Li-Tian Hu, Fei Sun, Guojun Chen · Genes & Diseases · 2015
Multiple sclerosis (MS), a leading cause of non-traumatic disability in young adults, is a chronic inflammatory demyelinating disease of the central nervous system (CNS) associated with aberrant autoimmune responses. It has long been thought that therapeutic development should be centered on immunomodulatory agents. However, none of the agents tested could prevent chronic progressive disease and disability. On the other hand, direct repair of injured myelin might represent an alternative strategy for treating MS. This may be achieved by either promoting the inherent repair mechanism of neurons or by recruiting cells derived from oligodendrocyte progenitor cells (OPCs), which are unfortunately silent in MS. The latter approach was recently demonstrated by Najm et al at Case Western Reserve University and Northwestern University.
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They demonstrated that miconazole and clobetasol, screened from a library of bioactive small molecules on mouse pluripotent epiblast stem cell-derived OPCs,2, 3, 4 promoted precocious myelination, significantly increased the number of new oligodendrocytes and enhanced remyelination. Strikingly, both small molecules reversed the disease severity in mouse models of MS.
The subsequent genome-wide RNA sequencing and phosphoproteomic analyses on mouse OPCs showed that the activity of clobetasol is mediated by the glucocorticoid receptor signaling axis, whereas miconazole functions through the mitogen-activated protein (MAP) kinase pathway, with potential cell-type specificity. To interpret the potential impact of these treatments on immune cell survival and function, subsequent immune response assays were performed, which showed that only clobetasol alters the naive T-cell differentiation and secretion of cytokines. These findings indicate that clobetasol plays a role in both immunomodulation and the promotion of myelination, whereas miconazole acts as a direct remyelinating agent, with no effect on the immune system. Most importantly, both drugs enhanced the generation of human oligodendrocytes from human OPCs in vitro, with miconazole exhibiting the most reproducible and potent effects. Although miconazole and clobetasol are currently only approved for topical administration in humans, meaning that significant optimization of the dosing, delivery and potentially the chemical constitution will be required to enhance the on-target pharmacology in OPCs, this study provides new hope for the currently untreatable chronic progressive phase of MS.
It remains unknown how the remyelinating and immune system effects interact, and the precise mechanisms underlying the resultant recovery after the administration of these two drugs remain unclear. However, the study by Najm et al suggests that OPCs can be selectively modified and differentiated into oligodendrocytes by two different drugs identified using a high-throughput screening method, both of which resulted in amelioration of the MS phenotype in vivo. Compared with genetically engineered stem cells, which may exhibit alterations of their structure and function that might interfere with the microenvironment and glia-neuron interactions, a major advantage of using drug-modified cells is that the treatment can be stopped at any time depending on the clinical outcome of the MS and the side effects. In addition, the manipulation of isolated target cells provides a new method for dealing not only with MS, but also with a variety of other diseases, such as cancer and neurodegenerative diseases. For instance, the drug-based high-throughput screening strategy used in this study could be useful to identify small molecules targeting cancer stem cells, which would ultimately lead to the optimized treatment of patients with cancer. Therefore, we think that the drug-based modulation of target cells represents a breakthrough in research related to physiology and disease.
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I. Gentil, B. Rémillard, P. Del Moral et al. · 2002
Les textes publiés dans la série des rapports de recherche HEC n’engagent que la responsabilité deleurs auteurs. La publication de ces rapports de recherche bénéficie d’une subvention du Fonds F.C.A.R.Filtering of Images for Detecting
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Robin J. Shattock · Retrovirology · 2006
Heterosexual transmission is the leading mode of HIV-1 infection worldwide, with women particularly vulnerable to HIV-1 infection as they often cannot control sexual encounters or insist on condom use. In the absence of an effective vaccine there is an urgent need to develop alternative prevention strategies. The immediate events between exposure to infectious virus and the establishment of infection are still poorly understood. Defining the mechanisms of HIV-1 transmission, the target cells involved and how the virus attaches to and fuses with these cells is revealing new ways to block the sexual spread of the virus. Initial efforts to develop vaginal microbicides focused on killing the virus through membrane disruption using surfactants, and blocking viral entry using polyanionic compounds that interact with the positively charged areas of the viral envelope proteins, many of which are currently in phase II/III trials. However recent advances in HIV pathogenesis and therapeutics are now bringing a wide range of new products into the development pipeline that specifically target different stages in the viral life cycle. This talk will present rigorous pre-clinical evaluation of candidate microbicides prior to selection for clinical trials, providing considerable savings in costs and time, given the expense and length of formal efficacy trials. Selection criteria include: high activity against cell free and cell associated virus in mucosal explant models; low irritation potential based on a range of preclinical irritation assays; high in vitro activity in the presence of semen; and effectiveness in animal models using challenge virus that is relevant to sexual HIV transmission. This presentation discussed how our increasing knowledge of the ways in which HIV-1 is transmitted has sharpened the development of new, more sophisticated intervention strategies based on the application of vaginal or rectal microbicides.
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Draelos, Mark, Viehland, Christian, McNabb, Ryan P. et al. · Figshare · 2022
Adaptive scanning of multiple moving targets in simulation.
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Ran Darshan (507608), Arthur Leblois (507609), David Hansel (33581) · Figshare · 2015
<p><b>A.</b> Average total number of target presentations required to learn the entire task <i>vs.</i> the number of presented targets, <i>m</i>. The targets are evenly distributed (between to ). Black: . Blue: . Purple: . Green: . Dashed black line corresponds to learning the targets independently from the p.d.f. of , which was estimated from adapting to one target. <b>B.</b> Examples of the <i>noiseless</i> error during the learning, plotted <i>vs.</i> the number of <i>rewarded</i> trials. The target direction is color coded. Dashed gray lines: The initial noiseless error for . <b>B.1</b> and <b>B.2</b> are examples of the noiseless error for narrow tuning curves () in the case of 3 and 6 targets respectively. The plateau in the noiseless errors indicates that there is no interference between the targets. <b>B.3</b> and <b>B.4</b> are examples of the noiseless error for wider tuning curves () in the case of 3 and 6 targets respectively. The increase in the noiseless error above the initial error for some of the targets is the result of the destructive interference between far targets. <b>C.</b> The fraction of ordered realizations when as function of . Chance level is . An ordered realization is defined as learning the targets in a close-to-far order, as in the example in <b>B.4</b>. The statistics were calculated over realizations. For all the results presented in this figure: .</p>
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C.A. Deacon, D.P. Atherton · IFAC Proceedings Volumes · 1990
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Draelos, Mark, Viehland, Christian, McNabb, Ryan P. et al. · Figshare · 2022
Adaptive scanning of multiple moving targets in simulation.
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Ruth S. Nussenzweig, Christopher J. Long · Science · 1994
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Ira T. Kaplan, Thomas Carvellas · Perceptual and Motor Skills · 1965
S scanned a list of random letters looking for 1 to 5 target letters, which were read to him just before the list was presented. His scanning rate was estimated from a graph of the time required to find a target at different positions in the list. The more targets S was seeking, the more slowly he scanned. The time spent processing each non-target letter in the list increased in direct proportion to the number of targets for which S was searching.
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Türker, Burcu · OpenMETU (Middle East Technical University) · 2019
Visual target tracking problem consists of two topics: Obtaining targets from camera measurements and target tracking. Even though it has been studied for more than 30 years, there are still some problems not completely solved. Especially in the case of multiple targets, association of measurements to targets, creation of new targets and deletion of old ones are among those. What is more, it is very important to deal with the occlusion and crossing targets problems suitably. We believe that a slightly modified version of multiple hypothesis tracking can successfully deal with most of the aforementioned problems with sufficient success. Distance, track size, track color, gate size and track history are used as parameters to evaluate the hypotheses generated for measurement to track association problem whereas size and color are used as parameters for occlusion problem. The overall tracker has been fine tuned over some scenarios and it has been observed that it performs well over the testing scenarios as well. Furthermore the performance of the tracker is analyzed according to those parameters in both association and occlusion handling situations.
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Hugh R.B. Pelham · Cell · 1991
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Shan Jiang (121292), Fuqiang Li (745173), Xiuli Li (133764) et al. · Figshare · 2019
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Hongliang Liang, Xinglin Yu, Xianglin Cheng et al. · IEEE Transactions on Dependable and Secure Computing · 2023
Directed greybox fuzzing (DGF) can quickly discover or reproduce bugs in programs by seeking to reach a program location or explore some locations in order. However, due to their static stage division and coarse-grained energy scheduling, prior DGF tools perform poorly when facing multiple target locations (targets for short). In this paper, we present multiple targets directed greybox fuzzing which aims to reach multiple programs locations in a fuzzing campaign. Specifically, we propose a novel strategy to adaptively coordinate exploration and exploitation stages, and a novel energy scheduling strategy by considering more relations between seeds and target locations. We implement our approaches in a tool called LeoFuzz and evaluate it on crash reproduction, true positives verification, and vulnerability exposure in real-world programs. Experimental results show that LeoFuzz outperforms six state-of-the-art fuzzers, i.e., QYSM, AFLGo, Lolly, Berry, Beacon and WindRanger in terms of effectiveness and efficiency. Moreover, LeoFuzz has detected 23 new vulnerabilities in real-world programs, and 12 of them have been assigned CVE IDs.
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Petrucio R. T. Medeiros, Rafael B. Gomes, Luiz Marcos Garcia Gonçalves · 2021
Target detection enables running a robotic task. However, their limited resources make large amount of data processing harder. Image foveation is an approach that can reduce processing demand by reducing the amount of data to be processed. However, as an important visual stimulli can be attenuated by this reduction, some strategy should be applied in order to keep/recover awareness of it. This work compares gradient descent (potential field), maximum likelihood, multilateration, trilateration, and barycentric coordinates to solve this problem in a multiple mobile foveas context. Our results demonstrate that the proposed methodology detects the target converging with an average euclidian distance of 51 pixels from the target&apos;s center position.
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Courant, E.D. · University of North Texas Digital Library (University of North Texas) · 1962
The efficiency of multiple traversal targets is defined as the probability that a proton dies by making a nuclear collision in the target rather than by hitting the limit of the synchrotron aperture. The efficiencies of Be, Al, Cu, and Pb targets are shown for 15 and 30-Bev protons in the Brooknaven AGS. Beryllium was found to be the most efficient. (M.C.G.)
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Oren Gutman, Z.J. Palmor · Journal of Guidance Control and Dynamics · 2011
The basic block diagrams of proportional navigation are revisited. The effect of initial conditions on the miss distance is studied. Using the important case of multiple targets, two proportional navigation block diagrams are compared. The first, the ideal proportional navigation, applies the true line-of-sight rate, which is calculated by an analytic derivative of the line-of-sight angle. The block diagram resulting from this guidance loop is minimal. The second applies an approximate derivative of the line-of-sight angle. Because of zero-pole cancellation at the origin, the block diagram resulting from this guidance loop is unobservable with respect to target displacement. The consequence is that for the target-displacement initial condition the two diagrams do not result in the same miss distance. Moreover, several solutions that can resolve the above difficulty are suggested. One of the solutions is to reset the derivative filter with the correct initial conditions. Another solution is to skip the first few samples of the derivative filter right after target separation. Nomenclature m = miss distance N 0 = navigation constant nT = target acceleration normal to line of sight tgo = time-to-go Vc = closing velocity VM = missile velocity y = relative position � = line-of-sight angle _ � = line-of-sight rate � = missile time constant
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Petrucio R. T. Medeiros, Rafael B. Gomes, Luiz Marcos Garcia Gonçalves · 2021
Target detection enables running a robotic task. However, their limited resources make large amount of data processing harder. Image foveation is an approach that can reduce processing demand by reducing the amount of data to be processed. However, as an important visual stimulli can be attenuated by this reduction, some strategy should be applied in order to keep/recover awareness of it. This work compares gradient descent (potential field), maximum likelihood, multilateration, trilateration, and barycentric coordinates to solve this problem in a multiple dynamic and fixed foveas context. Our results demonstrate that the proposed methodology detects the target converging with an average euclidian distance of 51 pixels from the target’s center position.
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Leonard D. Cohen, Richard D. Haracz, Ariel Cohen · 1987
Abstract : The Shifrin Acquista integral equation technique was modified to handle scattering from nonspherical, nonsymmetric particles, such as helices and toroids. This approach was applied to the analysis of an experiment on scattering by a helix with very good results. We also computed asymmetry factors for scattering from long cylinders. This result is useful in computing the average amount of light scattered in the forward direction from a collection of randomly oriented cylinders, such as a cloud of cylinders. Keywords: Light scattering, Cylinders.
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Schoemmel, Kristina · 2013
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Edgar Meinl · Journal of the Neurological Sciences · 2011
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