Submitted by Maria Medeiros (maria.dilva1@ufcg.edu.br) on 2018-06-08T11:13:01Z No. of bitstreams: 1 CLAUDEAM MARTINS DA GAMA - DISSERTAÇÃO (PPGRN) 2016.pdf: 6103233 bytes, checksum: fed3189fc228c5e2e93b1cfa20cff5f8 (MD5) / Made available in DSpace on 2018-06-08T11:13:01Z (GMT). No. of bitstreams: 1 CLAUDEAM MARTINS DA GAMA - DISSERTAÇÃO (PPGRN) 2016.pdf: 6103233 bytes, checksum: fed3189fc228c5e2e93b1cfa20cff5f8 (MD5) Previous issue date: 2016-05-10 / Capes / Indícios de degradação ambiental em território brasileiro datam da ocupação lusitana, inicialmente na zona litorânea nordestina, posteriormente direcionada para o interior do território (agreste e sertão). A espacialização das atividades desenvolvidas no sertão paraibano a exemplo da criação do gado bovino, da cotonicultura, do desmatamento, associados aos eventos de secas prolongadas e a vulnerabilidade da população rural provocaram impactos ambientais negativos. Em algumas microrregiões do Estado da Paraíba a exemplo do Cariri Oriental, apresentam áreas em estágio avançado de desertificação, o município de Barra de Santana foi escolhido para realização do presente estudo por se estar inserido na microrregião supracitada e estar susceptível ao processo de desertificação. O principal objetivo dessa pesquisa foi analisar a relação entre os condicionantes naturais e antrópicos no processo de degradação da cobertura vegetal no município de Barra de Santana-PB entre o período de 1987 a 2015 (28 anos) e suas consequências, justificando-se pela escassez de estudos sobre os processos de degradação ambiental na região do semiárido paraibano, em particular no município supracitado. Essa pesquisa foi desenvolvida a partir de três etapas, inicialmente com a revisão de literatura tratando de aspectos históricos, socioambientais e econômicos relacionados a degradação do Bioma Caatinga regional e local. A segunda etapa se deu a partir da aplicação de questionários objetivos semiestruturados na zona rural do município estudado. A terceira etapa foi realizada através do emprego de técnicas de Sensoriamento Remoto e dos Sistemas de Informações Geográficas (SIG’s) com a utilização de imagens de satélite que auxiliaram na análise de aspectos biofísicos da cobertura vegetal do município estudado através da dinâmica da cobertura vegetal da Caatinga e do cálculo do Índice de Vegetação Ajustado ao Solo (SAVI). Verificou-se a importância de alguns programas sociais na amenização das condições de vulnerabilidade da população rural, como o Programa Bolsa Família, Bolsa Estiagem, Seguro Safra, Água Para Todos e tecnologias sociais como as cisternas de placa que tem garantido o mínimo de segurança hídrica e alimentar para as famílias que residem na zona rural. Tendo em vista que, mesmo atendidos por alguns programas sociais, apenas a vulnerabilidade social se apresentou moderada (29,1%), as outras vulnerabilidades como a econômica (92,1%), a tecnológica (67,8%) e hídrica (64,7%) foram identificadas com altos níveis. Os resultados obtidos a partir da comparação entre as imagens de SAVI referentes os anos de 1987 e 2015 evidenciam uma redução de 37% da área ocupada por Caatinga Arbórea densa e Subarbórea densa presentes no ano 1987, representando uma taxa de desmatamento de 2,8 Km2/ano. Houve um aumento de 49,7% das classes de Caatinga Arbustivas abertas, Subarbustiva rala, Subarbustiva muito rala e Solo exposto, uma evolução de 2,9 Km2/ano. O mapeamento da Susceptibilidade Natural a Degradação Ambiental obtido a partir da sobreposição de mapas de vegetação, erodibilidade do solo e declividade indicam uma redução das áreas pertencentes as classes de susceptibilidade Muito Baixo de 25% (1987) para 11,2% (2015). Nas áreas pertencentes a classe com nível Alto de susceptibilidade houve uma aumento, entre 1987 e 2015 de 12,8% para 16%, a classe de susceptibilidade Muito Alta passou de 14,8% (1987) para 23,5% (2015), esse aumento ocorreu em áreas que possuem declividade acentuada e capacidade de perda de solo muito elevadas, neste caso deve-se reiterar a importância da preservação da vegetação nativa para garantir a estabilidade dos solos, o que não impede a utilização dessas áreas para o desenvolvimento de atividades econômicas que sejam sustentáveis. / Evidence of environmental degradation in the Brazilian territory date from the Lusitanian occupation initially on the northeastern coast zone, then directed into the territory (rural and backwoods). The spatialization of the developed activities in Paraíba backwoods, for instance livestock, the cotton industry, deforestation, associated with events of prolonged drought and the vulnerability of the rural population caused negative environmental impacts. In some microregions of Paraiba state, taking Eastern Cariri as an example, there are areas in advanced stage of desertification, which is not the case of the county Barra de Santana was taken for the realization of this study for being insert in the microregion previously mentioned as well as for being susceptible to the desertification process. The main objective of this research was to analyze the relationship between the natural and anthropogenic conditions in the process of degradation of the vegetation cover in the municipality of Barra de Santana between the period of 1987 to 2015 (28 years) and its consequences, justified by the scarce studies on the environmental degradation processes in the semi-arid region of Paraiba, in particular in the aforementioned municipality. This research was developed in three stages, initially with the review of literature dealing with historical, social, environmental and economic aspects related to degradation of regional and local Caatinga Biome. The second stage took place with the application of semi-structured questionnaires objectives in rural city studied. The third step was carried out through the use of Remote Sensing and Geographic Information Systems (GIS) with the use of satellite images that helped in the analysis of biophysical aspects of plant cover of the municipality studied by the dynamics of vegetation of Caatinga and the calculation of Soil Adjusted Vegetation Index (SAVI). It was verified the importance of some social programs in ameliorating the vulnerability of the rural population conditions, such as the Bolsa Família, Bolsa Estiagem, Seguro Safra, Água Para Todos and social technologies such as board tanks that have guaranteed minimum water security and food for families living in the countryside. Considering that, even being attended by some social programs, only the social vulnerability was presented as moderate (29,1%), the other ones such as economic (92,1%), technological (67,8%) e hydric (64,7%) were identified with high levels. The results obtained from the comparison between images of SAVI for the years 1987 and 2015 show a reduction of 37 % of the area occupied by dense Arboreal and Subarboreal Caatinga present in 1987, representing a deforestation rate of 2.8 Km² /year. There was an increase of 49.7% of the open Caatinga Shrub classes, sparse Subshrub, very thin Subshrub and soil exposed, an increase of 2.9 km2 /year. The mapping of Natural Susceptibility to Environmental Degradation obtained from overlapping vegetation maps, soil erodibility and slope indicate a reduction in susceptibility areas belonging to the Very Low Susceptibility classes from 25% (1987) to 11.2% (2015). In areas belonging to class with high level of susceptibility there was an increase between 1987 and 2015 from 12.8% to 16%, the susceptibility of Very High class increased from 14.8% (1987) to 23.5% (2015), this increase occurred in areas that have steep slopes and very high capacity loss ground, in this case it must be stressed the importance of preserving native vegetation to ensure the stability of the soil, which does not prevent the use of these areas for development economic activities that are sustainable.

Cytosolic DNA sensing plays a key role in autoimmune and autoinflammatory diseases. STING is a cytosolic adaptor protein which upon activation leads to induction of type I interferons and inflammatory cytokines. Recently, gain-of-function mutations in STING have been identified in patients with an autoinflammatory disease called STING-associated vasculopathy with onset in infancy (SAVI). We compared two independent SAVI mutant mouse models and revealed a hierarchy of immune abnormalities which were dependent on SAVI mutation in lymphocytes. We also showed that bone marrow from the V154M mutant mice transfers disease to the wild-type host, whereas the N153S does not, indicating mutation-specific disease outcomes. Collectively, these mutant mice recapitulate disease features seen in SAVI patients and highlight mutation-specific functions of STING. Other autoimmune mouse models such as DNAseII and DNAseIII-deficient mice, that fail to degrade DNA result in activation of the cGAS STING pathway. Deficiency of this pathway in these mouse models ameliorates lethality. By contrast, we previously reported that STING potently suppresses inflammation in a pristane-induced model of autoimmunity. In this model, we show that both cGAS- and STING-deficient mice exhibit exacerbated disease phenotypes compared to controls. We report that STING constrained TLR activation, and thereby limited autoimmune manifestations. Consistent with this premise, cGAS or STING deficient mice that lack a common TLR chaperone UNC93b develop less severe systemic autoimmunity than cGAS or STING deficient mice that are UNC93b sufficient. Overall, this study demonstrates that STING activation constrains systemic autoimmune disease and has important implications for cGAS STING-directed therapies.

Investors herd when they follow the investment decisions of other market participants and ignore their own private information, causing asset valuations to deviate from their fundamentals. This paper examines herding in the South African equity market by examining the impact of investor fear on herding behavior, using a survivorship-bias free daily dataset of companies within the JSE All Share Index over the period: 3 May 2002 to 31 December 2019. Using the cross-sectional absolute deviation (CSAD), this study examines market-wide herding behavior over multiple sub-periods, which consists of before, during and after the global financial crisis of 2007/08. The results suggest no evidence of herding towards the market return; on the contrary there is evidence of ‘anti-herding' behaviour during periods of market stress. However, there is significant herding towards the domestic fear index, which becomes more pronounced during the crisis period. Furthermore, investor herd behaviour appears to be sensitive to spill-over effects from the US investor fear-gauge, suggesting interconnectedness with global financial markets. Therefore, these findings suggest that fear plays an important role in enforcing irrational behaviour.

No description available.

Dissertation (D.M.A.)--The University of North Carolina at Greensboro, 2008. / Directed by Andrew Willis; submitted to the School of Music. Title from PDF t.p. (viewed Aug. 11, 2009). Includes bibliographical references (p. 108-113).

Cloud Computing is the next step in the evolution of the Internet. It provides seemingly unlimited computation and storage resources by abstracting the networking, hardware, and software components underneath. However, individual cloud service providers do not have unlimited resources to offer. Some of the tasks demand computational resources that these individual cloud service providers can not fulfill themselves. In such cases, it would be optimal for these providers to borrow resources from each other. The process where different cloud service providers pool their resources is called Cloud Federation. There are many aspects to Cloud Federation such as access control and interoperability. Access control ensures that only the permitted users can access these federated resources. Interoperability enables the end-user to have a seamless experience when accessing resources on federated clouds. In this thesis, we detail our project named GENI-SAVI Federation, in which we federated the GENI and SAVI cloud systems. We focus on the access control portion of the project while also discussing the interoperability aspect of it. / Graduate / 0984 / panjwani.riz@gmail.com

Bet koks nusikalstamas plačiai paviešintas įvykis ar reiškinys daro neigiamą įspūdį apie šalį – prisideda prie neigiamo šalies įvaizdžio kūrimo. Tačiau vienareikšmiškai neigiamai vertinti tokį istoriškai ir kultūriškai Italijos tapatybėje įsišaknijusį fenomeną kaip mafija, yra neteisinga. Šio tyrimo tikslas - remiantis Šiaurės, Pietų bei centrin��s Italijos dienraščių straipsnių mafijos tema kiekybine, kokybine bei žanrine analize, o taip pat mokslinės literatūros šaltinių analize, ištirti mafijos fenomeno pateikimą Italijos dienraščiuose kaip vieną iš Italijos įvaizdžio ir saviįvaizdžio formavimo prielaidų ir atskleisti skirtinguose dienraščiuose matomus minėto fenomeno įtakos skirtumus Italijos įvaizdžiui bei saviįvaizdžiui atskirose šalies dalyse. Tyrimo tikslas lemia ir tyrimo objektą, kuris yra straipsniai apie mafiją Italijos dienraščių „Corriere della Sera“, „La Repubblica“ ir „Il Mattino“ 2007 metų numeriuose. Tyrimo hipotezė teigia, jog būdama šalies identiteto dalis, mafija Italijos saviįvaizdžiui nedaro apčiuopiamos įtakos, tačiau dėl mafijos egzistavimo kenčia šalies įvaizdis, pozicionuojamas itališkoje spaudoje. Darbe atskleisti Italijos medijų sistemos ypatumai ir aptarta spaudos vieta Italijos medijų sistemoje; pristatyta agenda setting teorijos reikšmė šalies įvaizdžio kūrimui(si) bei tyrimui; identifikuota identiteto svarba šalies įvaizdžio ir saviįvaizdžio formavimui(si); apžvelgti Italijos įvaizdžio kūrimo ypatumai ir pristatyti ankstesni tyrimai... [toliau žr. visą tekstą] / This paper aims at analyzing the articles about mafia published in the present-day dailies of the Northern, Southern and Central Italy and revealing the presentation of the mafia phenomena like one of the Italy’s image and self image forming assumption and revealing the differences of the phenomena presentation in the different parts of the State. The main sources for this thesis are the articles concerning mafia published in the Italian dailies “Corriere della Sera”, “La Repubblica” and ��Il Mattino” covering the period from the 1st of January, till the 31st of December, 2007. It was hypothesized that being a part of the state’s identity, mafia doesn’t have tangible influence on Italian self image but because of its existence, the dailies positioned image of the State is negatively influenced. Content analysis quantitative and qualitative, genre analysis and scientific literature analysis methods were used for the research. The hypothesis was proven and some other facts regarding an image and a self image of Italy were discovered. / Ogni crimine ampiamente proclamato fa un effeto negativo sull’immagine dello stato. Il fenomeno mafioso, per il suo impatto storico e culturale all’idenità italiana, non può essere considerato come solamente negativo. L’obbiettivo di questa ricerca è, basandosi sull’analisi quantitativa, qualitativa, generica, degli articoli sulla mafia dei quotidiani, rappresentanti le diverse parti – Nord, Sud e Centrale – dell’Italia, e anche sull’analisi della letteratura scientifica, esaminare la rappresentazione del fenomeno mafioso come una premessa della formazione dell’immagine e dell’(auto)immagine d’Italia nelle parti diverse del paese. L‘oggetto della ricerca sono gli articoli sulla mafia pubblicati nei quotidiani „Corriere della Sera”, „La Repubblica” e „Il Mattino” nel 2007. L‘ipotesi della ricerca suppone che essendo una parte dell’identità dello stato, la mafia non ha un impatto significativo all’immagine d’Italia. Ma l’esistenza del fenomeno, fa un effetto negativo sull’immagine dello stato che viene posizionato nella stampa italiana. In questa ricerca sono stati rivelati le particolarità del sistema massmediatico italiano; presentata l’importanza della teoria dell’agenda setting per la costruzione e la ricerca dell’immagine di uno stato; identificata l’importanza d’identità per la formazione dell’immagine e dell’autoimmagine dello stato; presentate le particolarità della creazione dell’immagine d’Italia e le altre ricerche fatte su quell’immagine; definito il termine e... [toliau žr. visą tekstą]

Kandidatų požiūriai į įvairius atrankos metodus traukia organizacinės ir darbo psichologijos atstovų dėmesį dėl įvairių priežasčių, viena svarbiausių jų – tai, jog individų požiūriai į personalo atrankos metodus įtakoja jų vėlesnį elgesį. Ir nors tyrimų atlikta skirtingose šalyse nemažai, tačiau jokių duomenų nerandama Lietuvos ir Švedijos imtims. Šiame darbe iškeliamas tikslas - ištirti lietuvių studentų, lietuvių darbuotojų ir švedų studentų požiūrį į personalo atrankos metodus. Tiriamieji (197 studentai ir 86 darbuotojai) pildė Steiner ir Gilliland (1996) klausimyną, kurį sudaro trumpi 10 atrankos metodų aprašymai ir teiginiai apie šių metodų teisingumą. Rezultatai parodė, jog darbo pavyzdžio testai vertinami kaip teisingiausias personalo atrankos metodas lietuvių imtyje. Švedų imtyje teisingiausi personalo atrankos metodai yra šie: darbo pavyzdžio testai, interviu, gyvenimo aprašymas, asmeninės rekomendacijos. Lietuviai studentai palankiau vertina gebėjimų testų, sąžiningumo testų teisingumą nei švedai studentai, tačiau švedai studentai palankiau nei lietuviai studentai vertina interviu, gyvenimo aprašymą, asmenines rekomendacijas ir asmenines pažintis. Prasčiausiai teisingumo atžvilgiu lietuviai vertina asmenines pažintis ir grafologiją, o švedų grupėje vien tik grafologija vertinama kaip mažiausiai teisinga personalo atrankos procedūra. Lietuviai darbuotojai asmeninių rekomendacijų, asmeninių pažinčių ir grafologijos teisingumą vertina palankiau nei lietuviai... [toliau žr. visą tekstą] / Candidates’ attitudes towards various personnel selection methods get attention of organizational and work psychology specialists because of various reasons. The most important reason is that individuals’ attitudes towards personnel selection methods influence their latter behavior. Although there is a substantial amount of studies carried out in different countries, yet there is no data for Lithuanian and Swedish samples. The aim of current study is to analyze the attitudes towards personnel selection methods among Lithuanian students, Lithuanian employees and Swedish students. Participants of the study (197 students and 86 employees) filled in the questionnaire, which includes short descriptions of 10 personnel selection methods as well as items about fairness of these methods. According to the results of the study, work-sample tests are ranked as the fairest personnel selection method in Lithuanian sample. The fairest personnel selection methods in Swedish sample are work-sample tests, interview, resumes, and personal references. Lithuanian students rank the fairness of written ability test and honesty test more favorably than Swedish students, but Swedish students tend to rank more favorably interview, resumes, personal references and personal contacts. Personal contacts and graphology were ranked the lowest on fairness dimension in Lithuanian sample, and Swedes ranked only graphology as the least fair personnel selection method. Lithuanian employees rank personal... [to full text]

Résumé : Au Québec méridional, la principale source de dégradation du sol est l'érosion causée par la pluie. L'augmentation de la monoculture en rangs dans les secteurs à topographie accidentée, tel que l'Estrie, accroît les risques d'érosion hydrique. En effet, ce type de culture laisse les champs à découvert, sans protection, au cours des mois de l'année les plus propices à l'érosion hydrique. On peut alors affirmer que les risques d'érosion varient en fonction de plusieurs facteurs, en particulier le degré de protection offert par le couvert végétal en place. Ainsi, pour l'amélioration du calcul des pertes de sol causée par l'érosion hydrique, il devient important de pouvoir calculer le plus précisément possible le pourcentage de couverture au sol de différentes cultures pour une saison végétative, en plus de l'érosivité des pluies dont l'agressivité varie dans le temps et dont l'effet est intimement relié au couvert en place. Des mesures radiométriques (CIMEL) et photographiques furent prises sur le terrain à intervalle d'environ dix jours pour six cultures dominantes. Les mesures radiométriques nous permettent de calculer les indices de végétation tandis que les photographies servent à estimer le taux de couverture végétale pour une saison végétative. L'utilisation d'images SPOT multidates va permettre de déterminer les relations entre les indices de végétation mesurés sur le terrain et ceux calculés avec l'imagerie satellitaire. Par la suite, la relation entre le taux de couverture et les indices de végétation pour chaque culture est établie. Les résultats démontrent différents comportements en terme de couvert, qui correspondent aux périodes de forts et faibles risques d'érosion hydrique pour une saison végétative. Il est également intéressant de constater que l'indice de végétation, en général, surestime le taux de couverture en début de saison et le sous-estime en fin de saison végétative. De plus, la sénescence pose un problème au calcul du taux de couverture à l'aide des indices de végétation, ces cerniers ayant été conçu pour l'estimation de la végétation verte vivante.|| Abstract : In southern Quebec, the main source of soil degradation is erosion induced by rain fall. The growing use of in-row crop planting practices in areas of rough terrain, such as The Eastern Townships, increases the risk of water erosion. These agricultural practices leave the bare soil with no protection during the months of high erosion risk. Erosion risks are related to several factors however, the main factor is the level of protection offered by the vegetation cover. To achieve more accurate results from the Universal Soil Loss Equation, the percentage of ground cover for different crop types should be calculated as precisely as possible, for an entire growing season. It is equally important to measure the strength and quantity of rainfall over the affected area. Field radiometric and photographic data were taken on an interval of approximately ten days for six main crop types. The radiometric measurements allow us to calculate the vegetation indices and the photographic measurements are used to calculate the amount of vegetal cover throughout a growing season. The use of multitemporal SPOT imagery assisted in establishing the relationship between the vegetation indices calculated from the field data, and the ones calculated from the satellite imagery. The relationship between the amount of vegetation ground cover and the vegetation indices for each crop type was then calculated. The results show different behaviours in terms of cover, which are related to the periods of high and low water erosion over a growing season. We can also observe that as a general rule the vegetation indices over-estimate the amount of vegetation ground cover at the beginning of the growing season and under-estimate it at the end. Senescent vegetation creates a problem when calculating the amount of ground cover with the indices since the indices were created to estimate living vegetation.

Les interférons de type I (IFN I) sont des cytokines antivirales aux propriétés puissantes. L’induction, la transmission et la résolution de la réponse immunitaire engendrée par les IFN I est minutieusement régulée. Le concept d’interféronopathie de type I, récemment individualisé par notre équipe, repose sur l’hypothèse que certaines pathologies seraient secondaires au déséquilibre de ces voies de signalisation complexes et à la sécrétion excessive et inappropriée d’IFN I. L’inhibition de celle-ci par des thérapeutiques ciblées permettrait de valider cette hypothèse, si les symptômes allégués s’amélioraient, voire disparaissaient. Ce travail de thèse s’est initialement concentré sur la caractérisation clinique et biologique des interféronopathies monogéniques et polygéniques, et secondairement sur l’identification moléculaire de nouvelles mutations du gène TMEM173 à l’origine de l’interféronopathie liée à STING, également appelée SAVI (STING associated vasculopathy with onset in infancy), syndrome auto-inflammatoire associant une atteinte sévère cutanée et pulmonaire. De nouvelles techniques ont permis la sélection de patients présentant une augmentation de l’IFN I en comparaison à des contrôles sains : la signature IFN I, qPCR de 6 gènes stimulés par l’IFN (IFN stimulated genes – ISGs) et le dosage d’IFN alpha sérique ou plasmatique par méthode du SIMOA (single molecule array) permettant la détection de molécules d’IFN de l’ordre du femtogramme (10-18g). Ces méthodes nous ont ainsi permis d’élargir le spectre clinique phénotypique des interféronopathies de type I, initialement considéré comme essentiellement neurologique. Les patients atteints du syndrome d’Aicardi-Goutières, première interféronopathie monogénique décrite, présentaient les signes suivants : dystonie, spasticité, décalage des acquisitions, calcifications intra-cérébrales et anomalies de la substance blanche. Cependant, l’utilisation systématique de nos méthodes de criblage associée à l’avènement des technologies de séquençage à haut débit (next generation sequencing – NGS) a permis de révéler un phénotype plus large, caractéristique des interféronopathies de type I : sur le plan cutané (engelures, vascularite nécrosante des extrémités, sclérodermie), pulmonaire (pneumopathie interstitielle isolée ou non), musculo-squelettique (arthralgies, arthrites, arthropathie de Jaccoud, myalgies et myosites), ophtalmologique (glaucome), néphrologique (néphropathies lupiques), gastro-entérologique (maladies inflammatoires chroniques intestinales précoces), associées à de l’auto-immunité ou un déficit immunitaire inconstants. Notre méthode de sélection nous a notamment permis d’identifier des patients présentant de manière variable des signes cardinaux de SAVI et une de trois nouvelles mutations activatrices dans une région spécifique du gène TMEM173 (codant pour STING). Ces mutations circonscrivent une région de la protéine à ce jour encore jamais impliquée dans le contrôle de la voie de l’IFN I. STING est une protéine du réticulum endoplasmique qui agit comme adaptateur cytosolique de senseurs intracellulaires d’ADN viral dans une voie de signalisation de l’IFN I. STING active TBK1 (TANK-binding kinase) et permet la transcription des IFN I par la phosphorylation d’IRF3. La Janus Kinase 1 (JAK1) et la tyrosine kinase 2 (TYK2) sont activées suite à la stimulation des récepteurs de l’IFN I et phosphorylent les facteurs de transcription STAT1 et STAT2, conduisant à l’expression de nombreux ISGs. Les analyses génétiques, de conformation tridimensionnelle, sur un modèle cellulaire in vitro (HEK293T) et ex vivo sur cellules mononuclées périphériques des patients nous ont ainsi permis de mettre en évidence pour ces mutations un caractère constitutionnellement activé, indépendant de la liaison au ligand cGAMP, mais transmettant ce signal à travers la voie d’aval par TBK1. (...) / Type I interferons (IFN I) are antiviral cytokines with potent properties. Hence, the induction, transmission and resolution of the immune response generated by IFN I is tightly regulated. The concept of the type I interferonopathies, recently formulated by our team, rests on the assumption that some diseases arise from a disturbance of this complex signalling pathway, leading to excessive and inappropriate IFN I secretion. On this basis, targeted therapeutics should improve or cure features of such type I interferonopathies, thereby providing a validation of the underlying hypothesis. This PhD project initially focused on the clinical and biological characterisation of monogenic and polygenic interferonopathies, and secondarily on the molecular identification of novel mutations in the gene TMEM173 causing the interferonopathy called STING associated vasculopathy with onset in infancy (SAVI), an auto-inflammatory syndrome with severe cutaneous and pulmonary features. Our selection of patients in comparison to healthy controls was made possible through the use of novel screening tools: IFN signature (qPCR of 6 IFN stimulated genes – ISGs), and measurement of IFN alpha protein levels in serum or plasma (SIMOA-single molecule array - enabling the detection of molecules of IFN in the femtogram [10-18g]) range. In this way, we have been able to expand the phenotypic spectrum of the interferonopathies, which was initially considered as primarily neurological. Patients with Aicardi-Goutières syndrome (AGS), the first described of the monogenic interferonopathies, exhibit dystonia, spasticity, developmental delay, intra-cranial calcifications and white matter abnormalities. However, the systematic use of our interferon screening assays, plus the advent of next-generation sequencing technology, has revealed a much broader set of features relevant to this novel disease grouping – involving the skin (chilblains, necrotising vasculitis, scleroderma), lungs (isolated lung interstitial disease or associated with other signs), musculoskeletal system (joint pain, arthritis, Jaccoud’s arthropathy, muscle pain and myositis), eyes (glaucoma), kidneys (lupus nephritis) and gastro-intestinal tract (early inflammatory bowel disease), as well features of autoimmunity and immunodeficiency. Using our screening assays enabled us to identify three patients variably exhibiting the core features of SAVI, all of whom were found to harbour distinct novel activating mutations in STING. These mutations highlight a protein domain not previously implicated in the control of IFN I signalling. STING is an endoplasmic reticulum protein, acting as a cytosolic adaptor of intracellular sensors of viral DNA in the type I IFN signalling pathway. STING activates TANK-binding kinase (TBK1), allowing transcription of IFN I through phosphorylation of IRF3. Janus kinase 1 (JAK1) and tyrosine kinase 2 (TYK2) are activated following stimulation of the IFN I receptor, leading to phosphorylation of the transcription factors STAT1 and STAT2 and the subsequent induction of a large number of ISGs. Genetic analysis, conformational studies, an in vitro cellular model (HEK293T) and ex vivo experimental data (using patient peripheral blood mononuclear cells - PBMCs) enabled us to confirm the constitutive activating nature of these variants, and show that this activation did not require binding with cGAMP, but was dependent on signalling through TBK1. Ruxolitinib, a JAK1/2 inhibitor, could antagonise this constitutive activation ex vivo. These results indicate a promising therapeutic approach in such patients, and more widely in the monogenic, and perhaps even, polygenic, interferonopathy context.