<p><p><em>Transforming the Brute</em> addresses the ethical acceptability of creating painless animals for usage in biomedical experimentation.  In recent decades the possibility of creating genetically decerebrate animals or AMLs for human ends has been discussed in scientific, academic, and corporate communities.  While the ability to create animals that cannot feel, experience, and are more plant than animal remains science fiction, biomedicine may now be able to eliminate or significantly reduce the capacity to feel pain and nociception through genetic engineering.  With this new technology comes the opportunity to vastly increase the welfare of animals used in biomedical experimentation, yet this possibility has largely been ignored by the scientific and academic community.  This work seeks to reveal the moral necessity of creating painless animals for usage in biomedical experimentation for animal welfare ends.  Intrinsic objections relating to animal integrity, rights, companionship, the alteration of telos, humility and virtue are considered.  The benefit of eliminating nociceptive pain in experimental animals is addressed, and differences are examined between biomedical experimentation and other usage of animals for human ends which makes the proposed creation of painless animals ethically unique.  Finally, an argument is presented for the moral necessity of replacing normal animals with painless animals in biomedical experimentation with consideration given to genetically decerebrate animals.</p></p>

Transforming the Brute addresses the ethical acceptability of creating painless animals for usage in biomedical experimentation.  In recent decades the possibility of creating genetically decerebrate animals or AMLs for human ends has been discussed in scientific, academic, and corporate communities.  While the ability to create animals that cannot feel, experience, and are more plant than animal remains science fiction, biomedicine may now be able to eliminate or significantly reduce the capacity to feel pain and nociception through genetic engineering.  With this new technology comes the opportunity to vastly increase the welfare of animals used in biomedical experimentation, yet this possibility has largely been ignored by the scientific and academic community.  This work seeks to reveal the moral necessity of creating painless animals for usage in biomedical experimentation for animal welfare ends.  Intrinsic objections relating to animal integrity, rights, companionship, the alteration of telos, humility and virtue are considered.  The benefit of eliminating nociceptive pain in experimental animals is addressed, and differences are examined between biomedical experimentation and other usage of animals for human ends which makes the proposed creation of painless animals ethically unique.  Finally, an argument is presented for the moral necessity of replacing normal animals with painless animals in biomedical experimentation with consideration given to genetically decerebrate animals.

Submitted by Paulo Junior (paulo.jr@fgv.br) on 2011-05-04T17:44:15Z No. of bitstreams: 1 Augustinis_Viviane_2011.pdf: 4076827 bytes, checksum: 0747401637b89d16dcabd549e47c46cb (MD5) / Approved for entry into archive by Paulo Junior(paulo.jr@fgv.br) on 2011-05-04T17:44:52Z (GMT) No. of bitstreams: 1 Augustinis_Viviane_2011.pdf: 4076827 bytes, checksum: 0747401637b89d16dcabd549e47c46cb (MD5) / Made available in DSpace on 2011-05-05T12:29:45Z (GMT). No. of bitstreams: 1 Augustinis_Viviane_2011.pdf: 4076827 bytes, checksum: 0747401637b89d16dcabd549e47c46cb (MD5) Previous issue date: 2011-03-21 / This study aimed to investigate and compreehend how the emergence of network public management styles can contribute to construct public policies that attend public interest. The theoretical framework was based on interorganizational network theories and, more specifically, on public policy network theories. The main focus of the research was therefore to study relations of collaboration and cooperation that transcend organizacional boundaries and provide more flexibility and greater scope to the process of constructing public policies. The empirical context chosen for discussion was the relationship between brazilian institutions that work together in anti-money laundering efforts. This context has been chosen by the perception that the practice of financial crimes bring huge losses to countries that need to overcome economic and social inequalities. The construction of public policies that are relevant and effective in the prevention and punishment of money laundering crimes can be translated into benefits for the entire economy of a nation. The reflexive methodology proved to be the most suitable for achieving the goals of this research. From the construction of empirical data, it was possible to create constructs that sintetize benefits and challanges of public policy networks. The following interpretative conections reinforce the idea that the external network performance will be perceived by society as more effective the better the internal network performance. If internal network performance improves, it becomes possible to overcome endogeous and exogenous barriers to the network, what improves the results of interaction among participants, leading to more effective results for society. / O objetivo desta pesquisa foi compreender de que modo a emergência de estilos de gestão pública baseados em rede pode contribuir para a construção de políticas públicas relacionadas à prevenção e repressão à lavagem de dinheiro. O arcabouço teórico fundamentou-se nas teorias de redes interorganizacionais, mais especificamente, nas redes de políticas públicas. Foram estudadas relações de colaboração e cooperação que, por transcenderem os limites organizacionais, garantem maior flexibilidade e abrangência ao processo de construção de políticas públicas. As reflexões sobre estas teorias foram realizadas a partir de um contexto empírico específico: o da articulação entre instituições brasileiras que atuam na prevenção e repressão à lavagem de dinheiro. Este contexto foi escolhido pela percepção de que a prática de ilícitos financeiros traz enormes prejuízos a nações que precisam superar desigualdades econômicas e sociais. A escolha metodológica foi motivada por questões ontológicas e epistemológicas que apontaram a metodologia reflexiva como a mais adequada para o alcance dos objetivos propostos na pesquisa. A partir da construção dos dados empíricos foi possível criar construtos que sintetizam os benefícios e desafios da constituição de redes de políticas públicas. As conexões interpretativas subsequentes reforçam a ideia de que os espíritos democrático, republicano e de cooperação devem nortear os valores compartilhados na rede. Assim, se a atuação interna da rede se aprimora, torna-se possível superar entraves endógenos (foco apenas na boa reputação externa) e exógenos (pressão das elites corruptas) à rede, o que resulta em uma melhor interação entre os participantes, gerando resultados mais efetivos para a sociedade.

<p>DNA methylation is an epigenetic modification that is nearly ubiquitous. Eukaryotic DNA methylation contributes to the regulation of gene expression and maintaining genome integrity. In mammals, DNA methylation occurs primarily on the C5 carbon of cytosine in a CpG dinucleotide context and is catalyzed by the DNA methyltransferases, DNMT1, DNMT3A and DNMT3B. While <i>dnmt3a</i> and <i>dnmt3b</i> genes are highly homologous, the enzymes have distinct functions. Some previous reports suggested differences in the enzymatic behavior of DNMT3A and 3B, which could affect their biological roles. The goal of my thesis work was to characterize kinetics mechanisms of DNMT3A and 3B, and to identify the similarities and differences in their catalytic properties that contribute to their distinct biological functions. Given the sequence similarity between the enzymes, we asked whether DNMT3B was kinetically similar to DNMT3A. In a series of experiments designed to distinguish between various kinetics mechanisms, we reported that unlike DNMT3A, DNMT3B methylated tandem CpG on DNA in a processive manner. We also reported that the disruption of the R-D interface, critical for the cooperativity of DNMT3A, had no effect on DNMT3B activity, supporting the non-cooperative mechanism of this enzyme. </p> <p>DNMT3A is frequently mutated in numerous cancers. Acute Myeloid Leukemia (AML) is a malignancy of hematopoietic stem cells in which numerous patients exhibit a high frequency of the heterozygous somatic mutation Arg882His in DNMT3A. Through thorough consensus motif building, we discovered a strong similarity in CpG flanking sequence preference between DNMT3A Arg882His variant and DNMT3B enzyme. Moreover, we found that the variant enzyme has the same kinetics mechanism as DNMT3B, indicating a gain-of-function effect caused by the mutation. This change is significant because the variant enzyme can aberrantly methylate DNMT3B targets in AML cells and effect global gene expression. In particular, given that DNMT3B has been shown to have oncogenic properties, this suggests that the Arg882His variant can acquire similar oncogenic properties and drive AML development.</p> <p>Taken together, my thesis work provides novel insights into the relationship between the biochemical properties and the biological functions of DNMT3A and 3B. </p>

[ES] La consistencia de los datos de la HCE, como dimensión de la calidad, se considera un requisito esencial para la mejora de la prestación de la asistencia sanitaria, los procesos de toma de decisiones clínicas y la promoción de la investigación clínica. En este contexto, la cooperación entre la información y los modelos de dominio se considera esencial en la literatura, pero la comunidad científica no la ha abordado adecuadamente hasta la fecha. La contribución principal de esta tesis es el desarrollo de métodos y herramientas para la inclusión de expresiones de enlaces terminológicos en reglas de consistencia. Las contribuciones específicas son: - Definición de un método para ejecutar ECs sobre una base de datos de SNOMED CT orientada a grafos. - Definición de métodos para simplificar ECs antes y después de su ejecución, y su validación semántica conforme al Machine Readable Concept Model de SNOMED CT (MRCM). - Definición de un método para visualizar, explorar dinámicamente, comprender y validar subconjuntos de SNOMED CT. - Desarrollo de SNQuery, una plataforma que ejecuta, simplifica y valida ECs y visualiza los subconjuntos resultantes. - Definición de EHRules, un lenguaje de expresiones basado en el openEHR Expression Language para la especificación de reglas de consistencia en arquetipos, incluido el enlace terminológico de contenido, con el fin de enriquecer los arquetipos con conocimiento del dominio. - Definición de un método para ejecutar las expresiones de EHRules con el fin de validar la consistencia de los datos de la HCE mediante la ejecución de dichas expresiones sobre instancias de datos de pacientes. Nuestro objetivo es que estas contribuciones ayuden a mejorar la calidad de la HCE, ya que proporcionan métodos y herramientas para la validación y mejora de la consistencia de los datos de la HCE. Pretendemos, además, mediante la definición de enlaces de contenido entre modelos de información y terminologías clínicas, elevar el nivel de interoperabilidad semántica, para lo cual la definición de enlaces terminológicos es crucial. / [CA] La consistència de les dades de la HCE, com a dimensió de la qualitat, es considera un requisit essencial per a la millora de la prestació de l'assistència sanitària, els processos de presa de decisions clíniques i la promoció de la investigació clínica. En aquest context, la cooperació entre la informació i els models de domini es considera essencial en la literatura, però la comunitat científica no l'ha abordada adequadament fins hui. La contribució principal d'aquesta tesi és el desenvolupament de mètodes i ferramentes per a la inclusió d'expressions d'enllaços terminològics en regles de consistència. Les contribucions específiques són: - Definició d'un mètode per a executar ECs sobre una base de dades de SNOMED CT orientada a grafs. - Definició de mètodes per a simplificar ECs abans i després de la seua execució, i la seua validació semàntica conforme al Machine Readable Concept Model de SNOMED CT (MRCM). - Definició d'un mètode per a visualitzar, explorar dinàmicament, comprendre i validar subconjunts de SNOMED CT. - Desenvolupament de SNQuery, una plataforma que executa, simplifica i valida ECs i visualitza els subconjunts resultants. - Definició de EHRules, un llenguatge d'expressions basat en l'openEHR Expression Language per a l'especificació de regles de consistència en arquetips, inclòs l'enllaç terminològic de contingut, amb la finalitat d'enriquir els arquetips amb coneixement del domini. - Definició d'un mètode per a executar les expressions de EHRules amb la finalitat de validar la consistència de les dades de la HCE mitjançant l'execució d'aquestes expressions sobre instàncies de dades de pacients. El nostre objectiu és que aquestes contribucions ajuden a millorar la qualitat de la HCE, ja que proporcionen mètodes i ferramentes per a la validació i millora de la consistència de les dades de la HCE. Pretenem, a més, mitjançant la definició d'enllaços de contingut entre models d'informació i terminologies clíniques, elevar el nivell d'interoperabilitat semàntica, per a la qual cosa la definició d'enllaços terminològics és crucial. / [EN] Consistency of EHR data, as a dimension of quality, is considered an essential requirement to the improvement of healthcare delivery, clinical decision-making processes, and the promotion of clinical research. In this context, cooperation between information and domain models has been considered essential in the literature, but it has not been adequately addressed by the scientific community to date. The main contribution of this thesis is the development of methods and tools for the inclusion of terminology binding expressions in consistency rules. Specific contributions are: - Definition of a method to execute ECs over a SNOMED CT graph-oriented database. - Definition of methods to simplify ECs before and after its execution and semantic validation according to the SNOMED CT Machine Readable Concept Model (MRCM). - Definition of a method to visualize, dynamically explore, understand and validate SNOMED CT subsets. - Development of SNQuery, an execution platform that executes, simplifies and validates ECs, and visualizes the resulting subsets. - Definition of EHRules, an expression language based on the openEHR Expression Language for the specification of consistency expressions in archetypes, including value set bindings, in order to enrich archetypes with domain knowledge. - Definition of a method to execute EHRules expressions in order to validate the consistency of EHR data by executing such rules over patient data instances. Our objective is that these contributions help to enhance the quality of EHR, as they provide methods and tools for the validation and enhancement of the EHR data consistency. We also intend, by defining value set bindings between information models and clinical terminologies, to raise the level of semantic interoperability, for which the definition of terminological bindings is crucial. / This thesis was partially funded by Ministerio de Economía y Competitividad, “Doctorados Industriales”, grant DIN2018-009951, and by Universitat Politècnica de València, “Formación de Personal Investigador” (FPI-UPV). / Giménez Solano, VM. (2021). Enrichment of Archetypes with Domain Knowledge to Enhance the Consistency of Electronic Health Records [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/180082 / TESIS

Indiana University-Purdue University Indianapolis (IUPUI) / Gain-of-function mutations in the KIT receptor tyrosine kinase have been associated with highly malignant human neoplasms. In particular, an acquired somatic mutation at codon 816 in the second catalytic domain of KIT involving an aspartic acid to valine substitution is found in patients with systemic mastocytosis (SM) and acute myeloid leukemia (AML). The presence of this mutation in SM and AML is associated with poor prognosis and overall survival. This mutation changes the conformation of the KIT receptor resulting in altered substrate recognition and constitutive tyrosine autophosphorylation leading to constitutive ligand independent growth. As there are currently no efficacious therapeutic agents against this mutation, this study sought to define novel therapeutic targets that contribute to aberrant signaling downstream from KITD816V that promote transformation of primary hematopoietic stem/progenitor cells in diseases such as AML and SM. This study shows that oncogenic KITD814V (murine homolog) induced myeloproliferative neoplasms (MPN) occurs in the absence of ligand stimulation, and that intracellular tyrosines are important for KITD814V-induced MPN. Among the seven intracellular tyrosines examined, tyrosine 719 alone has a unique role in regulating KITD814V-induced proliferation and survival. Residue tyrosine 719 is vital for activation of the regulatory subunit of phosphatidylinositol 3-kinase (PI3K), p85α, downstream from KITD814V. Downstream effectors of the PI3K signaling pathway, in of leukemic cells bearing KITD814V with an allosteric inhibitor of Pak or its genetic inactivation results in growth repression due to enhanced apoptosis. To assess the role of Rac GEFs in KITD814V induced transformation, EHop-016, an inhibitor of Rac, was used to specifically target Vav1, and found to be a potent inhibitor of human and murine leukemic cell growth. In vivo, the inhibition of Vav or Rac or Pak delayed the onset of MPN and rescued the associated pathology in mice. These studies provide insight on mechanisms and potential novel therapeutic targets for hematological malignancies harboring an oncogenic KIT mutation.

La leucémie myéloïde aiguë (LMA) est causée par une prolifération anormale de cellules souches sanguines immatures. Notre laboratoire se concentre sur un sous-groupe de la LMA représentant près de 30% de la LAM pédiatrique et caractérisé par la translocation chromosomique KMT2A-MLLT3. L'analyse par séquençage de l’ARN (RNA-seq) dans notre modèle de LMA médiée par la fusion KMT2A-MLLT3 et des échantillons de patients leucémiques a révélé que les gènes codant la chimiokine CCL23 et son récepteur correspondant CCR1 sont surexprimés dans cette maladie. Bien qu'il ait été rapporté que CCL23 et CCR1 sont impliqués dans le trafic de leucocytes et le développement de l'inflammation, les rôles exacts de ces deux protéines dans la leucémogenèse sont inconnus. Pour illustrer les effets de la signalisation CCL23/CCR1 dans la leucémie causée par la fusion KMT2A-MLLT3, nous avons utilisé la technique de transfert d'énergie de résonance de bioluminescence 2 améliorée (ebBRET2) avec des tests d'immuno-empreintes. Nos résultats ont révélé que la signalisation de l'axe CCL23/CCR1 active plusieurs effecteurs de signalisation intermoléculaire, y compris Gi2, G12/13 et β-arrestine 1/2, mais avec un biais vers le recrutement de la β-arrestine. Nous avons également montré que le récepteur CCR1 présente une activité constitutive qui peut se coupler à une voie médiée par la protéine G et activer la voie impliquant les MAP kinases. Enfin, nous avons montré que la signalisation de l'axe CCL23/CCR1 provoque une activation de ERK1/2 dans les lignées cellulaires LMA potentiellement par une voie médiée par la β-arrestine. Ces résultats indiquent que la signalisation de l'axe CCL23/CCR1 active plusieurs voies biologiques pouvant fournir des avantages majeurs pour le développement et la progression de la LMA et présentent ainsi CCL23 et CCR1 comme deux candidats intéressants pour une thérapie ciblée contre la LMA de type KMT2A-MLLT3. / Acute Myeloid Leukemia (AML) is caused by abnormal proliferation of immature blood stem cells. Our lab focuses on an AML subgroup accounting for almost 20% of pediatric AML and characterized by a chromosomal translocation that generates the gene fusion: KMT2A-MLLT3 (KM3). Interestingly, RNA-seq analysis of our KM3 AML model and AML patient samples has revealed that the chemokine CCL23 and its corresponding receptor CCR1 are highly upregulated in this disease. Although it has been reported that CCL23 and CCR1 are implicated in leukocyte trafficking and development of inflammation, the exact roles of these two proteins in leukemia are unknown. To illustrate the effects of CCL23/CCR1 signaling in the KMT2A-MLLT3 rearranged leukemia we employed the enhanced bystander bioluminescence resonance energy transfer 2 (ebBRET2) technique along with phospho-immunoblots assays. Our results revealed that CCL23/CCR1 axis signaling activates multiple intermolecular signaling effectors, including Gi2, G12/13, and β-arrestin1/2 albeit with a bias towards β-arrestin recruitment. We also showed that the CCR1 receptor exhibits a constitutive activity which can couple to a G-protein mediated pathway to activate the MAPK cascade. Finally, we showed that CCL23/CCR1 axis signaling causes an activation of ERK1/2 in AML cell lines potentially through a β-arrestin-mediated pathway. These results indicate that the CCL23/CCR1 axis signaling activates several biological pathways than can provide major advantages for the AML disease development and progression thus presenting both CCL23 and CCR1 as interesting candidates for targeted therapy against KMT2A-MLLT3 AML.

Depuis le début des années 1970 la communauté internationale, sous l’impulsion des États-Unis, a progressivement abordé le blanchiment d’argent sale comme un nouveau problème de sécurité représentant une menace pour la sécurité intérieure des États et l’équilibre du système financier international. La création, en 1989, du Groupe d’action financière (GAFI) lors du sommet du G7 se tenant à Paris, marquera l’engagement politique international en faveur de la lutte contre le blanchiment de capitaux devant constituer « une contribution décisive à la lutte contre les activités criminelles et particulièrement contre le trafic de la drogue et permettre de renforcer la solidité du système financier international » [GAFI, 1991, p. 21]. À travers la publication en 1990, de ses quarante recommandations pour la mise en place d’un régime global de lutte contre le blanchiment de capitaux, les pays membres du GAFI – les membres du G7 auxquels se sont joints, dès la première année, la Commission européenne et huit autres pays dont la Suisse – viennent concrétiser l’« invention d’un nouveau crime » [Amicelle, 2016, p. 37] : le blanchiment d’argent et la nécessité d’une nouvelle forme de réaction sociale contre la criminalité lucrative. Créé au départ pour lutter contre les revenus issus du trafic de drogue, le dispositif englobe aujourd’hui l’ensemble des revenus issus d’une activité criminelle. En 2001, il a été adapté pour lutter contre le financement du terrorisme et en 2012 élargi aux infractions fiscales pénales et au financement de la prolifération des armes de destructions massives. Ainsi, le dispositif anti-blanchiment est aujourd’hui un instrument théoriquement mobilisable pour lutter contre toutes les formes de criminalité et toutes les personnes (physiques ou morales) – « des plus faibles aux plus puissantes » [Amicelle, 2014, p. 88] – associées à des flux financiers illicites. Plus de trente ans après sa création, le GAFI représente un réseau mondial de plus de 190 juridictions ayant adopté ses recommandations, conduisant en 2019 son président à célébrer « trente ans de succès » et à affirmer que la « valeur de l'organisation pour la sécurité de nos nations et l'intégrité du système financier international n'ont jamais été aussi claires » [GAFI, 2019, p. 5]. À travers l’adaptation de leur législation, la plupart des pays, se sont dotés d’un dispositif de lutte contre le blanchiment de capitaux et le financement du terrorisme (LBC/FT) reposant sur des pratiques inédites de coopération et d’échanges d’informations entre des acteurs provenant du monde de la finance et des acteurs publics d’application de la loi [Amicelle, 2018 ; Helgesson et Mörth, 2019 ; Huysmans, 2014 ; Sheptycki, 2002]. S'appuyant sur les travaux de Latour, de Goede [2018] introduit le concept de la « chaîne de sécurité » pour décrire l’architecture générale du dispositif de LBC/FT composée de trois maillons, décrivant la division du travail et les tâches relatives à la mise en œuvre d’un modèle théorique de policing guidé par le renseignement – financier – ou d’« Intelligence-led policing ». Le premier maillon concerne les institutions financières désignées comme entités déclarantes, obligées par la loi d’organiser la traçabilité des opérations financières devant supporter la surveillance, la détection et le signalement des opérations suspectes en matière de BC/FT dans leurs établissements. Le deuxième maillon concerne la cellule de renseignement financier (CRF) désignée dans chaque pays, comme le centre national chargé de la collecte et l’analyse des déclarations d’opérations suspectes et des autres informations concernant le BC/FT et de la production de renseignement financier mobilisable par les acteurs publics d’application de la loi – dernier maillon de la chaîne – devant lutter contre la criminalité en s’attaquant aux flux financiers illicites. À travers le concept de la « chaîne », de Geode [2018] décrit le dispositif anti-blanchiment selon un processus linéaire, suivant le cheminement des transactions suspectes – les traces financières – qui sont successivement « collectées, stockées, transférées et analysées afin d’aboutir à des actes de sécurité (par exemple des avoirs gelés, des comptes fermés, et des condamnations judiciaires) » (p. 27). Dans cette nouvelle configuration du policing – financier – , le processus de « fabrique de la criminalité » ou de « making crime » introduit par Ericson [1981] – pour décrire le processus à travers lequel les acteurs du policing sont confrontés à des problèmes de sécurité qu’ils vont transformer, en fonction de leur réaction, en crime et en criminel – se déplace a priori, dans une logique de « multilatéralisation du policing », des seules organisations policières vers d’autres acteurs devenant de nouveaux « promoteurs » et « prestataires » du policing [Bayley et Shearing, 2001]. Jusqu’ici, de nombreuses études ont été consacrées à l’analyse du premier maillon de la « chaine de sécurité » questionnant l’implication des acteurs financiers dans la mise en œuvre « réticente » des mesures de vigilance, de détection et de signalement des flux financiers illicites au sein de leurs institutions. Cependant, très peu d’études prêtent attention aux autres maillons de la « chaîne de sécurité » et encore moins lorsqu’il s’agit d’analyser la « chaîne de sécurité » dans son ensemble, seul moyen pour saisir empiriquement l’étendue des relations et la diversité des dispositifs de production de sécurité mis en œuvre, supportant dans sa globalité le processus de réaction sociale aux pratiques de BC/FT. Ainsi, c’est ce vide de connaissances académiques que cette recherche vise à combler à travers l’analyse empirique de la mise en œuvre du dispositif de LBC/FT en Suisse et au Canada. Plus de 30 ans après la création du GAFI et la mise en place par les États d’un dispositif de LBC/FT reposant sur un modèle opérant de policing guidé par le renseignement financier, cette recherche vise à comprendre dans sa globalité : « À quoi sert le renseignement financier ? » Répondre à cette question de recherche, c’est contribuer dans une triple dimension à (a) l’analyse de la mise en œuvre empirique d’un modèle opérant de policing guidé par le renseignement dans une environnement particulier : l’environnement financier, (b) dépassant la vision lacuneuse des travaux centrés sur les acteurs financiers de l’anti-blanchiment et (c) saisir la manière dont les pratiques de production et d’utilisation du renseignement financier contribuent à analyser dans son ensemble tout le processus qui détermine la visibilité des cas de BC/FT, leur signalement à une autorité de contrôle et leur éventuelle poursuite et condamnation. Le dispositif anti-blanchiment n’ayant plus vocation à cibler une forme de criminalité lucrative par rapport à une autre, notre étude est aussi une analyse du processus de « fabrique de la criminalité » décrit par Ericson [1981], par lequel les acteurs du policing financier vont désigner, en fonction de leurs intérêts et de leurs règles propres, les comportements criminels portés à leur connaissance qu’ils vont décider de poursuivre, d’ignorer, d’infirmer ou de vérifier. Alors cette recherche soutiendra la thèse que malgré toutes les promesses implicites portées par la reconfiguration des activités de policing dans ses logiques contemporaines de fonctionnement – redéfinissant a priori, la division du travail et la répartition des tâches situées au cœur du processus de « fabrique de la criminalité » –, l’exemple de la lutte anti-blanchiment en Suisse et au Canada, montre comment les acteurs publics d’application de la loi (APAL) ont su conserver la mainmise sur le processus de « making crime » en développant des stratégies pour détourner les normes anti-blanchiment et les dispositifs qu’elles impliquent, à leur avantage dans la poursuite de leurs priorités opérationnelles. Ainsi, les APAL replacent – dans un mouvement contre-intuitif aux reconfigurations contemporaines des activités de policing – les relations de pouvoir, associées au contrôle et au maintien de l’ordre, dans un rapport de verticalité entre l’État et la société et dont les manifestations contribuent à reproduire la « fabrique de la criminalité » selon, comme l’avait noté Manning [2010], « un ensemble d’habitudes et de suppositions axées sur le trope du crime qui envisage uniquement la nécessité de contrôler, de dissuader et de punir les contestataires visibles et connus » – justifiant aussi une analyse en termes de gestion différentielle des illégalismes. À travers l’accès à un matériau empirique – jamais mobilisé auparavant – dans deux pays membres fondateurs du GAFI, cette recherche repose sur une approche comparée à l’échelle internationale et une méthodologie d’analyse mixte, de la base de données, dénominalisées, colligeant l’ensemble des déclarations d’opérations suspectes et des informations associées reçues par la CRF suisse entre 2004 et 2014 – analyse quantitative – et des entretiens auprès d’une quarantaine d’agents au sein de la CRF suisse et d’un panel « représentatif » de l’ensemble des acteurs publics d’application de la loi habilités à mobiliser le renseignement financier en Suisse et au Canada – analyse qualitative. Alors cette recherche contribue empiriquement et conceptuellement à la littérature sur les transformations du policing soutenues par les modèles de policing guidé par le renseignement – ou d’« Intelligence-led policing » –, évitant l’écueil de penser les processus génériques de renseignement comme les manières de les organiser. De plus, cette recherche questionne à nouveaux frais la réaction sociale aux différentes formes de criminalité lucrative, justifiant une analyse en termes de gestion différentielle des illégalismes renvoyant aux diverses modalités pratiques de jeu avec les règles légales tout en situant socialement les groupes qui en usent. / Since the early 1970s, the international community, led by the United States, has progressively addressed money laundering as a new security problem representing a threat to the security of states and financial system. The creation of the Financial Action Task Force (FATF) in 1989 at the G7 summit in Paris marked the international political commitment to combat money laundering as “a decisive contribution to the fight against criminal activities, particularly drug trafficking, and will improve the soundness of the international financial system” [FATF, 1991, p. 20]. The FATF's forty recommendations, published in 1990, for the establishment of a global anti-money laundering regime, embody the “invention of a new crime” [Amicelle, 2016, p. 37]: money laundering and the need for a new form of social reaction against profit-making crime. Initially created to combat drug trafficking, the system now covers all profit from criminal activity. In 2001, it was adapted to combat the financing of terrorism and in 2012 extended to cover criminal tax offences and the financing of the proliferation of weapons of mass destruction. Thus, the anti-money laundering system is today an instrument that can theoretically be mobilised to combat all forms of crime and all persons – “from the weakest to the most powerful” [Amicelle, 2014, p. 88] - associated with illicit financial flows. More than thirty years after its creation, the FATF represents a global network of more than 190 jurisdictions that have adopted its Recommendations, leading its President in 2019 to celebrate “thirty years of success” and to assert that the “value of the organisation to the security of our nations and the integrity of the international financial system has never been clearer” [FATF, 2019, p. 5]. Today, most countries have anti-money laundering and combating the financing of terrorism (AML/CFT) systems based on innovative practices of cooperation and information exchange between financial and public law enforcement actors [Amicelle, 2018; Helgesson and Mörth, 2019; Huysmans, 2014; Sheptycki, 2002]. Building on Latour's work, de Goede [2018] introduces the concept of the “security chain” to describe the general architecture of the AML/CFT system composed of three links, describing the division of labour and tasks related to the implementation of a theoretical model of intelligence-led policing. The first link concerns the financial institutions designated as reporting entities, which are obliged by law to organise the traceability of financial transactions that should support the monitoring, detection and reporting of suspicious ML/FT transactions in their institutions. The second link concerns the financial intelligence unit (FIU) designated in each country as the national centre responsible for collecting and analysing suspicious transaction reports and other ML/FT information and producing financial intelligence that can be mobilised by public law enforcement actors - the last link in the chain - to fight crime by tackling illicit financial flows. Through the concept of the “chain”, de Geode [2018] describes the anti-money laundering system as a linear process, following the path of suspicious transactions - financial traces - which are successively “collected, stored, transferred and analysed in order to lead to security acts (e.g. frozen assets, closed accounts, and judicial convictions)” (p. 27). In this new configuration of financial policing, the process of “making crime” introduced by Ericson [1981] - to describe the process through which policing actors are confronted with security problems which they will transform, according to their reaction, into crime and criminality - is shifted a priori, in a logic of “multilateralization of policing”, from police organisations alone to other actors who become new “promoters” and “providers” of policing [Bayley and Shearing, 2001]. Many studies have been devoted to the analysis of the first link of the “security chain”, questioning the involvement of financial actors in the “reluctant” implementation of vigilance measures, detection and reporting of illicit financial flows within their institutions. However, very few studies pay attention to the other links in the “security chain” and even fewer analyse the “security chain” as a whole, which is the only way to empirically grasp the extent of the relationships and the diversity of the security production mechanisms implemented, which support the whole process of social reaction to ML/FT practices. It is this gap in academic knowledge that this research aims to fill through the empirical analysis of the implementation of the AML/CFT system in Switzerland and Canada. More than 30 years after the creation of the FATF and the implementation by States of an AML/CFT system based on an operational model of policing led by financial intelligence, this research aims to understand in its entirety: “What is financial intelligence used for?” Answering this research question means contributing in a triple dimension to (a) the analysis of the empirical implementation of an operating model of intelligence-led policing in a particular environment: the financial environment, (b) going beyond the flawed vision of work focused on the financial actors of anti-money laundering and (c) grasping the way in which the practices of production and use of financial intelligence contribute to analyse as a whole the process that determines the visibility of ML/FT cases, their reporting to a supervisory authority and their possible prosecution and conviction. As the anti-money laundering system is no longer intended to target one form of lucrative crime over another, our study is also an analysis of the “making crime” process described by Ericson [1981], whereby financial policing actors will designate, according to their own interests and rules, the criminal behaviour brought to their attention that they will decide to pursue, ignore, deny or verify. This research will therefore support the thesis that despite all the implicit promises made by the reconfiguration of policing activities in its contemporary operating logics - redefining a priori the division of labour and the distribution of tasks located at the heart of the “making crime” process –, the example of the fight against money laundering in Switzerland and Canada shows how public law enforcement agencies (APAL) have been able to maintain control over the process of “making crime” by developing strategies to turn anti-money laundering norms and the mechanisms they imply to their advantage in the pursuit of their operational priorities. Thus, public law enforcement actors situate the power relations associated with policing in a vertical relationship between state and society, the manifestations of which help to reproduce the “making crime” according to, as Manning [2010] noted, a set of habits and assumptions that “envisions only the need to control, deter and punish the visible and known contestants”. Through access to empirical material - never before mobilised - in two founding member countries of the FATF, this research is based on a comparative approach on an international scale and a mixed methodology of analysis of the database of all suspicious transaction reports and related information received by the Swiss FIU between 2004 and 2014 - quantitative analysis - and forty interviews with agents within the Swiss FIU and a "representative" panel of all public law enforcement actors empowered to mobilise financial intelligence in Switzerland and Canada - qualitative analysis. Thus, this research contributes empirically and conceptually to the literature on the transformations of policing supported by models of intelligence-led policing, avoiding the pitfall of thinking about generic intelligence processes as well as ways of organizing them. Moreover, this research questions the social reaction to the different forms of lucrative crime, justifying an analysis in terms of differential management of illegalisms referring to the various practical modalities of playing with the legal rules while socially situating the groups that use them.

La leucémie myéloïde aiguë (AML) est une forme agressive du cancer du sang qui est caractérisée par un haut taux de mortalité, tant chez les patients plus jeunes que plus âgés. Le développement de nouveaux traitements est ardu par l’hétérogénéité de cette maladie. Dans cette perspective, les études CCC phénotypiques menées à l’IRIC visent à déceler de nouveaux composés ayant une synergie contre des souches AML primaires de patients en vue de personnaliser les thérapies selon leur profil cytogénétique. Il a été découvert que le MG624, un antagoniste des récepteurs nicotiniques α7-nAChR inhibant la prolifération des cellules cancéreuses dans les SCLC, démontrait une activité spécifique contre la souche AML5. Dans cette recherche, les voies de synthèse des analogues du MG624 sont explorées afin de concevoir une série de sondes permettant d’identifier les cibles potentielles via une approche chimioprotéomique par affinité dans le lysat cellulaire. Cette méthode a permis d’identifier trois cibles potentielles à l’aide d’un essai par compétition et de contrôles négatifs, soit XIAP, NQO2 et U119B, toutes impliquées dans différentes formes de cancer. Ces expériences ont mené à une meilleure compréhension des motifs procurant l’activité du composé chez les cellules leucémiques. La synthèse d’une sonde par photoaffinité a ensuite été élaborée pour éventuellement lier les protéines identifiées de manière covalente dans l’environnement cellulaire natif afin de valider ces cibles. / Acute myeloid leukemia (AML) is an aggressive form of blood cancer characterized by a high mortality rate in both younger and older patients. The development of new treatments is hampered by the heterogeneity of this disease, which has led to the phenotypic CCC studies carried out at IRIC to identify new compounds that exhibit synergies against primary AML patient strains to personalize therapies according to their cytogenetic profile. MG624, an α7-nAChR nicotinic receptor antagonist that inhibits cancer cell proliferation in SCLC, was found to have specific activity against AML5. In this research, the synthetic pathways of MG624 analogues are explored to design a series of probes to identify potential targets via an affinity-based chemoproteomic approach in cell lysate. This method identified three potential targets using a competitive assay and negative controls, namely XIAP, NQO2 and U119B, all implicated in different forms of cancer. These experiments led to a better understanding of the motifs that provide the compound's activity in leukemic cells. A photo-affinity probe synthesis was then developed to covalently bind the identified proteins in the native cellular environment to eventually validate these targets.

<p dir="ltr">The research work presented in this thesis focuses on two highly important topics in the modern age. The first topic of research is the development of various image-based Network Intrusion Detection Systems (NIDSs) and performing a comprehensive analysis of their performance. Wi-Fi networks have become ubiquitous in enterprise and home networks which creates opportunities for attackers to target the networks. These attackers exploit various vulnerabilities in Wi-Fi networks to gain unauthorized access to a network or extract data from end users' devices. The deployment of an NIDS helps detect these attacks before they can cause any significant damages to the network's functionalities or security. Within the scope of our research, we provide a comparative analysis of various deep learning (DL)-based NIDSs that utilize various imaging techniques to detect anomalous traffic in a Wi-Fi network. The second topic in this thesis is the development of learning modules for security and privacy in Machine Learning (ML). The increasing integration of ML in various domains raises concerns about its security and privacy. In order to effectively address such concerns, students learning about the basics of ML need to be made aware of the steps that are taken to develop robust and secure ML-based systems. As part of this, we introduce a set of hands-on learning modules designed to educate students on the importance of security and privacy in ML. The modules provide a theoretical learning experience through presentations and practical experience using Python Notebooks. The modules are developed in a manner that allows students to easily absorb the concepts regarding privacy and security of ML models and implement it in real-life scenarios. The efficacy of this process will be obtained from the results of the surveys conducted before and after providing the learning modules. Positive results from the survey will demonstrate the learning modules were effective in imparting knowledge to the students and the need to incorporate security and privacy concepts in introductory ML courses.</p>