Studies demonstrated ADAMTS13 possesses unique properties with a mystifying regulatory mechanism. ADAMTS13’s role is in its proteolytic function to its VWF. The disparity in the hemostatic balance between ADAMTS13 activity and the distribution of VWF multimers could result in the bleeding disorder Von Willebrand Disease (VWD) or the thrombotic disorder thrombotic thrombocytopenic purpura (TTP). ADAMTS13 is constitutively secreted as an active protease, yet VWF retains its capacity to recruit platelets. This ability makes ADAMTS13 an enigmatic protease with an unknown regulatory mechanism. Currently, the postulated regulatory mechanism of ADAMTS13 is in its open/closed conformation, yet ADAMTS13 activity is retained in both forms. Literature showed that few proteases are capable of degrading ADAMTS13 in-vitro. We hypothesize that the partial degradation of ADAMTS13 regulates its activity, thereby stabilizing VWF and promoting thrombosis. The goals of this project were to develop and optimize in-vitro plasma BioID to identify novel interactions to ADAMTS13, validate novel interactions, identify proteases capable of degrading ADAMTS13 and their proteolytic sites, and develop protease-resistant ADAMTS13 mutants as novel therapeutics to thrombotic disorders. We optimized the BioID technique to be used in-vitro in plasma, to study novel interactions with ADAMTS13. Our results identified novel potential interactions with vitronectin or plasminogen. Validation studies disregarded vitronectin’s interaction and confirmed plasminogen’s interaction through the CUB and Kringle domains in a lysine-dependent manner. Further, the list of proteases capable of degrading ADAMTS13 was expanded to include FXIa and neutrophil-derived proteases including Cathepsin G, elastase, and hPR3. Activated neutrophils played a stronger role than coagulation proteases in degrading ADAMTS13 in vivo, while also demonstrating that elastase is a more potent regulator. Proteolytically degraded sites on ADAMTS13 were identified and proteolytic-resistant ADAMTS13 mutants were produced accordingly, which we aim to be utilized as a novel therapeutic to thrombotic disorders. / Thesis / Doctor of Philosophy (Medical Science)

La Bruton tyrosine kinase ou Btk est une protéine dont le rôle dans la maturation des lymphocytes B est connu depuis plusieurs années. Par contre, son rôle dans le contrôle de l’immunité innée est moins établi. Nous avons montré que, en réponse à la voie des Toll like Receptors ou TLRs, Btk régule la stabilité de l’ARN messager du TNF-α par l’intermédiairede la protéine TTP ou Tristétraproline. Par ailleurs, nous avons montré que l’expression d’un microARN, le miR-346, régulait négativement la protéine Btk et donc la synthèse de TNF-α. L’amplification de l’expression de ce miR-346 par transfection permet d’avoir un effet anti-TNF-α et anti-Btk interessant notamment dans le modèle cellulaire de la polyarthrite rhumatoïde. Enfin, nous avons montré que, en réponse au TLRs, la modulation de l’expression du TNF-α en fonction de l’état de méthylation de l’ADN et d’acétylation des histones dépendait directement de l’expression du couple miR-346 et Btk. Btk est donc une protéine charnière dans le contrôle de l’inflammation par les mécanismes épigénétiques que sont les miARNs, la méthylation de l’ADN et l’acétylation des histones. Sur le plan thérapeutique, l’inhibition de cette protéine par ces différents mécanismes de régulation semble donc être très interessante, à la fois dans les maladies inflammatoires et néoplasiques. / Bruton tyrosine kinase, or Btk, is a protein whose role in the maturation of B cells has been known for several years. However, its role in the control of innate immunity is less established. We have shown that, in response to Toll like Receptors pathway or TLRs, Btk regulates the stability of the mRNA of TNF-α via the TTP or Tristetraprolin protein. Furthermore, we showed that the expression of microRNA, the miR-346, negatively regulated the Btk protein and thus the synthesis of TNF-α. Upregulation of miR-346 by transfection act as an anti-TNF-α and anti-Btk drugs, especially in the cellular model of rheumatoid arthritis.Finally, we showed that, in response to TLRs, the modulation of the expression of TNF-α according to the state of DNA methylation and histone acetylation depended directly on crosstalk beetween miR-346 and Btk. Btk is a key protein in the control of inflammation by epigenetic mechanisms such as miRNAs, DNA methylation and histone acetylation. As therapeutic interest, inhibition of Btk by those different regulatory mechanisms seems to be very interesting, both in inflammatory and neoplastic diseases.

This work is about Hierarchical agregation and it describes its parts in the rst part of this work. Next is described its parts, main features and properties in this rst part. Document describes the possibilities of realization. Second part describes an analysis of the stability problem. Realizes the detection of failures of the Feedback target stations by the implemented protocol. The protocol is programaticly realized in JAVA language and tested in the real enviroment. In this document it is described an function of bandwidth on the speed of failure detection. The issues of detection of failure on the feedback target manager machine are discussed in this document.

This thesis deals with locating station in the digital television broadcast over the Internet Protocol. The aim of this thesis was to develop a general model for the location of stations in the system of internet TV. This work deals with the five known methods for locating stations in distributed systems, which compares as many criteria, such as coordinates of computation speed, accuracy of results. Based on the evaluation was selected optimal method, which has been incorporated into the simulation program IPTV and tested. The result of this work is the source code of the implemented methods.

This work is about Hierarchical agregation and it describes its parts in the rst part of this work. Next is described its parts, main features and properties in this rst part. Document describes the possibilities of realization. Second part describes an analysis of the stability problem. Realizes the detection of failures of the Feedback target stations by the implemented protocol. The protocol is programaticly realized in JAVA language and tested in the real enviroment. In this document it is described an function of bandwidth on the speed of failure detection. The issues of detection of failure on the feedback target manager machine are discussed in this document.

The number of reported cybercrimes in Sweden is increasing every year. Cybercrimes arebecoming more sophisticated and the attackers are more skilled than before. Attackers usedifferent tactics, techniques and procedures, TTP, to establish their goals. These TTP can beidentified and later used to combat future cyberattacks. This process is known as TacticalThreat Intelligence, TTI, and is characterized by the use of open source intelligence, OSINT, to gather information about previous attacks and TTP. This paper is a literature review toprovide a background of the topic. To further investigate the topic this paper also presents theanalyzis of three different threat intelligence sharing platforms to deepen the understanding ofhow TTI is used today. A statistical analysis is also presented in order to predict future ofcyberthreats. The results of the analysis of the threat intelligence sharing platforms clearly displays theneed to search for information in more than one source. This information will become thefoundation of intelligence, which makes information gathering one of the most importantsteps when working with TTI. The results of the statistical analysis show that cybercrime inSweden will continue to rise. One of the biggest challenges was to identify the current stateof the global cyberthreat landscape since global statistics for cybercrime could not be found.However, the Covid-19 pandemic has forced more people to work from home which hasincreased the number of potential cybercrime victims since home security tends to be lowerthan at a physical offic. Despite this, the number of reported cybercrimes has not increasedremarkably.

Submitted by Maike Costa (maiksebas@gmail.com) on 2017-05-23T14:51:55Z No. of bitstreams: 1 arquivototal.pdf: 7468223 bytes, checksum: d6989870b5f353c5592a40ac6ebb0333 (MD5) / Made available in DSpace on 2017-05-23T14:51:55Z (GMT). No. of bitstreams: 1 arquivototal.pdf: 7468223 bytes, checksum: d6989870b5f353c5592a40ac6ebb0333 (MD5) Previous issue date: 2016-05-07 / For many years the power transmission and movement for gears has been an important technology in the automotive, mechanical and aeronautical industries, justifying the considerable number of research carried out under the quality control of these components. Nowadays, involute profile inspections of cylindrical gears have been carried out using CNC Coordinate Measuring Machines (CMMs) with rotary tables and dedicated measurement software, equipped with contact scanning sensors, Touch Trigger Probes – TTP or non-contact, Laser. However, many companies that manufacture and inspect gears use manual CMMs with point to point sensors, thus being unable to issue the profile deviation report. In respect, the motivation for this research is to develop and validate inspection strategies for determining the Total Profile Deviation (Fα) of spur gears, according to ISO 1328, using of a mathematical tool NURBS (Non-Uniform Rational B-Splines) and CMMs manual. Strategies for changing the NURBS weight parameter wi also were applied to assist in inspection definition procedure, and this is one more degree of freedom. In the first moment, before the execution of experimental procedures, simulations were carried out on a computational system and showed satisfactory results. For the experimental tests, a manual CMM MICRO-HITE 3D model was used with point to point sensor. Simulations and experimental results showed that the NURBS technique contributes to manual CMM application using Touch Trigger Probes in measuring the spur gears involute profile. The experimental results showed the methodology efficacy. / Por muitos anos a transmissão de movimento e de potência por engrenagens tem sido uma tecnologia importante nas indústrias automotiva, mecânica e aeronáutica, justificando assim a considerável quantidade de pesquisas realizadas no âmbito do controle de qualidade destes componentes. Atualmente, inspeções dos perfis evolventes de engrenagens cilíndricas vêm sendo realizadas utilizando Máquinas de Medição por Coordenadas (MMCs) CNC com mesas rotativas e softwares de medição dedicados, equipadas com sensores por contato de escaneamento, do tipo Touch Trigger Probe – TTP, ou sem contato, Laser. Porém, muitas empresas que fabricam e inspecionam engrenagens utilizam MMCs manuais com sensores do tipo ponto a ponto, ficando assim impossibilitadas de emitir o relatório de desvio de perfil. Neste sentido, a motivação para esta pesquisa é desenvolver e validar estratégias de inspeção para determinação do Desvio Total de Perfil (Fα) de engrenagens cilíndrica de dentes retos, segundo a norma ISO 1328, fazendo o uso da ferramenta matemática NURBS (Non – Uniform Rational B-Splines) e de MMCs manuais. Estratégias para alteração do parâmetro peso wi das NURBS também serão aplicadas para auxiliar na definição do procedimento de inspeção, sendo este um grau de liberdade a mais do modelo. No primeiro momento, antes da execução dos procedimentos experimentais, simulações foram realizadas em um sistema computacional, e apresentaram resultados satisfatórios. Para os testes experimentais foi utilizada uma MMC manual modelo MICRO-HITE 3D, com sensor do tipo ponto a ponto. Resultados de simulações e experimentais mostraram que a técnica NURBS contribui para aplicação de MMC manual usando sensor Touch Trigger na medição do perfil evolvente de engrenagens cilíndricas de dentes retos. Os resultados experimentais demonstraram a eficácia da metodologia desenvolvida.

Abstract Background: Deficiency of Von Willebrand Factor Cleaving Protease (VWFCP) has been implicated as the cause of Thrombotic Thrombocytopenic Purpura (TTP). TTP is a lifethreatening disease characterised by microangiopathic thrombosis due to accumulation of Ultralarge Von Willebrand Factor (ULVWF) multimers. The clinical features of TTP include microangiopathic haemolysis and thrombocytopenia. TTP is being seen with increased frequency in the context of HIV. However, in the context of HIV infection, cytopenias are often multifactorial in nature and levels of VWFCP in HIV-related thrombocytopenia have not specifically been assessed. This study assessed VWFCP activity in the setting of patients with HIV and thrombocytopenia in the absence of TTP, in order to determine the utility of a VWFCP assay in the diagnosis of HIV-related TTP. Acquired VWFCP deficiency is generally assumed to be due to the presence of autoantibody inhibitors to the enzyme, but limited data are available regarding VWFCP activity in HIV positive TTP patients. There is also currently no assay available for measuring VWFCP activity in our laboratory. Aim of Study: To establish a practical assay for VWFCP activity for routine use in our laboratory. The rapid collagen binding assay, based on the ELISA method of Rick, et al., 2002, was chosen. This was initially used to measure VWFCP activity in patients with HIV with and without thrombocytopenia (of any cause except TTP), in order to ascertain whether assessment of VWFCP activity is likely to be of value in facilitating early diagnosis of HIV related TTP. The ELISA assay was performed to establish cut-off values for VWFCP in HIV negative controls and two HIV positive groups (HIV thrombocytopenia / low platelets and HIV normal platelets). Depending on the outcome of this, the assay could then be performed to assess VWFCP activity in HIV positive patients with TTP. Methods: The rapid collagen binding assay for VWFCP activity was established and optimised for routine use in our laboratory. The cut-off values for percentage Residual Collagen Binding Activity (RCBA) in both HIV negative and HIV positive groups were identified. The assay could then be used to assess VWFCP activity in 20 HIV positive patients with TTP at the time of presentation. In patients with reduced VWFCP activity, patient plasma was mixed with normal pool plasma in a 50:50 mix, to assess for the presence of inhibitors. Correlation of VWFCP activity, inhibitors and other laboratory and clinical parameters were performed. Results: The cut-off values for percentage RCBA in both HIV negative (<37.12%) and HIV positive (<51.51%) patients were established. The % RCBA for the HIV negative control group was statistically significantly different from the HIV positive group with normal platelets (p=0.0001) and from the HIV positive group with low platelets (p=0.0006). The cut-off value in the two HIV positive patient groups was higher than for HIV negative control patients, indicating mildly reduced VWFCP enzyme activity in HIV positive patients (regardless of the platelet count), in the absence of TTP. However, no significant difference in the cut-off value was noted between HIV positive patients with low platelet counts versus HIV positive patients with normal platelet counts (p=0.7783). The assay could therefore be used in HIV positive patients with TTP. VWFCP activity was assessed in twenty HIV positive patients with TTP. Two groups of HIV positive patients with TTP were identified based on VWFCP activity. Six patients (30%) had normal (one borderline) VWFCP activity (RCBA <51.51%), while the remaining 14 patients had severely reduced VWFCP levels (RCBA >90%). Of the patients with reduced VWFCP activity, only 5 patients had a detectable inhibitor, while an inhibitor was not detected in the remaining 8 patients. Conclusion: The rapid collagen binding ELISA assay is a cost effective semi-quantitative assay for the assessment of VWFCP activity. VWFCP activity in HIV positive patients appears to be slightly lower, however is not related to the platelet count. This suggests a slight baseline deficiency of VWFCP in the setting of HIV. The baseline VWFCP cut-off value in HIV allowed assessment of HIV positive patients with TTP. The results suggest heterogeneity of VWFCP activity in HIV-related TTP. A negative result (normal VWFCP activity) does not exclude TTP in patients with HIV-related TTP and other pathogenic factors may therefore be involved.

<p>The purpose of this master thesis project has been to analyze and document the Sirius 2001 Concept Car. In addition, it has also been a goal to get the car in a usable state by implementing new software on the on board computers. </p><p>The car is a Tiger Cat E1 that is modified with four wheel steering and an advanced X-by-Wire system. The computers in the X-by-Wire system consist of six TTP PowerNodes that communicate with each other over a redundant, fault tolerant TTP/C communications bus. The computers are connected to a number of sensors and actuators to be able to control the car. </p><p>This project has contributed to the car in several ways. A complete documentation of the systems implemented in the car is one. Another is a programmers manual which significantly lowers the threshold when working with the car. Last but not least is the modifications in hardware and software, which have made the car usable and show some of the possibilities with the system. </p><p>The results show that the Sirius 2001 Concept Car is a suitable platform for research in car dynamics and fault tolerant systems. The work has also shown that the TTP/C communication model works well in an application like this.</p>

The purpose of this master thesis project has been to analyze and document the Sirius 2001 Concept Car. In addition, it has also been a goal to get the car in a usable state by implementing new software on the on board computers. The car is a Tiger Cat E1 that is modified with four wheel steering and an advanced X-by-Wire system. The computers in the X-by-Wire system consist of six TTP PowerNodes that communicate with each other over a redundant, fault tolerant TTP/C communications bus. The computers are connected to a number of sensors and actuators to be able to control the car. This project has contributed to the car in several ways. A complete documentation of the systems implemented in the car is one. Another is a programmers manual which significantly lowers the threshold when working with the car. Last but not least is the modifications in hardware and software, which have made the car usable and show some of the possibilities with the system. The results show that the Sirius 2001 Concept Car is a suitable platform for research in car dynamics and fault tolerant systems. The work has also shown that the TTP/C communication model works well in an application like this.