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Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder worldwide. Clinically, it is characterized by a progressive degeneration of dopaminergic neurons (DAn), resulting in severe motor complications. Preclinical and clinical studies have indicated that neuroinflammation can play a role in PD pathophysiology, being associated with its onset and progression. Nevertheless, several key points concerning the neuroinflammatory process in PD remain to be answered. Bearing this in mind, in the present review, we cover the impact of neuroinflammation on PD by exploring the role of inflammatory cells (i.e., microglia and astrocytes) and the interconnections between the brain and the peripheral system. Furthermore, we discuss both the innate and adaptive immune responses regarding PD pathology and explore the gut–brain axis communication and its influence on the progression of the disease., The present work was supported by Prémios Santa Casa Neurociências— Prize Mantero Belard for Neurodegenerative Diseases Research (MB-28-2019), the Portuguese Foundation for Science and Technology (FCT) to S.M. (CEECIND/01902/2017) and F.G.T. (2021.00643.CEECIND), the European Regional Development Fund (FEDER), the Competitiveness Internationalization Operational Programme (POCI), national funds through the Foundation for Science and Technology (FCT), under the scope of projects UIDB/50026/2020, UIDP/50026/2020, POCI-01-0145-FEDER-029751, and EXPL/MED-PAT/0931/2021, project NORTE-01-0145-FEDER-000023, supported by the Northern Portugal Regional Operational Programme (NORTE 2020), and under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER).

Submitted by Ana Maria de Sousa Rebelo (amsr@isep.ipp.pt) on 2021-07-07T09:31:35Z No. of bitstreams: 1 DM_JoanaMacedo_2021_MEM.pdf: 5537532 bytes, checksum: 2be1fbc63c179fb962201590808af806 (MD5) Approved for entry into archive by Ana Maria de Sousa Rebelo (amsr@isep.ipp.pt) on 2021-07-07T09:32:06Z (GMT) No. of bitstreams: 1 DM_JoanaMacedo_2021_MEM.pdf: 5537532 bytes, checksum: 2be1fbc63c179fb962201590808af806 (MD5) Made available in DSpace on 2021-07-07T09:32:06Z (GMT). No. of bitstreams: 1 DM_JoanaMacedo_2021_MEM.pdf: 5537532 bytes, checksum: 2be1fbc63c179fb962201590808af806 (MD5) Previous issue date: 2021

Properdin, the only known positive regulator of the alternative complement pathway (AP), has been a focus of controversy since its discovery by Louis Pillemer in 1954 [1], [2]. In the last years evidence accumulated that this glycoprotein acts as a pattern recognition molecule and initiates the AP upon recognition of specific glycan markers, apart from its established role in the stabilization of AP convertases [3]. In this work, human full-length properdin was produced in mammalian cells and the purified protein was found to be active and to form the previously reported dimeric, trimeric and tetrameric cyclic structures. STD-NMR experiments performed with a set of glycans suggested that negative charge is required for binding to properdin and that glycosaminoglycans (GAGs) are potential pathogen-associated molecular patterns (PAMPs) for properdin and may mediate direct AP activation by properdin. The results also confirmed reports that both positive and negative regulators of the AP, namely properdin and complement Factor H, bind to different epitopes on identical glycans. The structural complexity that contributes to the diversity of GAGs and glycans represents a significant challenge for their isolation for functional and structural studies. A common approach involves the use of GAG-depolymerizing enzymes, such as heparinase I from Pedobacter heparinus, followed by fractionation of the obtained oligosaccharides [4], [5]. However, since the most biological relevant oligosaccharides have a higher degree of polymerization than those usually obtained from heparinase, a structure-based engineering approach to rationally design this enzyme could alter the product distribution. Although recombinant heparinase I could be produced in E. coli and expression constructs with varying N- and C-terminal sequences were tested, an intrinsic low thermal and conformational stability was observed and no protein crystals were obtained for structure determination by X-ray crystallography and subsequent enzyme engineering. Over the past decades, inhibition of the c-Jun N-terminal kinase 3 (JNK3), a mitogen-activated protein kinase (MAPK) involved in the regulation of cellular responses to extracellular stimuli has become a promising strategy for treatment of neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. However, up to date, no inhibitors targeting JNK3 have been approved by the FDA [6], [7]. Altering the substitution pattern of a pyridinylimidazole scaffold from a dual p38α/JNK3 MAPK inhibitor proved to be effective in shifting the selectivity towards JNK3 [8]. A similar binding mode of the two most potent inhibitors with an IC50 value

O estudo surge no contexto da Carta Portuguesa para a Diversidade e consiste numa análise de diagnóstico relativa à diversidade presente na Essilor Portugal, empresa signatária da Carta. Propõe-se identificar as necessidades da organização nesta área e propor estratégias para uma mais eficiente promoção e gestão da diversidade. Recorre-se a uma metodologia mista com aplicação de um questionário de auto-relato QAAD, a chefias e colaboradores/as, e de entrevistas semi-estruturadas a colaboradores/as. O estudo revela que o conceito de diversidade é familiar e abordado na organização em eventos, reuniões, no código de conduta e a nível de comunicações. As chefias têm uma avaliação mais positiva do que os/as colaboradores/as nas várias dimensões do questionário, exceto na Comunicação, sendo esta a dimensão com maior concordância entre os dois grupos. A gestão está comprometida com a temática da diversidade, registando-se, também, um compromisso com a diversidade a nível da Cultura – dimensão com maior discrepância na avaliação entre chefias e colaboradores/as –, e do Recrutamento e Seleção – não se regista fontes de discriminação, porém, há falta de critérios para colocar cada trabalhador(a) no lugar certo ou garantir um equilíbrio dentro de departamentos. A Formação e Desenvolvimento é apontada como a grande falha na organização – a formação não é igual para todos/as e há falta de um plano de carreira. As Condições de Trabalho são a dimensão menos positiva para os/as colaboradores/as, variando em função da antiguidade na organização – quanto mais tempo os/as trabalhadores/as estão na organização, mais negativa é a sua perceção. This study emerges in the context of the Portuguese Diversity Charter and consists of a diagnostic analysis of the diversity present in Essilor Portugal, a company that is a signatory of the Charter. It aims to identify the needs of the organization in this area and to propose strategies for more efficient promotion and management of diversity. It uses a mixed methodology with the application of a QAAD self-report questionnaire to managers and employees, and semi-structured interviews with employees. The study reveals that the concept of diversity is familiar and addressed in organizing events, meetings, the code of conduct, and at the communication level. The managers have a more positive evaluation than the employees in the various dimensions of the questionnaire, except in Communication, which is the dimension with the greater agreement between the two groups. Management is committed to the issue of diversity, and there is also a commitment to diversity at the Cultural level – dimension with the greatest discrepancy in the evaluation between managers and employees – and Recruitment and Selection – there are no sources of discrimination, however, there is a lack of criteria for putting each worker in the right place or ensuring a balance within departments. Training and Development are touted as the major flaw in the organization – training is not the same for everyone and a career path is lacking. Working Conditions are the least positive dimension for employees, varying according to seniority in the organization – the longer workers are in the organization, the more negative their perception is.

Mestrado em Fiscalidade Submitted by Filomena Borba (fmborba@iscal.ipl.pt) on 2021-02-04T19:13:09Z No. of bitstreams: 1 tese definitiva joana macedo - c¢pia.pdf: 1188501 bytes, checksum: 9a983d4265d6d631175bacff48c51e81 (MD5) Made available in DSpace on 2021-02-04T19:13:09Z (GMT). No. of bitstreams: 1 tese definitiva joana macedo - c¢pia.pdf: 1188501 bytes, checksum: 9a983d4265d6d631175bacff48c51e81 (MD5) Previous issue date: 2019-06 info:eu-repo/semantics/publishedVersion