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Gustafsson, Fredrik, and Erik Linder-Norén. "Automotive 3D Object Detection Without Target Domain Annotations." Thesis, Linköpings universitet, Datorseende, 2018. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-148585.
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In this thesis we study a perception problem in the context of autonomous driving. Specifically, we study the computer vision problem of 3D object detection, in which objects should be detected from various sensor data and their position in the 3D world should be estimated. We also study the application of Generative Adversarial Networks in domain adaptation techniques, aiming to improve the 3D object detection model's ability to transfer between different domains. The state-of-the-art Frustum-PointNet architecture for LiDAR-based 3D object detection was implemented and found to closely match its reported performance when trained and evaluated on the KITTI dataset. The architecture was also found to transfer reasonably well from the synthetic SYN dataset to KITTI, and is thus believed to be usable in a semi-automatic 3D bounding box annotation process. The Frustum-PointNet architecture was also extended to explicitly utilize image features, which surprisingly degraded its detection performance. Furthermore, an image-only 3D object detection model was designed and implemented, which was found to compare quite favourably with current state-of-the-art in terms of detection performance. Additionally, the PixelDA approach was adopted and successfully applied to the MNIST to MNIST-M domain adaptation problem, which validated the idea that unsupervised domain adaptation using Generative Adversarial Networks can improve the performance of a task network for a dataset lacking ground truth annotations. Surprisingly, the approach did however not significantly improve upon the performance of the image-based 3D object detection models when trained on the SYN dataset and evaluated on KITTI.
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Collins, K. M. "Target recognition by multi-domain RNA-binding proteins." Thesis, University College London (University of London), 2015. http://discovery.ucl.ac.uk/1460867/.
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Multi-functional RNA binding proteins regulate and coordinate the many steps of RNA metabolism. Accurate functioning of these processes is vital in cells and misregulation has been linked to many human diseases. RNA binding proteins contain multiple RNA binding domains. The ability to perform multiple functions depends on the recognition of a diverse range of targets and domains are used combinatorially to achieve this. In this thesis I ask how the sequence specificity of low affinity RNA-binding domains and the interplay between said domains plays a role in RNA target selectivity. Within this question I focus on three proteins; TUT4, a uridyl transferase involved in the regulation of both non-coding RNAs and histone mRNA; FMRP, a translational repressor whose loss in cells is the cause of Fragile X Syndrome; and RBM10 a regulator of alternative splicing and miRNA biogenesis. I found that through the use of separate RNA binding domains both TUT4 and RBM10 are able to exert flexibility in target recognition; TUT4 by using two CCHC-type zinc fingers, working independently to recognise short RNA stretches; and RBM10 by using different subsets of domains to recognise either specific high affinity splice site sequences or pre-miRNAs. In FMRP the determination of the sequence specificity of KH1 allowed us to isolate its contribution to target selection. In a secondary objective, looking at methodologies used in RNA-protein interaction, SIA was improved to make it both less laborious and to reduce the sample requirements, and with FMRP a novel mutational strategy was used in combination with SIA to determine the sequence specificity of this low affinity domain. In summary these data extend our understanding of the RNA binding mechanisms of the three systems studied and introduces improved or novel methodologies to the future study of protein-RNA interactions.
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Davis, Alicia Morgan. "CHARACTERIZATION OF INFLUENZA NUCLEOPROTEIN BODY DOMAIN AS ANTIVIRAL TARGET." CSUSB ScholarWorks, 2016. https://scholarworks.lib.csusb.edu/etd/364.
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Influenza is a segmented negative strand RNA virus. Each RNA segment is encapsulated by viral nucleoprotein (NP) and bound by the viral RNA dependent RNA polymerase (RdRP) to form viral ribonucleoproteins (vRNPs) responsible for RNA synthesis. NP is a structural component of the vRNP but also interacts with both viral and host factors to regulate viral RNA expression. NP is conserved among influenza A isolates, making NP interactions compelling antiviral targets. Here I characterize mutations within 5 amino acids of NP that comprise an accessible region of the NP body domain, as determined by NP crystal structure. This region was selected for mutagenesis to target interaction between NP and RdRP.
NPbd3 encodes glycine at 5 amino acids within the accessible NP body domain. Cellular fractionation and Western Blot, in addition to NP-GFP fusions and fluorescence, confirm NPbd3 was expressed and localized as WT-NP. Gel shift with purified NP protein confirm NPbd3 bound nucleic acids as WT-NP. Although NPbd3 was expressed, localized, and bound nucleic acid as WT-NP, I found NPbd3 was defective for RNA expression in reconstituted vRNPs, as evaluated by reverse transcription and quantitative polymerase chain reaction (RT-qPCR). To investigate this NP body domain further, single and double amino acid mutations were cloned. Analysis of NP single mutants revealed that all were nearly as functional as WT-NP for RNA expression in reconstituted vRNPs, suggesting these accessible amino acids in the NP body domain play a redundant role. However, four different combinations of two amino acid mutations resulted in NP double mutants that displayed a significant defect in RNA expression in reconstituted vRNPs, confirming these accessible amino acids in the NP body domain play a significant role for viral RNA synthesis.
A disruption in an essential NP interaction with the RdRP is likely the explanation for the RNA defect observed. In support of this, avian influenza virus passaged in human cells resulted in virus with one NP amino acid change in this domain consistently paired with specific changes in the PB2 subunit of the RdRP. I reason this accessible body domain of NP is a viable antiviral target. Indeed, two amino acids in this NP body domain comprise a novel groove implicated in binding the small molecule inhibitor nucleozin. My thesis highlights this conserved NP body domain as an important interaction surface essential for viral RNA synthesis and support further investigation of antiviral drugs that target this region of NP.
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Atkins, Jane. "Biochemical characterisation of the catalytic domain of neuropathy target esterase." Thesis, University of Leicester, 2000. http://hdl.handle.net/2381/29643.
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Neuropathy target esterase (NTE) is an integral membrane protein found predominantly in neurones. Covalent modification of NTE's active site serine, by certain organophosphates (OPs), results in a neurodegenerative syndrome. NTE's physiological substrate is unknown and its catalytic activity does not seem to be vital in the adult animal. The enzyme domain of human NTE (residues 727-1216), called NEST, was expressed in E. coli and reacted with a carboxyl ester substrate and OP inhibitors the same as native NTE. During purification catalytic activity was lost, but was restored by reconstitution into the liposomes. Site-directed mutagenesis revealed that S966, D960 and D1086 were critical for catalysis. Mutation of two histidines, H860 and H885, also resulted in a loss of activity. Reacting NEST with [3H]diisopropylfluorophosphate, confirmed S966 as the active site serine and showed that an isopropyl group is transferred to an aspartate residue. Standard hydropathy analysis predicts no membrane-spanning helices in NEST; however, biochemical evidence indicated that NEST is an integral membrane protein. TMpred analysis, on the other hand, predicts three transmembrane helices (TM2-4), with S966 at the centre of TM4. For S966 to be located within the membrane, TM4 would need to line the lumen of an aqueous pore to allow access of water for catalysis. Patch clamp studies on NEST-containing giant liposomes indicated that NEST forms a pore in vitro, while other experiments demonstrated that NEST monomers are catalytically active: this raises the possibility that NEST forms a -barrel structure in the membrane.
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Bishoff, Josef P. "Target detection using oblique hyperspectral imagery : a domain trade study /." Online version of thesis, 2008. http://hdl.handle.net/1850/7834.
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Kucheruk, Liliya. "Modern English Legal Terminology : linguistic and cognitive aspects." Thesis, Bordeaux 3, 2013. http://www.theses.fr/2013BOR30016/document.
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La présente étude intitulée «Terminologie juridique moderne de la langue anglaise: aspects linguistiques et cognitifs » aborde le langage juridique contemporain dans le cadre de la linguistique cognitive. Les objectifs de l'étude sont d'étudier les particularités de la terminologie juridique et de proposer des principes de systématisation, en se référant à la théorie cognitive de la métaphore. Il s’agit principalement : 1) de déterminer les concepts de base utilisés métaphoriquement dans la langue juridique ; 2) d'établir les correspondances principales entre domaines et les corrélations entre des éléments particuliers dans des domaines spécifiques. Pour répondre à cette question, un corpus d’anglais juridique a été constitué et soumis à une étude quantitative. Les expressions métaphoriques liées à la terminologie juridique ont été retirés et classés selon leur sens métaphorique. Il est ainsi apparu que les métaphores conceptuelles de la GUERRE, de la MEDECINE, du SPORT et de la CONSTRUCTION étaient les plus nombreuses et prégnantes en anglais juridique. Les projections et correspondances entre ces domaines sources et le domaine cible de la LOI ont été établies.Cette étude empirique repose sur 156 textes juridiques qui ont été rassemblés au sein d’un même corpus (COLE – Corpus of Legal English). Les sources renvoient à différentes catégories thématiques. Le corpus a été utilisé pour établir la réalité de certains phénomènes et interpréter les résultats quantitatifs dans le cadre de la théorie de la métaphore conceptuelle<br>The present doctoral dissertation entitled “Modern English Legal Terminology: linguistic and cognitive aspects” investigates the contemporary legal idiom, from a cognitive linguistics perspective. The aim of this study is to map out the peculiarities of English legal terminology and develop principles of systematization, within the framework of conceptual metaphor theory. This means 1) determining the basic concepts used metaphorically in English legal language, and 2) establishing the main cross-domain mappings and correlations between separate items within concrete domains.The Corpus of Legal English (COLE) was set up and a quantitative analysis performed, in which metaphorical expressions related to legal terminology were searched for and classified on the basis of meanings, conceptual domains and mappings. Thus, the conceptual metaphors of WAR, MEDICINE, SPORT and CONSTRUCTION were found to be the most numerous and valuable in Legal English. The main cross-domain mappings between these source domains and the target domain of LAW were established.In order to carry out this data-driven study, 156 legal texts were selected and compiled into the Corpus of Legal English (COLE). The source-texts represent various thematic categories. The COLE was systematically used to interpret frequency counts from the point of view of conceptual metaphor theory<br>Дисертаційне дослідження на тему «Сучасна англійська юридична термінологія: лінгвокогнитивний аспект» досліджує сучасну мову права з точки зору когнітивної лінгвістики. Головною метою дослідження було дослідження особливостей англійської юридичної термінології та принципів її систематизації з точки зору когнітивної теорії і власне теорії концептуальної метафори. В ході написання роботи були поставлені наступні цілі: 1) визначити головні концепти які використовуються у якості метафор в англійській мові права; 2) встановити головні концептуальні зв’язки між окремими елементами доменів.З метою вирішення цих питань і задач був проведений кількісний аналіз корпусу юридичної англійської мови. В ході цього аналізу біли виділені та класифіковані метафоричні вирази які пов’язані з юридичною термінологією згідно їх метафоричного значення. В результаті аналізу було виявлено що концептуальні метафори WAR, MEDICINE, SPORT та CONSTRUCTION займають домінуюче положення в мові права. Також були встановлені основні концептуальні зв’язки між сферою-джерелом та сферою-ціллю.В даному дослідженні було використано спеціально створений корпус, який включає в себе 156 правових текстів різноманітної сюжетної направленості, для проведення кількісного аналізу з точки зору концептуальної метафори
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Niemiec, Moritz Sebastian. "Human copper ion transfer : from metal chaperone to target transporter domain." Doctoral thesis, Umeå universitet, Kemiska institutionen, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-100511.
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Many processes in living systems occur through transient interactions among proteins. Those interactions are often weak and are driven by small changes in free energy. Due to the short-living nature of these interactions, our knowledge about driving forces, dynamics and structures of these types of protein-protein heterocomplexes are though limited. This is especially important for cellular copper (Cu) trafficking: Copper ions are essential for all eukaryotes and most bacteria. As a cofactor in many enzymes, copper is especially vital in respiration or detoxification. Since the same features that make copper useful also make it toxic, it needs to be controlled tightly. Additionally, in the reducing environment of the cytosol, Cu is present as insoluble Cu(I). To circumvent both toxicity and solubility issues, a system has evolved where copper is comforted by certain copper binding proteins, so-called Cu-chaperones. They transiently interact with each other to distribute the Cu atoms in a cell. In humans, one of them is Atox1. It binds copper with a binding site containing two thiol residues and transfers it to other binding sites, mostly those of a copper pump, ATP7B (also known as Wilsons disease protein). My work was aimed at understanding copper-mediated protein-protein interactions on a molecular and mechanistic level. Which amino acids interact with the metal? Which forces drive the transfer from one protein to the other? Using biophysical and biochemical methods such as chromatography and calorimetry on wild type and point-mutated proteins in vitro, we found that the copper is transferred via a dynamic intermediate complex that keeps the system flexible while shielding the copper against other interactions. Although similar transfer interactions can be observed in other organisms, and many conclusions in the copper field are drawn from bacterial and yeast analogs, we believe that it is important to investigate human proteins, too. Not only is their regulation different, but also only in humans we find the diseases linked to the proteins: Copper level regulation diseases are to be named first, but atypical copper levels have also been linked to tumors and amyloid dispositions. In summary, my observations and conclusions are of basic research character and can be of importance for both general copper and human medicinal research.
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Schaus, Brian M. "Improving maritime domain awareness using neural networks for target of interest classification." Thesis, Monterey, California: Naval Postgraduate School, 2015. http://hdl.handle.net/10945/45252.
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Approved for public release; distribution is unlimited<br>Techniques for classifying maritime domain targets-of-interest within images are explored in this thesis. Geometric and photometric features within each image are extracted from processed images and are used to train a neural network. The trained neural network is tested with features of a known object. In the binary classification case, the neural network is used to determine whether a ship is present or not present in the image. In the multi-class and multi-level classification cases, the neural network is used to determine if the object belongs to one of four classes specified: warship, cargo ship, small boat, or other. The Hough transformation is used to identify and characterize linear patterns exhibited by objects in images. As an alternative to geometric and photometric features to classify targets-of-interest, these linear patterns are used to train a neural network. The performance of the neural network is then tested for binary, multi-class, and multi-level classification schemes. The development of neural-network-based techniques for automated target-of-interest classification is a significant result of this thesis.
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Ferrari, Giovanna Maria. "The interaction of the α2 chimaerin SH2 domain with target proteins." Thesis, University College London (University of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.325678.
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Chen, Yen-Lun. "Margin and Domain Classifications for Target Detection over Huge Population of Outliers." The Ohio State University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=osu1269539889.
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Rydh, Sandra. "Mr Metaphor Man : A study of Bob Dylan's lyrics." Thesis, Linnéuniversitetet, Institutionen för språk och litteratur, SOL, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:lnu:diva-16879.
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This study was carried out in order to investigate the purpose of Bob Dylan’s creative metaphors. Focus was on whether they were used for artistic effect or to simplify and concretize abstract concepts. Ten songs written in the last five decades were randomly selected and searched for occurrences of creative metaphors. The metaphors found were chronologically listed and discussed in terms of potential source and target domains in order to determine their purpose. The results showed rather clearly that Dylan’s creative metaphors, regardless of whether the domains were abstract or concrete, seemed to complicate rather than simplify the interpretation of a line. There were a few instances where the creative metaphors could be interpreted as being explanatory; however, this was regarded as a secondary effect since it was clear that the primary purpose for Dylan’s creative metaphors was to add an artistic touch. Moreover, this purpose did not seem to have changed in any way during the last five decades.
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Behrle, Charles D. "Computer simulation studies of multiple broadband target localization via frequency domain beamforming for planar arrays." Thesis, Monterey, California. Naval Postgraduate School, 1988. http://hdl.handle.net/10945/22976.
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Approved for public release; distribution is unlimited<br>Computer simulation studies of a frequency domain adaptive beamforming algorithm are presented. These simulation studies were conducted to determine the multiple broadband target localization capability and the full angular coverage capability of the algorithm. The algorithm was evaluated at several signal-to-noise ratios with varying sampling rates. The number of iterations that the adaptive algorithm took to reach a minimum estimation error was determined. Results of the simulation studies indicate that the algorithm can localize multiple broadband targets and has full angular coverage capability.<br>http://archive.org/details/computersimulati00behr<br>Lieutenant, United States Navy
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Boichenko, Iuliia [Verfasser], and Andrei [Akademischer Betreuer] Lupas. "The CULT domain of cereblon : a pharmacological target and teratogenicity gateway / Iuliia Boichenko ; Betreuer: Andrei Lupas." Tübingen : Universitätsbibliothek Tübingen, 2018. http://d-nb.info/1168728347/34.
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Parrish, Denwood. "TARGET ELEMENT SIZES FOR FINITE ELEMENT TIDAL MODELS FROM A DOMAIN-WIDE, LOCALIZED TRUNCATION ERROR ANALYSIS INCORPORATING BOTTO." Doctoral diss., University of Central Florida, 2007. http://digital.library.ucf.edu/cdm/ref/collection/ETD/id/3587.
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A new methodology for the determination of target element sizes for the construction of finite element meshes applicable to the simulation of tidal flow in coastal and oceanic domains is developed and tested. The methodology is consistent with the discrete physics of tidal flow, and includes the effects of bottom stress. The method enables the estimation of the localized truncation error of the nonconservative momentum equations throughout a triangulated data set of water surface elevation and flow velocity. The method's domain-wide applicability is due in part to the formulation of a new localized truncation error estimator in terms of complex derivatives. More conventional criteria that are often used to determine target element sizes are limited to certain bathymetric conditions. The methodology developed herein is applicable over a broad range of bathymetric conditions, and can be implemented efficiently. Since the methodology permits the determination of target element size at points up to and including the coastal boundary, it is amenable to coastal domain applications including estuaries, embayments, and riverine systems. These applications require consideration of spatially varying bottom stress and advective terms, addressed herein. The new method, called LTEA-CD (localized truncation error analysis with complex derivatives), is applied to model solutions over the Western North Atlantic Tidal model domain (the bodies of water lying west of the 60° W meridian). The convergence properties of LTEACD are also analyzed. It is found that LTEA-CD may be used to build a series of meshes that produce converging solutions of the shallow water equations. An enhanced version of the new methodology, LTEA+CD (which accounts for locally variable bottom stress and Coriolis terms) is used to generate a mesh of the WNAT model domain having 25% fewer nodes and elements than an existing mesh upon which it is based; performance of the two meshes, in an average sense, is indistinguishable when considering elevation tidal signals. Finally, LTEA+CD is applied to the development of a mesh for the Loxahatchee River estuary; it is found that application of LTEA+CD provides a target element size distribution that, when implemented, outperforms a high-resolution semi-uniform mesh as well as a manually constructed, existing, documented mesh.<br>Ph.D.<br>Department of Civil and Environmental Engineering<br>Engineering and Computer Science<br>Civil Engineering PhD
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Manning, Lauren Brooke. "Experimental Evaluation of Discoid Domain Receptor 2 as an Ideal Target for Development of Disease-Modifying Osteoarthritis Drugs." Thesis, Harvard University, 2015. http://nrs.harvard.edu/urn-3:HUL.InstRepos:17331959.
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Abstract:
Osteoarthritis (OA) affects 250 million people worldwide. Currently, no targets for disease-modifying osteoarthritis drugs exist. Matrix metalloproteinase-13 (MMP-13) would make it an ideal target; however, its broad biological effects restrict its application as a target enzyme of inhibitory drugs in the treatment of OA. The expression and activation of discoidin domain receptor 2 (DDR2) is increased in human OA tissues and mouse models of OA and was co-localized with elevated expression of MMP-13 in degenerative articular cartilages. In healthy articular cartilage, DDR2 is kept inactivated by the pericellular matrix, which separates the receptor from its ligand, type II collagen. Once enzymes capable of degrading the pericellular molecules expose chondrocytes to type II collagen, DDR2 is activated and induces expression of MMP-13 leading to degradation of type II collagen and proteoglycans resulting in joint destruction and OA.
We tested the hypothesis that complete removal of Ddr2 from the knee joint of mouse adult articular cartilage can delay progression of osteoarthritis prior to or after initiation of articular cartilage degeneration.
To accomplish this goal, conditional knock out techniques were used with Aggrecan-CreERT2 mice and floxed Ddr2 mice, Ddr2 was removed from articular cartilage of knee joints in mice at 8 weeks of age via intraperitoneal Tamoxifen injection (2mg/10g body weight) for 5 consecutive days (Group A). Mice were subjected to destabilization of the medial meniscus (DMM) or sham surgery at 10 weeks of age. An additional experimental group was subjected to DMM or sham surgery at 10 weeks of age and then DDR2 was removed by intraperitoneal Tamoxifen injection 8 weeks later (Group B). Knee joints from mice in Group A and their corresponding controls were harvested at 8 weeks or 16 weeks post-surgery and mice from Group B and their controls were harvested at 16 weeks post surgery. Histology was performed and the OARSI Modified Mankin Score was used to evaluate articular cartilage degeneration. Statistically significant differences were determined via T-test.
We found the average modified score for Group A 8 week control was 1.64 (n=7) whereas with Ddr2 removed was 0.64 (n=7) [P<0.05]. 2) The average modified score for Group A 16 week control was 4.67 (n=7) and with Ddr2 removed was 1.27 (n=9) [P<0.05]. 3) The average modified score for Group B was 1.1 (n=5).
In conclusion, conditional removal of Ddr2 in articular cartilage attenuated articular cartilage degeneration in mature knee joints of mouse models of OA.
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Monaghan, Amy Elizabeth. "The amino terminal domain of steroid hormone receptors as a novel drug target : identification of small molecule inhibitors." Thesis, University of Aberdeen, 2016. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=230709.
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Steroid hormone receptors (SHRs) are well validated therapeutic targets in a number of diseases. Current therapies competitively antagonise the ligand binding domain (LBD), blocking activation of the receptor and downstream signalling pathways. However cross-reactivity can be seen amongst the antagonists of different SHRs eliciting unwanted side effects. Additionally the acquisition of resistance to current therapies in diseases such as prostate cancer limits their use. The amino-terminal domain (NTD) of SHRs provides an alternative target for antagonism by allowing potential therapies to block receptor transactivation and inhibit interactions with co-activator proteins. Reduced homology between different SHR NTDs also increases the specificity of drug interactions. However development of targeted therapies using rational drug design has been hindered by its intrinsically disordered structure. Establishing cell lines which stably express a SHR responsive reporter gene alongside variants of SHRs lacking the LBD provides a method by which small molecules specifically targeting the NTD of each receptor can be identified. This assay has been designed to overcome the barriers to drug discovery that are presented by an intrinsically disordered protein. The project follows the design, development, optimisation and implementation of a high throughput screening assay with the potential to identify novel small molecule inhibitors of SHRs. The applications of these inhibitors are highlighted throughout, with specific reference to their potential to inhibit the androgen receptor in prostate cancer.
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Гнаповська, Людмила Вадимівна, Людмила Вадимовна Гнаповская, Liudmyla Vadymivna Hnapovska та М. В. Дука. "Концепт "Культура" в номінативному просторі "Кохання"". Thesis, Редакційно-видавничий відділ Житомирського державного університету ім. Івана Франка, 2005. http://essuir.sumdu.edu.ua/handle/123456789/62458.
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Ономасіологічний простір концепту "Кохання" розглядається у статті з позицій когнітивного підходу до вивчення природи мовних одиниць. Аналізуються концептуальні засади метафоричних переносів, за допомогою яких людина як мовна особистість інтерпретує концепт "Кохання" у термінах понять, що належать до концептосфери "Культура".<br>Onomasiological space of the concept of "Love" is viewed in the article in terms of cognitive approach to studying the nature of language units. The paper considers conceptual principles of metaphoric shifts through which a man as a language personality interprets the concept of "Love" by means of concepts belonging to the domain of "Culture".
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Musgrave, Christopher S. A. "Development of high energy laser target materials : synthesis of low density porous polymers, and characterisation using time domain nuclear magnetic resonace." Thesis, University of St Andrews, 2014. http://hdl.handle.net/10023/7074.
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This work details the synthesis of low density porous polymers, and characterisation with an emphasis on Time Domain Nuclear Magnetic Resonance (TD-NMR). High energy laser physics utilises low density porous polymers to study astrophysical phenomena at high pressures and temperatures in the form of plasma. Low Z, low density Polymerised High Internal Phase Emulsions (PolyHIPE) and aerogels form a large part of these capabilities, however increasingly stringent laser target parameters are now required to develop new capabilities. For low density porous polymers, this demands greater control over properties such as pore size, density, composition (C[sub]nH[sub](>n)) and homogeneity through novel synthesis and characterisation. Microstructure inhomogeneity of styrene-co-divinyl benzene (S-co-DVB) polyHIPEs in conjunction with novel t-butyl styrene and para divinyl benzene polyHIPEs were investigated using ¹H spin-lattice (T₁) and spin-lock (T[sub](1ρ)) NMR relaxation experiments using TD-NMR. The strong relationship between ¹H spin-lattice relaxation times and Dynmaic Mechanical Analysis (DMA) data, and application of relaxation experiments at varied temperatures reveal that structural inhomogeneity is based on poor emulsion stability and clustering of DVB polymer affecting bulk molecular motion. Divinyl benzene (DVB) aerogels and a range of innovative C[sub]nH[sub](>n) aerogels such as poly-5-vinyl-2-norbornene were synthesised using free-radical, cationic or ring opening metathesis polymerisation techniques. A one-step synthesis of homogeneous density gradient DVB aerogels was developed for the first time, which is fundamental to be able to study plasma shock fronts. Characterisation using X-ray tomography revealed the homogeneous density gradient. Successful carbonisation of dichloroparaxylene (DCPX) aerogels has similar properties to resorcinol-formaldehyde (RF) aerogels, but is produced in significantly less time and shrinkage, presents as a candidate for future laser experiments. Correlation between NMR relaxation times to established techniques of DMA and mercury porosimetry was explored to determine the suitability of TD-NMR in characterisation of low density porous polymers.
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Chen, Yinghua. "Solution structure of the target recognition domain of zoocin A, an antibacterial enzyme, and the metal binding site of zoocin A." Thesis, [Tuscaloosa, Ala. : University of Alabama Libraries], 2009. http://purl.lib.ua.edu/2202.
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Jariwala, Nidhi H. "Characterization of Staphylococcal nuclease and tudor domain containing protein 1 (SND1) as a molecular target in Hepatocellular carcinoma and Non-alcoholic steatohepatitis." VCU Scholars Compass, 2017. https://scholarscompass.vcu.edu/etd/5183.
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CHARACTERIZATION OF STAPHYLOCOCCAL NUCLEASE AND TUDOR DOMAIN CONTAINING PROTEIN 1 (SND1) AS A MOLECULAR TARGET IN HEPATOCELLULAR CARCINOMA AND NON-ALCOHOLIC STEATOHEPATITIS
Nidhi Jariwala, PhD
A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Integrative Life Sciences
Virginia Commonwealth University, 2017
Devanand Sarkar, M.B.B.S., PhD.
Associate Professor, Department of Human and Molecular Genetics
Virginia Commonwealth University
Richmond, Virginia
SND1, a subunit of the miRNA regulatory complex RISC, has been implicated as an oncogene in hepatocellular carcinoma (HCC). Oncoprotein SND1 regulates gene expression at a post-transcriptional level in multiple cancers including hepatocellular carcinoma (HCC). In the present study, we characterize oncogenic functions of SND1 in HCC employing a novel transgenic mouse model (Alb/SND1) and present SND1 as a potential molecular target in HCC management. We show that Alb/SND1 mice develop spontaneous HCC with partial penetrance and exhibit more highly aggressive HCC induced by chemical carcinogenesis. Livers from Alb/SND1 mice exhibit a relative increase in inflammatory markers and spheroid-generating tumor initiating cells (TiC). Mechanistic investigations defined roles for Akt and NF-κB signaling pathways in promoting TiC formation in Alb/SND1 mice. Intravenous administration of the selective SND1 inhibitor 3', 5'-deoxythymidine bisphosphate (pdTp) inhibited tumor formation without effects on body weight or liver function. We conclude that SND1 drives pro-oncogenic transcriptomic and proteomic changes in hepatocyte resulting in aggressive HCC. SND1 specific RNA interactome is identified with RNA immunoprecipitation sequencing (RIPSeq) approach. With an adjusted p value of2-fold enrichment over control, 282 mRNAs were identified to significantly associate with SND1 protein. We focused on the tumor suppressor Protein Tyrosine Phosphatase non-receptor type 23 (PTPN23) because its regulation by SND1 and its role in HCC are not known. In current study, we confirm that SND1 post-transcriptionally downregulates PTPN23. Pursuing functional studies with tetracycline inducible overexpression system, we validate that PTPN23 inhibits tyrosine kinase signaling, proliferation, epithelial to mesenchymal transition, migration, invasion and in vivo tumorigenesis.
Alb/SND1 mice also manifest steatosis and fibrosis at one year of age. Coupled with a pro-inflammatory hepatic phenotype, we conclude that Alb/SND1 livers present NASH. High fat diet causes severe NASH and aggressive NASH induced HCC in Alb/SND1 mice. Serum and hepatic lipid profiling shows that hepatocyte specific SND1 overexpression associate with elevated triglyceride and cholesterol LDL levels. Contrarily, hepatocyte specific deletion of SND1 (SND1ΔHEP) in vivo, significantly protects against age dependent steatosis. Association of SND1 in NASH pathology is novel discovery and we present preliminary evidence confirming role of SND1 in promoting NASH.
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Collins, Kelly J. "Structure-Function Analysis of the Notch Signaling CSL-KyoT2 and SPOC-NCoR Corepressor Complexes: understanding how corepressor assembly is regulated at Notch target genes." University of Cincinnati / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1393236995.
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Pettersson, Max, and Viktor Jansson. "Predicting rifle shooting accuracy from context and sensor data : A study of how to perform data mining and knowledge discovery in the target shooting domain." Thesis, Tekniska Högskolan, Högskolan i Jönköping, JTH, Datateknik och informatik, 2019. http://urn.kb.se/resolve?urn=urn:nbn:se:hj:diva-45396.
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The purpose of this thesis is to develop an interpretable model that gives predictions for what factors impacted a shooter’s results. Experiment is our chosen research method. Our three independent variables are weapon movement, trigger pull force and heart rate. Our dependent variable is shooting accuracy. A random forest regression model is trained with the experiment data to produce predictions of shooting accuracy and to show correlation between independent and dependent variables. Our method shows that an increase in weapon movement, trigger pull force and heart rate decrease the predicted accuracy score. Weapon movement impacted shooting results the most with 53.61%, while trigger pull force and heart rateimpacted shooting results 22.20% and 24.18% respectively. We have also shown that LIME can be a viable method to give explanations on how the measured factors impacted shooting results. The results from this thesis lay the groundwork for better training tools for target shooting using explainable prediction models with sensors.
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Brodell, Josefin. "LA MÚSICA ES AMOR y otras metáforas conceptuales por las que vivimos : La semántica y la estructura gramatical de metáforas traducidas." Thesis, Uppsala universitet, Institutionen för moderna språk, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-216182.
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In this thesis I have combined cognitive metaphor theory, based mostly on the theories of the book Metaphors we live by by Lakoff & Johnson, with translation theory in order to try and show how the former can contribute with useful analytical tools within me- taphor translation. More specifically, my objective is to try and show how the knowled- ge of how metaphor works according to the cognitive perspective can help translating metaphors in a way that corresponds to the recommendations established by Peter Newmark (1992), i.e. try to maintain, in as much as posible, both grammatical structure and semantics. Through a qualitative analysis I considered gramatical structure and se- mantics of three original literary metaphors taken from the swedish book ”Gösta Ber- lings saga” by Selma Lagerlöf, and their translations to spanish made by Slaby (1955). I identified how well the translations corresponded to the recommendations of Newmark, as well as suggested new translations based on the results of the cognitive analysis. As a result we could see the importance, not only of maintaining both source domain and tar- get domain of the original metaphor, or at least the epistemical correspondences in case the source domain changed, but also the ontological correspondences, the specific con- tact, that the original metaphor establishes between these two domains, for a translation that better follows the norms defined by Newmark. In other words, limited to these th- ree examples, I managed to confirm that a cognitive approach to metaphor can be very useful within translation.
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Mervin, Lewis. "Improved in silico methods for target deconvolution in phenotypic screens." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/283004.
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Target-based screening projects for bioactive (orphan) compounds have been shown in many cases to be insufficiently predictive for in vivo efficacy, leading to attrition in clinical trials. Phenotypic screening has hence undergone a renaissance in both academia and in the pharmaceutical industry, partly due to this reason. One key shortcoming of this paradigm shift is that the protein targets modulated need to be elucidated subsequently, which is often a costly and time-consuming procedure. In this work, we have explored both improved methods and real-world case studies of how computational methods can help in target elucidation of phenotypic screens. One limitation of previous methods has been the ability to assess the applicability domain of the models, that is, when the assumptions made by a model are fulfilled and which input chemicals are reliably appropriate for the models. Hence, a major focus of this work was to explore methods for calibration of machine learning algorithms using Platt Scaling, Isotonic Regression Scaling and Venn-Abers Predictors, since the probabilities from well calibrated classifiers can be interpreted at a confidence level and predictions specified at an acceptable error rate. Additionally, many current protocols only offer probabilities for affinity, thus another key area for development was to expand the target prediction models with functional prediction (activation or inhibition). This extra level of annotation is important since the activation or inhibition of a target may positively or negatively impact the phenotypic response in a biological system. Furthermore, many existing methods do not utilize the wealth of bioactivity information held for orthologue species. We therefore also focused on an in-depth analysis of orthologue bioactivity data and its relevance and applicability towards expanding compound and target bioactivity space for predictive studies. The realized protocol was trained with 13,918,879 compound-target pairs and comprises 1,651 targets, which has been made available for public use at GitHub. Consequently, the methodology was applied to aid with the target deconvolution of AstraZeneca phenotypic readouts, in particular for the rationalization of cytotoxicity and cytostaticity in the High-Throughput Screening (HTS) collection. Results from this work highlighted which targets are frequently linked to the cytotoxicity and cytostaticity of chemical structures, and provided insight into which compounds to select or remove from the collection for future screening projects. Overall, this project has furthered the field of in silico target deconvolution, by improving the performance and applicability of current protocols and by rationalizing cytotoxicity, which has been shown to influence attrition in clinical trials.
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Warell, Peter. "Metaphors of populists – A cognitive linguistic study of conceptual metaphors in political speeches by Donald J. Trump and Nigel Farage." Thesis, Umeå universitet, Institutionen för språkstudier, 2020. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-171752.
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The purpose of this thesis is to explore the use of conceptual metaphors in political speeches by Donald Trump and Nigel Farage. Conceptual metaphor theory is applied as the framework for the study. Metaphorical linguistic expressions are identified with help of the method Metaphor Identification Procedure (MIP). The conceptual metaphors giving rise to the metaphorical linguistic expressions are identified and categorized into different domains in the study. The analysis demonstrates that the use of metaphors is ubiquitous. The metaphors related to the salient domains of politics, nation, immigration, economy, and morality are discussed and further investigated in the analysis. The analysis shows that metaphors are employed in the construction of populist discourse and to evoke the emotion of fear by mainly drawing from embodied elements. A notable parallel between Trump and Farage is the use of the Moral Order metaphor which subsequently reveal their moral values.
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Dorison, Aude. "Le récepteur à domaine discoïdine de type 1 : un acteur majeur des pathologies rénales chroniques et aiguës." Thesis, Paris 6, 2016. http://www.theses.fr/2016PA066144/document.
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Les maladies rénales ont un impact socio-économique majeur sur la santé publique nécessitant le développement de nouvelles stratégies thérapeutiques. Le Récepteur à Domaine Discoïdine de type 1 (DDR1) est un récepteur non-intégrine des collagènes, à activité tyrosine-kinase. Son expression anormale est un facteur clé de la pathologie rénale qui promeut le développement de l’inflammation et de la fibrose.Ces travaux de thèse nous ont permis de démontrer que l'inhibition de DDR1 freinait la progression des maladies rénales dans trois modèles, dont l'un d'évolution aiguë, l'ischémie-reperfusion (I/R). Après I/R, les cellules épithéliales tubulaires proximales (CETP) exprimaient anormalement DDR1 et l'inhibition de ce récepteur empêchait l'acquisition d'un phénotype pro-inflammatoire par ce type cellulaire. Nous avons démontré in vitro que le stress du réticulum endoplasmique (RE), secondaire à l'hypoxie, était responsable de l'induction de DDR1, via l'activation du facteur de transcription CHOP. De plus, le profil d'expression de DDR1 dans des biopsies de patients transplantés était similaire à celui obtenu dans l'I/R expérimentale.Enfin, les résultats préliminaires obtenus dans un nouveau modèle de souris triples transgéniques ont montré l'installation d'une inflammation et d'une fibrose rénales secondaires à la surexpression génétiquement définie de DDR1 durant 4 semaines dans les cellules épithéliales tubulaires.En conclusion, nos résultats suggèrent que la surexpression de DDR1 joue un rôle délétère dans les néphropathies chroniques et aiguës, ce qui renforce l’intérêt du développement d’inhibiteurs spécifiques de DDR1 capables de bloquer la fonction de ce récepteur<br>Renal diseases lead to severe long-term complications of kidney function and only few preventive and therapeutic options exist. Discoidin Domain Receptor 1 (DDR1) is a non-integrin collagen receptor expressed in several cell types within the kidney. Its abnormal expression has a deleterious role in experimental chronic kidney diseases (CKD) by promoting renal inflammation and fibrosis.The inhibition of DDR1 stopped the progression of renal disease in two models of experimental CKD and protected renal function and structure in a model of acute kidney disease, ischemia-reperfusion (I/R). DDR1 expression was strongly induced in proximal epithelial tubular cells (PETCs) after I/R. Moreover, isolated PETCs from DDR1 heterozygous mice after I/R did not acquire the pro-inflammatory phenotype displayed by PETCs from WT mice. Endoplasmic reticulum (ER) stress was responsible for DDR1 pathological expression in hypoxic PETCs after I/R through the activation of CHOP transcription factor. Interestingly, biopsies of transplant patients with prolonged ischemia during transplantation had a very similar expression profile of DDR1 in proximal tubules as in experimental I/R.Finally, DDR1 overexpression in epithelial tubular cells for four weeks, in a new conditional transgenic mouse model, led to the development of renal inflammation and fibrosis.To conclude, our results suggest that the genetically-induced or the pathological overexpression of DDR1 promotes renal inflammation and fibrosis. Thus, targeting DDR1 can be a promising strategy in the treatment of renal diseases
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Dorison, Aude. "Le récepteur à domaine discoïdine de type 1 : un acteur majeur des pathologies rénales chroniques et aiguës." Electronic Thesis or Diss., Paris 6, 2016. http://www.theses.fr/2016PA066144.
Full textAbstract:
Les maladies rénales ont un impact socio-économique majeur sur la santé publique nécessitant le développement de nouvelles stratégies thérapeutiques. Le Récepteur à Domaine Discoïdine de type 1 (DDR1) est un récepteur non-intégrine des collagènes, à activité tyrosine-kinase. Son expression anormale est un facteur clé de la pathologie rénale qui promeut le développement de l’inflammation et de la fibrose.Ces travaux de thèse nous ont permis de démontrer que l'inhibition de DDR1 freinait la progression des maladies rénales dans trois modèles, dont l'un d'évolution aiguë, l'ischémie-reperfusion (I/R). Après I/R, les cellules épithéliales tubulaires proximales (CETP) exprimaient anormalement DDR1 et l'inhibition de ce récepteur empêchait l'acquisition d'un phénotype pro-inflammatoire par ce type cellulaire. Nous avons démontré in vitro que le stress du réticulum endoplasmique (RE), secondaire à l'hypoxie, était responsable de l'induction de DDR1, via l'activation du facteur de transcription CHOP. De plus, le profil d'expression de DDR1 dans des biopsies de patients transplantés était similaire à celui obtenu dans l'I/R expérimentale.Enfin, les résultats préliminaires obtenus dans un nouveau modèle de souris triples transgéniques ont montré l'installation d'une inflammation et d'une fibrose rénales secondaires à la surexpression génétiquement définie de DDR1 durant 4 semaines dans les cellules épithéliales tubulaires.En conclusion, nos résultats suggèrent que la surexpression de DDR1 joue un rôle délétère dans les néphropathies chroniques et aiguës, ce qui renforce l’intérêt du développement d’inhibiteurs spécifiques de DDR1 capables de bloquer la fonction de ce récepteur<br>Renal diseases lead to severe long-term complications of kidney function and only few preventive and therapeutic options exist. Discoidin Domain Receptor 1 (DDR1) is a non-integrin collagen receptor expressed in several cell types within the kidney. Its abnormal expression has a deleterious role in experimental chronic kidney diseases (CKD) by promoting renal inflammation and fibrosis.The inhibition of DDR1 stopped the progression of renal disease in two models of experimental CKD and protected renal function and structure in a model of acute kidney disease, ischemia-reperfusion (I/R). DDR1 expression was strongly induced in proximal epithelial tubular cells (PETCs) after I/R. Moreover, isolated PETCs from DDR1 heterozygous mice after I/R did not acquire the pro-inflammatory phenotype displayed by PETCs from WT mice. Endoplasmic reticulum (ER) stress was responsible for DDR1 pathological expression in hypoxic PETCs after I/R through the activation of CHOP transcription factor. Interestingly, biopsies of transplant patients with prolonged ischemia during transplantation had a very similar expression profile of DDR1 in proximal tubules as in experimental I/R.Finally, DDR1 overexpression in epithelial tubular cells for four weeks, in a new conditional transgenic mouse model, led to the development of renal inflammation and fibrosis.To conclude, our results suggest that the genetically-induced or the pathological overexpression of DDR1 promotes renal inflammation and fibrosis. Thus, targeting DDR1 can be a promising strategy in the treatment of renal diseases
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Baumlé, Véronique. "New insights into Bax-dependent cell death : characterization of inhibitory peptide aptamers and their targets." Thesis, Lyon, École normale supérieure, 2011. http://www.theses.fr/2011ENSL0698.
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Les aptamères peptidiques sont des protéines combinatoires capables de moduler spécifiquement une fonction de leur cible. Une sélection fonctionelle d’aptamères peptidiques capables d’inhiber la mort cellulaire Bax-dependante chez la levure et en cellules mammaifères a été effectuée. Deux aptamères peptidiques ont été sélectionnés (Apta-32 et Apta-34). L’objectif de ce travail de thèse a été de caractériser ces deux aptamères peptidiques et leur(s) cible(s) dans le contexte de la mort cellulaire Bax-dependante. La première partie est l’étude de l’Apta-34 qui cible une protéine (C34) contenant un domaine de mort et ayant des fonctions pro-apoptotiques. Nous avons montré que lors de l’induction de l’apoptose, C34 est transloquée du noyau (sa localisation principale) au cytoplasme. Dans les mêmes conditions, Apta-34 co-localise avec C34 dans le noyau, empêchant, ou du moins retardant, sa sortie du noyau. De plus nous avons identifié le site de liaison d’Apta-34 sur C34, qui est localisé dans les 215 amino acides en N-terminale de la protéine, une région qui contient un site prédictif d’export nucléaire. Finalement, nous avons montré que la délétion de l’homologue de C34 protège contre la mort induite par hBax en levure. La seconde partie est l’étude d’Apta-32 qui cible deux paralogues (C32a et b) d’une famille de protéine impliquée dans le traffic membranaire dans les voies de l’endocytose. Nous avons montré qu’Apta-32 se lie à un domaine fonctionnel de C32. Des études in silico de docking ont permis d’identifier trois sites distincts de liaison d’Apta-32 sur ce domaine. Le site dominant est composé d’acides aminés qui partagent des propriétés physico-chimiques communes entre les différents interacteurs d’Apta-32 (C32a, C32b et l’homologue levure) mais pas avec des homologues qui ne lient pas Apta-32. De plus un screening double hybride d’une banque de cDNA levure a permis d’identifier des cibles mevure d’Apta-32. Finalement, des études préliminaires chez l’embryons de drosophile, permettent de suggérer que l’expression d’Apta-32 peut entraîner un défaut de la phagocytose. Cette étude a permis d’identifier des régulateurs de la mort cellulaires impliqués dans deux processus cellulaires distincts<br>Peptide aptamers are small combinatorial proteins able to specifically modulate a function of their target. A functional selection of peptide aptamers able to inhibit Bax-dependent cell death in yeast and mammalian systems has been performed. Two peptide aptamers have been selected (Apta-32 and Apta-34). The aim of this thesis project was to characterize those two inhibitory peptide aptamers and their targets in order to understand their function in the Bax-dependent cell death. The first part focuses on Apta-34 that targets a Death Domain-containing protein (T34) that has pro-apoptotic functions. We showed that during the induction of apoptosis T34 translocates from nucleus (its major localization site) to the cytoplasm. In the same conditions, Apta-34 co-localizes with T34 in the nucleus, inhibiting or at least delaying its exit from the nucleus. Moreover we identified that Apta-34 binds to the well conserved 215 N-terminal amino acids of T34 that contains a putative Nuclear Export Signal. Finally we showed that the deletion of its homologue prevents hBax-induced cell death in yeast. The second part focuses on Apta-32 that targets two paralogues (T32a and b) of a family of proteins involved in the endocytotic membrane trafficking. We showed that Apta-32 is binding to a functional domain of T32. By in silico docking studies we identified 3 distinct binding sites of Apta-32 on this domain. The dominant binding site is composed by amino acid that share physico-chemical properties between binders of Apta-32 (T32a, T32b and a yeast homologue) but not with homologues that do not bind Apta-32. Moreover we identified yeast targets of Apta-32 by yeast two hybrid yeast cDNA library screening. Finally preliminary observations on drosophila embryos expressing Apta-32 suggest that Apta-32 expression could lead to a defect on phagocytosis. This study leads to the identification of regulators of the cell death acting on two distinct pathways
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Turner, Kenneth James. "Higher-order filtering for nonlinear systems using symmetric tensors." Thesis, Queensland University of Technology, 1999.
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Xie, He Fang. "Understanding the interaction between xylan-binding domains and their target ligands." Thesis, University of Newcastle Upon Tyne, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.324858.
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Wright, Roni H. G. "Identification of TOPBP1 chromatin modification domains and transcriptional targets." Thesis, University of Glasgow, 2007. http://theses.gla.ac.uk/30970/.
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Topoisomerase II β-binding protein 1 (TopBP1) is an essential BRCT domain containing protein involved in DNA damage signalling, replication and repair. BRCT domains have the ability to bind single and double stranded DNA as well as phosphopeptides and are found within a large group of proteins involved in the DNA damage response. These domains give the proteins the ability to bind damaged DNA and change their interacting partners following DNA damage, making their role in the DNA damage response essential for efficient signal transduction and the activation of DNA damage checkpoint and repair. TopBP1 binds single and double stranded DNA and co-localises to sites of DNA damage with other sensory proteins including BRCA1, NBS1 and Rad9 and is an essential protein in the activation of the downstream checkpoints and the initiation of cell cycle arrest. No other protein contains as many as eight BRCT domains indicating that TopBP1 plays an essential role in these responses. TopBP1 has been implicated as a possible transcription factor activating transcription of the HPV16 transcription/replication protein E2 and repressing the activation of E2F1 and Miz1. The modification of chromatin is essential for all functions of TopBP1; this thesis has describes the identification of three chromatin modification domains within three distinct BRCT domains of TopBP1. The function of one of these domains is mediated by a direct interaction with the chromatin remodelling enzyme Brgl and the transcriptional regulation by this protein-protein interaction is regulated by DNA damage. The identification of these domains and their regulation by DNA damage provides further insight into the mechanism of DNA damage signalling, repair, transcription and replication by TopBP1 via the modification of chromatin. In addition to the identification of chromatin modification domains, gene targets of TopBP1 were also identified. This was carried out using MCF7 cells with endogenous TopBP1 down-regulated by siRNA treatment. These studies identified several pathways regulated by TopBP1 expression, all of which play a role in breast carcinogenesis. These results provide more evidence supporting a role for TopBP1 in the development of breast cancer; previous studies have shown aberrant expression of TopBP1 in breast cancers as well as polymorphisms pre-disposing towards this disease.
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Chapman, Edwin R. "Functional domains of neuromodulin and the interaction of calmodulin with target peptides /." Thesis, Connect to this title online; UW restricted, 1992. http://hdl.handle.net/1773/6288.
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Plotkowski, Megan Lynn. "Characterization and modulation of transmembrane domain interactions in membrane protein drug-targets." Diss., Restricted to subscribing institutions, 2008. http://proquest.umi.com/pqdweb?did=1666392021&sid=2&Fmt=2&clientId=1564&RQT=309&VName=PQD.
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Woodbury, Nathan Scott. "Representation and Reconstruction of Linear, Time-Invariant Networks." BYU ScholarsArchive, 2019. https://scholarsarchive.byu.edu/etd/7402.
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Network reconstruction is the process of recovering a unique structured representation of some dynamic system using input-output data and some additional knowledge about the structure of the system. Many network reconstruction algorithms have been proposed in recent years, most dealing with the reconstruction of strictly proper networks (i.e., networks that require delays in all dynamics between measured variables). However, no reconstruction technique presently exists capable of recovering both the structure and dynamics of networks where links are proper (delays in dynamics are not required) and not necessarily strictly proper.The ultimate objective of this dissertation is to develop algorithms capable of reconstructing proper networks, and this objective will be addressed in three parts. The first part lays the foundation for the theory of mathematical representations of proper networks, including an exposition on when such networks are well-posed (i.e., physically realizable). The second part studies the notions of abstractions of a network, which are other networks that preserve certain properties of the original network but contain less structural information. As such, abstractions require less a priori information to reconstruct from data than the original network, which allows previously-unsolvable problems to become solvable. The third part addresses our original objective and presents reconstruction algorithms to recover proper networks in both the time domain and in the frequency domain.
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Antoniadou, Eleni. "Studies on the biochemistry of the targetin domain of Lysostaphin." Thesis, University of Nottingham, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.411404.
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Benavides, Iglesias Alfonso. "Experimental time-domain controlled source electromagnetic induction for highly conductive targets detection and discrimination." Texas A&M University, 2003. http://hdl.handle.net/1969.1/5810.
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The response of geological materials at the scale of meters and the response
of buried targets of different shapes and sizes using controlled-source electromagnetic
induction (CSEM) is investigated. This dissertation focuses on three topics; i) frac-
tal properties on electric conductivity data from near-surface geology and processing
techniques for enhancing man-made target responses, ii) non-linear inversion of spa-
tiotemporal data using continuation method, and iii) classification of CSEM transient
and spatiotemporal data.
In the first topic, apparent conductivity profiles and maps were studied to de-
termine self-affine properties of the geological noise and the effects of man-made con-
ductive metal targets. 2-D Fourier transform and omnidirectional variograms showed
that variations in apparent conductivity exhibit self-affinity, corresponding to frac-
tional Brownian motion. Self-affinity no longer holds when targets are buried in the
near-surface, making feasible the use of spectral methods to determine their pres-
ence. The difference between the geology and target responses can be exploited using
wavelet decomposition. A series of experiments showed that wavelet filtering is able
to separate target responses from the geological background.
In the second topic, a continuation-based inversion method approach is adopted,
based on path-tracking in model space, to solve the non-linear least squares prob-
lem for unexploded ordnance (UXO) data. The model corresponds to a stretched-
exponential decay of eddy currents induced in a magnetic spheroid. The fast inversion of actual field multi-receiver CSEM responses of inert, buried ordnance is also shown.
Software based on the continuation method could be installed within a multi-receiver
CSEM sensor and used for near-real-time UXO decision.
In the third topic, unsupervised self-organizing maps (SOM) were adapted for
data clustering and classification. The use of self-organizing maps (SOM) for central-
loop CSEM transients shows potential capability to perform classification, discrimi-
nating background and non-dangerous items (clutter) data from, for instance, unex-
ploded ordnance. Implementation of a merge SOM algorithm showed that clustering
and classification of spatiotemporal CSEM data is possible. The ability to extract tar-
get signals from a background-contaminated pattern is desired to avoid dealing with
forward models containing subsurface response or to implement processing algorithm
to remove, to some degree, the effects of background response and the target-host
interactions.
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Webb, Stacy. "Viral Fusion Protein TM-TM Interactions: Modulators of Protein Function and Potential Antiviral Targets." UKnowledge, 2017. http://uknowledge.uky.edu/biochem_etds/30.
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Enveloped viruses, such as HIV, influenza, and Ebola, utilize surface glycoproteins to bind and fuse with a target cell membrane. This fusion event is necessary for release of viral genomic material so the virus can ultimately reproduce and spread. The recently emerged Hendra virus (HeV) is a negative-sense, single-stranded RNA paramyxovirus that presents a considerable threat to human health as there are currently no human vaccines or antivirals available. The HeV utilizes two surface glycoproteins, the fusion protein (F) and the attachment protein (G), to drive membrane fusion. Through this process, the F protein undergoes an irreversible conformational change, transitioning from a meta-stable pre-fusion conformation to a more thermodynamically stable post-fusion structure. Understanding the elements which control stability of the pre-fusion state and triggering to the post-fusion conformation is important for understanding F protein function. Studies that replace or mutate the TM domain of the F protein of several viruses implicated the TM domain in the fusion process, but the structural and molecular details in fusion remain unclear. Previously, analytical ultracentrifugation was used to demonstrate that isolated TM domains of HeV F protein associate in a monomer-trimer equilibrium. To determine factors driving this association, we analyzed the sequence of several paramyxovirus F protein TM domains and found a heptad repeat of β-branched residues. Analysis of the HeV F TM domain specifically revealed a heptad repeat leucine-isoleucine zipper motif (LIZ). Replacement of the LIZ with alanine resulted in dramatically reduced TM-TM association. Mutation of the LIZ in the whole protein resulted in decreased protein expression and pre-fusion conformation. To further understand the role of the TM domain, the TM domain was targeted as a potential modulator of F protein stability and function. Exogenous HeV F TM constructs were co-expressed with the full length F protein in Vero cells to analyze the effects on protein expression. Co-expression of the exogenous HeV F TM constructs dramatically reduced the expression of HeV F. However, the co-expression of exogenous HeV F TM constructs with a different paramyxovirus F protein, PIV5 F, did not strongly affect PIV5 F expression levels, suggesting that the interaction of the exogenous TM constructs is specific. Fusion assays revealed that HeV F TM constructs dramatically reduced HeV F, but not PIV5 F fusion activity. We hypothesize that the short exogenous HeV TM constructs associate with the TM domain from full-length HeV F, resulting in pre-mature triggering or protein misfolding. The work presented here demonstrates that specific elements in the TM domain contribute to TM association and pre-fusion protein stability. Furthermore, targeting these interactions may be a viable approach for antiviral development against this important pathogen.
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Marshall, Jolene, Eric R. LeMay, Joshua Tapp, et al. "An Analysis of the Open Architecture Warfare System Domain Model for surface time critical targets." Thesis, Monterey, California. Naval Postgraduate School, 2007. http://hdl.handle.net/10945/6933.
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This study's objective is to evaluate the Open Architecture Warfare System Domain Model (OAWSDM) against time critical targets with specific focus on command, control, and communication processes. A functional analysis of the OAWSDM was conducted and synthesized to create the Open Architecture Time Critical Target Engagement Process Model (OATCTEPM). This model represents the notional engagement cycle of a Navy cruiser. Two scenarios were developed to exercise the system: a surprise assault from a number of personal watercraft and a saturation assault in which approximately fifty craft of varying sizes attack. Results from these scenarios were analyzed for system bottlenecks and recommendations were made to improve decision making processes and reduce engagement time. This study concludes that while the OAWSDM may offer no technical flaws in its design, it fails to factor in the role of the human in the decision making and engagement processes. In doing so it overlooks a key factor in the effectiveness of the architecture against surface TCT engagements.
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Stenvi, Teddie. "An automated testing strategy targeted for efficient use in the consulting domain." Thesis, Blekinge Tekniska Högskola, Avdelningen för programvarusystem, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:bth-2863.
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Test automation can decrease release cycle time for software systems compared to manual test execution. Manual test execution is also considered inefficient and error-prone. However, few companies have gotten far within the field of test automation. This thesis investigates how testing and test automation is conducted in a test consulting setting. It has been recognized that low test process maturity is common in customer projects and this has led to equally low system testability and stability. The study started with a literature survey which summarized the current state within the field of automated testing. This was followed by a consulting case study. In the case study it was investigated how the identified test process maturity problems affect the test consulting services. The consulting automated testing strategy (CATS) been developed to meet the current identified challenges in the domain. Customer guidelines which aim to increase the test process maturity in the customer organization have also been developed as a support to the strategy. Furthermore, the study has included both industrial and academic validation which has been conducted through interviews with consultant practitioners and researchers.
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Vallabh, Sushmitha. "Targeted Epigenetic Suppression of Th2 Cytokines Expression." University of Cincinnati / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1505131225205869.
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Sala, Margaux. "Implication des récepteurs à domaine discoïdine dans la résistance à la thérapie ciblée au cours du mélanome." Thesis, Bordeaux, 2019. http://www.theses.fr/2019BORD0400.
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La combinaison de deux traitements, un anti-BRAF et un anti-MEK est actuellement utilisée en première ligne de traitement dans la prise en charge des patients ayant un mélanome métastatique porteur de la mutation somatique BRAF V600E. Cependant, le problème majeur dans le mélanome est l'acquisition d'une résistance cellulaire chez 80% des patients, qui est associée à une augmentation de la formation de métastases, notamment due à l'hyper-activation de la voie des MAP kinases. Or, les récepteurs à domaine discoïdine DDR1 et DDR2 sont capables d’activer cette voie de signalisation. Les DDRs sont surexprimés dans de nombreux cancers où ils sont associés à des phénomènes de résistance et de récidives. Notre projet a donc pour but d’analyser l’implication des DDRs dans la résistance des cellules tumorales de mélanome à la thérapie ciblée. En premier lieu, nous avons déterminé que les DDRs sont surexprimés dans les cellules résistantes au Vemurafenib par rapport aux cellules sensibles. L’hypothèse posée est que les lignées cellulaires résistantes, malgré la bithérapie, sont capables de suractiver la voie des MAP kinases par l'induction des DDRs. De plus, nous avons démontré que la diminution de l’expression des DDRs par des inhibiteurs des DDRs, comme le Dasatinib ou le CR-13542, induit une diminution de la prolifération tumorale due à une baisse du niveau d’activité de la voie MAP kinase. Enfin, nous avons confirmé ces résultats in vivo, dans un modèle murin de xénogreffe. Par conséquent, nous avons identifié les DDRs comme étant de nouvelles cibles thérapeutiques chez les patients résistants atteints de mélanome métastatique. De ce fait, nous proposons que le Dasatinib (possédant déjà une autorisation de mise sur le marché) puisse être utilisé en deuxième intention, après un traitement à la bithérapie ciblée, chez les patients résistants surexprimant les DDRs<br>The combination of two treatments, an anti-BRAF plus an anti-MEK is currently used in first line in patient management presenting metastatic melanomas and harboring the BRAF V600E somatic mutation. However, the main issue during targeted therapy is the acquisition of cellular resistance in 80% of the patients, which is associated with an increase of metastasis formation, notably due to the hyperactivation of MAP kinase pathway. Different receptors are known to activate this signaling pathway and previous reports have indicated that Discoidin Domain Receptors (DDRs) 1 and 2 can activate MAP kinase pathway. Then, in order to study the role of DDRs in melanoma cells resistance to the targeted therapy, we firstly determined, that DDRs are overexpressed in Vemurafenib resistant cells compared to sensitive ones. We hypothesized that resistant cell lines, despite the bi-therapy, are able to over-activate MAP kinase pathway through DDRs activation. We also reported that DDRs depletion or inactivation by DDRs inhibitors such as Dasatinib or CR-13542 reduced tumor cell proliferation, due to a decrease of MAP kinase pathway activity in resistant cells. We finally confirmed those results in vivo, in a xenograft mouse model. As a result, we characterized DDRs as new therapeutic targets in resistant patient with metastatic melanoma. Therefore, we propose that Dasatinib, an FDA approved drug, could be a second treatment after the targeted bi-therapy in resistant patients overexpressing DDRs
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Kontitsis, Michail. "Design and implementation of an integrated dynamic vision system for autonomous systems operating in uncertain domains." [Tampa, Fla] : University of South Florida, 2009. http://purl.fcla.edu/usf/dc/et/SFE0002852.
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Appleton, Caroline E. "Standard Practice in Early Intervention: Targeted Domains Within Individualized Family Service Plans." The Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1397730621.
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Kota, Madhava Reddy, and Binod Shrestha. "Global Backprojection for Imaging of Targets Using M-sequence UWB radar system." Thesis, Högskolan i Gävle, Akademin för teknik och miljö, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:hig:diva-15656.
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Synthetic Aperture Radar (SAR) is an emerging technique in remote sensing. The technology is capable of producing high-resolution images of the earth surface in all-weather conditions. Thesis work describes the present available methods for positioning and imaging targets using M-sequence UWB (Ultra-Wideband) radar signals with moving antennas and SAR algorithm to retrieve position and image of the target. M-sequence UWB radar technology used as signal source for transmission and receiving echoes of target. Pseudo random binary sequence is used as a transmitted signal. These radars have an ability to penetrate signal through natural and unnatural objects. It offers low cost and quality security system. Among a number of techniques of image retrieval in Synthetic Aperture Radar, study of Global back projection (GBP) algorithm is presented. As a time domain algorithm, GBP possesses inherent advantages over frequency domain algorithm like ability to handle long integration angle, wider bandwidth and unlimited aperture size. GBP breaks the full synthesis aperture into numbers of sub-apertures. These sub-apertures are treated pixel by pixel. Each sub-aperture is converted to a Cartesian image grid to form an image. During this conversion the signal is treated with linear interpolation methods in order to achieve the best quality of the images. The objective of this thesis is the imaging of target using M-sequence UWB radar and processing SAR raw data using Global back projection algorithm.
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Roßbach, André Christian. "Evaluation of Software Architectures in the Automotive Domain for Multicore Targets in regard to Architectural Estimation Decisions at Design Time." Master's thesis, Universitätsbibliothek Chemnitz, 2015. http://nbn-resolving.de/urn:nbn:de:bsz:ch1-qucosa-163372.
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In this decade the emerging multicore technology will hit the automotive industry. The increasing complexity of the multicore-systems will make a manual verification of the safety and realtime constraints impossible. For this reason, dedicated methods and tools are utterly necessary, in order to deal with the upcoming multicore issues. A lot of researchprojects for new hardware platforms and software frameworks for the automotive industry are running nowadays, because the paradigms of the “High-Performance Computing” and “Server/Desktop Domain” cannot be easily adapted for the embedded systems. One of the difficulties is the early suitability estimation of a hardware platform for a software architecture design, but hardly a research-work is tackling that. This thesis represents a procedure to evaluate the plausibility of software architecture estimations and decisions at design stage. This includes an analysis technique of multicore systems, an underlying graph-model – to represent the multicore system – and a simulation tool evaluation. This can guide the software architect, to design a multicore system, in full consideration of all relevant parameters and issues<br>In den nächsten Jahren wird die aufkommende Multicore-Technologie auf die Automobil-Branche zukommen. Die wachsende Komplexität der Multicore-Systeme lässt es nicht mehr zu, die Verifikation von Sicherheits- und Echtzeit-Anforderungen manuell auszuführen. Daher sind spezielle Methoden und Werkzeuge zwingend notwendig, um gerade mit den bevorstehenden Multicore-Problemfällen richtig umzugehen. Heutzutage laufen viele Forschungsprojekte für neue Hardware-Plattformen und Software-Frameworks für die Automobil-Industrie, weil die Paradigmen des “High-Performance Computings” und der “Server/Desktop-Domäne” nicht einfach so für die Eingebetteten Systeme angewendet werden können. Einer der Problemfälle ist das frühe Erkennen, ob die Hardware-Plattform für die Software-Architektur ausreicht, aber nur wenige Forschungs-Arbeiten berücksichtigen das. Diese Arbeit zeigt ein Vorgehens-Model auf, welches ermöglicht, dass Software-Architektur Abschätzungen und Entscheidungen bereits zur Entwurfszeit bewertet werden können. Das beinhaltet eine Analyse Technik für Multicore-Systeme, ein grundsätzliches Graphen-Model, um ein Multicore-System darzustellen, und eine Simulatoren Evaluierung. Dies kann den Software-Architekten helfen, ein Multicore System zu entwerfen, welches alle wichtigen Parameter und Problemfälle berücksichtigt
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PICCI, CRISTINA. "Exploitation of new pharmacological targets for neuropathic pain reliefe." Doctoral thesis, Università degli Studi di Cagliari, 2015. http://hdl.handle.net/11584/266610.
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Neuropathic pain is a complex chronic condition which affects the somatosensory system, poorly managed with the conventional treatments despite the immense advances in pain treatment strategies. Damage of peripheral nervous system, due to injury or disease, leads to abnormal responses to painful and not-painful stimuli; conventional analgesics can only alleviate pain in acute situation, and finding an effective treatment which can relief chronic neuropathic pain remains still challenging.
Mammalian STOML3, a MEC-2 homologue, is a member of a large family of stomatin proteins characterized by a common stomatin domain, expressed by DRG sensory neurons involved in regulation of mechanosensation, which is required for normal mechanoreceptor function. Previous data revealed that in STOML3 null mice 30-40% of Aδ and Aβ fibers lacked all mechanosensitivity; in addition, tactile behaviors are impaired and symptoms of neuropathic pain in CCI mice are also largely attenuated (Wetzel et al, 2007).
Here I investigated the mechanisms by which STOML3 acts as an important contributor in the neuropathic pain symptoms and I demonstrate that small molecule modulation that both reversibly silence mechanoreceptors in vivo and attenuate touch perception in mice can reverse established neuropathic pain symptoms, making STOML3 a promising novel peripheral target for the treatment of sensory disorders.
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Schreiber, Sabine [Verfasser]. "Targeted loss of SET domain-containing protein 5 impairs cardiac morphology and function in vivo / Sabine Schreiber." Ulm : Universität Ulm, 2019. http://d-nb.info/1177882574/34.
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Magyar, Matthew A. "A novel technique for determining the calcium-binding properties of the two domains of calmodulin in the presence of target peptides." Connect to resource, 2010. http://hdl.handle.net/1811/45465.
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GRILLO, BARBARA. "PARTNERS, TARGETS AND MODULATORS OF LSD1 IN STRESS-RESPONSE REGULATION." Doctoral thesis, Università degli Studi di Milano, 2019. http://hdl.handle.net/2434/612975.
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In mammals, different forms of stress, including psychosocial stress, can affect various aspects of human health, promoting mood and anxiety disorders. However, very little is known about the mechanisms underlying the brain physiology of stress response, hindering the development of new therapeutic strategies. We uncover a role for the transcriptional corepressor Lysine Specific Demethylase-1 (LSD1) and its dominant negative splicing isoform neuroLSD1, in the modulation of emotional behavior. In the mouse hippocampus, LSD1 and neuroLSD1 interacting with the transcription factor Serum Response Factor (SRF) and SRFΔ5 participate as molecular transducers of stress stimuli. Likewise LSD1, also SRF is modulated by an alternative splicing isoform without transactivation domain, SRFΔ5. Psychosocial stress acutely reduces the expression of neuroLSD1 through a splicing-based modulation that results in an increase in the amount of LSD1, while the relative ratio between SRF and SRFΔ5 is sensitive both to ASDS and CSDS. Furthermore, SRFΔ5 shows SUS-restricted downregulation that might contribute to shaping psychosocial stress vulnerability, through interfering with homeostatic mechanisms underlying stress resiliency. All these data suggest the involvement of the dual LSD1/neuroLSD1 and SRF/SRFΔ5 in the adaptive response to stress.
Alternative splicing is a strategic biological mechanism that allows to create a set of functionally different gene products from a single gene, diversifying gene functions without an increase in the number of genes. neuroLSD1, an activity-dependent splicing isoform that differs from LSD1 for the inclusion of exon 8a, was related to important homeostatic neuronal functions impacting emotional processing. It has recently been published that MALAT1(metastasis associated lung adenocarcinoma transcript 1), a long non-coding RNA, has a crucial role in the alternative splicing mechanism of some genes through the regulation of the splicing factor SRSF1, belonging to the SR protein family. In particular MALAT1 is mainly localized at the level of the nuclear speckles, where it seems to regulate the alternative splicing through the retention of SRSF1 in these nuclear domains and the modulation of their phosphorylation state through an unknown mechanism. We already published that alternative splicing involving LSD1 is positively regulated in trans by two splicing factors NOVA1 and nSR100. In particular, nSR100 is a splicing factor belonging to the SR protein family, as SRSF1, and regulates tissue-specific alternative splicing in a manner dependent on its concentration and its phosphorylation status.
We propose MALAT1 as a negative modulator of the neurospecific splicing of LSD1, in particular following ASDS the increased levels of MALAT1 lead to the sequestration of nSR100 at the level of nuclear speckles, making clear the mechanism behind the decrease of the dominant negative neuroLSD1 expression levels following stress
We found that following a chronic psychosocial stress the expression levels of MALAT1 seem to be positively regulated only in resilient individuals who manage to maintain physiological expression levels of IEG in the hippocampus. Our hypothesis is that only resilient subjects are still able to modulate maladaptive stress-related transcription, thanks to the increased levels of MALAT1, bringing the system back to basal physiological conditions through the negative regulation of neuroLSD1 formation. All this suggests that MALAT1 could be considered a possible hallmark of resilience.
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Pagano, Mario Angelo Primo. "Dismantling the aberrant signaling network in chronic lymphocytic leukemia: PP2A and SHP-1 as promising targets for drug discovery." Doctoral thesis, Università degli studi di Padova, 2017. http://hdl.handle.net/11577/3426201.
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Reversible protein phosphorylation is a fundamental post-translational modification by which virtually all cellular events are regulated, enabling cells to properly respond to intra- and extracellular cues. Protein kinases and protein phosphatases are the principal factors involved in this in this dynamic process and are placed at the different levels of cellular signalling, and, albeit traditionally considered as functionally opposed to one another, not rarely act in an interplay to finely orchestrate and appropriately drive signal transduction. The imbalance of their expression and function affects the cell life and fate, which frequently underlies the onset and progression of a plethora of diseases. B cell chronic lymphocytic leukemia (CLL), the most common leukemia in the Western world, is no exception to this paradigm, many studies having highlighted a crucial role of kinases in the sustained signals from the signalosome downstream of the B cell receptor (BCR), and having led to the development of the promising second-line drugs, but also the blockade of a number of phosphatases underlying pro-survival and anti-apoptotic signals. In this regard, Protein Phosphatase 2A (PP2A) and the Src homology 2 domain-containing phosphatase 1 (SHP-1) exhibit a marked functional inhibition in this disease, which can be properly circumvented by a pharmacological approach, thereby inducing apoptosis of cancer cells. Nintedanib and MP-0766, a drug acting as an angiokinase inhibitor and a new fingolimod analogue devoid of immunosuppressive action, activating respectively SHP-1 and PP2A have enabled for the discovery of a signalling axis that when activated provokes massive cell death, and might provide a new paradigm for the treatment of CLL, which now endorses kinase inhibitors.<br>La fosforilazione proteica è una fondamentale modificazione post-traduzionale che regola virtualmente tutti i processi cellulari, permettendo alla cellula di rispondere a stimoli intra- ed extracellulari. Le protein chinasi e le protein fosfatasi sono i fattori principali coinvolti in questo processo dinamico e si localizzano a diversi livelli del signaling cellulare, e, sebbene tradizionalmente considerate opposte le une alle altre sotto il profilo funzionale, non raramente compartecipano per finemente modulare e opportunamente dirigere la trasduzione del segnale. Uno squilibrio di espressione e/o funzione di questi fattori si riflette sulla vita e il destino della cellula, cosa che frequentemente è alla base dell’insorgenza nocnhé l’evoluzione di un gran numenro di patologie. La leucemia linfatica cronica a cellule B (B Chronic Lymphocytic Leukemia, CLL), la più comune leucemia in occidente, non fa eccezione a tale paradigma e, sebbene la ricerca per lo più si è concentrata sull’anomala attività di diverse protein chinasi con lo sviluppo di promettenti farmaci di seconda linea, sempre più di frequente viene confermata l’ipotesi che la sopravvivenza e la resistenza all’apoptosis delle cellule tumorali dipende anche dalla ridotta espressione o funzionalità delle protein fosfatasi. A questo riguardo, la protein fosfatasi 2A (Protein Phosphatase 2A, PP2A) e la fosfatasi 1 contenente domini Src homology 2 (Src Homology 2 domain-containing phosphatase 1 (SHP-1) in questa patologia si dimostrano funzionalmente inibiti, ma che, quando opportunamente attivate farmacologicamente, inducono morte delle cellule tumorali. Nintedanib, un farmaco che agisce come inibitore 'angiochinasico”, e MP-0766, un nuovo analogo del fingolimod privo di azione immunosoppressiva, si sono dimostrati in grado di attivare SHP-1 e PP2A rispettivamente, permettendo inoltre di individuare un asse di signaling cellulare che provoca la morte di celle cellule leucemiche, potenzialmente rappresentando un nuovo paradigma per il trattamento della CLL, che ad oggi privilegia gli inibitori chinasici.