning, N; Tymieniecka, T; Umemori, K; Vaiciulis, A W; Velthuis, J J; Verkerke, W; Voci, C; Vossebeld, Joost Herman; Votano, L; Walczak, R; Walker, R; Wang, S M; Waters, D S; Waugh, R; Weber, A; Westphal, D; Whitmore, J J; Wichmann, R; Wick, K; Wieber, H; Wiggers, L; Wildschek, T; Williams, D C; Wills, H H; Wing, M; Wodarczyk, M; Wolf, G; Wölfle, S; Wollmer, U; Wróblewski, A K; Yamada, S; Yamashita, T; Yamauchi, K; Yamazaki, Y; Yoshida, R; Youngman, C; Zajac, J; Zakrzewski, J A; Zamora Garcia, Y; Zawiejski, L; Zetsche, F; Zeuner, W; Zhu, Q; Zichichi, Antonino; Zotkin, S A; De Wolf, E; Del Peso, J; Van Sighem, A

    1999-01-01

    Charged particle production in neutral current deep inelastic scattering (DIS) has been studied using the ZEUS detector.The evolution of the mean multiplicities, scaled momenta and transverse momenta in Q^2 and x for $10 6\\times 10^{-4}$ has been investigated in the current and target fragmentation regions of the Breit frame. Distributions in the target region, using HERA data for the first time, are compared to distributions in the current region. Predictions based on MLLA and LPHD are inconsistent with the data.

  10. Cobalt-mediated radical polymerization of vinyl monomers: investigation of cobalt-coordination

    OpenAIRE

    2009-01-01

    Controlled Radical Polymerization techniques have been developed to obtain well-defined architectures and to control polymer parameters. Among these systems is Cobalt-Mediated Radical Polymerization (CMRP), which is based on the reversible deactivation of the growing radical chains with a cobalt complex, the cobalt (II) bis(acetylacetonate). The interest of this system is not only due to its ability to control the polymerization of very reactive monomers such as vinyl acetate (VAc) and N-viny...

  11. Flotation of cobalt bearing minerals from a mixed copper-cobalt oxidized ore

    OpenAIRE

    2012-01-01

    M.Tech. (Extraction Metallurgy) The techniques for the flotation of mixed copper and cobalt bearing oxide ores using the sulphidization method in order to recover the oxidized copper and cobalt bearing minerals have been well documented by previous researchers. These processes have been successfully implemented in many of the metallurgical plant operations in the Democratic Republic of Congo (DRC). The mixed copper and cobalt oxidised ores from this region present significant chal-lenges t...

  12. Galvanic cells including cobalt-chromium alloys.

    Science.gov (United States)

    Gjerdet, N R

    1980-01-01

    Galvanic cells may be created when dentures made of cobalt-chromium alloys are placed on teeth with metallic restorations. The power of such cells was evaluated in an in vitro galvanic using amalgams, gold alloy, and nickel-chromium alloys. The amalgams and one of the nickel-chromium alloys revealed high corrosion currents when placed in contact with cobalt-chromium alloy, the conventional amalgam showing the highest values. The gold alloy and another nickel-chromium alloy exhibited low corrosion currents and they were noble with respect to cobalt-chromium.

  13. Mechanochemical Preparation of Cobalt Nanoparticles through a Novel Intramolecular Reaction in Cobalt(II) Complexes

    OpenAIRE

    2015-01-01

    A novel solid state reaction involving a series of cobalt(II) hydrazine-azides has been used to prepare metallic cobalt nanoparticles. The reactions of [Co(N2H4)(N3)2], [Co(N2H4)2(N3)2], and [Co(N2H4)(N3)Cl]·H2O via NaOH, KOH as reactants were carried out in the solid state. These complexes undergo an intramolecular two-electron oxidation-reduction reaction at room temperature, producing metallic cobalt nanoparticles (Co1–Co6). The aforementioned complexes contain cobalt(II) that is an oxidiz...

  14. Electrocatalytic miRNA Detection Using Cobalt Porphyrin-Modified Reduced Graphene Oxide

    Directory of Open Access Journals (Sweden)

    Camille De Souza

    2014-06-01

    Full Text Available Metalated porphyrins have been described to bind nucleic acids. Additionally, cobalt porphyrins present catalytic properties towards oxygen reduction. In this work, a carboxylic acid-functionalized cobalt porphyrin was physisorbed on reduced graphene oxide, then immobilized on glassy carbon electrodes. The carboxylic groups were used to covalently graft amino-terminated oligonucleotide probes which are complementary to a short microRNA target. It was shown that the catalytic oxygen electroreduction on cobalt porphyrin increases upon hybridization of miRNA strand (“signal-on” response. Current changes are amplified compared to non-catalytic amperometric system. Apart from oxygen, no added reagent is necessary. A limit of detection in the sub-nanomolar range was reached. This approach has never been described in the literature.

  15. Route planning method for multiple vehicles coordinated target assignment%多机协同与多目标分配任务规划方法

    Institute of Scientific and Technical Information of China (English)

    魏铁涛; 屈香菊

    2009-01-01

    多架飞机攻击多个目标区域是现代作战方式的重要特征,多机协同与多目标分配问题是提高团队作战效能的关键.针对该问题,综合考虑飞机能力差异、协同方式和任务环境的变化,提出多机协同目标分配的任务规划方法.建立了基于能力裕度评价的多机协同目标分配问题的数学模型.对多目标分配问题,通过约束飞机的能力裕度对分配方案进行筛选,保证在战场环境发生改变时任务兵力的完整性.仿真结果表明,采用这种方法得到的目标分配方案,适应任务目标突发性变化的能力更强.%Multiple vehicles coordinated target assignment is the key problem to improve the efficiency of team fighting in the mission of multiple vehicles attacking multiple target regions. A route planning method for this problem was presented with consideration of the differences in vehicle ability, cooperation mode and the abrupt change of the battle field situation. Based on the evaluation of vehicle residual ability, a mathematical model of multiple vehicles coordinated target assignment had been built. The target assignment schemes were chosen by constraints on the vehicle residual ability, then the integrity of the military strength was ensured. The final simulation results of this model show that a stronger adaptability for abrupt change of mission objective can be gained.

  16. Bromodomain inhibition of the transcriptional coactivators CBP/EP300 as a therapeutic strategy to target the IRF4 network in multiple myeloma

    Science.gov (United States)

    Conery, Andrew R; Centore, Richard C; Neiss, Adrianne; Keller, Patricia J; Joshi, Shivangi; Spillane, Kerry L; Sandy, Peter; Hatton, Charlie; Pardo, Eneida; Zawadzke, Laura; Bommi-Reddy, Archana; Gascoigne, Karen E; Bryant, Barbara M; Mertz, Jennifer A; Sims, Robert J

    2016-01-01

    Pharmacological inhibition of chromatin co-regulatory factors represents a clinically validated strategy to modulate oncogenic signaling through selective attenuation of gene expression. Here, we demonstrate that CBP/EP300 bromodomain inhibition preferentially abrogates the viability of multiple myeloma cell lines. Selective targeting of multiple myeloma cell lines through CBP/EP300 bromodomain inhibition is the result of direct transcriptional suppression of the lymphocyte-specific transcription factor IRF4, which is essential for the viability of myeloma cells, and the concomitant repression of the IRF4 target gene c-MYC. Ectopic expression of either IRF4 or MYC antagonizes the phenotypic and transcriptional effects of CBP/EP300 bromodomain inhibition, highlighting the IRF4/MYC axis as a key component of its mechanism of action. These findings suggest that CBP/EP300 bromodomain inhibition represents a viable therapeutic strategy for targeting multiple myeloma and other lymphoid malignancies dependent on the IRF4 network. DOI: http://dx.doi.org/10.7554/eLife.10483.001 PMID:26731516

  17. Automated high multiplex qPCR platform for simultaneous detection and quantification of multiple nucleic acid targets.

    Science.gov (United States)

    Hlousek, Louis; Voronov, Sergey; Diankov, Vesselin; Leblang, Amy B; Wells, Patrick J; Ford, Donna M; Nolling, Jork; Hart, Kyle W; Espinoza, Patricio A; Bristol, Michael R; Tsongalis, Gregory J; Yen-Lieberman, Belinda; Slepnev, Vladimir I; Kong, Lilly I; Lee, Ming-Chou

    2012-05-01

    Quantitative PCR (qPCR) using real-time detection of amplification is limited to a small number of targets within a single reaction. The ICEPlex system, using our scalable target analysis routine (STAR) technology, was developed to provide an automated, high multiplexing PCR solution. ICEPlex combines PCR thermal cycling with dynamic, sequential amplicon separation by capillary electrophoresis and two-color quantitative detection in a single integrated system. In contrast to probe-based qPCR, ICEPlex directly measures amplicon accumulation through incorporation of labeled primers. Three orders of magnitude of optical detection range and at least 7 logs of detectable target concentration range are demonstrated. The system can separate more than 50 amplicons per color channel, ranging from 100 to 500 bases, providing broad multiplexing capabilities for a wide spectrum of nucleic acid amplification applications. ICEPlex can be used for analysis of viral DNA or RNA targets, detection of genetic variants, and for reverse-transcriptase PCR gene expression panels.

  18. 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.

  19. Importance of the HIF pathway in cobalt nanoparticle-induced cytotoxicity and inflammation in human macrophages.

    Science.gov (United States)

    Nyga, Agata; Hart, Alister; Tetley, Teresa D

    2015-01-01

    Recent, unexpected high failure rates of metal-on-metal hip implants have reintroduced the issue of cobalt toxicity. An adverse reaction to cobalt ions and cobalt-induced lung injury occurs during environmental exposure and is now strictly controlled. Currently adverse reaction occurs to cobalt nanoparticles during wear and tear of metal-on-metal hip implants of which the underlying mechanism is not fully understood. The putative role of the hypoxia-inducible factor (HIF) pathway in the mechanism of cobalt nanoparticle (Co-NPs) toxicity was examined using the U937 cell line, human alveolar macrophages and monocyte-derived macrophages. Co-NPs (5-20 μg/ml)-induced cytotoxicity (viability ranged from 75% to cobalt ions (Co(II); up to 350 μM) did not. Co-NPs induced HIF-1α stabilization. Addition of ascorbic acid (100 µM) and glutathione (1 mM) both prevented the increased ROS. However, only treatment with ascorbic acid reduced HIF-1α levels and prevented cell death, indicating that a ROS-independent pathway is involved in Co-NPs-induced cytotoxicity. Replenishing intracellular ascorbate, which is crucial in preventing HIF pathway activation, modified Co-induced HIF target gene expression and the inflammatory response, by decreasing interleukin-1 beta (IL-1β) mRNA and protein expression. Addition of glutathione had no effect on Co-NPs-induced HIF target gene expression or inflammatory response. Thus, Co-NPs induce the HIF pathway by depleting intracellular ascorbate, leading to HIF stabilization and pathway activation. This suggests a strong, ROS-independent role for HIF activation in Co-NPs-induced cytotoxicity and a possible role for HIF in metal-on-metal hip implant pathology.

  20. 40 CFR 415.650 - Applicability; description of the cobalt salts production subcategory.

    Science.gov (United States)

    2010-07-01

    ... cobalt salts production subcategory. 415.650 Section 415.650 Protection of Environment ENVIRONMENTAL... SOURCE CATEGORY Cobalt Salts Production Subcategory § 415.650 Applicability; description of the cobalt... cobalt salts. ...

  1. Characterization of a Cobalt-Tungsten Interconnect

    DEFF Research Database (Denmark)

    Harthøj, Anders; Holt, Tobias; Caspersen, Michael

    2012-01-01

    A ferritic steel interconnect for a solid oxide fuel cell must be coated in order to prevent chromium evaporation from the steel substrate. The Technical University of Denmark and Topsoe Fuel Cell have developed an interconnect coating based on a cobalt-tungsten alloy. The purpose of the coating...... is to act both as a diffusion barrier for chromium and provide better protection against high temperature oxidation than a pure cobalt coating. This work presents a characterization of a cobalt-tungsten alloy coating electrodeposited on the ferritic steel Crofer 22 H which subsequently was oxidized in air...... of oxidation time. The coating had completely oxidized during the 300 h oxidation time. GDOES measurements showed that the tungsten was located in an inner zone in the coating/substrate interface. The outer layer of the coating did not contain any tungsten after oxidation but consisted mainly of cobalt...

  2. Cobalt-related defects in silicon

    Science.gov (United States)

    Gibbons, T. M.; Backlund, D. J.; Estreicher, S. K.

    2017-01-01

    Transition metals from the 3d series are unavoidable and unwanted contaminants in Si-based devices. Cobalt is one of the most poorly understood impurities with incomplete experimental information and few theoretical studies. In this contribution, the properties of interstitial cobalt (Coi) in Si and its interactions with the vacancy, self-interstitial, hydrogen, and substitutional boron are calculated using the first-principles tools. The stable configurations, gap levels, and binding energies are predicted. The activation energy for diffusing Coi is calculated with the nudged-elastic-band method and found to be slightly lower than that of interstitial copper and nickel. The binding energies and gap levels of the substitutional cobalt (Cos) and of the {Cos,H} and {Cos,H,H} complexes are close to the experimental data. The properties of the cobalt-boron pair are calculated.

  3. A Real-Time High Performance Computation Architecture for Multiple Moving Target Tracking Based on Wide-Area Motion Imagery via Cloud and Graphic Processing Units

    Directory of Open Access Journals (Sweden)

    Kui Liu

    2017-02-01

    Full Text Available This paper presents the first attempt at combining Cloud with Graphic Processing Units (GPUs in a complementary manner within the framework of a real-time high performance computation architecture for the application of detecting and tracking multiple moving targets based on Wide Area Motion Imagery (WAMI. More specifically, the GPU and Cloud Moving Target Tracking (GC-MTT system applied a front-end web based server to perform the interaction with Hadoop and highly parallelized computation functions based on the Compute Unified Device Architecture (CUDA©. The introduced multiple moving target detection and tracking method can be extended to other applications such as pedestrian tracking, group tracking, and Patterns of Life (PoL analysis. The cloud and GPUs based computing provides an efficient real-time target recognition and tracking approach as compared to methods when the work flow is applied using only central processing units (CPUs. The simultaneous tracking and recognition results demonstrate that a GC-MTT based approach provides drastically improved tracking with low frame rates over realistic conditions.

  4. A Real-Time High Performance Computation Architecture for Multiple Moving Target Tracking Based on Wide-Area Motion Imagery via Cloud and Graphic Processing Units.

    Science.gov (United States)

    Liu, Kui; Wei, Sixiao; Chen, Zhijiang; Jia, Bin; Chen, Genshe; Ling, Haibin; Sheaff, Carolyn; Blasch, Erik

    2017-02-12

    This paper presents the first attempt at combining Cloud with Graphic Processing Units (GPUs) in a complementary manner within the framework of a real-time high performance computation architecture for the application of detecting and tracking multiple moving targets based on Wide Area Motion Imagery (WAMI). More specifically, the GPU and Cloud Moving Target Tracking (GC-MTT) system applied a front-end web based server to perform the interaction with Hadoop and highly parallelized computation functions based on the Compute Unified Device Architecture (CUDA©). The introduced multiple moving target detection and tracking method can be extended to other applications such as pedestrian tracking, group tracking, and Patterns of Life (PoL) analysis. The cloud and GPUs based computing provides an efficient real-time target recognition and tracking approach as compared to methods when the work flow is applied using only central processing units (CPUs). The simultaneous tracking and recognition results demonstrate that a GC-MTT based approach provides drastically improved tracking with low frame rates over realistic conditions.

  5. A Real-Time High Performance Computation Architecture for Multiple Moving Target Tracking Based on Wide-Area Motion Imagery via Cloud and Graphic Processing Units

    Science.gov (United States)

    Liu, Kui; Wei, Sixiao; Chen, Zhijiang; Jia, Bin; Chen, Genshe; Ling, Haibin; Sheaff, Carolyn; Blasch, Erik

    2017-01-01

    This paper presents the first attempt at combining Cloud with Graphic Processing Units (GPUs) in a complementary manner within the framework of a real-time high performance computation architecture for the application of detecting and tracking multiple moving targets based on Wide Area Motion Imagery (WAMI). More specifically, the GPU and Cloud Moving Target Tracking (GC-MTT) system applied a front-end web based server to perform the interaction with Hadoop and highly parallelized computation functions based on the Compute Unified Device Architecture (CUDA©). The introduced multiple moving target detection and tracking method can be extended to other applications such as pedestrian tracking, group tracking, and Patterns of Life (PoL) analysis. The cloud and GPUs based computing provides an efficient real-time target recognition and tracking approach as compared to methods when the work flow is applied using only central processing units (CPUs). The simultaneous tracking and recognition results demonstrate that a GC-MTT based approach provides drastically improved tracking with low frame rates over realistic conditions. PMID:28208684

  6. MRPrimerW: a tool for rapid design of valid high-quality primers for multiple target qPCR experiments.

    Science.gov (United States)

    Kim, Hyerin; Kang, NaNa; An, KyuHyeon; Koo, JaeHyung; Kim, Min-Soo

    2016-07-08

    Design of high-quality primers for multiple target sequences is essential for qPCR experiments, but is challenging due to the need to consider both homology tests on off-target sequences and the same stringent filtering constraints on the primers. Existing web servers for primer design have major drawbacks, including requiring the use of BLAST-like tools for homology tests, lack of support for ranking of primers, TaqMan probes and simultaneous design of primers against multiple targets. Due to the large-scale computational overhead, the few web servers supporting homology tests use heuristic approaches or perform homology tests within a limited scope. Here, we describe the MRPrimerW, which performs complete homology testing, supports batch design of primers for multi-target qPCR experiments, supports design of TaqMan probes and ranks the resulting primers to return the top-1 best primers to the user. To ensure high accuracy, we adopted the core algorithm of a previously reported MapReduce-based method, MRPrimer, but completely redesigned it to allow users to receive query results quickly in a web interface, without requiring a MapReduce cluster or a long computation. MRPrimerW provides primer design services and a complete set of 341 963 135 in silico validated primers covering 99% of human and mouse genes. Free access: http://MRPrimerW.com. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

  7. Dual Targeting of CDK4 and ARK5 Using a Novel Kinase Inhibitor ON123300 Exerts Potent Anticancer Activity against Multiple Myeloma.

    Science.gov (United States)

    Perumal, Deepak; Kuo, Pei-Yu; Leshchenko, Violetta V; Jiang, Zewei; Divakar, Sai Krishna Athaluri; Cho, Hearn Jay; Chari, Ajai; Brody, Joshua; Reddy, M V Ramana; Zhang, Weijia; Reddy, E Premkumar; Jagannath, Sundar; Parekh, Samir

    2016-03-01

    Multiple myeloma is a fatal plasma cell neoplasm accounting for over 10,000 deaths in the United States each year. Despite new therapies, multiple myeloma remains incurable, and patients ultimately develop drug resistance and succumb to the disease. The response to selective CDK4/6 inhibitors has been modest in multiple myeloma, potentially because of incomplete targeting of other critical myeloma oncogenic kinases. As a substantial number of multiple myeloma cell lines and primary samples were found to express AMPK-related protein kinase 5(ARK5), a member of the AMPK family associated with tumor growth and invasion, we examined whether dual inhibition of CDK4 and ARK5 kinases using ON123300 results in a better therapeutic outcome. Treatment of multiple myeloma cell lines and primary samples with ON123300 in vitro resulted in rapid induction of cell-cycle arrest followed by apoptosis. ON123300-mediated ARK5 inhibition or ARK5-specific siRNAs resulted in the inhibition of the mTOR/S6K pathway and upregulation of the AMPK kinase cascade. AMPK upregulation resulted in increased SIRT1 levels and destabilization of steady-state MYC protein. Furthermore, ON123300 was very effective in inhibiting tumor growth in mouse xenograft assays. In addition, multiple myeloma cells sensitive to ON123300 were found to have a unique genomic signature that can guide the clinical development of ON123300. Our study provides preclinical evidence that ON123300 is unique in simultaneously inhibiting key oncogenic pathways in multiple myeloma and supports further development of ARK5 inhibition as a therapeutic approach in multiple myeloma.

  8. Transport properties of cobalt at low temperatures

    DEFF Research Database (Denmark)

    Radharkishna, P.; Nielsen, Mourits

    1965-01-01

    Measurements are made of electrical resistivity, absolute thermoelectric power, and thermal conductivity of polycrystalline cobalt between 1.2 and 6 K; results are discussed on basis of inter-electronic scattering.......Measurements are made of electrical resistivity, absolute thermoelectric power, and thermal conductivity of polycrystalline cobalt between 1.2 and 6 K; results are discussed on basis of inter-electronic scattering....

  9. Nickel acts as an adjuvant during cobalt sensitization.

    Science.gov (United States)

    Bonefeld, Charlotte Menné; Nielsen, Morten Milek; Vennegaard, Marie T; Johansen, Jeanne Duus; Geisler, Carsten; Thyssen, Jacob P

    2015-03-01

    Metal allergy is the most frequent form of contact allergy with nickel and cobalt being the main culprits. Typically, exposure comes from metal-alloys where nickel and cobalt co-exist. Importantly, very little is known about how co-exposure to nickel and cobalt affects the immune system. We investigated these effects by using a recently developed mouse model. Mice were epicutaneously sensitized with i) nickel alone, ii) nickel in the presence of cobalt, iii) cobalt alone, or iv) cobalt in the presence of nickel, and then followed by challenge with either nickel or cobalt alone. We found that sensitization with nickel alone induced more local inflammation than cobalt alone as measured by increased ear-swelling. Furthermore, the presence of nickel during sensitization to cobalt led to a stronger challenge response to cobalt as seen by increased ear-swelling and increased B and T cell responses in the draining lymph nodes compared to mice sensitized with cobalt alone. In contrast, the presence of cobalt during nickel sensitization only induced an increased CD8(+) T cell proliferation during challenge to nickel. Thus, the presence of nickel during cobalt sensitization potentiated the challenge response against cobalt more than the presence of cobalt during sensitization to nickel affected the challenge response against nickel. Taken together, our study demonstrates that sensitization with a mixture of nickel and cobalt leads to an increased immune response to both nickel and cobalt, especially to cobalt, and furthermore that the adjuvant effect appears to correlate with the inflammatory properties of the allergen. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  10. Intolerability of cobalt salt as erythropoietic agent.

    Science.gov (United States)

    Ebert, Bastian; Jelkmann, Wolfgang

    2014-03-01

    Unfair athletes seek ways to stimulate erythropoiesis, because the mass of haemoglobin is a critical factor in aerobic sports. Here, the potential misuse of cobalt deserves special attention. Cobalt ions (Co(2+) ) stabilize the hypoxia-inducible transcription factors (HIFs) that increase the expression of the erythropoietin (Epo) gene. Co(2+) is orally active, easy to obtain, and inexpensive. However, its intake can bear risks to health. To elaborate this issue, a review of the pertinent literature was retrieved by a search with the keywords 'anaemia', 'cobalt', 'cobalt chloride', 'erythropoiesis', 'erythropoietin', 'Epo', 'side-effects' and 'treatment', amongst others. In earlier years, cobalt chloride was administered at daily doses of 25 to 300 mg for use as an anti-anaemic agent. Co(2+) therapy proved effective in stimulating erythropoiesis in both non-renal and renal anaemia, yet there were also serious medical adverse effects. The intake of inorganic cobalt can cause severe organ damage, concerning primarily the gastrointestinal tract, the thyroid, the heart and the sensory systems. These insights should keep athletes off taking Co(2+) to stimulate erythropoiesis.

  11. [Are the cobalt hip prosthesis dangerous?].

    Science.gov (United States)

    Mistretta, Virginie; Kurth, William; Charlier, Corinne

    The placement of a hip prosthesis is one of the most common orthopedic surgical procedures. Some implants contain metal and are therefore capable of releasing metal particles like cobalt in patients who wear metal prostheses. Cobalt can be responsible of local toxicity (including metallosis, hypersensitivity reaction, and benign tumor) or systemic toxicity (including cardiomyopathy, polycythemia, hypothyroidism, and neurological disorders). To monitor potential toxicity of metal hip prostheses, an annual monitoring of patients implanted is recommended and includes clinical examination, radiological examination and blood cobalt determination. The cobalt concentration in blood allows to estimate the risk of toxicity and to evaluate the performance of the implant. The currently recommended threshold value is equal to 7 µg of cobalt per liter of blood. Our study, conducted on 251 patients over a period of 4 years, has shown that the cobalt concentration average was 2.51 µg/l in blood, with 51 patients having a cobaltemia higher than the threshold of 7 µg/l. © 2016 médecine/sciences – Inserm.

  12. RNA Polymerase I Inhibition with CX-5461 as a Novel Therapeutic Strategy to Target MYC in Multiple Myeloma.

    Science.gov (United States)

    Lee, Hans C; Wang, Hua; Baladandayuthapani, Veerabhadran; Lin, Heather; He, Jin; Jones, Richard J; Kuiatse, Isere; Gu, Dongmin; Wang, Zhiqiang; Ma, Wencai; Lim, John; O'Brien, Sean; Keats, Jonathan; Yang, Jing; Davis, Richard E; Orlowski, Robert Z

    2017-04-01

    Dysregulation of MYC is frequently implicated in both early and late myeloma progression events, yet its therapeutic targeting has remained a challenge. Among key MYC downstream targets is ribosomal biogenesis, enabling increases in protein translational capacity necessary to support the growth and self-renewal programmes of malignant cells. We therefore explored the selective targeting of ribosomal biogenesis with the small molecule RNA polymerase (pol) I inhibitor CX-5461 in myeloma. CX-5461 induced significant growth inhibition in wild-type (WT) and mutant TP53 myeloma cell lines and primary samples, in association with increases in downstream markers of apoptosis. Moreover, Pol I inhibition overcame adhesion-mediated drug resistance and resistance to conventional and novel agents. To probe the TP53-independent mechanisms of CX-5461, gene expression profiling was performed on isogenic TP53 WT and knockout cell lines and revealed reduction of MYC downstream targets. Mechanistic studies confirmed that CX-5461 rapidly suppressed both MYC protein and MYC mRNA levels. The latter was associated with an increased binding of the RNA-induced silencing complex (RISC) subunits TARBP2 and AGO2, the ribosomal protein RPL5, and MYC mRNA, resulting in increased MYC transcript degradation. Collectively, these studies provide a rationale for the clinical translation of CX-5461 as a novel therapeutic approach to target MYC in myeloma.

  13. 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

    , signalling molecules and transcription factors. Subsequent comprehensive in silico analysis identified 24 target genes, of which 22 genes were qPCR validated. We identified seven genes involved in AngII signalling pathways. CONCLUSION: We here report novel insight of an extensive network of molecular......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...... function including regulation of cardiac hypertrophy, heart failure and blood pressure possibly through AT1R signalling. However, the miR-132/212 targets in the heart remain unknown. MATERIALS AND METHODS: To understand the role of these miRNAs in cardiac signalling networks, we undertook comprehensive...

  14. 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

  15. The primate EAE model points at EBV-infected B cells as a preferential therapy target in multiple sclerosis

    NARCIS (Netherlands)

    't Hart, Bert A.; Jagessar, S. Anwar; Haanstra, Krista; Verschoor, Ernst; Laman, Jon D.; Kap, Yolanda S.

    2013-01-01

    The remarkable clinical efficacy of anti-CD20 monoclonal antibodies (mAb) in relapsing-remitting multiple sclerosis points at the critical involvement of B cells in the disease. However, the exact pathogenic contribution of B cells is poorly understood. In this publication we review new data on the

  16. The primate EAE model points at EBV-infected B cells as a preferential therapy target in multiple sclerosis

    NARCIS (Netherlands)

    B.A. 't Hart (Bert); S.A. Jagessar (Anwar); K.G. Haanstra (Krista); E.J. Verschoor (Ernst); J.D. Laman (Jon); Y.S. Kap (Yolanda)

    2013-01-01

    textabstractThe remarkable clinical efficacy of anti-CD20 monoclonal antibodies (mAb) in relapsing-remitting multiple sclerosis points at the critical involvement of B cells in the disease. However, the exact pathogenic contribution of B cells is poorly understood. In this publication we review new

  17. Cobalt release from inexpensive jewellery: has the use of cobalt replaced nickel following regulatory intervention?

    DEFF Research Database (Denmark)

    Thyssen, Jacob Pontoppidan; Jellesen, Morten S; Menné, Torkil

    2010-01-01

    Before the introduction of the EU Nickel Directive, concern was raised that manufacturers of jewellery might turn from the use of nickel to cobalt following the regulatory intervention on nickel exposure.......Before the introduction of the EU Nickel Directive, concern was raised that manufacturers of jewellery might turn from the use of nickel to cobalt following the regulatory intervention on nickel exposure....

  18. Calcium-assisted reduction of cobalt ferrite nanoparticles for nanostructured iron cobalt with enhanced magnetic performance

    Science.gov (United States)

    Qi, B.; Andrew, J. S.; Arnold, D. P.

    2017-03-01

    This paper demonstrates the potential of a calcium-assisted reduction process for synthesizing fine-grain ( 100 nm) metal alloys from metal oxide nanoparticles. To demonstrate the process, an iron cobalt alloy (Fe66Co34) is obtained by hydrogen annealing 7-nm cobalt ferrite (CoFe2O4) nanoparticles in the presence of calcium granules. The calcium serves as a strong reducing agent, promoting the phase transition from cobalt ferrite to a metallic iron cobalt alloy, while maintaining high crystallinity. Magnetic measurements demonstrate the annealing temperature is the dominant factor of tuning the grain size and magnetic properties. Annealing at 700 °C for 1 h maximizes the magnetic saturation, up to 2.4 T (235 emu/g), which matches that of bulk iron cobalt.

  19. Global detection and semi-quantification of Fritillaria alkaloids in Fritillariae Ussuriensis Bulbus by a non-targeted multiple reaction monitoring approach.

    Science.gov (United States)

    Wang, Li; Yao, Zhong Ping; Li, Ping; Chen, Si-Bao; So, Pui-Kin; Shi, Zi-Qi; Hu, Bin; Liu, Li-Fang; Xin, Gui-Zhong

    2016-01-01

    Methods based on triple quadrupole tandem mass spectrometry have been widely used and reported as highly selective and sensitive methods for quantifying substances of herbal medicines. However, most of them were limited to targeted components, due to the difficulties to optimize the multiple reaction monitoring transitions without authentic standards. This study proposed a novel strategy for non-targeted optimization of multiple reaction monitoring method based on the diagnostic ion guided family classifications, tandem mass spectrometry database establishment, and transitions and collision energy screening. Applying this strategy, 59 Fritillaria alkaloids in Fritillariae Ussuriensis Bulbus have been classified, and 51 of these Fritillaria alkaloids were successfully detected by the optimal multiple reaction monitoring method. For semi-quantification, the easy-to-obtain Fritillaria alkaloids of each type, such as verticinone for cevanine type and peimisine for jervine type, were used as the reference standards to calibrate the other Fritillaria alkaloids in the same type. The method was demonstrated a good linearity (R(2) > 0.998) with satisfactory accuracy and precision, and the lower limits of quantification of verticinone and peimisine were estimated to be 0.076 and 0.216 pg, respectively. In addition, the results suggested that the proposed strategy might obtained high quality metabolomics data in discrimination of Fritillaria unibracteata and Fritillaria ussuriensis.

  20. Establishing human heart chromium, cobalt and vanadium concentrations by inductively coupled plasma mass spectrometry.

    Science.gov (United States)

    Day, Patrick L; Eckdahl, Steven J; Maleszewski, Joseph J; Wright, Thomas C; Murray, David L

    2017-05-01

    Chromium, cobalt, and vanadium are used in metallic joint prosthesis. Case studies have associated elevated heart tissue cobalt concentrations with myocardial injury. To document the long term heart metal ion concentrations, a validated inductively coupled plasma mass spectroscopy (ICP-MS) method was needed. The method utilized a closed-vessel microwave digestion system to digest the samples. An ICP-MS method utilizing Universal Cell Technology was used to determine our target analyte concentrations. Accuracy was verified using reference materials. Precision, sensitivity, recovery and linearity studies were performed. This method was used to establish a reference range for a non-implant containing cohort of 80 autopsy human heart tissues RESULTS: This method demonstrated an analytic measurement range of 0.5-100ng/mL for each element. Accuracy was within ±10% of target value for each element. Within-run precision for each element was below 20% CV. The chromium, vanadium and cobalt concentrations (mean±SD) were 0.1523±0.2157μg/g, 0.0094±0.0211μg/g and 0.1039±0.1305μg/g respectively in 80 non-implant containing human heart tissue samples. This method provides acceptable recovery of the chromium, cobalt and vanadium in heart tissue; allowing assessment of the effects of metallic joint prosthesis on myocardial health. Copyright © 2017 Elsevier GmbH. All rights reserved.

  1. 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...... factors for cardiovascular disease is capable of reducing the risk for a combined endpoint of cardiovascular mortality, non-fatal myocardial infarction, non-fatal stroke, coronary interventions, revascularisation to legs, and amputations by 50%....

  2. The Primate EAE Model Points at EBV-Infected B Cells as a Preferential Therapy Target in Multiple Sclerosis

    OpenAIRE

    ‘t Hart, Bert A.; Jagessar, S. Anwar; Haanstra, Krista; Verschoor, Ernst; Laman, Jon D; Kap, Yolanda S.

    2013-01-01

    The remarkable clinical efficacy of anti-CD20 monoclonal antibodies (mAb) in relapsing-remitting multiple sclerosis points at the critical involvement of B cells in the disease. However, the exact pathogenic contribution of B cells is poorly understood. In this publication we review new data on the role of CD20+ B cells in a unique experimental autoimmune encephalomyelitis (EAE) model in common marmosets (Callithrix jacchus), a small-bodied neotropical primate. We will also discuss the releva...

  3. The primate EAE model points at EBV-infected B cells as a preferential therapy target in multiple sclerosis

    OpenAIRE

    Hart, Bert A. 'T; Sunil Anwar Jagessar; Krista eHaanstra; Ernst eVerschoor; Jon eLaman; Yolanda eKap

    2013-01-01

    The remarkable clinical efficacy of anti-CD20 monoclonal antibodies (mAb) in relapsing-remitting multiple sclerosis (RRMS) points at the critical involvement of B cells in the disease. However, the exact pathogenic contribution of B cells is poorly understood. In this publication we review new data on the role of CD20+ B cells in a unique experimental autoimmune encephalomyelitis (EAE) model in common marmosets (Callithrix jacchus), a small-bodied neotropical primate. We will also discuss the...

  4. Polymalic Acid-based Nano Biopolymers for Targeting of Multiple Tumor Markers: An Opportunity for Personalized Medicine?

    Science.gov (United States)

    Ljubimova, Julia Y.; Ding, Hui; Portilla-Arias, Jose; Patil, Rameshwar; Gangalum, Pallavi R.; Chesnokova, Alexandra; Inoue, Satoshi; Rekechenetskiy, Arthur; Nassoura, Tala; Black, Keith L.; Holler, Eggehard

    2014-01-01

    Tumors with similar grade and morphology often respond differently to the same treatment because of variations in molecular profiling. To account for this diversity, personalized medicine is developed for silencing malignancy associated genes. Nano drugs fit these needs by targeting tumor and delivering antisense oligonucleotides for silencing of genes. As drugs for the treatment are often administered repeatedly, absence of toxicity and negligible immune response are desirable. In the example presented here, a nano medicine is synthesized from the biodegradable, non-toxic and non-immunogenic platform polymalic acid by controlled chemical ligation of antisense oligonucleotides and tumor targeting molecules. The synthesis and treatment is exemplified for human Her2-positive breast cancer using an experimental mouse model. The case can be translated towards synthesis and treatment of other tumors. PMID:24962356

  5. Cell-to-cell transmission can overcome multiple donor and target cell barriers imposed on cell-free HIV.

    Science.gov (United States)

    Zhong, Peng; Agosto, Luis M; Ilinskaya, Anna; Dorjbal, Batsukh; Truong, Rosaline; Derse, David; Uchil, Pradeep D; Heidecker, Gisela; Mothes, Walther

    2013-01-01

    Virus transmission can occur either by a cell-free mode through the extracellular space or by cell-to-cell transmission involving direct cell-to-cell contact. The factors that determine whether a virus spreads by either pathway are poorly understood. Here, we assessed the relative contribution of cell-free and cell-to-cell transmission to the spreading of the human immunodeficiency virus (HIV). We demonstrate that HIV can spread by a cell-free pathway if all the steps of the viral replication cycle are efficiently supported in highly permissive cells. However, when the cell-free path was systematically hindered at various steps, HIV transmission became contact-dependent. Cell-to-cell transmission overcame barriers introduced in the donor cell at the level of gene expression and surface retention by the restriction factor tetherin. Moreover, neutralizing antibodies that efficiently inhibit cell-free HIV were less effective against cell-to-cell transmitted virus. HIV cell-to-cell transmission also efficiently infected target T cells that were relatively poorly susceptible to cell-free HIV. Importantly, we demonstrate that the donor and target cell types influence critically the extent by which cell-to-cell transmission can overcome each barrier. Mechanistically, cell-to-cell transmission promoted HIV spread to more cells and infected target cells with a higher proviral content than observed for cell-free virus. Our data demonstrate that the frequently observed contact-dependent spread of HIV is the result of specific features in donor and target cell types, thus offering an explanation for conflicting reports on the extent of cell-to-cell transmission of HIV.

  6. Cell-to-cell transmission can overcome multiple donor and target cell barriers imposed on cell-free HIV.

    Directory of Open Access Journals (Sweden)

    Peng Zhong

    Full Text Available Virus transmission can occur either by a cell-free mode through the extracellular space or by cell-to-cell transmission involving direct cell-to-cell contact. The factors that determine whether a virus spreads by either pathway are poorly understood. Here, we assessed the relative contribution of cell-free and cell-to-cell transmission to the spreading of the human immunodeficiency virus (HIV. We demonstrate that HIV can spread by a cell-free pathway if all the steps of the viral replication cycle are efficiently supported in highly permissive cells. However, when the cell-free path was systematically hindered at various steps, HIV transmission became contact-dependent. Cell-to-cell transmission overcame barriers introduced in the donor cell at the level of gene expression and surface retention by the restriction factor tetherin. Moreover, neutralizing antibodies that efficiently inhibit cell-free HIV were less effective against cell-to-cell transmitted virus. HIV cell-to-cell transmission also efficiently infected target T cells that were relatively poorly susceptible to cell-free HIV. Importantly, we demonstrate that the donor and target cell types influence critically the extent by which cell-to-cell transmission can overcome each barrier. Mechanistically, cell-to-cell transmission promoted HIV spread to more cells and infected target cells with a higher proviral content than observed for cell-free virus. Our data demonstrate that the frequently observed contact-dependent spread of HIV is the result of specific features in donor and target cell types, thus offering an explanation for conflicting reports on the extent of cell-to-cell transmission of HIV.

  7. Characterization of TCF21 Downstream Target Regions Identifies a Transcriptional Network Linking Multiple Independent Coronary Artery Disease Loci.

    Science.gov (United States)

    Sazonova, Olga; Zhao, Yuqi; Nürnberg, Sylvia; Miller, Clint; Pjanic, Milos; Castano, Victor G; Kim, Juyong B; Salfati, Elias L; Kundaje, Anshul B; Bejerano, Gill; Assimes, Themistocles; Yang, Xia; Quertermous, Thomas

    2015-05-01

    To functionally link coronary artery disease (CAD) causal genes identified by genome wide association studies (GWAS), and to investigate the cellular and molecular mechanisms of atherosclerosis, we have used chromatin immunoprecipitation sequencing (ChIP-Seq) with the CAD associated transcription factor TCF21 in human coronary artery smooth muscle cells (HCASMC). Analysis of identified TCF21 target genes for enrichment of molecular and cellular annotation terms identified processes relevant to CAD pathophysiology, including "growth factor binding," "matrix interaction," and "smooth muscle contraction." We characterized the canonical binding sequence for TCF21 as CAGCTG, identified AP-1 binding sites in TCF21 peaks, and by conducting ChIP-Seq for JUN and JUND in HCASMC confirmed that there is significant overlap between TCF21 and AP-1 binding loci in this cell type. Expression quantitative trait variation mapped to target genes of TCF21 was significantly enriched among variants with low P-values in the GWAS analyses, suggesting a possible functional interaction between TCF21 binding and causal variants in other CAD disease loci. Separate enrichment analyses found over-representation of TCF21 target genes among CAD associated genes, and linkage disequilibrium between TCF21 peak variation and that found in GWAS loci, consistent with the hypothesis that TCF21 may affect disease risk through interaction with other disease associated loci. Interestingly, enrichment for TCF21 target genes was also found among other genome wide association phenotypes, including height and inflammatory bowel disease, suggesting a functional profile important for basic cellular processes in non-vascular tissues. Thus, data and analyses presented here suggest that study of GWAS transcription factors may be a highly useful approach to identifying disease gene interactions and thus pathways that may be relevant to complex disease etiology.

  8. Characterization of TCF21 Downstream Target Regions Identifies a Transcriptional Network Linking Multiple Independent Coronary Artery Disease Loci.

    Directory of Open Access Journals (Sweden)

    Olga Sazonova

    2015-05-01

    Full Text Available To functionally link coronary artery disease (CAD causal genes identified by genome wide association studies (GWAS, and to investigate the cellular and molecular mechanisms of atherosclerosis, we have used chromatin immunoprecipitation sequencing (ChIP-Seq with the CAD associated transcription factor TCF21 in human coronary artery smooth muscle cells (HCASMC. Analysis of identified TCF21 target genes for enrichment of molecular and cellular annotation terms identified processes relevant to CAD pathophysiology, including "growth factor binding," "matrix interaction," and "smooth muscle contraction." We characterized the canonical binding sequence for TCF21 as CAGCTG, identified AP-1 binding sites in TCF21 peaks, and by conducting ChIP-Seq for JUN and JUND in HCASMC confirmed that there is significant overlap between TCF21 and AP-1 binding loci in this cell type. Expression quantitative trait variation mapped to target genes of TCF21 was significantly enriched among variants with low P-values in the GWAS analyses, suggesting a possible functional interaction between TCF21 binding and causal variants in other CAD disease loci. Separate enrichment analyses found over-representation of TCF21 target genes among CAD associated genes, and linkage disequilibrium between TCF21 peak variation and that found in GWAS loci, consistent with the hypothesis that TCF21 may affect disease risk through interaction with other disease associated loci. Interestingly, enrichment for TCF21 target genes was also found among other genome wide association phenotypes, including height and inflammatory bowel disease, suggesting a functional profile important for basic cellular processes in non-vascular tissues. Thus, data and analyses presented here suggest that study of GWAS transcription factors may be a highly useful approach to identifying disease gene interactions and thus pathways that may be relevant to complex disease etiology.

  9. Multiple chimeric antigen receptors successfully target chondroitin sulfate proteoglycan 4 in several different cancer histologies and cancer stem cells

    OpenAIRE

    Beard, Rachel E; Zheng, Zhili; Lagisetty, Kiran H.; Burns, William R.; Tran, Eric; Hewitt, Stephen M.; Abate-Daga, Daniel; Rosati, Shannon F.; Fine, Howard A.; Ferrone, Soldano; Rosenberg, Steven A.; Morgan, Richard A.

    2014-01-01

    Background The development of immunotherapy has led to significant progress in the treatment of metastatic cancer, including the development of genetic engineering technologies that redirect lymphocytes to recognize and target a wide variety of tumor antigens. Chimeric antigen receptors (CARs) are hybrid proteins combining antibody recognition domains linked to T cell signaling elements. Clinical trials of CAR-transduced peripheral blood lymphocytes (PBL) have induced remission of both solid ...

  10. Characteristics of Polyaniline Cobalt Supported Catalysts for Epoxidation Reactions

    Directory of Open Access Journals (Sweden)

    Grzegorz Kowalski

    2014-01-01

    Full Text Available A study of polyaniline (PANI doping with various cobalt compounds, that is, cobalt(II chloride, cobalt(II acetate, and cobalt(II salen, is presented. The catalysts were prepared by depositing cobalt compounds onto the polymer surface. PANI powders containing cobalt ions were obtained by one- or two-step method suspending PANI in the following acetonitrile/acetic acid solution or acetonitrile and then acetic acid solution. Moreover different ratios of Co(II : PANI were studied. Catalysts obtained with both methods and at all ratios were investigated using various techniques including AAS and XPS spectroscopy. The optimum conditions for preparation of PANI/Co catalysts were established. Catalytic activity of polyaniline cobalt(II supported catalysts was tested in dec-1-ene epoxidation with molecular oxygen at room temperature. The relationship between the amount of cobalt species, measured with both AAS and XPS techniques, and the activity of PANI-Co catalysts has been established.

  11. Characteristics of Polyaniline Cobalt Supported Catalysts for Epoxidation Reactions

    Science.gov (United States)

    Kowalski, Grzegorz; Pielichowski, Jan; Grzesik, Mirosław

    2014-01-01

    A study of polyaniline (PANI) doping with various cobalt compounds, that is, cobalt(II) chloride, cobalt(II) acetate, and cobalt(II) salen, is presented. The catalysts were prepared by depositing cobalt compounds onto the polymer surface. PANI powders containing cobalt ions were obtained by one- or two-step method suspending PANI in the following acetonitrile/acetic acid solution or acetonitrile and then acetic acid solution. Moreover different ratios of Co(II) : PANI were studied. Catalysts obtained with both methods and at all ratios were investigated using various techniques including AAS and XPS spectroscopy. The optimum conditions for preparation of PANI/Co catalysts were established. Catalytic activity of polyaniline cobalt(II) supported catalysts was tested in dec-1-ene epoxidation with molecular oxygen at room temperature. The relationship between the amount of cobalt species, measured with both AAS and XPS techniques, and the activity of PANI-Co catalysts has been established. PMID:24701183

  12. Cobalt: A vital element in the aircraft engine industry

    Science.gov (United States)

    Stephens, J. R.

    1981-01-01

    Recent trends in the United States consumption of cobalt indicate that superalloys for aircraft engine manufacture require increasing amounts of this strategic element. Superalloys consume a lion's share of total U.S. cobalt usage which was about 16 million pounds in 1980. In excess of 90 percent of the cobalt used in this country was imported, principally from the African countries of Zaire and Zambia. Early studies on the roles of cobalt as an alloying element in high temperature alloys concentrated on the simple Ni-Cr and Nimonic alloy series. The role of cobalt in current complex nickel base superalloys is not well defined and indeed, the need for the high concentration of cobalt in widely used nickel base superalloys is not firmly established. The current cobalt situation is reviewed as it applies to superalloys and the opportunities for research to reduce the consumption of cobalt in the aircraft engine industry are described.

  13. Supported cobalt catalysts - preparation, characterization and reaction studies

    OpenAIRE

    Backman, Leif

    2009-01-01

    The aim of this work was to understand on the effect of thermal treatments, precursor and support on the interaction between the support and cobalt species, and further how the interaction affects the reducibility and dispersion of the catalyst. Silica and alumina supported cobalt catalysts were prepared, characterised and tested for catalytic activity. The catalysts were prepared by gas phase deposition techniques from cobalt acetylacetonate and cobalt carbonyl and by incipient wetness impre...

  14. Effect of cobalt on Escherichia coli metabolism and metalloporphyrin formation

    OpenAIRE

    Majtan, Tomas; Frerman, Frank E.; Kraus, Jan P.

    2010-01-01

    Toxicity in Escherichia coli resulting from high concentrations of cobalt has been explained by competition of cobalt with iron in various metabolic processes including Fe–S cluster assembly, sulfur assimilation, production of free radicals and reduction of free thiol pool. Here we present another aspect of increased cobalt concentrations in the culture medium resulting in the production of cobalt protoporphyrin IX (CoPPIX), which was incorporated into heme proteins including membrane-bound c...

  15. Synthesis of Samarium Cobalt Nanoblades

    Energy Technology Data Exchange (ETDEWEB)

    Darren M. Steele

    2010-08-25

    As new portable particle acceleration technologies become feasible the need for small high performance permanent magnets becomes critical. With particle accelerating cavities of a few microns, the photonic crystal fiber (PCF) candidate demands magnets of comparable size. To address this need, samarium cobalt (SmCo) nanoblades were attempted to be synthesized using the polyol process. Since it is preferable to have blades of 1-2 {micro}m in length, key parameters affecting size and morphology including method of stirring, reaction temperature, reaction time and addition of hydroxide were examined. Nanoparticles consisting of 70-200 nm spherical clusters with a 3-5 nm polyvinylpyrrolidone (PVP) coating were synthesized at 285 C and found to be ferromagnetic. Nanoblades of 25nm in length were observed at the surface of the nanoclusters and appeared to suggest agglomeration was occurring even with PVP employed. Morphology and size were characterized using a transmission electron microscope (TEM). Powder X-Ray Diffraction (XRD) analysis was conducted to determine composition but no supportive evidence for any particular SmCo phase has yet been observed.

  16. C. elegans RNA-binding protein GLD-1 recognizes its multiple targets using sequence, context, and structural information to repress translation.

    Science.gov (United States)

    Doh, Jung H; Jung, Yuchae; Reinke, Valerie; Lee, Min-Ho

    2013-10-01

    Caenorhabditis elegans GLD-1, a maxi-KH motif containing RNA-binding protein, has various functions mainly during female germ cell development, suggesting that it likely controls the expression of a selective group of maternal mRNAs. To gain an insight into how GLD-1 specifically recognizes these mRNA targets, we identified 38 biochemically proven GLD-1 binding regions from multiple mRNA targets that are among over 100 putative targets co-immunoprecipitated with GLD-1. The sequence information of these regions revealed three over-represented and phylogenetically conserved sequence motifs. We found that two of the motifs, one of which is novel, are important for GLD-1 binding in several GLD-1 binding regions but not in other regions. Further analyses indicate that the importance of one of the sequence motifs is dependent on two aspects: (1) surrounding sequence information, likely acting as an accessory feature for GLD-1 to efficiently select the sequence motif and (2) RNA secondary structural environment where the sequence motif resides, which likely provides "binding-site accessibility" for GLD-1 to effectively recognize its targets. Our data suggest some mRNAs recruit GLD-1 by a distinct mechanism, which involves more than one sequence motif that needs to be embedded in the correct context and structural environment.

  17. Attaching lures to multiple-funnel traps targeting saproxylic beetles (Coleoptera) in pine stands: inside or outside funnels?

    Science.gov (United States)

    Miller, Daniel R; Crowe, Christopher M; Barnes, Brittany F; Gandhi, Kamal J K; Duerr, Donald A

    2013-02-01

    We conducted two field trapping experiments with multiple-funnel traps in 2008 and one experiment in 2010 to determine the effects of lure placement (inside or outside funnels) on catches of saproxylic species of beetles (Coleoptera). The experiments were conducted in southern pine (Pinus spp.) stands in central Georgia using combinations of ethanol, alpha-pinene, ipsenol, and ipsdienol lures. We report on a modification to the multiple-funnel trap that allows placement of large lures inside the confines of the funnels with minimal blockage. In general, catches of five species of common longhorn beetles (Cerambycidae), two species of regeneration weevils (Curculionidae), four species of bark beetles (Curculionidae: Scolytinae), and seven species of beetle predators and ectoparasites (Cleridae, Histeridae, Tenebrionidae, Trogossitidae, and Zopheridae) were higher in funnel traps with lures attached inside the funnels than in those with lures attached outside of the funnels. Catches of the remaining species were unaffected by lure placement. In no instance were catches of any species lower in funnel traps with lures attached inside the funnels than in those with lures attached outside of the funnels. For most species, catches in modified funnel traps with ethanol, alpha-pinene, ipsenol, and ipsdienol lures attached inside funnels were comparable with those in cross-vane panel traps.

  18. 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.

  19. Palladium-cobalt particles as oxygen-reduction electrocatalysts

    Science.gov (United States)

    Adzic, Radoslav; Huang, Tao

    2009-12-15

    The present invention relates to palladium-cobalt particles useful as oxygen-reducing electrocatalysts. The invention also relates to oxygen-reducing cathodes and fuel cells containing these palladium-cobalt particles. The invention additionally relates to methods for the production of electrical energy by using the palladium-cobalt particles of the invention.

  20. 21 CFR 73.1015 - Chromium-cobalt-aluminum oxide.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 1 2010-04-01 2010-04-01 false Chromium-cobalt-aluminum oxide. 73.1015 Section 73... LISTING OF COLOR ADDITIVES EXEMPT FROM CERTIFICATION Drugs § 73.1015 Chromium-cobalt-aluminum oxide. (a) Identity. The color additive chromium-cobalt-aluminum oxide is a blue-green pigment obtained by calcining a...

  1. A combination algorithm of Chaos optimization and genetic algorithm and its application in maneuvering multiple targets data association

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    The most important problem in targets tracking is data association which may be represented as a sort of constraint combinational optimization problem. Chaos optimization and adaptive genetic algorithm were used to deal with the problem of multi-targets data association separately. Based on the analysis of the limitation of chaos optimization and genetic algorithm, a new chaos genetic optimization combination algorithm was presented. This new algorithm first applied the "rough" search of chaos optimization to initialize the population of GA, then optimized the population by real-coded adaptive GA. In this way, GA can not only jump out of the "trap" of local optimal results easily but also increase the rate of convergence. And the new method can also avoid the complexity and time-consumed limitation of conventional way. The simulation results show that the combination algorithm can obtain higher correct association percent and the effect of association is obviously superior to chaos optimization or genetic algorithm separately. This method has better convergence property as well as time property than the conventional ones.

  2. Anchoring Intrinsically Disordered Proteins to Multiple Targets: Lessons from N-Terminus of the p53 Protein

    Directory of Open Access Journals (Sweden)

    Yongqi Huang

    2011-02-01

    Full Text Available Anchor residues, which are deeply buried upon binding, play an important role in protein–protein interactions by providing recognition specificity and facilitating the binding kinetics. Up to now, studies on anchor residues have been focused mainly on ordered proteins. In this study, we investigated anchor residues in intrinsically disordered proteins (IDPs which are flexible in the free state. We identified the anchor residues of the N-terminus of the p53 protein (Glu17–Asn29, abbreviated as p53N which are involved in binding with two different targets (MDM2 and Taz2, and analyzed their side chain conformations in the unbound states. The anchor residues in the unbound p53N were found to frequently sample conformations similar to those observed in the bound complexes (i.e., Phe19, Trp23, and Leu26 in the p53N-MDM2 complex, and Leu22 in the p53N-Taz2 complex. We argue that the bound-like conformations of the anchor residues in the unbound state are important for controlling the specific interactions between IDPs and their targets. Further, we propose a mechanism to account for the binding promiscuity of IDPs in terms of anchor residues and molecular recognition features (MoRFs.

  3. Improving Theory of Mind in Schizophrenia by Targeting Cognition and Metacognition with Computerized Cognitive Remediation: A Multiple Case Study.

    Science.gov (United States)

    Thibaudeau, Élisabeth; Cellard, Caroline; Reeder, Clare; Wykes, Til; Ivers, Hans; Maziade, Michel; Lavoie, Marie-Audrey; Pothier, William; Achim, Amélie M

    2017-01-01

    Schizophrenia is associated with deficits in theory of mind (ToM) (i.e., the ability to infer the mental states of others) and cognition. Associations have often been reported between cognition and ToM, and ToM mediates the relationship between impaired cognition and impaired functioning in schizophrenia. Given that cognitive deficits could act as a limiting factor for ToM, this study investigated whether a cognitive remediation therapy (CRT) that targets nonsocial cognition and metacognition could improve ToM in schizophrenia. Four men with schizophrenia received CRT. Assessments of ToM, cognition, and metacognition were conducted at baseline and posttreatment as well as three months and 1 year later. Two patients reached a significant improvement in ToM immediately after treatment whereas at three months after treatment all four cases reached a significant improvement, which was maintained through 1 year after treatment for all three cases that remained in the study. Improvements in ToM were accompanied by significant improvements in the most severely impaired cognitive functions at baseline or by improvements in metacognition. This study establishes that a CRT program that does not explicitly target social abilities can improve ToM.

  4. Improving Theory of Mind in Schizophrenia by Targeting Cognition and Metacognition with Computerized Cognitive Remediation: A Multiple Case Study

    Directory of Open Access Journals (Sweden)

    Élisabeth Thibaudeau

    2017-01-01

    Full Text Available Schizophrenia is associated with deficits in theory of mind (ToM (i.e., the ability to infer the mental states of others and cognition. Associations have often been reported between cognition and ToM, and ToM mediates the relationship between impaired cognition and impaired functioning in schizophrenia. Given that cognitive deficits could act as a limiting factor for ToM, this study investigated whether a cognitive remediation therapy (CRT that targets nonsocial cognition and metacognition could improve ToM in schizophrenia. Four men with schizophrenia received CRT. Assessments of ToM, cognition, and metacognition were conducted at baseline and posttreatment as well as three months and 1 year later. Two patients reached a significant improvement in ToM immediately after treatment whereas at three months after treatment all four cases reached a significant improvement, which was maintained through 1 year after treatment for all three cases that remained in the study. Improvements in ToM were accompanied by significant improvements in the most severely impaired cognitive functions at baseline or by improvements in metacognition. This study establishes that a CRT program that does not explicitly target social abilities can improve ToM.

  5. Improving Theory of Mind in Schizophrenia by Targeting Cognition and Metacognition with Computerized Cognitive Remediation: A Multiple Case Study

    Science.gov (United States)

    Cellard, Caroline; Reeder, Clare; Wykes, Til; Ivers, Hans; Maziade, Michel; Lavoie, Marie-Audrey; Pothier, William

    2017-01-01

    Schizophrenia is associated with deficits in theory of mind (ToM) (i.e., the ability to infer the mental states of others) and cognition. Associations have often been reported between cognition and ToM, and ToM mediates the relationship between impaired cognition and impaired functioning in schizophrenia. Given that cognitive deficits could act as a limiting factor for ToM, this study investigated whether a cognitive remediation therapy (CRT) that targets nonsocial cognition and metacognition could improve ToM in schizophrenia. Four men with schizophrenia received CRT. Assessments of ToM, cognition, and metacognition were conducted at baseline and posttreatment as well as three months and 1 year later. Two patients reached a significant improvement in ToM immediately after treatment whereas at three months after treatment all four cases reached a significant improvement, which was maintained through 1 year after treatment for all three cases that remained in the study. Improvements in ToM were accompanied by significant improvements in the most severely impaired cognitive functions at baseline or by improvements in metacognition. This study establishes that a CRT program that does not explicitly target social abilities can improve ToM. PMID:28246557

  6. Genome-wide identification of transcriptional targets of RORA reveals direct regulation of multiple genes associated with autism spectrum disorder.

    Science.gov (United States)

    Sarachana, Tewarit; Hu, Valerie W

    2013-05-22

    We have recently identified the nuclear hormone receptor RORA (retinoic acid-related orphan receptor-alpha) as a novel candidate gene for autism spectrum disorder (ASD). Our independent cohort studies have consistently demonstrated the reduction of RORA transcript and/or protein levels in blood-derived lymphoblasts as well as in the postmortem prefrontal cortex and cerebellum of individuals with ASD. Moreover, we have also shown that RORA has the potential to be under negative and positive regulation by androgen and estrogen, respectively, suggesting the possibility that RORA may contribute to the male bias of ASD. However, little is known about transcriptional targets of this nuclear receptor, particularly in humans. Here we identify transcriptional targets of RORA in human neuronal cells on a genome-wide level using chromatin immunoprecipitation (ChIP) with an anti-RORA antibody followed by whole-genome promoter array (chip) analysis. Selected potential targets of RORA were then validated by an independent ChIP followed by quantitative PCR analysis. To further demonstrate that reduced RORA expression results in reduced transcription of RORA targets, we determined the expression levels of the selected transcriptional targets in RORA-deficient human neuronal cells, as well as in postmortem brain tissues from individuals with ASD who exhibit reduced RORA expression. The ChIP-on-chip analysis reveals that RORA1, a major isoform of RORA protein in human brain, can be recruited to as many as 2,764 genomic locations corresponding to promoter regions of 2,544 genes across the human genome. Gene ontology analysis of this dataset of genes that are potentially directly regulated by RORA1 reveals statistically significant enrichment in biological functions negatively impacted in individuals with ASD, including neuronal differentiation, adhesion and survival, synaptogenesis, synaptic transmission and plasticity, and axonogenesis, as well as higher level functions such as

  7. Multiple Targets on the Gln3 Transcription Activator Are Cumulatively Required for Control of Its Cytoplasmic Sequestration

    Directory of Open Access Journals (Sweden)

    Rajendra Rai

    2016-05-01

    Full Text Available A remarkable characteristic of nutritional homeostatic mechanisms is the breadth of metabolite concentrations to which they respond, and the resolution of those responses; adequate but rarely excessive. Two general ways of achieving such exquisite control are known: stoichiometric mechanisms where increasing metabolite concentrations elicit proportionally increasing responses, and the actions of multiple independent metabolic signals that cumulatively generate appropriately measured responses. Intracellular localization of the nitrogen-responsive transcription activator, Gln3, responds to four distinct nitrogen environments: nitrogen limitation or short-term starvation, i.e., nitrogen catabolite repression (NCR, long-term starvation, glutamine starvation, and rapamycin inhibition of mTorC1. We have previously identified unique sites in Gln3 required for rapamycin-responsiveness, and Gln3-mTor1 interaction. Alteration of the latter results in loss of about 50% of cytoplasmic Gln3 sequestration. However, except for the Ure2-binding domain, no evidence exists for a Gln3 site responsible for the remaining cytoplasmic Gln3-Myc13 sequestration in nitrogen excess. Here, we identify a serine/threonine-rich (Gln3477–493 region required for effective cytoplasmic Gln3-Myc13 sequestration in excess nitrogen. Substitutions of alanine but not aspartate for serines in this peptide partially abolish cytoplasmic Gln3 sequestration. Importantly, these alterations have no effect on the responses of Gln3-Myc13 to rapamycin, methionine sulfoximine, or limiting nitrogen. However, cytoplasmic Gln3-Myc13 sequestration is additively, and almost completely, abolished when mutations in the Gln3-Tor1 interaction site are combined with those in Gln3477–493 cytoplasmic sequestration site. These findings clearly demonstrate that multiple individual regulatory pathways cumulatively control cytoplasmic Gln3 sequestration.

  8. Electrochemical formation of holmium-cobalt alloys

    Institute of Scientific and Technical Information of China (English)

    2003-01-01

    The electrochemical formation processes of holmium-cobalt alloys on cobalt cathode in molten HoC13-KC1 wereinvestigated by cyclic voltammetry and open current potential-time curve after potentiostatic electrolysis. The structure ofHo-Co alloys' films deposited on cobalt electrode by potentiostatic electrolysis was characterized by X-ray diffraction. Thestandard Gibbs free energies of formation for the intermetallic compounds of Ho and Co were determined. The diffusioncoefficient and diffusion activation energy of Ho atom in the alloy phase were calculated to be 10-10-10-11 cm2/s and 96.0kJ/mol, respectively, from the current-time curve at potential step.

  9. Total quality management of cobalt-60 sources

    Science.gov (United States)

    Malkoske, G. R.

    1999-06-01

    Total Quality Management of Cobalt-60 sources by a supplier requires a life cycle approach to source management. This covers various aspects, including design, manufacturing, installation, field inspection, source surveillance and return of cobalt-60 sources at the end of their useful life. The Total Quality Management approach demonstrates a strong industry commitment to the beneficial use of gamma technology for industrial irradiation applications in both developed nations and in those nations who are developing their infrastructure and techniques for the beneficial use of this technology. MDS Nordion continues to demonstrate its support and commitment to the industry by developing and implementing state-of-the-art standards for the safe use of cobalt-60 sources.

  10. Controlled cobalt doping in biogenic magnetite nanoparticles

    Science.gov (United States)

    Byrne, J. M.; Coker, V. S.; Moise, S.; Wincott, P. L.; Vaughan, D. J.; Tuna, F.; Arenholz, E.; van der Laan, G.; Pattrick, R. A. D.; Lloyd, J. R.; Telling, N. D.

    2013-01-01

    Cobalt-doped magnetite (CoxFe3 −xO4) nanoparticles have been produced through the microbial reduction of cobalt–iron oxyhydroxide by the bacterium Geobacter sulfurreducens. The materials produced, as measured by superconducting quantum interference device magnetometry, X-ray magnetic circular dichroism, Mössbauer spectroscopy, etc., show dramatic increases in coercivity with increasing cobalt content without a major decrease in overall saturation magnetization. Structural and magnetization analyses reveal a reduction in particle size to less than 4 nm at the highest Co content, combined with an increase in the effective anisotropy of the magnetic nanoparticles. The potential use of these biogenic nanoparticles in aqueous suspensions for magnetic hyperthermia applications is demonstrated. Further analysis of the distribution of cations within the ferrite spinel indicates that the cobalt is predominantly incorporated in octahedral coordination, achieved by the substitution of Fe2+ site with Co2+, with up to 17 per cent Co substituted into tetrahedral sites. PMID:23594814

  11. Perfluorinated cobalt phthalocyanine effectively catalyzes water electrooxidation

    KAUST Repository

    Morlanes, Natalia Sanchez

    2014-12-08

    Efficient electrocatalysis of water oxidation under mild conditions at neutral pH was achieved by a fluorinated cobalt phthalocyanine immobilized on fluorine-doped tin oxide (FTO) surfaces with an onset potential at 1.7 V vs. RHE. Spectroscopic, electrochemical, and inhibition studies indicate that phthalocyanine molecular species are the operational active sites. Neither free cobalt ions nor heterogeneous cobalt oxide particles or films were observed. During long-term controlled-potential electrolysis at 2 V vs. RHE (phosphate buffer, pH 7), electrocatalytic water oxidation was sustained for at least 8 h (TON ≈ 1.0 × 105), producing about 4 μmol O2 h-1 cm-2 with a turnover frequency (TOF) of about 3.6 s-1 and no measurable catalyst degradation.

  12. 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.

  13. 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.

  14. Cobalt and marine redox evolution

    Science.gov (United States)

    Swanner, Elizabeth D.; Planavsky, Noah J.; Lalonde, Stefan V.; Robbins, Leslie J.; Bekker, Andrey; Rouxel, Olivier J.; Saito, Mak A.; Kappler, Andreas; Mojzsis, Stephen J.; Konhauser, Kurt O.

    2014-03-01

    Cobalt (Co) is a bio-essential trace element and limiting nutrient in some regions of the modern oceans. It has been proposed that Co was more abundant in poorly ventilated Precambrian oceans based on the greater utilization of Co by anaerobic microbes relative to plants and animals. However, there are few empirical or theoretical constraints on the history of seawater Co concentrations. Herein, we present a survey of authigenic Co in marine sediments (iron formations, authigenic pyrite and bulk euxinic shales) with the goal of tracking changes in the marine Co reservoir throughout Earth's history. We further provide an overview of the modern marine Co cycle, which we use as a platform to evaluate how changes in the redox state of Earth's surface were likely to have affected marine Co concentrations. Based on sedimentary Co contents and our understanding of marine Co sources and sinks, we propose that from ca. 2.8 to 1.8 Ga the large volume of hydrothermal fluids circulating through abundant submarine ultramafic rocks along with a predominantly anoxic ocean with a low capacity for Co burial resulted in a large dissolved marine Co reservoir. We tentatively propose that there was a decrease in marine Co concentrations after ca. 1.8 Ga resulting from waning hydrothermal Co sources and the expansion of sulfide Co burial flux. Changes in the Co reservoir due to deep-water ventilation in the Neoproterozoic, if they occurred, are not resolvable with the current dataset. Rather, Co enrichments in Phanerozoic euxinic shales deposited during ocean anoxic events (OAE) indicate Co mobilization from expanded anoxic sediments and enhanced hydrothermal sources. A new record of marine Co concentrations provides a platform from which we can reevaluate the role that environmental Co concentrations played in shaping biological Co utilization throughout Earth's history.

  15. Sonochemical Synthesis of Cobalt Ferrite Nanoparticles

    Directory of Open Access Journals (Sweden)

    Partha P. Goswami

    2013-01-01

    Full Text Available Cobalt ferrite being a hard magnetic material with high coercivity and moderate magnetization has found wide-spread applications. In this paper, we have reported the sonochemical synthesis of cobalt ferrite nanoparticles using metal acetate precursors. The ferrite synthesis occurs in three steps (hydrolysis of acetates, oxidation of hydroxides, and in situ microcalcination of metal oxides that are facilitated by physical and chemical effects of cavitation bubbles. The physical and magnetic properties of the ferrite nano-particles thus synthesized have been found to be comparable with those reported in the literature using other synthesis techniques.

  16. Cation distributions on rapidly solidified cobalt ferrite

    Science.gov (United States)

    De Guire, Mark R.; Kalonji, Gretchen; O'Handley, Robert C.

    1990-01-01

    The cation distributions in two rapidly solidified cobalt ferrites have been determined using Moessbauer spectroscopy at 4.2 K in an 8-T magnetic field. The samples were obtained by gas atomization of a Co0-Fe2O3-P2O5 melt. The degree of cation disorder in both cases was greater than is obtainable by cooling unmelted cobalt ferrite. The more rapidly cooled sample exhibited a smaller departure from the equilibrium cation distribution than did the more slowly cooled sample. This result is explained on the basis of two competing effects of rapid solidification: high cooling rate of the solid, and large undercooling.

  17. Cation distributions on rapidly solidified cobalt ferrite

    Science.gov (United States)

    De Guire, Mark R.; Kalonji, Gretchen; O'Handley, Robert C.

    1990-01-01

    The cation distributions in two rapidly solidified cobalt ferrites have been determined using Moessbauer spectroscopy at 4.2 K in an 8-T magnetic field. The samples were obtained by gas atomization of a Co0-Fe2O3-P2O5 melt. The degree of cation disorder in both cases was greater than is obtainable by cooling unmelted cobalt ferrite. The more rapidly cooled sample exhibited a smaller departure from the equilibrium cation distribution than did the more slowly cooled sample. This result is explained on the basis of two competing effects of rapid solidification: high cooling rate of the solid, and large undercooling.

  18. Kinome-wide RNAi studies in human multiple myeloma identify vulnerable kinase targets, including a lymphoid-restricted kinase, GRK6

    Science.gov (United States)

    Zhu, Yuan Xiao; Schmidt, Jessica; Yin, Hongwei; Shi, Chang-Xin; Que, Qiang; Basu, Gargi; Azorsa, David; Perkins, Louise M.; Braggio, Esteban; Fonseca, Rafael; Bergsagel, P. Leif; Mousses, Spyro; Stewart, A. Keith

    2010-01-01

    A paucity of validated kinase targets in human multiple myeloma has delayed clinical deployment of kinase inhibitors in treatment strategies. We therefore conducted a kinome-wide small interfering RNA (siRNA) lethality study in myeloma tumor lines bearing common t(4;14), t(14;16), and t(11;14) translocations to identify critically vulnerable kinases in myeloma tumor cells without regard to preconceived mechanistic notions. Fifteen kinases were repeatedly vulnerable in myeloma cells, including AKT1, AK3L1, AURKA, AURKB, CDC2L1, CDK5R2, FES, FLT4, GAK, GRK6, HK1, PKN1, PLK1, SMG1, and TNK2. Whereas several kinases (PLK1, HK1) were equally vulnerable in epithelial cells, others and particularly G protein–coupled receptor kinase, GRK6, appeared selectively vulnerable in myeloma. GRK6 inhibition was lethal to 6 of 7 myeloma tumor lines but was tolerated in 7 of 7 human cell lines. GRK6 exhibits lymphoid-restricted expression, and from coimmunoprecipitation studies we demonstrate that expression in myeloma cells is regulated via direct association with the heat shock protein 90 (HSP90) chaperone. GRK6 silencing causes suppression of signal transducer and activator of transcription 3 (STAT3) phosphorylation associated with reduction in MCL1 levels and phosphorylation, illustrating a potent mechanism for the cytotoxicity of GRK6 inhibition in multiple myeloma (MM) tumor cells. As mice that lack GRK6 are healthy, inhibition of GRK6 represents a uniquely targeted novel therapeutic strategy in human multiple myeloma. PMID:19996089

  19. UCAV协同攻击多目标的任务分配技术研究%Research on Task Allocation for UCAVs Cooperatively Attacking Multiple Targets

    Institute of Scientific and Technical Information of China (English)

    程聪; 吴庆宪; 刘敏; 陈谋

    2012-01-01

    Task allocation model based on single objective function can not provide more useful information for the fire-control decision makers. In order to make up the deficiency, the wastage cost of UCAV (Unmanned Combat Aerial Vehicle) and damage value of target are treated as two optimization objective functions of the task allocation for Multi-UCAV cooperatively attacking multiple targets, and a new task allocation model is established. Based on the optimization model, an improved NSGA-Ⅱ(Nondominated Sorting Genetic Algorithm Ⅱ) with elitist strategy is adopted for searching the Pareto optimal solutions of the task allocation of cooperative attacking multiple targets for Multi-UCAV. The decision makers select the best task allocation scheme according to their preferences. Simulation results demonstrate that the algorithm of task allocation is convergent and effective.%为解决单目标函数构建的任务分配模型不能给火控决策者提供更多有用信息的问题,将无人机(UCAV:Unmanned Combat Aerial Vehicle)损耗代价和目标毁伤价值作为UCAV协同攻击任务分配的两个目标函数,对其进行多目标优化,建立新型任务分配模型.在此基础上,采用一种改进带精英策略的快速非支配排序遗传算法(NSGA-Ⅱ:Nondominated Sorting Genetic Algorithm Ⅱ)进行求解,得到多目标协同攻击任务分配的Pareto最优解集,然后根据决策者的偏好选取最佳的任务分配方案.最后通过仿真算例,验证了该算法的收敛性及有效性.

  20. A new cobalt oxide electrodeposit bath for solar absorbers

    Energy Technology Data Exchange (ETDEWEB)

    Barrera, Enrique [Departmento de IPH, Area de Ingenieria en Recursos Energeticos, Universidad Autonoma Metropolitana - Iztapalapa, Mexico D.F. (Mexico); Gonzalez, Ignacio [Departmento de Quimica, Area de Electroquimica, Universidad Autonoma Metropolitana - Iztapalapa, Mexico D.F. (Mexico); Viveros, Tomas [Departmento de IPH, Area de Ingenieria Quimica, Universidad Autonoma Metropolitana - Iztapalapa, Mexico D.F. (Mexico)

    1997-12-19

    A study was carried out in a Hull cell in order to optimize the deposition conditions of cobalt oxide (black cobalt) in an electrolytic bath, which uses cobalt nitrate for direct obtention of black cobalt. Thermal stability of the material was surveyed on several samples of black cobalt prepared on stainless-steel with a thickness of approximately of 2.5 {mu}m. It was found that the optical properties change, in respect to the initial values, with time of treatment until an equilibrium is reached. This equilibrium depends on the substrate and the temperature of the treatment used

  1. Effect of cobalt on the primary productivity of Spirulina platensis

    Energy Technology Data Exchange (ETDEWEB)

    Sharma, R.M.; Panigrahi, S.; Azeez, P.A.

    1987-10-01

    Cobalt, a micronutrient for biological organisms, is a metal of wide use. Main sources of Co to the environment are combustion of fossil fuels, smelters, cobalt processing facilities, sewage and industrial wastes. Atomic power plants and nuclear weapon detonations form an important source of radioisotopes of this metal to the environment. Cobalt has been included in the 14 toxic trace elements of critical importance from the point of view of environmental pollution and health hazards. Cobalt deficiency leads to diseases like stunted growth. At toxic level, Co inhibits heme biosynthesis and enzyme activities. The present study reports the effect of cobalt on biomass productivity of blue-green alga Spirulina platensis.

  2. Telescoping ore targets by geochemical exploration at multiple scales in Eastern Yunnan Pt geochemical province,southwestern China

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    Platinum has been one of the highly needed mineral resources in China.The geochemical exploration at two survey scales was applied in telescoping ore targets for the first time in Eastern Yunnan Pt geochemical province that was delineated using Pt data from flood plain sediments with extra-low sampling density.Our study was based on the delineations and assessments of both regional and local Pt anomalies using the Pt data by analyzing with C-OES the composite samples with two sampling densities.The composite samples were obtained by recomposing at two sampling densities the original stream sediment samples collected by the National Geochemical Mapping Project.Semivariograms were used to quantitatively describe the variability of Pt anomalies and further analyze the factors controlling the variability.Pt resource potentials of both the regional Pt anomalies and the local Pt anomalies in the study area were estimated based on the geochemical block methods,respectively.It comes to the conclusions as follows.(1) From the regional to local Pt anomaly,the factors controlling their variability from the deep seated faults-basalts turn into the basalts-branch faults,which suggest that Semivariograms could identify the geological factors controlling the variability of the Pt anomalies identified by the Pt data from the stream sediments with different sampling densities.(2) There exist two types of Pt anomalies in the study area.One is those displaying at sampling densities,and its average Pt concentration significantly increases with sampling density increasing.The other is getting weaker and/or disappears with sampling density increasing.This shows that TOTGEMS could gradu-ally eliminate non-ore anomalies and keep ore anomalies.(3) The average Pt concentration of the local Pt anomaly blocks delineated using Pt data from stream sediments with sampling density of one composite per 16 km2 is twice as much as that of the regional Pt anomaly blocks delineated using Pt data from

  3. Ultra-thin strut cobalt chromium bare metal stent usage in a complex real-world setting. (SOLSTICE Registry)

    NARCIS (Netherlands)

    Suttorp, M. J.; Stella, P. R.; Dens, J.; McKenzie, J. M.; Park, K. S.; Frambach, P.

    2015-01-01

    Aim To report clinical follow-up at 6 months after implantation of the ultra-thin strut cobalt chromiumSolarFlex stent in a real-world setting. Methods and results Patients (n=240) with single or multiple vessel coronary artery disease undergoing percutaneous coronary intervention (PCI) at four site

  4. 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.

  5. The small-molecule VEGF receptor inhibitor pazopanib (GW786034B) targets both tumor and endothelial cells in multiple myeloma.

    Science.gov (United States)

    Podar, Klaus; Tonon, Giovanni; Sattler, Martin; Tai, Yu-Tzu; Legouill, Steven; Yasui, Hiroshi; Ishitsuka, Kenji; Kumar, Shaji; Kumar, Rakesh; Pandite, Lini N; Hideshima, Teru; Chauhan, Dharminder; Anderson, Kenneth C

    2006-12-19

    A critical role for vascular endothelial factor (VEGF) has been demonstrated in multiple myeloma (MM) pathogenesis. Here, we characterized the effect of the small-molecule VEGF receptor inhibitor pazopanib on MM cells in the bone marrow milieu. Pazopanib inhibits VEGF-triggered signaling pathways in both tumor and endothelial cells, thereby blocking in vitro MM cell growth, survival, and migration, and inhibits VEGF-induced up-regulation of adhesion molecules on both endothelial and tumor cells, thereby abrogating endothelial cell-MM cell binding and associated cell proliferation. We show that pazopanib is the first-in-class VEGF receptor inhibitor to inhibit in vivo tumor cell growth associated with increased MM cell apoptosis, decreased angiogenesis, and prolonged survival in a mouse xenograft model of human MM. Low-dose pazopanib demonstrates synergistic cytotoxicity with conventional (melphalan) and novel (bortezomib and immunomodulatory drugs) therapies. Finally, gene expression and signaling network analysis show transcriptional changes of several cancer-related genes, in particular c-Myc. Using siRNA, we confirm the role of c-Myc in VEGF production and secretion, as well as angiogenesis. These preclinical studies provide the rationale for clinical evaluation of pazopanib, alone and in combination with conventional and novel therapies, to increase efficacy, overcome drug resistance, reduce toxicity, and improve patient outcome in MM.

  6. Targeting the insulin-like growth factor-1 receptor to overcome bortezomib resistance in preclinical models of multiple myeloma.

    Science.gov (United States)

    Kuhn, Deborah J; Berkova, Zuzana; Jones, Richard J; Woessner, Richard; Bjorklund, Chad C; Ma, Wencai; Davis, R Eric; Lin, Pei; Wang, Hua; Madden, Timothy L; Wei, Caimiao; Baladandayuthapani, Veerabhadran; Wang, Michael; Thomas, Sheeba K; Shah, Jatin J; Weber, Donna M; Orlowski, Robert Z

    2012-10-18

    Proteasome inhibition with bortezomib is a validated approach to the treatment of multiple myeloma, but drug resistance often emerges and limits its utility in the retreatment setting. To begin to identify some of the mechanisms involved, we developed bortezomib-resistant myeloma cell lines that, unlike previously reported models, showed no β5 subunit mutations. Instead, up-regulation of the insulin-like growth factor (IGF)-1 axis was identified, with increased autocrine and paracrine secretion of IGF-1, leading to increased activation of the IGF-1 receptor (IGF-1R). Exogenous IGF-1 reduced cellular sensitivity to bortezomib, whereas pharmacologic or small hairpin RNA-mediated IGF-1R suppression enhanced bortezomib sensitivity in cell lines and patient samples. In vitro studies with OSI-906, a clinically relevant dual IGF-1R and insulin receptor inhibitor, showed it acted synergistically with bortezomib, and potently resensitized bortezomib-resistant cell lines and patient samples to bortezomib. Importantly, OSI-906 in combination with bortezomib also overcame bortezomib resistance in an in vivo model of myeloma. Taken together, these data support the hypothesis that signaling through the IGF-1/IGF-1R axis contributes to acquired bortezomib resistance, and provide a rationale for combining bortezomib with IGF-1R inhibitors like OSI-906 to overcome or possibly prevent the emergence of bortezomib-refractory disease in the clinic.

  7. Retroviral Replicating Vectors Deliver Cytosine Deaminase Leading to Targeted 5-Fluorouracil-Mediated Cytotoxicity in Multiple Human Cancer Types.

    Science.gov (United States)

    Twitty, Chris G; Diago, Oscar R; Hogan, Daniel J; Burrascano, Cindy; Ibanez, Carlos E; Jolly, Douglas J; Ostertag, Derek

    2016-02-01

    Toca 511 is a modified retroviral replicating vector based on Moloney γ-retrovirus with an amphotropic envelope. As an investigational cancer treatment, Toca 511 preferentially infects cancer cells without direct cell lysis and encodes an enhanced yeast cytosine deaminase that converts the antifungal drug 5-fluorocytosine to the anticancer drug, 5-fluorouracil. A panel of established human cancer cell lines, derived from glioblastoma, colon, and breast cancer tissue, was used to evaluate parameters critical for effective anticancer activity. Gene transfer, cytosine deaminase production, conversion of 5-fluorocytosine to 5-fluorouracil, and subsequent cell killing occurred in all lines tested. We observed >50% infection within 25 days in all lines and 5-fluorocytosine LD50 values between 0.02 and 6 μg/ml. Although we did not identify a small number of key criteria, these studies do provide a straightforward approach to rapidly gauge the probability of a Toca 511 and 5-fluorocytosine treatment effect in various cancer indications: a single MTS assay of maximally infected cancer cell lines to determine 5-fluorocytosine LD50. The data suggest that, although there can be variation in susceptibility to Toca 511 and 5-fluorocytosine because of multiple mechanistic factors, this therapy may be applicable to a broad range of cancer types and individuals.

  8. The primate EAE model points at EBV-infected B cells as a preferential therapy target in multiple sclerosis

    Directory of Open Access Journals (Sweden)

    Bert A 'T Hart

    2013-06-01

    Full Text Available The remarkable clinical efficacy of anti-CD20 monoclonal antibodies (mAb in relapsing-remitting multiple sclerosis (RRMS points at the critical involvement of B cells in the disease. However, the exact pathogenic contribution of B cells is poorly understood. In this publication we review new data on the role of CD20+ B cells in a unique experimental autoimmune encephalomyelitis (EAE model in common marmosets (Callithrix jacchus, a small-bodied neotropical primate. We will also discuss the relevance of these data for MS.Different from rodent EAE models, but similar to MS, disease progression in marmosets can develop independent of autoantibodies. Progressive disease is mediated by MHC class Ib (Caja-E restricted cytotoxic T cells, which are activated by γ-herpesvirus-infected B cells and cause widespread demyelination of cortical grey matter. B-cell directed monoclonal antibody therapies (anti-CD20 versus anti-BLyS and anti-APRIL have a variable effect on EAE progression, which we found associated with variable depletion of the EBV-like γ-herpesvirus CalHV3 from lymphoid organs. These findings support an important pathogenic role of CD20+ B cell in MS, especially of the subset infected with Epstein Barr virus (EBV.

  9. The Primate EAE Model Points at EBV-Infected B Cells as a Preferential Therapy Target in Multiple Sclerosis.

    Science.gov (United States)

    't Hart, Bert A; Jagessar, S Anwar; Haanstra, Krista; Verschoor, Ernst; Laman, Jon D; Kap, Yolanda S

    2013-01-01

    The remarkable clinical efficacy of anti-CD20 monoclonal antibodies (mAb) in relapsing-remitting multiple sclerosis points at the critical involvement of B cells in the disease. However, the exact pathogenic contribution of B cells is poorly understood. In this publication we review new data on the role of CD20+ B cells in a unique experimental autoimmune encephalomyelitis (EAE) model in common marmosets (Callithrix jacchus), a small-bodied neotropical primate. We will also discuss the relevance of these data for MS. Different from rodent EAE models, but similar to MS, disease progression in marmosets can develop independent of autoantibodies. Progressive disease is mediated by MHC class Ib (Caja-E) restricted cytotoxic T cells, which are activated by γ-herpesvirus-infected B cells and cause widespread demyelination of cortical gray matter. B-cell directed monoclonal antibody therapies (anti-CD20 versus anti-BLyS and anti-APRIL) have a variable effect on EAE progression, which we found associated with variable depletion of the Epstein Barr virus (EBV)-like γ-herpesvirus CalHV3 from lymphoid organs. These findings support an important pathogenic role of CD20+ B cell in MS, especially of the subset infected with EBV.

  10. Efficient downregulation of multiple mRNA targets with a single shRNA-expressing lentiviral vector.

    Science.gov (United States)

    Chumakov, Stepan P; Kravchenko, Julia E; Prassolov, Vladimir S; Frolova, Elena I; Chumakov, Peter M

    2010-05-01

    Gene silencing based on RNA interference is widely used in fundamental research and in practical applications. However, a commonly incomplete functional suppression represents a serious drawback of this technology. We describe a series of lentiviral vectors each containing a single or multiple shRNA-expression cassette(s) driven by a RNA-polymerase III specific promoter and localized within the 3'-LTR of the lentiviral DNA backbone. The vectors also contain an antibiotic-resistance gene that allows positive selection of recipient cells. The combined expression of three different shRNAs specific to a single mRNA was shown to improve dramatically the level of mRNA inhibition, while the use of three different RNA-polymerase III specific promoters avoids the loss of shRNA-expression cassettes through the homologous recombination. The vector system was used for successful simultaneous suppression of three related SESN1, SESN2 and SESN3 genes, which suggests its particular value for testing phenotypes of functionally redundant genes.

  11. Algorithm of reentry ballistic target tracking based on multiple model%基于多模型的再入弹道目标跟踪算法

    Institute of Scientific and Technical Information of China (English)

    钮俊清; 任清安; 刘军伟

    2015-01-01

    In the anti-missile defense system, the tracking and identification of reentry ballistic target are the critical problems. However, the traditional method could not applied to the tracking for different types of reentry ballistic targets and identification of the true or fake warhead. This paper focus on an algorithm of reentry ballistic target tracking based on multiple model. In this scheme, the multiple model configuration is used for tracking the different types of reentry ballistic targets, thus improving the tracking accuracy effectively, and meanwhile, possessing the fast rate of convergence and better precision for the ballistic coefficient estimation. Simulation results indicate that this proposed method improves the precision of target tracking greatly, compared to the conventional EKF algorithm, and has especially a higher precision for the ballistic coefficient estimation and a certain capability of identifying the true or fake warhead and robust tracking performance.%再入弹道导弹目标的跟踪和识别是反导防御体系中最关键的问题。针对传统的跟踪方法不能适用于不同类型的再入弹道目标的跟踪和真假弹头的识别问题,提出一种基于多模型的再入段弹道目标跟踪算法。该算法采用多模型的结构,适用于跟踪不同类型的再入弹道目标,可有效地提高跟踪精度;同时对于弹道系数的估计具有很快的收敛速度和较好的估计精度。仿真结果表明,与传统的EKF算法相比较,本文算法大幅提高了目标跟踪的精度,特别在弹道系数估计上精度较高,具有一定的识别真假弹头的能力和鲁棒的跟踪性能。

  12. Preparation of surface multiple-coated polylactide acid drug-loaded nanoparticles for intranasal delivery and evaluation on its brain-targeting efficiency.

    Science.gov (United States)

    Bian, Junjie; Yuan, Zhixiang; Chen, Xiaoliang; Gao, Yuan; Xu, Chaoqun; Shi, Jianyou

    2016-01-01

    To prepare a mixture of multiple-coated aniracetam nasal polylactic-acid nanoparticles (M-C-PLA-NP) and evaluate its stability preliminarily in vitro and its brain-targeting efficiency in vivo. The solvent diffusion-evaporation combined with magnetic stirring method has been chosen for the entrapment of aniracetam. The M-C-PLA-NP was characterized with respect to its morphology, particle size, size distribution and aniracetam entrapment efficiency. The in vivo distribution was studied in male SD rats after an intranasal administration. In vitro release of M-C-PLA-NP showed two components with an initial rapid release due to the surface-associated drug and followed by a slower exponential release of aniracetam, which was dissolved in the core. The AUC0 → 30 min of M-C-PLA-NP in brain tissues resulted in a 5.19-fold increase compared with aniracetam solution. The ratios of AUC in brain to that in other tissues obtained after nasal application of M-C-PLA-NP were significantly higher than those of aniracetam solution. Therefore, it can be concluded that M-C-PLA-NP demonstrated its potential on increasing the brain-targeting efficiency of drugs and will be used as novel brain-targeting agent for nasal drug delivery.

  13. A Rapid In Situ Colorimetric Assay for Cobalt Detection by the Naked Eye

    Directory of Open Access Journals (Sweden)

    Sung-Min Kang

    2016-05-01

    Full Text Available A simple, rapid, and convenient colorimetric chemosensor of a specific target toward the end user is still required for on-site detection and real-time monitoring applications. In this study, we developed a rapid in situ colorimetric assay for cobalt detection using the naked eye. Interestingly, a yellow to light orange visual color transition was observed within 3 s when a Chrysoidine G (CG chemosensor was exposed to cobalt. Surprisingly, the CG chemosensor had great selectivity toward cobalt without any interference of other metal ions. Under optimized conditions, a lower detection limit of 0.1 ppm via a spectrophotometer and a visual detection limit of 2 ppm with a linear range from 0.4 to 1 ppm (R2 = 0.97 were determined. Moreover, the CG chemosensor is reversible and maintains its functionality after treatment with chelating agents. In conclusion, we show the superior capabilities of the CG chemosensor, which has the potential to provide extremely facile handling, high sensitivity, and a fast response time for applications of on-site detection to real-time cobalt monitoring for the general public.

  14. Open-Loop Flight Testing of COBALT Navigation and Sensor Technologies for Precise Soft Landing

    Science.gov (United States)

    Carson, John M., III; Restrepo, Caroline I.; Seubert, Carl R.; Amzajerdian, Farzin; Pierrottet, Diego F.; Collins, Steven M.; O'Neal, Travis V.; Stelling, Richard

    2017-01-01

    An open-loop flight test campaign of the NASA COBALT (CoOperative Blending of Autonomous Landing Technologies) payload was conducted onboard the Masten Xodiac suborbital rocket testbed. The payload integrates two complementary sensor technologies that together provide a spacecraft with knowledge during planetary descent and landing to precisely navigate and softly touchdown in close proximity to targeted surface locations. The two technologies are the Navigation Doppler Lidar (NDL), for high-precision velocity and range measurements, and the Lander Vision System (LVS) for map-relative state esti- mates. A specialized navigation filter running onboard COBALT fuses the NDL and LVS data in real time to produce a very precise Terrain Relative Navigation (TRN) solution that is suitable for future, autonomous planetary landing systems that require precise and soft landing capabilities. During the open-loop flight campaign, the COBALT payload acquired measurements and generated a precise navigation solution, but the Xodiac vehicle planned and executed its maneuvers based on an independent, GPS-based navigation solution. This minimized the risk to the vehicle during the integration and testing of the new navigation sensing technologies within the COBALT payload.

  15. MALT1--a universal soldier: multiple strategies to ensure NF-κB activation and target gene expression.

    Science.gov (United States)

    Afonina, Inna S; Elton, Lynn; Carpentier, Isabelle; Beyaert, Rudi

    2015-09-01

    The paracaspase MALT1 (mucosa associated lymphoid tissue lymphoma translocation gene 1) is an intracellular signaling protein that plays a key role in innate and adaptive immunity. It is essential for nuclear factor κB (NF-κB) activation and proinflammatory gene expression downstream of several cell surface receptors. MALT1 has been most studied in the context of T-cell receptor-induced NF-κB signaling, supporting T-cell activation and proliferation. In addition, MALT1 hyperactivation is associated with specific subtypes of B-cell lymphoma, where it controls tumor cell proliferation and survival. For a long time, MALT1 was believed to function solely as a scaffold protein, providing a platform for the assembly of other NF-κB signaling proteins. However, this view changed dramatically when MALT1 was found to have proteolytic activity that further fine-tunes signaling. MALT1 proteolytic activity is essential for T-cell activation and lymphomagenesis, suggesting that MALT1 is a promising therapeutic target for the treatment of autoimmune diseases and distinct lymphoma entities. However, interference with MALT1 activity may pose a dangerous threat to the normal functioning of the immune system and should be evaluated with great care. Here we discuss the current knowledge on the scaffold and protease functions of MALT1, including an overview of its substrates and the functional implications of their cleavage.

  16. Miniprimer PCR assay targeting multiple genes: a new rapid and reliable tool for genotyping Pantoea stewartii subsp. stewartii.

    Science.gov (United States)

    Xu, R; Chen, Q; Robleh Djama, Z; Tambong, J T

    2010-02-01

    Development of a 'miniprimer' PCR assay for genotyping Pantoea stewartii subsp. stewartii, the causal agent of the Stewart's bacterial wilt on maize. Four 10-nucleotide (10-nt) 'miniprimer' sets were designed and evaluated in the presence of Titanium Taq DNA polymerase. Under optimal reaction conditions, the miniprimer pair Uni-BacF-10/Uni-BacR-10 reproducibly generated identical banding patterns among 10 strains of P. stewartii subsp. stewartii, different patterns from strains of P. stewartii subsp. indologenes, other Panteoa species, Clavibacter michiganensis, Pectobacterium spp., Pseudomonas spp. and other bacterial species. The amplicons of Pantoea stewartii subsp. stewartii were cloned and sequenced to identify genes or DNA fragments that are targeted by the miniprimer PCR assay. Of the 14 'clone types' identified, sequences of a 1.23-kb fragment had a 99.8% similarity to part of the Pantoea stewartii zeaxanthin diglucoside biosynthetic operon (AY166713). Other dominant cloned fragments included a 411-bp amplicon that exhibited 99.8% similarity to the psaU gene (syn:ysaU; GQ249669), a type III protein-secretion system complex of P. stewartii subsp. stewartii strain DC283, and a 548-bp fragment showed 63% homology to the Asp/Glu racemase encoding gene in Erwinia tasmaniensis strain ET1/99. The miniprimer PCR assay reported here is highly discriminatory and reproducible in genotyping Pantoea stewartii subsp. stewartii. This miniprimer PCR assay could be a new reliable and rapid tool for fingerprinting the Stewart's wilt pathogen of maize.

  17. Protective effects of Zn(2+) against cobalt nanoparticles and cobalt chloride-induced cytotoxicity of RAW 264.7cells via ROS pathway.

    Science.gov (United States)

    Zhu, Hai; Liu, Yake; Hong, Hongxiang; Wang, Wei; Liu, Fan

    2017-04-29

    Recent concerns have emerged surrounding the toxicity that cobalt may represent when used in MOM implants. Owing to corrosion and wear of MOM implants, the subsequent released cobalt nanoparticles (CoNPs) or Co ions (Co(2+)) can cause adverse reactions, such as the generation of pseudotumors, extensive necrosis, early osteolysis, and implants failure. The present study confirmed that CoNPs and Co(2+) can induce dose- and time-dependent cytotoxicity with increasing reactive oxygen species (ROS) levels. Additionally, using metallothionein (MT), a heavy metal-binding protein, the present study assessed the protective effects of Zn(2+) against CoNPs and Co(2+)-induced cytotoxicity of RAW 264.7 cells through ROS pathway. Further studies are needed to explore the underlying protective mechanisms in vitro. However, the current findings indicate that the ROS pathway may be a potential target for therapeutic interventions. Copyright © 2017. Published by Elsevier Inc.

  18. 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.

  19. Ursolic acid simultaneously targets multiple signaling pathways to suppress proliferation and induce apoptosis in colon cancer cells.

    Directory of Open Access Journals (Sweden)

    Jingshu Wang

    Full Text Available Ursolic acid (UA, a natural pentacyclic triterpenoid carboxylic acid distributed in medical herbs, exerts antitumor effects and is emerging as a promising compound for cancer prevention and therapy, but its excise mechanisms of action in colon cancer cells remains largely unknown. Here, we identified the molecular mechanisms by which UA inhibited cell proliferation and induced apoptosis in human colon cancer SW480 and LoVo cells. Treatment with UA led to significant inhibitions in cell viability and clone formation and changes in cell morphology and spreading. UA also suppressed colon cancer cell migration by inhibiting MMP9 and upregulating CDH1 expression. Further studies showed that UA inhibited the phosphorylation of Akt and ERK proteins. Pretreatment with an Akt or ERK-specific inhibitor considerably abrogated the proliferation inhibition by UA. UA also significantly inhibited colon cancer cell COX-2 expression and PGE2 production. Pretreatment with a COX-2 inhibitor (celecoxib abrogated the UA-induced cell proliferation. Moreover, we found that UA effectively promoted NF-κB and p300 translocation from cell nuclei to cytoplasm, and attenuated the p300-mediated acetylation of NF-κB and CREB2. Pretreatment with a p300 inhibitor (roscovitine abrogated the UA-induced cell proliferation, which is reversed by p300 overexpression. Furthermore, UA treatment induced colon cancer cell apoptosis, increased the cleavage of PARP, caspase-3 and 9, and trigged the release of cytochrome c from mitochondrial inter-membrane space into cytosol. These results indicate that UA inhibits cell proliferation and induces apoptosis in colon cancer cells through simultaneous modulation of the multiple signaling pathways such as MMP9/CDH1, Akt/ERK, COX-2/PGE2, p300/NF-κB/CREB2, and cytochrome c/caspase pathways.

  20. An Ehrlichia chaffeensis tandem repeat protein interacts with multiple host targets involved in cell signaling, transcriptional regulation, and vesicle trafficking.

    Science.gov (United States)

    Wakeel, Abdul; Kuriakose, Jeeba A; McBride, Jere W

    2009-05-01

    Ehrlichia chaffeensis is an obligately intracellular bacterium that exhibits tropism for mononuclear phagocytes forming cytoplasmic membrane-bound microcolonies called morulae. To survive and replicate within phagocytes, E. chaffeensis exploits the host cell by modulating a number of host cell processes, but the ehrlichial effector proteins involved are unknown. In this study, we determined that p47, a secreted, differentially expressed, tandem repeat (TR) protein, interacts with multiple host proteins associated with cell signaling, transcriptional regulation, and vesicle trafficking. Yeast two-hybrid analysis revealed that p47 interacts with polycomb group ring finger 5 (PCGF5) protein, Src protein tyrosine kinase FYN (FYN), protein tyrosine phosphatase non-receptor type 2 (PTPN2), and adenylate cyclase-associated protein 1 (CAP1). p47 interaction with these proteins was further confirmed by coimmunoprecipitation assays and colocalization in HeLa cells transfected with p47-green fluorescent fusion protein (AcGFP1-p47). Moreover, confocal microscopy demonstrated p47-expressing dense-cored (DC) ehrlichiae colocalized with PCGF5, FYN, PTPN2, and CAP1. An amino-terminally truncated form of p47 containing TRs interacted only with PCGF5 and not with FYN, PTPN2, and CAP1, indicating differences in p47 domains that are involved in these interactions. These results demonstrate that p47 is involved in a complex network of interactions involving numerous host cell proteins. Furthermore, this study provides a new insight into the molecular and functional distinction of DC ehrlichiae, as well as the effector proteins involved in facilitating ehrlichial survival in mononuclear phagocytes.

  1. A targeted spatial-temporal proteomics approach implicates multiple cellular trafficking pathways in human cytomegalovirus virion maturation.

    Science.gov (United States)

    Moorman, Nathaniel J; Sharon-Friling, Ronit; Shenk, Thomas; Cristea, Ileana M

    2010-05-01

    The assembly of infectious virus particles is a complex event. For human cytomegalovirus (HCMV) this process requires the coordinated expression and localization of at least 60 viral proteins that comprise the infectious virion. To gain insight into the mechanisms controlling this process, we identified protein binding partners for two viral proteins, pUL99 (also termed pp28) and pUL32 (pp150), which are essential for HCMV virion assembly. We utilized HCMV strains expressing pUL99 or pUL32 carboxyl-terminal green fluorescent protein fusion proteins from their native location in the HCMV genome. Based on the presence of ubiquitin in the pUL99 immunoisolation, we discovered that this viral protein colocalizes with components of the cellular endosomal sorting complex required for transport (ESCRT) pathway during the initial stages of virion assembly. We identified the nucleocapsid and a large number of tegument proteins as pUL32 binding partners, suggesting that events controlling trafficking of this viral protein in the cytoplasm regulate nucleocapsid/tegument maturation. The finding that pUL32, but not pUL99, associates with clathrin led to the discovery that the two viral proteins traffic via distinct pathways during the early stages of virion assembly. Additional investigation revealed that the majority of the major viral glycoprotein gB initially resides in a third compartment. Analysis of the trafficking of these three viral proteins throughout a time course of virion assembly allowed us to visualize their merger into a single large cytoplasmic structure during the late stages of viral assembly. We propose a model of HCMV virion maturation in which multiple components of the virion traffic independently of one another before merging.

  2. Cobalt reduction of NSSS valve hardfacings for ALARA

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Joo Hak; Lee, Sang Sub [Korea Atomic Energy Research Institute, Taejon (Korea, Republic of)

    1994-07-01

    This report informs NSSS designer that replacement of materials is one of the major means of ALARA implementation, and describes that NSSS valves with high-cobalt hardfacing are significant contributors to post-shutdown radiation fields caused by activation of cobalt-59 to cobalt-60. Generic procedures for implementing cobalt reduction programs for valves are presented. Discussions are presented of the general and specific design requirements for valve hardfacing in nuclear service. The nuclear safety issues involved with changing valve hardfacing materials are discussed. The common methods used to deposit hardfacing materials are described together with an explanation of the wear measurements. Wear resistance, corrosion resistance, friction coefficient, and mechanical properties of candidate hardfacing alloys are given. World-wide nuclear utility experience with cobalt-free hardfacing alloys is described. The use of low-cobalt or cobalt-free alloys in other nuclear plant components is described. 17 figs., 38 tabs., 18 refs. (Author).

  3. Association between cobalt allergy and dermatitis caused by leather articles

    DEFF Research Database (Denmark)

    Bregnbak, David; Thyssen, Jacob P; Zachariae, Claus

    2015-01-01

    BACKGROUND: Cobalt is a strong skin sensitizer and a prevalent contact allergen. Recent studies have recognized exposure to leather articles as a potential cause of cobalt allergy. OBJECTIVES: To examine the association between contact allergy to cobalt and a history of dermatitis resulting from ....... CONCLUSIONS: Our study suggests a positive association between cobalt allergy and a history of dermatitis caused by non-occupational exposure to leather articles.......BACKGROUND: Cobalt is a strong skin sensitizer and a prevalent contact allergen. Recent studies have recognized exposure to leather articles as a potential cause of cobalt allergy. OBJECTIVES: To examine the association between contact allergy to cobalt and a history of dermatitis resulting from...... as the most frequent exposure source causing dermatitis in the case group. Although the case group significantly more often reported non-occupational dermatitis caused by leather exposure (p

  4. 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

  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. Mechanochemical Preparation of Cobalt Nanoparticles through a Novel Intramolecular Reaction in Cobalt(II Complexes

    Directory of Open Access Journals (Sweden)

    Seyed Abolghasem Kahani

    2015-01-01

    Full Text Available A novel solid state reaction involving a series of cobalt(II hydrazine-azides has been used to prepare metallic cobalt nanoparticles. The reactions of [Co(N2H4(N32], [Co(N2H42(N32], and [Co(N2H4(N3Cl]·H2O via NaOH, KOH as reactants were carried out in the solid state. These complexes undergo an intramolecular two-electron oxidation-reduction reaction at room temperature, producing metallic cobalt nanoparticles (Co1–Co6. The aforementioned complexes contain cobalt(II that is an oxidizing agent and also hydrazine ligand as a reducing agent. Other products produced include sodium azide and ammonia gas. The cobalt metal nanoparticles were characterized using X-ray powder diffraction (XRD, scanning electron microscopy (SEM, and vibrating sample magnetometer (VSM. The synthesized cobalt nanoparticles have similar morphologies; however, their particle size distributions are different.

  7. Controlled crystalline structure and surface stability of cobalt nanocrystals.

    Science.gov (United States)

    Bao, Yuping; Beerman, Michael; Pakhomov, Alexandre B; Krishnan, Kannan M

    2005-04-21

    The synthesis of monodispersed 10 nm cobalt nanocrystals with controlled crystal morphology and investigation of the surface stability of these nanocrystals are described. Depending on the surfactants used, single crystalline or multiple grain nanocrystals can be reproducibly produced. The relative surface stability of these nanocrystals is analyzed using the temperature dependences of the dc magnetic susceptibility. The novel method, which allows sensitive monitoring of the surface stability, is based on the observation that, with particle oxidation, an anomalous peak appears at 8 K in zero-field-cooled magnetization measurements. It is found that the surfactant protective layer is more important for long-term stability at room temperature, while the high-temperature oxidation rate is controlled by the crystal morphology of the nanoparticles.

  8. Combining multiple measurement and isotope techniques to help target erosion hot-spots in the Great Barrier Reef catchments

    Science.gov (United States)

    Bartley, Rebecca; Croke, Jacky; Bainbridge, Zoe; Wilkinson, Scott; Hancock, Gary; Austin, Jen; Kuhnert, Petra

    2016-04-01

    There is considerable evidence that the amount of sediment reaching the Great Barrier Reef (GBR), Australia, has increased since agricultural development commenced in the 1870's. This is having deleterious effects on freshwater and marine ecosystems. However, understanding the primary source and processes driving the increased sediment delivery has been challenging due to the large size and hydrogeomorphic diversity of adjacent catchments. This paper presents the results from several projects that employed a diverse range of measurement techniques all aimed at understanding the spatial and temporal changes in sediment yield from the 130,000 km2 Burdekin catchment, Australia. Cosmogenic nuclides (10Be) were combined with contemporary sediment flux monitoring to help identify high risk sub-catchments that have anthropogenically accelerated erosion. Within the sub-catchments, fallout radionuclides (137Cs, 7Pb and 7Be) were uses to determine the dominant erosion process (surface vs sub-surface erosion). Long term monitoring of improved grazing land management (using nested flumes and gauges), were used to evaluate the effectiveness of land management changes on sediment yields at paddock and catchment scales over 10 years. The results suggest that the Bowen and Upper Burdekin sub-catchments are the dominant anthropogenic source of sediment to the GBR having an accelerated erosion factor of 7.47 (± 3.71) and 3.64 (± 0.5), respectively. Within these sub-catchments, most of the fine sediment is coming from vertical channel walls (50%) or horizontal sub-surface soils (~42%). Remediating these catchments and reducing sediment delivery is likely to take greater than 10 years, and will require a range of approaches including pasture and rangeland management, as well as targeted erosion control in highly gullied landscapes. Together, these data sets help elucidate the often complex sediment delivery processes to the GBR. This helps policy and management determine where to

  9. A spot test for detection of cobalt release – early experience and findings

    DEFF Research Database (Denmark)

    Thyssen, Jacob P.; Menné, Torkil; Johansen, Jeanne D.

    2010-01-01

    Background: It is often difficult to establish clinical relevance of metal exposure in cobalt-allergic patients. Dermatologists and patients may incorrectly assume that many metallic items release cobalt at levels that may cause cobalt dermatitis. Cobalt-allergic patients may be unaware...... that they are exposed to cobalt from handling work items, causing hand dermatitis. Objectives: To present early findings with a newly developed cobalt spot test. Methods and Results: A cobalt spot test based on disodium-1-nitroso-2-naphthol-3,6-disulfonate was able to identify cobalt release at 8.3 ppm. The test may...... also be used as a gel test if combined with an agar preparation. We found no false-positive reactions when testing metals and alloys known not to contain cobalt. However, one cobalt-containing alloy, which elicited cobalt dermatitis in cobalt-allergic patients, was negative upon cobalt gel testing...

  10. Surface magnetism in iron, cobalt, and nickel

    DEFF Research Database (Denmark)

    Alde´n, M.; Mirbt, S.; Skriver, Hans Lomholt

    1992-01-01

    We have calculated magnetic moments, work functions, and surface energies for several of the most closely packed surfaces of iron, cobalt, and nickel by means of a spin-polarized Green’s-function technique based on the linear muffin-tin orbitals method within the tight-binding and atomic sphere...

  11. Spinel cobalt ferrite by complexometric synthesis

    NARCIS (Netherlands)

    Pham Duc Thang, P.D.T.; Rijnders, Augustinus J.H.M.; Blank, David H.A.

    2005-01-01

    Magnetic fine particles of cobalt ferrite (CoFe2O4) have been synthesized using complexometric method in which ethylene diamine tetra acetic acid C10H16N2O8 (EDTA) acts as a complexing agent. The crystallographic structure, microstructure and magnetic properties of the synthesized powder were

  12. Evidence of Formation of Superdense Nonmagnetic Cobalt

    Science.gov (United States)

    Banu, Nasrin; Singh, Surendra; Satpati, B.; Roy, A.; Basu, S.; Chakraborty, P.; Movva, Hema C. P.; Lauter, V.; Dev, B. N.

    2017-02-01

    Because of the presence of 3d transition metals in the Earth’s core, magnetism of these materials in their dense phases has been a topic of great interest. Theory predicts a dense face-centred-cubic phase of cobalt, which would be nonmagnetic. However, this dense nonmagnetic cobalt has not yet been observed. Recent investigations in thin film polycrystalline materials have shown the formation of compressive stress, which can increase the density of materials. We have discovered the existence of ultrathin superdense nonmagnetic cobalt layers in a polycrystalline cobalt thin film. The densities of these layers are about 1.2–1.4 times the normal density of Co. This has been revealed by X-ray reflectometry experiments, and corroborated by polarized neutron reflectometry (PNR) experiments. Transmission electron microscopy provides further evidence. The magnetic depth profile, obtained by PNR, shows that the superdense Co layers near the top of the film and at the film-substrate interface are nonmagnetic. The major part of the Co film has the usual density and magnetic moment. These results indicate the possibility of existence of nonmagnetic Co in the earth’s core under high pressure.

  13. Nano cobalt oxides for photocatalytic hydrogen production

    KAUST Repository

    Mangrulkar, Priti A.

    2012-07-01

    Nano structured metal oxides including TiO 2, Co 3O 4 and Fe 3O 4 have been synthesized and evaluated for their photocatalytic activity for hydrogen generation. The photocatalytic activity of nano cobalt oxide was then compared with two other nano structured metal oxides namely TiO 2 and Fe 3O 4. The synthesized nano cobalt oxide was characterized thoroughly with respect to EDX and TEM. The yield of hydrogen was observed to be 900, 2000 and 8275 mmol h -1 g -1 of photocatalyst for TiO 2, Co 3O 4 and Fe 3O 4 respectively under visible light. It was observed that the hydrogen yield in case of nano cobalt oxide was more than twice to that of TiO 2 and the hydrogen yield of nano Fe 3O 4 was nearly four times as compared to nano Co 3O 4. The influence of various operating parameters in hydrogen generation by nano cobalt oxide was then studied in detail. Copyright © 2012, Hydrogen Energy Publications, LLC. Published by Elsevier Ltd. All rights reserved.

  14. Cobalt Biogeochemistry in the South Atlantic: A Full-Depth Zonal Ocean Section of Total Dissolved Cobalt, and Development of a High Throughput Cobalt ICP-MS Method

    Science.gov (United States)

    Noble, A. E.; Saito, M. A.; Goepfert, T. J.

    2008-12-01

    This study presents the first high-resolution full-depth zonal section of total dissolved cobalt from a recent cruise transecting the South Atlantic Ocean along approximately 11S. This section demonstrates that current electrochemical analytical techniques are capable of producing the high precision and high resolution datasets for total dissolved cobalt expected to be generated as a part of the international GEOTRACES Program. The micronutritive role of cobalt may affect community structure in different regions of the oceans, a compelling reason to include cobalt in the trace element analyses planned for the GEOTRACES Program. This cobalt section reveals an advective source of cobalt from the African coast near Namibia, which we propose to be due to the Benguela Current interacting with reducing shelf sediments. These high concentrations of cobalt were also observed within the oxygen minimum zone that extends across much of the South Atlantic basin in this section, and are likely indicative of redox cycling of cobalt in the water column. Nutrient-like vertical structure of cobalt was observed in the surface waters across the majority of the basin due to biological utilization, and the expected hybrid-type trend is observed at depth, with scavenging of cobalt below the nutricline. Deepwater concentrations of cobalt were around 50pM across the basin below 3000m. Analysis of the shelf-life of refrigerated filtered samples stored without acidification for electrochemical cobalt analysis demonstrated that those samples which were collected specifically within oxygen minimum zones may underestimate cobalt if not analyzed within a few weeks of collection. These results motivate our on-going development of a method to measure cobalt in acidified samples via inductively coupled plasma mass spectrometry (ICP-MS). The benefit of this technique would be twofold: acidification would extend the shelf-life of the samples significantly, and samples would be preserved identically

  15. 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.

  16. A spot test for detection of cobalt release - early experience and findings

    DEFF Research Database (Denmark)

    Thyssen, Jacob P; Menné, Torkil; Johansen, Jeanne D

    2010-01-01

    It is often difficult to establish clinical relevance of metal exposure in cobalt-allergic patients. Dermatologists and patients may incorrectly assume that many metallic items release cobalt at levels that may cause cobalt dermatitis. Cobalt-allergic patients may be unaware that they are exposed...... to cobalt from handling work items, causing hand dermatitis....

  17. Simultaneous spectrophotometric determination of cobalt,copper and nickel using 1-(2-thiazolylazo)-2-naphthol by chemometrics methods

    Institute of Scientific and Technical Information of China (English)

    Ali Niazi; Ateesa Yazdanipour

    2008-01-01

    The simultaneous determination of cobalt,copper and nickel using 1-(2-thiazolylazo)-2-naphthol (first figure of this article) by spectrophotometric method is a difficult problem in analytical chemistry,due to spectral interferences.By multivariate calibration methods,such as partial least squares (PLS) regression,it is possible to obtain a model adjusted to the concentration values of the mixtures used in the calibration range.Orthogonal signal correction (OSC) is a preprocessing technique used for removing the information unrelated to the target variables based on constrained principal component analysis.OSC is a suitable preprocessing method for PLS calibration of mixtures without loss of prediction capacity using spectrophotometric method.In this study,the calibration model is based on absorption spectra in the 550-750-nm range for 21 different mixtures of cobalt,copper and nickel.Calibration matrices were formed from samples containing 0.05-1.05,0.05-1.30 and 0.05-0.80 μg mL-1 for cobalt,copper and nickel,respectively.The root mean square error of prediction (RMSEP) for cobalt,copper and nickel with OSC and without OSC were 0.007,0.008,0.011 and 0.031,0.037,0.032 μg mL-1,respectively.This procedure allows the simultaneous determination of cobalt,copper and nickel in synthetic and real samples and good reliability of the determination was proved.

  18. Exposure to cobalt causes transcriptomic and proteomic changes in two rat liver derived cell lines.

    Science.gov (United States)

    Permenter, Matthew G; Dennis, William E; Sutto, Thomas E; Jackson, David A; Lewis, John A; Stallings, Jonathan D

    2013-01-01

    Cobalt is a transition group metal present in trace amounts in the human diet, but in larger doses it can be acutely toxic or cause adverse health effects in chronic exposures. Its use in many industrial processes and alloys worldwide presents opportunities for occupational exposures, including military personnel. While the toxic effects of cobalt have been widely studied, the exact mechanisms of toxicity remain unclear. In order to further elucidate these mechanisms and identify potential biomarkers of exposure or effect, we exposed two rat liver-derived cell lines, H4-II-E-C3 and MH1C1, to two concentrations of cobalt chloride. We examined changes in gene expression using DNA microarrays in both cell lines and examined changes in cytoplasmic protein abundance in MH1C1 cells using mass spectrometry. We chose to closely examine differentially expressed genes and proteins changing in abundance in both cell lines in order to remove cell line specific effects. We identified enriched pathways, networks, and biological functions using commercial bioinformatic tools and manual annotation. Many of the genes, proteins, and pathways modulated by exposure to cobalt appear to be due to an induction of a hypoxic-like response and oxidative stress. Genes that may be differentially expressed due to a hypoxic-like response are involved in Hif-1α signaling, glycolysis, gluconeogenesis, and other energy metabolism related processes. Gene expression changes linked to oxidative stress are also known to be involved in the NRF2-mediated response, protein degradation, and glutathione production. Using microarray and mass spectrometry analysis, we were able to identify modulated genes and proteins, further elucidate the mechanisms of toxicity of cobalt, and identify biomarkers of exposure and effect in vitro, thus providing targets for focused in vivo studies.

  19. Exposure to cobalt causes transcriptomic and proteomic changes in two rat liver derived cell lines.

    Directory of Open Access Journals (Sweden)

    Matthew G Permenter

    Full Text Available Cobalt is a transition group metal present in trace amounts in the human diet, but in larger doses it can be acutely toxic or cause adverse health effects in chronic exposures. Its use in many industrial processes and alloys worldwide presents opportunities for occupational exposures, including military personnel. While the toxic effects of cobalt have been widely studied, the exact mechanisms of toxicity remain unclear. In order to further elucidate these mechanisms and identify potential biomarkers of exposure or effect, we exposed two rat liver-derived cell lines, H4-II-E-C3 and MH1C1, to two concentrations of cobalt chloride. We examined changes in gene expression using DNA microarrays in both cell lines and examined changes in cytoplasmic protein abundance in MH1C1 cells using mass spectrometry. We chose to closely examine differentially expressed genes and proteins changing in abundance in both cell lines in order to remove cell line specific effects. We identified enriched pathways, networks, and biological functions using commercial bioinformatic tools and manual annotation. Many of the genes, proteins, and pathways modulated by exposure to cobalt appear to be due to an induction of a hypoxic-like response and oxidative stress. Genes that may be differentially expressed due to a hypoxic-like response are involved in Hif-1α signaling, glycolysis, gluconeogenesis, and other energy metabolism related processes. Gene expression changes linked to oxidative stress are also known to be involved in the NRF2-mediated response, protein degradation, and glutathione production. Using microarray and mass spectrometry analysis, we were able to identify modulated genes and proteins, further elucidate the mechanisms of toxicity of cobalt, and identify biomarkers of exposure and effect in vitro, thus providing targets for focused in vivo studies.

  20. Exposure to Cobalt Causes Transcriptomic and Proteomic Changes in Two Rat Liver Derived Cell Lines

    Science.gov (United States)

    Permenter, Matthew G.; Dennis, William E.; Sutto, Thomas E.; Jackson, David A.; Lewis, John A.; Stallings, Jonathan D.

    2013-01-01

    Cobalt is a transition group metal present in trace amounts in the human diet, but in larger doses it can be acutely toxic or cause adverse health effects in chronic exposures. Its use in many industrial processes and alloys worldwide presents opportunities for occupational exposures, including military personnel. While the toxic effects of cobalt have been widely studied, the exact mechanisms of toxicity remain unclear. In order to further elucidate these mechanisms and identify potential biomarkers of exposure or effect, we exposed two rat liver-derived cell lines, H4-II-E-C3 and MH1C1, to two concentrations of cobalt chloride. We examined changes in gene expression using DNA microarrays in both cell lines and examined changes in cytoplasmic protein abundance in MH1C1 cells using mass spectrometry. We chose to closely examine differentially expressed genes and proteins changing in abundance in both cell lines in order to remove cell line specific effects. We identified enriched pathways, networks, and biological functions using commercial bioinformatic tools and manual annotation. Many of the genes, proteins, and pathways modulated by exposure to cobalt appear to be due to an induction of a hypoxic-like response and oxidative stress. Genes that may be differentially expressed due to a hypoxic-like response are involved in Hif-1α signaling, glycolysis, gluconeogenesis, and other energy metabolism related processes. Gene expression changes linked to oxidative stress are also known to be involved in the NRF2-mediated response, protein degradation, and glutathione production. Using microarray and mass spectrometry analysis, we were able to identify modulated genes and proteins, further elucidate the mechanisms of toxicity of cobalt, and identify biomarkers of exposure and effect in vitro, thus providing targets for focused in vivo studies. PMID:24386269

  1. Elevated Th22 as well as Th17 cells associated with therapeutic outcome and clinical stage are potential targets in patients with multiple myeloma.

    Science.gov (United States)

    Wang, Min; Chen, Ping; Jia, Yan; He, Na; Li, Daqi; Ji, Chunyan; Ma, Daoxin

    2015-07-20

    T helper (Th) cell imbalance plays important roles in tumor development and their effects in Multiple myeloma (MM) remain unclear. In the present study, we investigated the levels and clinical significance of Th22, Th17 and Th1 cells in patients with MM. Th subsets were examined by flow cytometry. Plasma IL-22, IL-17A and IFN-γ concentrations were measured by ELISA. AHR and RORC mRNA expression was examined by RT-PCR. Here, we found that the frequency of Th22 cells was significantly elevated in peripheral blood (PB) and bone marrow (BM) of newly-diagnosed MM patients, and recovered in complete remission patients after chemotherapy. The circulating Th17 cells accompanied by IL-17A levels were also up-regulated in MM patients and decreased after remission. We also found that there was a significantly positive correlation between Th22 and Th17 cells in MM patients. Moreover, the frequencies of Th22 and Th17 cells were higher in stage III than in stage I+II of MM. Our data demonstrated that Th22 and Th17 cells might be important therapeutic targets in multiple myeloma and could facilitate the effect of antitumor immunotherapy.

  2. 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.

  3. miR-124 suppresses multiple steps of breast cancer metastasis by targeting a cohort of pro-metastatic genes in vitro

    Institute of Scientific and Technical Information of China (English)

    Xiao-Bin Lv; Yu Jiao; Yanwei Qing; Haiyan Hu; Xiuying Cui; Tianxin Lin; Erwei Song; Fengyan Yu

    2011-01-01

    Metastasis is a multistep process involving modification of morphology to suit migration,reduction of tumor cell adhesion to the extracellular mattrix,increase of cell mobility,tumor cell resistance to anoikis,and other steps.MicroRNAs are well-suited to regulate tumor metastasis due to their capacity to repress numerous target genes in a coordinated manner,thereby enabling their intervention at multiple steps of the invasion-metastasis cascade.In this study,we identified a microRNA exemplifying these attributes,miR124,whose expression was reduced in aggressive MDA-MB-231 and SK-3rd breast cancer cells.Downregulation of miR-124 expression in highly aggressive breast cancer cells contributed in part to DNA hypermethylation around the promoters of the three genes encoding miR-124.Ectopic expression of miR124 in MDA-MB-231 cells suppressed metastasis-related traits including formation of spindle-like morphology,migratory capacity,adhesion to fibronectin,and anoikis.These findings indicate that miR-124 suppresses multiple steps of metastasis by diverse mechanisms in breast cancer cells and suggest a potential application of miR-124 in breast cancer treatment.

  4. Multi-Layer Identification of Highly-Potent ABCA1 Up-Regulators Targeting LXRβ Using Multiple QSAR Modeling, Structural Similarity Analysis, and Molecular Docking

    Directory of Open Access Journals (Sweden)

    Meimei Chen

    2016-11-01

    Full Text Available In this study, in silico approaches, including multiple QSAR modeling, structural similarity analysis, and molecular docking, were applied to develop QSAR classification models as a fast screening tool for identifying highly-potent ABCA1 up-regulators targeting LXRβ based on a series of new flavonoids. Initially, four modeling approaches, including linear discriminant analysis, support vector machine, radial basis function neural network, and classification and regression trees, were applied to construct different QSAR classification models. The statistics results indicated that these four kinds of QSAR models were powerful tools for screening highly potent ABCA1 up-regulators. Then, a consensus QSAR model was developed by combining the predictions from these four models. To discover new ABCA1 up-regulators at maximum accuracy, the compounds in the ZINC database that fulfilled the requirement of structural similarity of 0.7 compared to known potent ABCA1 up-regulator were subjected to the consensus QSAR model, which led to the discovery of 50 compounds. Finally, they were docked into the LXRβ binding site to understand their role in up-regulating ABCA1 expression. The excellent binding modes and docking scores of 10 hit compounds suggested they were highly-potent ABCA1 up-regulators targeting LXRβ. Overall, this study provided an effective strategy to discover highly potent ABCA1 up-regulators.

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

    Science.gov (United States)

    Zhao, Ming; Ma, Jian; Zhu, Hai-Yan; Zhang, Xu-Hui; Du, Zhi-Yan; Xu, Yuan-Ji; Yu, Xiao-Dan

    2011-08-29

    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. 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. 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.

  6. 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.

  7. 多靶点阿尔茨海默症治疗药物的研究进展%Development of multiple-target anti-Alzheimer's agents

    Institute of Scientific and Technical Information of China (English)

    黄淑芳; 黄文海; 胡永洲

    2011-01-01

    Alzheimer's disease( AD) ,the most common form of dementia,is ascribed to a considerably complex neurodegenerative disorder. Currently, drugs approved for AD treatment are mainly AChE inhibitors and NMDA antagonists, as single-target anti-AD drugs, both of which can only be employed to alleviate the symptoms of AD. Thus,more effective AD treatment is more attractive and becoming one of the hotspots. Because of the complexity and multiple etiologies of AD, multi-target-directed ligand raises as a potentially more effective strategy for AD treatment. This review mainly focused on the discovery, structural optimization, biological activity and potential prospect of a variety of reported multi-target-directed compounds.%临床上用于治疗阿尔茨海默症(AD)的药物多属于针对单靶标的化合物,这类化合物可缓解AD症状,但未能从根本上改善疾病状态或终止疾病的进程.基于AD的发生和发展涉及到多个复杂的调控网络和调控因子的共同作用,寻求针对多个靶点的化合物成了AD治疗药物研发的热点和趋势.本文对近几年报道的各类多靶点抗AD药物或化合物进行综述,从其发现、设计思路、生物活性及应用前景等方面进行系统阐述.

  8. 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.

  9. Identif