abstract: The role of climate change, as measured in terms of changes in the climatology of geophysical variables (such as temperature and rainfall), on the global distribution and burden of vector-borne diseases (VBDs) remains a subject of considerable debate. This dissertation attempts to contribute to this debate via the use of mathematical (compartmental) modeling and statistical data analysis. In particular, the objective is to find suitable values and/or ranges of the climate variables considered (typically temperature and rainfall) for maximum vector abundance and consequently, maximum transmission intensity of the disease(s) they cause. Motivated by the fact that understanding the dynamics of disease vector is crucial to understanding the transmission and control of the VBDs they cause, a novel weather-driven deterministic model for the population biology of the mosquito is formulated and rigorously analyzed. Numerical simulations, using relevant weather and entomological data for Anopheles mosquito (the vector for malaria), show that maximum mosquito abundance occurs when temperature and rainfall values lie in the range [20-25]C and [105-115] mm, respectively. The Anopheles mosquito ecology model is extended to incorporate human dynamics. The resulting weather-driven malaria transmission model, which includes many of the key aspects of malaria (such as disease transmission by asymptomatically-infectious humans, and enhanced malaria immunity due to repeated exposure), was rigorously analyzed. The model which also incorporates the effect of diurnal temperature range (DTR) on malaria transmission dynamics shows that increasing DTR shifts the peak temperature value for malaria transmission from 29C (when DTR is 0C) to about 25C (when DTR is 15C). Finally, the malaria model is adapted and used to study the transmission dynamics of chikungunya, dengue and Zika, three diseases co-circulating in the Americas caused by the same vector (Aedes aegypti). The resulting model, which is fitted using data from Mexico, is used to assess a few hypotheses (such as those associated with the possible impact the newly-released dengue vaccine will have on Zika) and the impact of variability in climate variables on the dynamics of the three diseases. Suitable temperature and rainfall ranges for the maximum transmission intensity of the three diseases are obtained. / Dissertation/Thesis / Doctoral Dissertation Applied Mathematics 2018

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Considered viral diseases of major re-emerging in the world, the dengue, chikungunya and Zika have as the main vector Aedes aegypti (L.) (Diptera: Culicidae). Larvicidal vector control is an important measure to prevent the transmission of such infections. A major challenge in the control of this arthropod is the low sensitivity of its population through the use of conventional larvicides. Thus, the insect acquires resistance, reducing the effectiveness of these pesticides. Consequently, it will lead to an increase in the risks of toxicity in nontarget organisms and a change in the environment. An alternative to avoid problems caused by the use of these products is the search for new compounds with less environmental impact and better benefits to human health. The indole molecule ring represents one of the subunits of great importance in the discovery of new pesticide products for the pharmaceutical market. By Friedel-Crafts acylation reaction, the C-3 of this ring makes it susceptible to chemically react. Thus, 12 indole analogues were synthesized as potential larvicidal agents against Ae. aegypti in its 3rd larval stage followed by the evaluation of the toxicity in nauplii of Artemia sp. The compounds were identified by analytical thin-layer chromatography, purified on a silica gel 60 chromatographic column (using the Hexane: Ethyl acetate (90:10, v / v) binary system as the mobile phase) and characterized by melting point, 13C and 1H NMR (using a residual solvent peak or TMS as reference for 1 H NMR spectra), mass spectrum and infrared. Bioassays were performed using 20 larvae per test, disposable cups containing 20mL of the test solution in triplicate. Branched aliphatic side chain derivatives were more potent than the others were, and the linear ones exhibited potency oscillation as the addition of the methylene chains. Toxicity tests indicated that (3-chlorophenyl)1-(1H-indol-3-yl)methanone, with moderate larvicidal potency (LC50 = 50.59 ppm), showed the highest selectivity index (SI >19.7), being less toxic to Artemia sp. than Ae. aegypti. The relationships between structural changes in indole derivatives and their LC50 results provide information that may contribute to the understanding of the influence of physicochemical properties on the larvicidal action of this class of compounds, without damage to the ecosystem. / Consideradas doenças virais de grande reemergência no mundo, a dengue, chikungunya e zika têm como principal vetor o Aedes aegypti (L.) (Diptera:Culicidae). O controle vetorial baseado em larvicidas é uma medida importante de prevenir a transmissão de tais infecções. Um grande desafio nas formas de controle desse artrópode está na baixa sensibilidade de sua população através do uso de larvicidas convencionais. Assim, o inseto adquire resistência, reduzindo a eficácia desses pesticidas. Consequentemente, levará a um aumento nos riscos de toxicidade em organismos não-alvo e uma alteração ao meio ambiente. Uma alternativa para evitar problemas ocasionados pela utilização desses produtos é a pesquisa por novos compostos com menos impacto ambiental e melhores benefícios à saúde humana. O anel da molécula do indol representa uma das subunidades com grande importância na descoberta de novos produtos pesticidas para o mercado farmacêutico. Por reação de acilação de Friedel-Crafts, o C-3 deste anel torna suscetível a reagir quimicamente. Assim, foram sintetizados 12 análogos do indol como potenciais agentes larvicidas contra o Ae. aegypti no seu 3º estágio larvar, seguido pela avaliação da toxicidade em náuplios de Artemia sp. Os compostos sintetizados foram identificados por cromatografia em camada delgada analítica, purificados em coluna cromatográfica de sílica gel 60 (utilizando o sistema binário Hexano: Acetato de etila (90:10, v/v) como fase móvel), e caracterizados por ponto de fusão, RMN de 13C e 1H (utilizando um pico de solvente residual ou TMS como referência para os espectros de RMN 1H), espectro de massas e infravermelho. Os bioensaios foram realizados utilizando 20 larvas por teste, copos descartáveis contendo 20 mL da solução teste em triplicata. Derivados de cadeias laterais alifáticas ramificadas foram mais potentes que os demais, e os lineares exibiram oscilação de potência conforme acréscimo das cadeias de metileno. Ensaios de toxicidade apontaram que a (3-clorofenila)1-(1H-indol-3- ila)metanona, com potência larvicida moderada (CL50 = 50,59 ppm), exibiu o maior índice de seletividade (IS >19,7), sendo menos tóxico para Artemia sp do que para o Ae. aegypti. As relações entre mudanças estruturais dos derivados do indol e seus resultados de CL50 fornecem informações que podem contribuir para a compreensão da influência de propriedades físico-químicas na ação larvicida desta classe de compostos, sem prejuízos ao ecossistema. / São Cristóvão, SE

Submitted by Franciele Moreira (francielemoreyra@gmail.com) on 2017-12-06T14:22:57Z No. of bitstreams: 2 Dissertação - Ricardo Lemes Gonçalves - 2017.pdf: 6297486 bytes, checksum: 3393a7cb0ffe26eafd0acd04f1198ab0 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2017-12-07T10:18:10Z (GMT) No. of bitstreams: 2 Dissertação - Ricardo Lemes Gonçalves - 2017.pdf: 6297486 bytes, checksum: 3393a7cb0ffe26eafd0acd04f1198ab0 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2017-12-07T10:18:10Z (GMT). No. of bitstreams: 2 Dissertação - Ricardo Lemes Gonçalves - 2017.pdf: 6297486 bytes, checksum: 3393a7cb0ffe26eafd0acd04f1198ab0 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2017-10-05 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Flavivirus-induced pathogens are considered a serious public health problem in the world, because they affect primarily the poor populations of underdeveloped tropical countries. This family of viruses has an enveloped positive RNA genome encoding tree structural proteins and seven non-structural proteins. In particular, non-structural protein 1 (NS1) is associated mainly with the viral replication process and immune system leakage, and can be found in different glycosylated oligomeric forms, but only "mature" after its dimerization, or when in the hexamer form. In this context, inhibition of the dimerization process of NS1 has been pointed as a great target for the rational design of drugs. However, for this type of rationalized approach to be successful, it is necessary to understand the molecular mechanisms involved in the process of dimerization, as well as characterize its functional regions. In this study, through Molecular Dynamics (DM) simulations, the structural behavior of the NS1's of the Dengue and Zika were evaluated and compared in the monomeric and dimeric forms, from structures crystallized with glycosylations. For the structure of the Dengue (PDB: 5k6k), there was a need to previously model the regions of missing residues, then making necessary to replace the sugars in the structures. All of the N-glycosylations and intercysteine bonds of each monomer and dimer were performed in the Amber14 software. Specific histidine protonation was predicted by the H++ assay before proceeding with DM. All structures were submitted to DM by 100ns using the GROMACS 5.1.2 software. The stability and flexibility of the structures observed in the trajectories were used to elucidate the mechanisms responsible for the monomer-monomer interaction, as well as to understand the singularities between the regions that stood out. In the monomeric form of the two species, large conformational fluctuations were observed in their N-terminal loops involved in the β-roll composition, which in the dimeric form were stabilized by the triad Ile/Val19 - Phe20 - Ile21 for creating a framework favorable to the interlacing of the N-terminal loops between the A and B chains. Concomitantly, Lysines-189 of the β-ladder domain acted as a key residue (staple) to stabilize the central portion of β-roll. The stability mechanisms of NS1 revealed in this work for the Zika and Dengue species, contribute to make the possibility of pharmacological intervention more accessible, in a rationalized way, whose approach could be directed at specific structural points responsible for its biological role. / As patogenias causadas pelos Flavivírus são consideradas um sério problema de saúde pública no mundo, pois afetam principalmente populações pobres de países tropicais subdesenvolvidos. Esta família de vírus apresenta um genoma de RNA positivo envelopado que codifica três proteínas estruturais e sete proteínas não estruturais. Em particular, a proteína não estrutural 1 (NS1) está associada principalmente aos processos de replicação viral e escape do sistema imune, sendo encontrada em diferentes formas oligoméricas glicosiladas, mas na sua forma “madura” somente após sua dimerização, ou quando na forma de hexâmero. Neste contexto, a inibição do processo de dimerização da NS1 tem sido apontada como um ótimo alvo para o design racional de fármacos. Contudo, para que este tipo de abordagem racional seja bem sucedida, é necessário compreender os mecanismos moleculares que estão envolvidos no seu processo de dimerização, bem como caracterizar suas regiões funcionais. Neste estudo, através de simulações de Dinâmica Molecular (DM), o comportamento estrutural das NS1’s do Zika e Dengue foram analisados e comparados nas formas monoméricas e diméricas, partindo de estruturas cristalizadas nas formas glicosiladas. No caso da estrutura do Dengue (PDB: 5k6k) houve a necessidade de modelar previamente as regiões dos resíduos faltantes, tornando em seguida necessária a recolocação dos açucares nas estruturas. Todas as N-glicosilações e ligações entre cisteínas de cada monômero e dímero, foram efetuadas a partir do software Amber 14. A protonação especifica das histidinas foi predita pelo servirdor H++ antes de proceder com a DM. Todas as estruturas foram submetidas à DM por 100ns usando o software GROMACS 5.1.2. A estabilidade e flexibilidade das estruturas observadas nas trajetórias foram usadas para elucidar os mecanismos responsáveis pela interação monômero-monômero, bem como compreender as singularidades entre as regiões que se destacaram. Na forma monomérica das duas espécies, observou-se grandes flutuações conformacionais nas suas alças N-terminais envolvidas na composição do β-roll, que na forma dimérica foram estabilizadas pela tríade Ile/Val19 - Phe20 - Ile21 por criar um arcabouço favorável ao entrelaço das alças N-terminais entre as cadeias A e B. Concomitantemente, as Lisinas-189 do domínio β-leadder atuaram como um resíduo chave (grampo) para estabilizar a porção central do β-roll. Os mecanismos de estabilidade da NS1 revelados neste trabalho para as espécies Zika e Dengue, contribuem para tornar mais acessível a possibilidade de uma intervenção farmacológica de forma racionalizada, cuja abordagem poderia ser dirigida em pontos estruturais específicos responsáveis por seu papel biológico.

<div><p>Zika virus (ZIKV) is a mosquito-borne pathogen that stayed unnoticed for over half a century. Only after the 2015-16 Brazilian outbreak did the severity of the infectious outcome, particularly the Congenital Zika Syndrome, become apparent. ZIKV is associated with severe neurodevelopmental impairments in human fetuses, including microencephaly, ventriculomegaly, retinopathy, and sensorineural hearing loss. Though the pandemic is now under control in the Latin American countries, several tropical countries could still be at risk of widespread infection. This warrants a better understanding of the congenital Zika syndrome; this project attempts to contribute towards this goal.</p><p><br></p><p>Previous reports examining neural progenitor tropism of ZIKV in organoid and animal models did not address whether the virus infects all neural progenitors uniformly. To explore this, ZIKV was injected into the neural tube of 2-day-old chicken embryos, resulting in non-uniform periventricular infection 3 days later. Recurrent foci of intense infection were present at specific signaling centers that influence neuroepithelial patterning at a distance through secretion of morphogens. ZIKV infection reduced transcript levels for 3 morphogens, SHH, BMP7, and FGF8, expressed at the midbrain basal plate, hypothalamic floor plate, and isthmus, respectively. Levels of Patched1, a SHH-pathway downstream gene, were also reduced and a SHH-dependent cell population in the ventral midbrain was shifted in position. Thus, the diminishment of signaling centers through ZIKV-mediated apoptosis may yield broader, non-cell autonomous changes in brain patterning.</p><p><br></p></div><p>Sensorineural hearing loss is a relatively understudied consequence of congenital Zika syndrome, and balance disorders are essentially unreported to date. ZIKV pathogenesis was explored in the developing inner ear using the accessible chicken embryo model system. One goal was to assess the spatiotemporal susceptibility of otic epithelial-derived structures to ZIKV infectivity. Direct injections of the inner ear or the inner ear primordium were performed <i>in ovo</i>with subsequent harvests at 2 to 8 days-post-infection. The degree of infection in sensory/prosensory organs was evaluated histologically to determine the susceptibility of one auditory and five vestibular organs. ZIKV infection of the sensory as well as non-sensory epithelia was observed at most stages of analysis, with no apparent preference for one over the other. The lagena, the ventral most tip of the chicken inner ear, and the endolymphatic sac/duct were least frequently infected. In this report, two novel findings in sequela of ZIKV infection are presented: the vestibular labyrinth can present with stalled canal morphogenesis, and the auditory ganglion can be severely shrunken, perhaps due to an increased cell death upon early ZIKV infection of the inner ear.</p><p><br></p><p>Additional methods of peripheral infection in the chicken embryos were tested to examine ZIKV transmission to the central nervous system: E3 blood vessel, E4 limb bud, and E10 chorioallantoic membrane infections. Although none of these methods resulted in a histologically significant infection of the developing brain 3 to 6 days-post-infection, evidence of ZIKV genome replication and viremia was detected in several tissue types.<br></p>

abstract: Flaviviruses (FVs) are among the most medically important arboviruses of the world with the Dengue virus (DENV) accounting for a large percentage of infections observed in tropical and subtropical regions of the world. Globalization, travel, and the expanding range of mosquito vectors, such as Aedes aegypti, have increased the potential of infection rates and illnesses associated with FVs. The DENV and the Zika (ZIKV) FVs frequently co-circulate and generally cause mild self-liming febrile illnesses. However, a secondary infection with a heterologous DENV serotype may lead to life threatening dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). DHF/DSS have been linked to antibody dependent enhancement of infection (ADE), a phenomenon that occurs when antibodies (Abs) formed against an initial infection with one serotype of DENV cross-reacts but does not neutralize a heterologous DENV serotype in a secondary infection. Furthermore, Abs raised against the ZIKV have been observed to cross-react with the DENV and vice versa, which can potentially cause ADE and lead to severe DENV disease. The ZIKV can be transmitted vertically and has been linked to devastating congenital defects such as microcephaly in newborns. FDA approved treatments do not exist for DENV and ZIKV illnesses. Thus, there is a need for safe and effective treatments for these co-circulating viruses. Here, a tetravalent bispecific antibody (bsAb) targeting the ZIKV and all four serotypes of the DENV was expressed in the Nicotiana benthamiana (N. benthamiana) plant. Functional assays of the DENV/ZIKV bsAb demonstrated binding, neutralization, and a significant reduction in ADE activity against both the DENV and the ZIKV. A single chain variable fragment (scFv) and a diabody based on an antibody directed against the immune checkpoint inhibitor PD-L1, were also expressed in N. benthamiana leaves. The smaller sizes of the scFv and diabody confers them with the ability to penetrate deeper tissues making them beneficial in diagnostics, imaging, and possibly cancer therapy. The past few decades has seen long strives in recombinant protein production in plants with significant improvements in production, safety, and efficacy. These characteristics make plants an attractive platform for the production of recombinant proteins, biologics, and therapeutics. / Dissertation/Thesis / Doctoral Dissertation Molecular and Cellular Biology 2019

and keywords Abstract and keywords The ubiquitin-proteasome system (UPS) is a tightly and specifically regulated system of protein degradation in eukaryotic cells. Inhibition of an UPS component might represent a strategy to control human diseases, including cancer. Modulation of the UPS can also be employed in basic research strategies. This thesis deals with two independent yet methodologically connected research aims - first, to search for the target of the newly identified UPS inhibitor CBU79, and second, to develop a fluorescent cell-based reporter exploiting proteasomal degradation. In the first part of my work, previous findings regarding the molecular mechanisms of CBU79 inhibiton on the UPS were confirmed. In the next step, I characterized how the UPS inhibitor CBU79 affects protein synthesis using the metabolic labelling of proteins based on click chemistry. I also examined the cytotoxic effect of CBU79 treatment on different cell lines. Finally, I performed a CRISPR/Cas9 whole-genome enrichment screen with the aim to find a potential target of the inhibitor. I found out that CBU79 probably decreases levels of protein synthesis by triggering cellular signalling via the unfolded protein response (UPR). Using the screen, I found 22 potential targets of the CBU79 inhibitor that will be...

Las enfermedades metaxénicas en el Perú constituyen uno de los principales problemas de salud, teniendo gran impacto sobre la salud pública nacional; debido a esta problemática se planteó la pregunta de investigación ¿cuál es el rol de la enfermera en la prevención y control del dengue, chikungunya y zika en red de servicios de salud de Chiclayo, Perú 2017?, tuvo como objetivos describir y analizar el rol de la enfermera (o) en la prevención y control en la red de servicios de salud Chiclayo. Teniendo como bases teórico conceptuales al autor Ayuso D. en su libro enfermería familiar y comunitaria, y la norma técnica peruana de prevención y control de enfermedades metaxénicas. Esta Investigación fue de tipo cualitativa con abordaje metodológico estudio de caso. Los sujetos de estudio fueron 10 enfermeras de los centros de salud de la red de servicios de salud Chiclayo escenario II y III según riesgo entomológico. El tamaño de la muestra se determinó con técnica de saturación y redundancia, se utilizó la entrevista semiestructurada para la recolección de datos, siendo analizadas en tres fases: pre análisis, codificación, categorización. Así mismo se tuvo como base los principios éticos y los criterios de rigor científico. Del análisis realizado se obtuvo como resultado cuatro categorías: Educación para la prevención y control de enfermedades como dengue, chikungunya y zika, cuidado de enfermería en la vigilancia epidemiologia y entomológica, limitantes para la prevención y control de enfermedades antes mencionadas y concertación multisectorial en enfermería en enfermedades de vigilancia epidemiológica.

L’importance et l’expansion des arboviroses comme la dengue ou le virus Zika nécessite des modèles pour mieux comprendre et prédire leurs dynamiques. La propagation vectorielle de ces maladies est influencée par de multiples facteurs humains et environnementaux qui rendent complexe la construction de modèles épidémiologiques parcimonieux. Parallèlement, de nombreux outils théoriques et computationnels existent désormais pour confronter ces modèles aux données observées. L’objectif de ce travail de thèse est donc d’apporter l’éclairage des données sur les modèles de propagation des arboviroses. Dans un premier temps, il s’agit d’identifier les éléments les plus importants à incorporer pour modéliser les dynamiques de la dengue en milieu rural, dans la région de Kampong Cham (Cambodge). Différents modèles sont comparés, complexifiant à la fois le détail de l’histoire de la maladie et la prise en compte des formes de stochasticité. Dans le cadre déterministe, on a pu souligner l’importance des interactions entre sérotypes, et le faible intérêt pour la représentation explicite des moustiques vecteurs et des individus asymptomatiques. Par ailleurs, la prise en compte des incertitudes indique qu’une large part de la dynamique est capturée seulement par la stochasticité et non par les éléments du squelette déterministe du modèle. Aussi étudie-t-on dans un second temps d’autres aspects de la transmission de la dengue, comme la saisonnalité et la structure spatiale, grâce à des données d’épidémies à Rio de Janeiro (Brésil). Dans un dernier temps, ces méthodes et modèles sont appliqués à l’étude d’un arbovirus émergent, le virus Zika. A partir de données d’épidémies survenues dans le Pacifique, les paramètres-clé de la propagation du virus sont estimés dans le cadre stochastique, et leur variabilité est envisagée à la fois en termes de contexte géographique et de modèle épidémiologique, par la comparaison de quatre îles et de deux modèles à transmission vectorielle. Par ailleurs, la question des interactions potentielles du virus Zika avec celui de la dengue est explorée. / Arboviruses such as the dengue and Zika viruses are expanding worldwide and mo- deling their dynamics can help to better understand and predict their propagation, as well as experiment control scenarios. These mosquito-borne diseases are influenced by a multiplicity of human and environmental factors that are complex to include in parsimonious epidemiological models. In parallel, statistical and computational tools are nowadays available to confront theore- tical models to the observed data. The objective of this PhD work is therefore to study arbovirus propagation models in the light of data. Firstly, in order to identify the most important elements to incorporate in models for dengue dynamics in a rural setting, several dengue models are com- pared using data from the Kampong Cham region in Cambodia. Models incorporate increasing complexity both in the details of disease life history and in the account for several forms of sto- chasticity. In the deterministic framework, including serotype interactions proved decisive, whereas explicit modeling of mosquito vectors and asymptomatic infections had limited added value, when seasonality and underreporting are already accounted for. Moreover, including several forms of un- certainties highlighted that a large part of the disease dynamics is only captured by stochasticity and not by the elements of the deterministic skeleton. Therefore, secondly, we explore other aspects of transmission, such as seasonality and spatial structure, in the case of dengue epidemics in Rio de Janeiro (Brazil). Finally, the models and estimation methods are applied to study an emerging arbovirus, the Zika virus. Using data from epidemics in the Pacific, we estimate the key parameters of disease propagation in the stochastic framework and explore their variability in terms of geogra- phic setting and model formulation by comparing four islands and two models with vector-borne transmission. In addition, potential interactions with the dengue virus are explored.

Arbovirus infections are widespread, and their disease burden has increased in the past decade. In Africa, arbovirus infections and fever with unknown etiology are common. Due to the lack of well-established epidemiologic surveillance systems and accurate differential diagnosis in most African countries, little is known about the prevalence of human arbovirus infections in Africa. The aim of this review is to summarize the available epidemiological data and diagnostic laboratory tools of infections with dengue, yellow fever, Zika, and chikungunya viruses, all transmitted by Aedes mosquitoes. Studies indicate that these arboviral infections are endemic in most of Africa. Surveillance of the incidence and prevalence of the infections would enable medical doctors to improve the diagnostic accuracy in patients with typical symptoms. If possible, arboviral diagnostic tests should be added to the routine healthcare systems. Healthcare providers should be informed about the prevalent arboviral diseases to identify possible cases.

Background Dengue is a significant problem of international health concern. According to the World Health Organization in 2012, globally, dengue is “the most important mosquito borne viral disease” with incidence 30 higher than it had been 50 years ago. While most of the burden of disease associated with dengue is located in areas with a tropical and sub-tropical climate, increasing evidence suggests temperate areas are also at risk. Considering the recent introduction of relevant mosquito vectors into Southern Europe, and increasing numbers of imported dengue via travelers, Europe and other temperate areas may be increasingly at risk for dengue emergence, establishment and local transmission in the foreseeable future. Methods Recent dengue emergence in Madeira and reemergence in Tokyo underline the hypothesis that passenger air-travel can be an important conduit for the importation of vector-borne disease leading to emergence in naïve areas climatically suitable for dengue transmission, including parts of Europe. Combining information on travel with virus genetic similarity was useful in discerning likely pathways of for the importation of infections. Generalizing information learned from outbreaks in Tokyo and Madeira with global epidemic intelligence, global travel networks, and climate change projections, leads to more refined understanding of the magnitude of dengue infectious imported into temperate areas and these virus introduction events’ potential implications for seeding epidemics in the 21st century. Results While compared to total travel, imported dengue events and epidemics of dengue outside the tropics are rare, our combined evidence and modeled estimations suggest strongly that epidemic dengue emergence in temperate areas is possible and will continue to increase. We found that global change dynamics including warming temperatures in the much of the northern hemisphere and increasing passenger interconnectivity between areas endemic for dengue and dengue free areas are key mechanisms partly explaining these unprecedented epidemiological transitions. Conclusion While we calibrated our models on information known about dengue, many elements of the methods and conclusions may increase understanding of the potentially global implications for imported infections of other climate-sensitive infectious diseases’ that may have similar parameters. During 2016 and the years to come, techniques developed in this doctoral research will contribute to models used in risk analysis for vector-borne diseases of interest, including the increasing important potential for imported Chikungunya and Zika viruses into a variety of unexposed areas.