Development of CO-releasing molecular for the treatment of inflammatory diseases

Dissertation presented to obtain a Ph.D. degree (Doutoramento) in Chemistry at the Instituto de Tecnologia Quimica e Biol6gica da Universidade Nova de Lisboa

Studying the impact of co-authorship with external researchers:the case of research community in Portugal using social network analysis.

Project work presented as a partial requirement to obtain a Master Degree in Information Management

Sudden sensorineural hearing loss : evaluation of co-morbidities and potential clinical associations

RESUMO: A surdez súbita (SS) caracteriza-se por uma perda abrupta de audição, mais frequentemente unilateral e associada a sensação de preenchimento aural, acufenos e vertigem. Afecta 5-20/100.000pessoas/ano (sobretudo adultos em fase activa na década de 40), com grande impacto na qualidade de vida. Possíveis causas incluem doenças infecciosas, circulatórias, traumáticas, imunológicas, neoplásicas, neurológicas, tóxicas e cocleares. No entanto, a causa da SS permanece desconhecida na maioria dos casos (80%), o que origina tratamentos controversos e frequentemente ineficientes. Os tratamentos disponíveis variam desde corticosteróides a antivirais, vasodilatadores, anti-agregantes, anticoagulantes, vitaminas e oxigénio hiperbárico (OHB). Atendendo a falta de informação relativa à etiologia e fisiopatologia da SS, pretendemos avaliar a evolução clínica dos doentes com SS tratados com OHB no Centro de Medicina Subaquática e Hiperbárica (CMSH) de Lisboa entre 2000 e 2005, durante um período mínimo de 5 anos, na tentativa de identificar eventuais factores de risco ou noxas clínicas com a SS. O estudo retrospectivo proposto baseia-se na revisão de processos clínicos do CMSH e na aplicação telefónica de questionários médicos de “follow-up” confidenciais – tanto a doentes (grupo de estudo), como aos respectivos esposos/companheiros/membros próximos da família (grupo de controlo) –, com particular ênfase nos antecedentes médicos e história clínica actual. Um estudo preliminar de 20 pessoas (10 doentes e 10 controlos) foi efectuado para antecipar dificuldades e estimar as necessidades logísticas. As dificuldades identificadas foram: 1) selecção dos doentes com números de telefone válidos e processos clínicos completos (com audiograma inicial e final); 2) contacto telefónico com os participantes de ambos os grupos (de estudo e controlo); 3) recursos humanos requeridos. Dado que a SS não é uma doença em si, mas um sintoma de uma doença subjacente, acreditamos que este estudo epidemiológico seja importante e útil, capaz de gerar novas luzes sobre a fisiopatologia e mecanismos desta entidade clínica.-------------ABSTRACT:Sudden sensorineural hearing loss (SSHL) is characterized by abrupt, mostly unilateral loss of hearing, frequently associated to aural fullness, tinnitus and vertigo. It affects 5-20/100.000 people/year (particularly working adults in the 40ths), with huge impact on quality of life. Possible causes include infectious, circulatory, traumatic, immunologic, metabolic, neoplastic, neurologic, toxic and unidentified cochlear diseases. Nevertheless, SSHL’s etiology remains unknown in most cases (80%), giving rise to controversial (and frequently ineffective) treatments. Available therapies range from corticosteroids to antivirals, vasodilators, antiaggregants, anticoagulants, vitamins and hyperbaric oxygen (HBO). Given the lack of data concerning SSHL’s etiology and physiopathology, we intend to evaluate clinical evolution of such patients treated with HBO in the Underwater and Hyperbaric Medical Center (UHMC) at Lisbon from 2000 to 2005 during a minimum period of 5 years, in an attempt to identify eventual risk factors or clinical associations to SSHL. The intended retrospective study is based on the review of patients’ medical charts from UHMC and confidential follow-up questionnaires applied telephonically both to patients (study group) and patients’ spouse/partner/close family member (control group), focusing past and present medical history. A preliminary study of 20 subjects (10 of each group) was performed to anticipate difficulties and to estimate the required logistics. The identified difficulties were: 1) selection of subjects with valid phone numbers and complete medical charts (with initial and final audiograms); 2) telephonic contact with subjects from the study and control group; 3) human logistics required. As it is believed that SSHL is not a disease by itself but rather a symptom of an underlying disease, we believe that this epidemiologic study is important and will hopefully generate sound scientific knowledge concerning physiopathology and mechanism of disease of SSHL.

Co-Authorship of scientists in the energy field: an exploratory study of the ETDE World Energy Database (ETDEWEB) using Social Network Analysis

Paper presented at the 5th European Conference Economics and Management of Energy in Industry, Vilamoura, Algarve. Apr. 14-17, 2009, 11p. URL: http:// www.cenertec.pt/ecemei/

Co-Authorship of scientists in the energy field: a study of the ETDE World Energy Database (ETDEWEB) using social network analysis

Dissertação apresentada como requisito parcial para obtenção do grau de Mestre em Gestão de Informação

Selection of a co-operation agreement between EMOVE – Innovative Technologies and WavEC – Wave Energy Center

A Work Project, presented as part of the requirements for the Award of a Masters Degree in Management from the NOVA – School of Business and Economics

A matter of time: Phases of customer co-creation community participation and their impact on customer behavior

Despite the growing relevance of co-creating customer communities only little scientific evidence is available on their impact on transactional behavior of participants. Previous research has mostly used self-reported data or distinguished only between during and pre-community phases obtaining mixed results. However, the author proposes that co-creating community activity takes place in five distinguishable phases and changes in transactional behavior are limited to certain phases. Using 33 months of transactional data of a Dutch online auction provider a study was conducted covering all five phases of the community co-creation process from community planning over community set-up, co-development and co-testing to post-launch. The overall results indicate mixed effects of community participation on the different transactional variables during the co-creation process. Community participation had positive effects on auctions listing behavior at the community set-up, co-development and post-launch phases, whereby the number of auctions listed peaked during the community set-up phase. These results suggest that the impact on transactional behavior differs between co-creation phases and different psychological mechanism limited to certain phases might trigger the respective changes.

A first analysis of the atmospheric measurements from TANSO/GOSAT

Dissertação apresentada na Faculdade de Ciências e Tecnologia da Universidade Nova de Lisboa para obtenção do grau em Mestre em Engenharia Física

Parallel run-time for CO-OPN

Dissertação para obtenção do Grau de Mestre em Engenharia Informática

Novel insights into the action of antimicrobial agents against human pathogens

Dissertation presented to obtain the Ph.D degree in Biochemistry

Non-cell autonomous neuroprotective effect of carbon monoxide : microglia-to-neuron communication

RESUMO: A isquémia cerebral é uma das doenças mais predominantes a nivel mundial, sendo uma das principais causas de mortalidade e invalidez. Parte da propagação de dano no cérebro é causado por inflamação descontrolada, causada principalmente por disfunção da microglia. Desta forma, existe a necessidade de tentar desenvolver estratégias para melhor compreender e modular as acções destas células. O monóxido de carbono (CO), é uma molécula endógena com provas dadas como anti-neuroinflamatório em vários modelos. Assim, o principal objectivo do trabalho foi o estudo do CO como um modulador da acção da microglia, com principal foco dado à comunicação entre estas células e neurónios, tentando entender se existe um efeito neuroprotector por inibição da inflamação. Um protocolo de meio condicionado foi estabelecido usando as linhas celulares BV2 e SH-SY5Y, de microglia e neurónio. A molécula CORM-A1, que liberta expontaniamente CO, foi usada como método de entrega da molécula às celulas. Demonstrámos que o pre-tratamento de células BV2 com CORM-A1 gera neuroprotecção já que reduz a morte celular de neurónios SH-SY5Y quando são incubados com meio condicionado de microglia activada em conjunto com o pró-oxidante t-BHP (tert-butil hidroperóxido). Assim, considerámos que o CO promove neuroprotecção ao inibir as acções inflamatórias da microglia. O papel anti-inflamatório da molécula CORM-A1 foi confirmado quando se verificou que pré-tratamento desta molécula em microglia BV2 limita a secreção de TNF-α mas estimula a secreção de IL-10. Por último, a CORM-A1 induziu a expressão do receptor da microglia CD200R1, molécula que participa na comunicação neurónio-microglia e fundamental para a modulação das acções inflamatórias destas últimas. Em suma, o nosso trabalho reforçou as propriedades anti-neuroinflamatórias do CO e uma capacidade de modular viabilidade neuronal através do seu efeito a nível de comunicação célula-célula. ---------------------------- ABSTRACT: Brain ischemia is a widespread disease worldwide, being one of the main causes of mortality and permanent disability. A portion of the damage that ensues following the ischemic event is caused by unrestrained inflammation, which is mainly orchestrated by exacerbated microglial activity. Hence, developing strategies for modulating microglial inflammation is a major concern nowadays. The endogenous molecule carbon monoxide (CO) has been shown to possess anti-neuroinflammatory properties using in vitro and in vivo approaches. Thus, our objective was to study CO as modulator of microglial activity, in particular in what concerns their communication with neurons, by promoting neuronal viability and limiting inflammatory output of activated microglia. A conditioned media strategy was established with BV2 microglia and SH-SY5Y neurons as cell models. CO-releasing molecule A1 (CORM-A1), a compound that releases CO spontaneously, was used as method of CO delivery to cells. We found that CORM-A1 pre-treatment in BV2 cells yields neuroprotective results, as it limits cell death when SH-SY5Y neurons are challenged with conditioned media from LPS-activated microglia and the pro-oxidant t-BHP (tert-butyl-hydroperoxide). Thus, we assumed carbon monoxide promotes neuroprotection via inhibition of microglial inflammation, displaying a non-cell autonomous role. CORM-A1 pre-treatment limited inflammation by inhibiting BV2 secretion of TNF-α and stimulating IL-10 production. These results reinforce that CO’s anti-inflammatory role confers neuroprotection, as the alterations in these cytokines occur concurrently with the increase in SH-SY5Y viability. Finally, we showed for the first time that carbon monoxide promotes the expression of CD200R1, a microglial receptor involved in neuron-glia communication and modulation of microglia inflammation. Further studies are necessary to clarify this role. Altogether, other than just highlighting CO as an anti-inflammatory and neuroprotective molecule, this work set the foundation for disclosing its involvement in cell-to-cell communication.

Magnetotransport properties of metal/LaAlO3/SrTiO3 heterostructures

The quasi two-dimensional electron gas (q2DEG) hosted in the interface of an epitaxially grown lanthanum aluminate (LaAlO3) thin film with a TiO2-termi-nated strontium titanate (SrTiO3) substrate (001) has been massively studied in the last few years. The confinement of mobile electrons to within a few nanome-ters from the interface, superconductive behavior at low temperatures and elec-tron mobility exceeding 1000 cm2/(V.s) make this system an interesting candi-date to explore the physics of spin injection and transport. However, due to the critical thickness for conduction of 4 unit cells (uc) of LaAlO3, a high tunneling resistance hampers electrical access to the q2DEG, preventing proper injection of spin polarized current. Recently, our group found that depositing a thin overlayer of Co on LaAlO3 reduces the critical thickness, enabling conduction with only 1 uc of LaAlO3. Two scenarios arise to explain this phenomenon: a pinning of the Fermi level in the metal, inducing charge transfer in the SrTiO3; the creation of oxygen vacancies at the interface between LaAlO3 and the metal, leading to an n-type doping of the SrTiO3. In this dissertation, we will report on magnetotransport of metal/LaAlO3/SrTiO3 (metal: Ti, Ta, Co, Py, Au, Pt, Pd) heterostructures with 2 uc of LaAlO3 studied at low temperatures (2 K) and high magnetic fields (9 T). We have analyzed the transport properties of the gas, namely, the carrier concen-tration, mobility and magnetotransport regime and we will discuss the results in the light of the two scenarios mentioned above.