Social impact measurement model for just a change

The emerging and growth of the social sector is setting the beginning of a new era: a global society concerned about social problems and seeking for social impact as an important result of an organization’s output. Accordingly, a new management process is gaining importance nowadays: impact measurement. The current paper intends to demonstrate the overall importance of impact measurement and how it should be implemented by Just a Change, a Portuguese-based social enterprise. A qualitative model to measure its impact on its beneficiaries and volunteers is developed and recommendations on implementation and analysis are provided

In vitro assessment of the efficacy of a macrocyclic chelator in reversing methylmercury toxicity

PTDC/MED-FAR/31136/2017 UID/DTP/04138/2019 project REDE/1518/REM/2005 Norma Transitoria-DL57/2016/CP1376/CT002Methylmercury (MeHg) is a highly neurotoxic compound to which human populations are exposed via fish consumption. Once in cells, MeHg actively binds thiols and selenols, interfering with the activity of redox enzymes such as thioredoxin (Trx) and the selenoenzyme thioredoxin reductase (TrxR) which integrate the thioredoxin system. In fact, it has been shown that inhibition of this system by MeHg is a critical step in the unfolding of cell death. Current clinical approaches to mitigate the toxicity of MeHg rely on the use of chelators, such as meso-2,3-dimercaptosuccinic acid (DMSA) which largely replaced British anti-Lewisite or 2,3-dimercapto-1-propanol (BAL) as the prime choice. However, therapeutic efficacy is limited and therefore new therapeutic options are necessary. In this work, we evaluated the efficacy of a macrocyclic chelator, 1-thia-4,7,10,13-tetraazacyclopentadecane ([15]aneN4S), in preventing MeHg toxicity, namely by looking at the effects over relevant molecular targets, i.e., the thioredoxin system, using both purified enzyme solutions and cell experiments with human neuroblastoma cells (SH-SY5Y). Results showed that [15]aneN4S had a similar efficacy to DMSA and BAL in reversing the inhibition of MeHg over purified TrxR and Trx by looking at both the 5,5′-dithiobis(2-nitrobenzoic acid) (DTNB) reduction assay and insulin reduction capability. In experiments with cells, none of the chelating agents could reverse the inhibition of TrxR by MeHg, which corroborates the high affinity of MeHg to the selenol in TrxR active site. [15]aneN4S and BAL, unlike DMSA, could prevent inhibition of Trx, which allows the maintenance of downstream functions, although BAL showed higher toxicity to cells. Overall these findings highlight the potential of using [15]aneN4S in the treatment of MeHg poisoning and encourage further studies, namely in vivo.publishersversionpublishe

Neuronal cholesterol metabolism increases dendritic outgrowth and synaptic markers via a concerted action of GGTase-I and Trk

We are deeply thankful to Professor David W. Russell (University of Texas Southwestern Medical Center) for the kind gift of the anti-CYP46A1 antibody. This work was supported by FEDER (COMPETE Programme) and national funds from Fundacao para a Ciencia e a Tecnologia (FCT), Portugal, research grants iMed.ULisboa (UID/DTP/04138/2013), PTDC/SAU/NMC/110809/2009 (to E.R.), SFRH/BD/78041/2011 (to M.M.) SFRH/BPD/95855/2013 (to M.J.N), and, Swedish Research Council (J.L.R. and I.B.), Marie Curie Career Integration Grant and Novo Nordisk Fonden (J.L.R.) and Swedish Brain Power (I.B.).Cholesterol 24-hydroxylase (CYP46A1) is responsible for brain cholesterol elimination and therefore plays a crucial role in the control of brain cholesterol homeostasis. Altered CYP46A1 expression has been associated with several neurodegenerative diseases and changes in cognition. Since CYP46A1 activates small guanosine triphosphate-binding proteins (sGTPases), we hypothesized that CYP46A1 might be affecting neuronal development and function by activating tropomyosin-related kinase (Trk) receptors and promoting geranylgeranyl transferase-I (GGTase-I) prenylation activity. Our results show that CYP46A1 triggers an increase in neuronal dendritic outgrowth and dendritic protrusion density, and elicits an increase of synaptic proteins in the crude synaptosomal fraction. Strikingly, all of these effects are abolished by pharmacological inhibition of GGTase-I activity. Furthermore, CYP46A1 increases Trk phosphorylation, its interaction with GGTase-I, and the activity of GGTase-I, which is crucial for the enhanced dendritic outgrowth. Cholesterol supplementation studies indicate that cholesterol reduction by CYP46A1 is the necessary trigger for these effects. These results were confirmed in vivo, with a significant increase of p-Trk, pre- and postsynaptic proteins, Rac1, and decreased cholesterol levels, in crude synaptosomal fractions prepared from CYP46A1 transgenic mouse cortex. This work describes the molecular mechanisms by which neuronal cholesterol metabolism effectively modulates neuronal outgrowth and synaptic markers.publishersversionpublishe

Tauroursodeoxycholic Acid Improves Motor Symptoms in a Mouse Model of Parkinson's Disease

Parkinson's disease (PD) is characterized by severe motor symptoms, and currently there is no treatment that retards disease progression or reverses damage prior to the time of clinical diagnosis. Tauroursodeoxycholic acid (TUDCA) is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD; however, its effect in PD motor symptoms has never been addressed. In the present work, an extensive behavior analysis was performed to better characterize the MPTP model of PD and to evaluate the effects of TUDCA in the prevention/improvement of mice phenotype. MPTP induced significant alterations in general motor performance paradigms, including increased latency in the motor swimming, adhesive removal and pole tests, as well as altered gait, foot dragging, and tremors. TUDCA administration, either before or after MPTP, significantly reduced the swimming latency, improved gait quality, and decreased foot dragging. Importantly, TUDCA was also effective in the prevention of typical parkinsonian symptoms such as spontaneous activity, ability to initiate movement and tremors. Accordingly, TUDCA prevented MPTP-induced decrease of dopaminergic fibers and ATP levels, mitochondrial dysfunction and neuroinflammation. Overall, MPTP-injected mice presented motor symptoms that are aggravated throughout time, resembling human parkinsonism, whereas PD motor symptoms were absent or mild in TUDCA-treated animals, and no aggravation was observed in any parameter. The thorough demonstration of improvement of PD symptoms together with the demonstration of the pathways triggered by TUDCA supports a subsequent clinical trial in humans and future validation of the application of this bile acid in PD.National funds, through the Foundation for Science and Technology (Portugal) (FCT), under the scope of the projects PTDC/NEU-NMC/0248/2012, UID/DTP/04138/2013 and POCI-01-0145-FEDER-007038, and post-doctoral grants SFRH/BPD72891/2010 (to A.I.R.), SFRH/BPD/95855/2013 (to M.J.N.), SFRH/BPD/98023/2013 (to A.N.C.), SFRH/BPD/91562/2012 (to A.S.F.) and UMINHO/BI/248/2016 (to S.D.S.). This work has also been developed under the scope of the project NORTE-01-0145-FEDER-000013, supported by the Northern Portugal Regional Operational Program (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER), and by FEDER funds, through the Competitiveness Factors Operational Program (COMPETE)info:eu-repo/semantics/publishedVersio

Linking Glycation and Glycosylation With Inflammation and Mitochondrial Dysfunction in Parkinson’s Disease

Parkinson’s disease (PD) is the second most common neurodegenerative disorder, affecting about 6.3 million people worldwide. PD is characterized by the progressive degeneration of dopaminergic neurons in the Substantia nigra pars compacta, resulting into severe motor symptoms. The cellular mechanisms underlying dopaminergic cell death in PD are still not fully understood, but mitochondrial dysfunction, oxidative stress and inflammation are strongly implicated in the pathogenesis of both familial and sporadic PD cases. Aberrant post-translational modifications, namely glycation and glycosylation, together with age-dependent insufficient endogenous scavengers and quality control systems, lead to cellular overload of dysfunctional proteins. Such injuries accumulate with time and may lead to mitochondrial dysfunction and exacerbated inflammatory responses, culminating in neuronal cell death. Here, we will discuss how PD-linked protein mutations, aging, impaired quality control mechanisms and sugar metabolism lead to up-regulated abnormal post-translational modifications in proteins. Abnormal glycation and glycosylation seem to be more common than previously thought in PD and may underlie mitochondria-induced oxidative stress and inflammation in a feed-forward mechanism. Moreover, the stress-induced post-translational modifications that directly affect parkin and/or its substrates, deeply impairing its ability to regulate mitochondrial dynamics or to suppress inflammation will also be discussed. Together, these represent still unexplored deleterious mechanisms implicated in neurodegeneration in PD, which may be used for a more in-depth knowledge of the pathogenic mechanisms, or as biomarkers of the disease

Influência das hormonas esteróides na síntese e secreção da anexina 1 e na actividade do factor de transcrição NF-KB : estudo in vitro na linha celular linfoblástica CCRF-CEM

Tese de doutoramento em Biologia (Biologia Celular) apresentada à Fac. de Ciências e Tecnologia de Coimbr

Estratégias de actores: prospectiva e avaliação

Neste artigo discutem-se as diferenças entre o conceito tradicional de planeamento e o planeamento estratégico. Apresenta-se uma metodologia prospectiva - o Método dos Cenários -, com um estudo de caso da "Baixa Pombalina", em Lisboa. Discutem-se ainda os elementos desta metodologia que podem orientar a construção de uma metodologia de avaliação "interactiva".This paper discusses the differences between the traditional and the strategic concepts of planning, presents a prospective methodology - the Scenarios Method - illustrating it with an application to the case of "Baixa Pombalina" in Lisbon. Also accessed are elements of this method that can guide the research towards an "interactive" methodology of evaluation.Cette article discute les différences entre les conceptions traditionnelles de planification et planification stratégique. On présente une méthodologie prospective - le Méthode des Scénarios -, avec un étude du cas de la "Baixa Pombalina", de Lisbonne. On discute aussi les éléments de cette méthodologie qui puissent orienter la construction d"une méthodologie d"évaluation "interactive".En este artículo se discuten las diferencias entre el concepto tradicional de planeamiento y el planeamiento estratégico. Se presenta una metodología prospectiva- el método de los Escenarios-, con un estudio del caso de la "Baixa Pombalina" en Lisboa. Se discuten además los elementos de esta metodología que pueden orientar la construcción de una metodología de evaluación "interactiva"

Relatório estágio profissional

Relatório final do estágio profissionalizante do 6.º an