Identificação de modificadores da proteotoxicidade da ataxina-3 em modelos animais para a doença de Machado-Joseph

Tese doutoramento em Ciências da Saúde (especialidade de Ciências da Saúde)At least nine human neurodegenerative diseases are caused by the expansion of CAG repeats within otherwise unrelated genes. In these diseases, including Machado-Joseph disease (MJD), polyglutamine (polyQ) expansions cause the appearance of misfolded protein species, that ultimately lead to the formation of aggregates and neuronal loss. Along with the pathogenic motif, all these diseases have in common the fact that the associated gene products are widely expressed but affect only specific subsets of neurons. This specificity suggests that protein misfolding and its toxic outcomes may be determined by the polyQ-flanking sequences of the specific disease-associated proteins. Ataxin- 3 (ATXN3) is a polyQ protein and expansion of its repetitive glutamine tract causes MJD. MJD is characterized by the formation of ubiquitylated intra-neuronal inclusions but the mechanism underlying mutant ATXN3-mediated neuronal dysfunction still remains unsolved. Caenorhabditis elegans offers unique advantages for examining the aggregation dynamics of aggregation-prone proteins and its toxic effects on individual neurons, since the transparency of all 959 cells allows easy detection of fluorescent proteins in live animals. Despite having relatively few neurons, C. elegans display a wide array of complex behaviors and a clear link exists between the behavior and the function of neuronal subsets. In this study, we established a novel pan-neuronal C. elegans model for the study of ATXN3 pathogenesis. Pan-neuronal expression of mutant ATXN3 leads to a polyQ-length dependent, neuron subtype-specific aggregation and neuronal dysfunction. Analysis of different neurons revealed a pattern of dorsal nerve cord and sensory neuron processes susceptibility to mutant ATXN3 that was distinct from the aggregation and toxicity profiles of polyQ-alone proteins. This suggests that the sequences flanking the polyQ-stretch in ATXN3 have a dominant influence on cell-intrinsic neuronal factors that modulate polyQ-mediated pathogenesis. We investigated the role of the wild-type (WT) ATXN3 in polyQ-related pathogenesis and found that WT ATXN3 is irreversibly recruited into polyQ-containing cellular aggregates, aggravating the animals’ motor dysfunction. In contrast, genetic ablation of endogenous C. elegans ATX-3 did not modulate MJD pathogenesis. Our findings support the idea that, unlike what happens in other polyQ disorders, WT ATXN3 does not seem to display a neuroprotective role in MJD. We have also found that in C. elegans mutations reducing insulin/insulin growth factor (IGF)-1- like signaling (IIS) pathway partially rescues mutant ATXN3-mediated aggregation and toxicity. Strikingly, other longevity-related pathways showed different effects on ATXN3 proteotoxicity: dietary restricted animals succumbed to neuronal ATXN3 pathogenesis at similar rates to those of regularly fed animals. In turn, mutations leading to altered mitochondrial function and known to lead to increased longevity showed heterogeneous effects: clk-1 mutation severely aggravated mutant ATXN3 pathogenesis, whereas isp-1 mutation caused a significant delay in the appearance of aggregates. These results suggest that, in spite of improving global organism survival, aging-related pathways may not always show a positive effect on conformational disorders. Heat shock factor 1 (HSF-1) plays a neuroprotective role in ATXN3-mediated pathology in C. elegans. However, in mice, genetic reduction of Hsf-1 resulted in comparable motor uncoordination and pathology, when compared with MJD transgenic mice with two copies of Hsf-1 gene, suggesting that one copy of Hsf-1 is sufficient to cope with ATXN3(Q94) proteotoxicity in mice. Lastly, we validated our novel C. elegans model as a tool for identification of potential therapeutic compounds for MJD and established five compounds, potentially involved in heat shock response, autophagy, transcription regulation and longevity, as good candidates to test in higher model organisms for MJD. In summary, this work provided new clues for the study of ATXN3 pathogenesis and the role of the WT protein in disease. It raised new hypotheses regarding the mechanistic link(s) between aging determinants and proteotoxicity. It also made available a valuable C. elegans model/tool for drug discovery and target identification that can be very useful in future therapy development in MJD.Diferentes doenças neurodegenerativas humanas são causadas por uma expansão de uma repeticão CAG em genes que, de outra forma, não estão relacionados. Neste tipo de doenças, nomeadamente na doença de Machado-Joseph (DMJ), a expansão de poliglutaminas (poliQ) está associada a uma alteração da conformação das proteínas, com consequente formação de agregados e perda de células neuronais. Além do domínio patogénico, todas estas doenças têm em comum o facto de as suas proteínas causadoras terem uma expressão ubíqua, mas somente afectarem populações específicas de neurónios características de cada uma das doenças. Esta especificidade sugere que a agregação proteica e os seus efeitos tóxicos podem ser determinados pela sequência aminoacídica de cada proteína. A ataxina-3 (ATXN3) contém um segmento de poliQ cuja expansão está na origem da DMJ. A DMJ, assim como outras doenças de poliQ, é caracterizada pela formação de inclusões intraneuronais ubiquitiladas, mas o mecanismo associado à disfunção neuronal causada pela expressão da ATXN3 mutante não é totalmente compreendido. O nemátode Caenorhabditis elegans proporciona grandes vantagens no estudo dos efeitos tóxicos de proteínas poliQ em neurónios, uma vez que a transparência das suas 959 células facilita a detecção de proteínas fluorescentes in vivo. Apesar de apresentarem um número reduzido de neurónios, os C. elegans apresentam inúmeros comportamentos complexos, existindo uma relação clara entre a função de determinados subtipos neuronais e o comportamentos regulados por esses grupos de neurónios. Neste estudo, estabelecemos um novo modelo animal com expressão da ATXN3 humana em todas as células do sistema nervoso dos C. elegans, para o estudo da patogénese da DMJ. A expressão da ATXN3 mutada resulta no aparecimento de agregados e em disfunção neurológica. Ambos os fenótipos dependem do tamanho da sequência de poliQ da ATXN3. A análise de neurónios específicos revelou que os processos de neurónios sensoriais e do cordão nervoso dorsal são especificamente afectados em animais que expressam a ATXN3 mutante e não em animais que expressam proteínas poliQ. Estes resultados sugerem que o efeito das sequências flanqueantes da ATXN3 se sobrepõe a factores intrínsecos ao ambiente neuronal, modulando a patogénese mediada pelo tracto de poliQ. O papel da ATXN3 normal na patogénese da DMJ foi também investigado. Verificámos que a proteína normal é irreversivelmente recrutada para agregados de poliQ, provocando um agravamento do fenótipo motor destes animais. Em contraste, a deleção da ataxina-3 endógena (ATX-3) não modifica o fenótipo do modelo da DMJ em C. elegans. Estes resultados sugerem que, ao contrário do que acontece noutras doenças de poliQ, a ATXN3 WT não parece ter um papel neuroprotector na DMJ. Em C. elegans, mutações que reduzem a sinalização da via da insulina/factor de crescimento da insulina 1 (IIS) revertem parcialmente a agregação e toxicidade causada pela ATXN3 mutante. Surpreendentemente, outras vias que afectam a longevidade de organismos mostraram efeitos diversos na proteotoxicidade da ATXN3: animais em restrição calórica não apresentaram diferenças na patogénese da mediada pela ATXN3 mutada relativamente a animais com uma dieta ad libitum. Mutações que alteram a função mitocondrial e causam aumento da longevidade em C. elegans apresentaram efeitos heterogéneos: a mutação do gene clk-1 agravou o fenótipo de agregação, enquanto que a mutação do gene isp-1 atrasou o aparecimento dos agregados. Estes resultados sugerem que as vias da longevidade, embora aumentem a sobrevivência global dos organismos, nem sempre têm um impacto positivo no tratamento de doenças associadas a conformações proteicas. O factor de choque térmico 1 (HSF-1) desempenha um papel neuro-protector relativamente à proteotoxicidade da ATXN3 em C. elegans. Contudo, em ratinhos esse efeito não é claro. A redução dos níveis do gene Hsf-1 em ratinho resultou num fenótipo de descoordenação motora semelhante ao de ratinhos contendo duas cópias do gene. Este resultado sugere que uma cópia do Hsf-1 é suficiente para combater a proteotoxicidade causada pela ATXN3 quando mutada. Finalmente, validámos o nosso modelo em C. elegans como uma ferramenta para a identificação de potenciais compostos terapêuticos para a DMJ e identificámos cinco compostos, potencialmente envolvidos na regulação da resposta ao choque térmico nas células, na autofagia, na regulação da transcrição e na longevidade, como bons candidatos para testar em modelos da DMJ desenvolvidos em organismos evolutivamente mais próximos do humano, como é o caso do ratinho. Em resumo, este trabalho trouxe novas pistas para o estudo da patogénese da DMJ e para o papel da ATXN3 normal na doença. Também levantou novas possíveis hipóteses no que diz respeito a ligações mecanísticas entre factores que determinam a longevidade dos organismos e a proteotoxicidade. Este novo modelo passou a estar disponível para a comunidade como uma ferramenta para a potencial descoberta de novas drogas e identificação de alvos que podem ser úteis para o desenvolvimento de terapias para a DMJ

Physician burnout in primary care during the COVID-19 pandemic: a cross-sectional study in Portugal

Primary care physicians have been present on the frontline during the ongoing pandemic, adding new tasks to already high workloads. Our aim was to evaluate burnout in primary care physicians during the COVID-19 pandemic, as well as associated contributing factors. Cross-sectional study with an online questionnaire disseminated through social media, applying the snowball technique. The target population was primary care physicians working in Portugal during the first outbreak of the COVID-19 pandemic. In addition to sociodemographic data, the questionnaire collected responses to the Copenhagen Burnout Inventory (CBI), the Resilience Scale and the Depression, Anxiety, and Stress Scales (DASS-21). Data were collected from May 9 to June 8, 2020, a period comprising the declaration of a national calamity and then state of emergency, and the subsequent ease of lockdown measures. Levels of burnout in 3 different dimensions (personal, work, and patient-related), resilience, stress, depression, and anxiety were assessed. Logistic regression analyses were conducted to identify factors associated with burnout levels. Results: Among the 214 physician respondents, burnout levels were high in the 3 dimensions. A strong association was found between gender, years of professional experience, depression and anxiety, and burnout levels. Physician burnout in primary care is high and has increased during the pandemic. More studies are needed in the long term to provide a comprehensive assessment of COVID-19’simpact on burnout levels and how to best approach and mitigate it during such unprecedented times.info:eu-repo/semantics/publishedVersio

The mediating role of psychological resilience

During the COVID-19 pandemic, healthcare workers (HCW) have been exposed to multiple psychosocial stressors. Resilience might protect employees from the negative consequences of chronic stress. The aim of this study was to explore the mediating role of resilience in the relationship between depression and burnout (personal, work-related, and client-related). A cross-sectional study was performed using an online questionnaire distributed via social networks. A survey was conducted comprising standardized measures of resilience (Resilience Scale-25 items), depression (subscale of Depression Anxiety Stress Scales-21 items), and burnout (Copenhagen Burnout Inventory Scale-19 items). A total of 2008 subjects completed the survey, and a hierarchical regression model was estimated for each burnout dimension. The results revealed that depression had not only a directed effect on personal, work- and client-related burnout, but also an indirect small effect on it through resilience. Psychological resilience played a partial mediating role between depression and all burnout dimensions. This partial mediation suggests that there may be other possible variables (e.g., social connection, self-compassion, gratitude, sense of purpose) that further explain the associations.info:eu-repo/semantics/publishedVersio

The mediating role of life satisfaction in the relationship between depression, anxiety, stress and burnout among Portuguese nurses during COVID-19 pandemic

Background The COVID-19 pandemic had a large consequence on healthcare systems, increasing the risks of psychological issues in health professionals. Nurses, in particular, have been exposed to multiple psychosocial stressors and struggled with intensive work, insufficiency of resources and uncertainty in the face of an unknown disease. Life satisfaction might protect nurses from the consequences of chronic stress. The aim of this study was to explore the mediating role of satisfaction with life in the relationship between depression, stress, anxiety and burnout (personal, work-related, and client-related). Methods A cross-sectional, descriptive, correlational study design was performed, using an online questionnaire distributed via social networks. A total of 379 nurses completed the survey, comprising standardized measures of satisfaction with life, resilience (Resilience Scale), depression, anxiety, stress (Depression Anxiety Stress Scales), and burnout (Copenhagen Burnout Inventory Scale). A hierarchical regression model was estimated for each burnout dimension. Results Participants showed high levels of work, personal and client-related burnout, 57.3%, 57%, and 35.1%, respectively. More than 70% of the respondents had a normal level of depressive symptoms, 66.8% presented normal level of anxiety and 33.5% of the respondents reported mild, moderate, severe or extremely severe symptoms of stress. The results revealed that life satisfaction partially mediated the association between stress and personal burnout, depression and work-related burnout, and the association between anxiety and client-related burnout in nurses. Conclusions The COVID-19 pandemic brought added difficulties for nurses’ work conditions, whereby it became necessary to develop adaptative measures that reduce stressors in work environment and promote nurses’ life satisfaction.info:eu-repo/semantics/publishedVersio

The impact of teleworking in psychologists during COVID-19: Burnout, depression, anxiety, and stress

Background: The COVID-19 pandemic has forced mental health professionals to adapt quickly. The pandemic has created multiple new tasks for the psychologist. In addition to the various stressors closely linked to the COVID-19 pandemic, psychologists were forced to make their services more flexible. Teleworking was a way of continuing to work. Objective: This study aimed to identify the impact of working pattern on the levels of burnout, depression, anxiety, and stress. Methods: This was a cross-sectional study based on an online questionnaire applied to eighty-three Portuguese psychologists. Data were collected from May 9 to June 8, 2020, a period comprising the declaration of a national calamity and then state of emergency, and the subsequent ease of lockdown measures. The Copenhagen Burnout Inventory Scale and Depression Anxiety and Stress Scale were used. Univariate multiple linear regression models were estimated for each mental health outcome. Results: Significant differences were found between psychologists working in the workplace and in teleworking at the personal burnout, work-related burnout, client-related burnout, depression, and stress. In multiple linear regression, teleworking, not working, and being unmarried was significantly associated with higher levels of depression. Teleworking was significantly associated with higher stress scores and client-related and work burnout. Conclusions: This exceptional time of sudden, mandatory, and high-intensity teleworking, required rapid adaptation, giving rise to new stressors that might have been responsible for burnout levels in psychologists.info:eu-repo/semantics/publishedVersio

O processo de tomada de decisão sentencial: análise de fatores implicados na concretização do Direito penal

Tese apresentada à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Doutor em Ciências Sociais, especialidade em PsicologiaEste trabalho pretende analisar o sentenciar de juízes e juízas em Portugal, enquanto agentes sociais atuantes em contexto real, procurando perceber melhor como a sua discricionariedade técnica se concretiza. A investigação das ciências sociais, tem apresentado dificuldade em encontrar um modelo de tomada de decisão que esgote ou explique de forma consensual o processo de sentenciar, e revelado a existência de uma série de aspetos que o influenciam. Estas influências, frequentemente associadas a fenómenos de discriminação e disparidade ao nível das sentenças, podem prender-se com várias faces do processo, designadamente com quem sentencia, com quem delinquiu e com o próprio contexto do tribunal. Com o propósito de explorar este processo decisório realizámos três estudos, dois qualitativos e um quantitativo. No primeiro, fizemos a análise de conteúdo de 93 leituras de acórdãos, especificamente no que diz respeito aos conteúdos verbalizados, para além da leitura daquele documento. No segundo, analisámos as respostas de 49 juízes/as dos tribunais criminais de Porto, Coimbra e Lisboa ao ‘Questionário de Análise da Tomada de Decisões Judiciais’, desenvolvido por Castro-Rodrigues e Sacau. No terceiro, procedemos à análise de conteúdo de entrevistas a juízes e juízas que agregavam as temáticas surgidas nos estudos anteriores, permitindo a sua exploração de forma mais aprofundada. Globalmente, os resultados mostraram que os/as juízes/as apresentam diferenças nas suas escolhas com base na sua abordagem à interpretação da lei, e detetaram uma série de ‘áreas sensíveis’ passíveis de maior discórdia e subjetivação, entre as quais, as regras da experiência, as situações que diminuem ou aumentam a gravidade dos atos, a avaliação de arrependimento e da postura dos/as arguidos/as em tribunal, as considerações respeitantes a aspetos sociais e psicológicos de quem delinquiu, assim como situações que podem estar na base da criminalidade, quer enquanto causa, quer enquanto motivação. Vários destes elementos substanciam-se em áreas do sentenciar onde as avaliações e considerações efetuadas demonstram lacunas em termos sociais e psicológicos, o que apela à necessidade de formação intencional e de apoio técnico nestas matérias.This research intends to analyse the reality of sentencing by judges in Portugal, as social agents acting in real professional context, with the intention of better understanding how judicial discretion is implemented. Research in the social sciences areas, has presented difficulties in finding a consensual decision making model that fully addresses and explains the sentencing process, and such research also has demonstrated the existence of several influences over the decision-making process. Such influences, which frequently are associated to discrimination and sentence disparities, may relate to different elements of the sentencing process, namely the judge, the defendant and even the context of the court. For the purpose of exploring this decisional process we developed three studies, two qualitative and one quantitative. In the first we carried out a content analysis of 93 sentence pronouncements, looking at the content beyond the reading of the sentence. In the second we analysed the responses of 49 judges from the criminal courts of Porto, Lisbon and Coimbra to the “Judicial Decision-Making Analysis Questionnaire”, developed by Castro-Rodrigues e Sacau. In the third, we analysed the judges’ answers to an interview that aimed to aggregate and explore the themes that arose from the first two studies. On the whole, the results demonstrated that judges differ considerably in their choices based on the way they approach the interpretation of law, and revealed a number of ‘sensitive themes’ prone to disagreement and subjectivity, such as, the rules of experience, the circunstances that mitigate and aggravate the seriousness of the offense, the assessment of defendant’s repentance and behavior in court, the considerations regarding social and psychological aspects of the defendant, as well as situations that might be in the basis of criminality, either as a cause, or as a motivation. Several of these elements substantiate sentencing areas where the considerations and judgements reveal some gaps in terms of social and psychological knowledge, which call for more intentional training and technical support on those themes.Ce travail veut analyser les sentences rendues par des juges, dans le contexte portugais, tandis que des agentes sociaux en actuation effective et en situation réelle, cherchant meilleur comprendre comme la discrétionairité technique de qui fait les jugements, se concrétise. La recherche en sciences sociales, a montrée des difficultés pour trouver un modèle de prise de décision capable d’épuiser le processus sententielle ou de l'expliquer de façon consensuelle, et en même temps ont démontre l'existence d'une série d'influences auxquelles ce processus est sujet. Ces influences, souvent associées à des phénomènes de discrimination et disparités sententielles, peuvent être associées à plusieurs aspects du processus, notamment à ceux qui prononcent le jugement, ceux qui sont jugés et au propre contexte du tribunal. Avec l’objectif d’explorer ce procès de décisions, on a réalisé trois études, deux qualitatives et une quantitative. Dans la première, on a fait une analyse du contenu de 93 moments de lecture des décisions de justice, spécifiquement dans ce qui concerne les contenus verbalises qui sont au-delà de la lecture de ce type de document. Dans la deuxième, on a analysé les réponses des 49 juges des tribunaux criminels de Porto, Coimbra et Lisbonne au “Questionnaire d'Analyse de Prise de Décisions Judiciaires”, élaboré par Castro-Rodrigues et Sacau. Dans la troisième étude, on a analysé les réponses des entrevues aux juges qui visait à agréger et explorer de façon plus approfondie les thématiques qu’on a trouvé dans les deux études précédentes. Généralement les résultats ont démontré que les juges présentent des différences dans l’interprétation de la loi et ont aussi montré une série de “matières sensibles” passibles d’une plus grande discorde et subjectivité parmi lesquelles les règles de l’expérience, les situations qui atténuent ou font grandir l’importance des actions, l’évaluation du regret et l’attitude des accusés, au tribunal, les considérations dans ce qui concerne à leurs problèmes sociaux et psychologiques si bien que d’autres problèmes qui peuvent être la cause ou la motivation de leurs crimes. Plusieurs de ces éléments à l'appui certains domaines du processus sententielle où les considérations et les évaluations effectuées montrent lacunes en termes des savoirs sociaux et psychologiques, ce qui en rend nécessaire la formation et le support des techniques spécialisés

O processo de tomada de decisão sentencial: análise de fatores implicados na concretização do Direito penal

Tese apresentada à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Doutor em Ciências Sociais, especialidade em PsicologiaEste trabalho pretende analisar o sentenciar de juízes e juízas em Portugal, enquanto agentes sociais atuantes em contexto real, procurando perceber melhor como a sua discricionariedade técnica se concretiza. A investigação das ciências sociais, tem apresentado dificuldade em encontrar um modelo de tomada de decisão que esgote ou explique de forma consensual o processo de sentenciar, e revelado a existência de uma série de aspetos que o influenciam. Estas influências, frequentemente associadas a fenómenos de discriminação e disparidade ao nível das sentenças, podem prender-se com várias faces do processo, designadamente com quem sentencia, com quem delinquiu e com o próprio contexto do tribunal. Com o propósito de explorar este processo decisório realizámos três estudos, dois qualitativos e um quantitativo. No primeiro, fizemos a análise de conteúdo de 93 leituras de acórdãos, especificamente no que diz respeito aos conteúdos verbalizados, para além da leitura daquele documento. No segundo, analisámos as respostas de 49 juízes/as dos tribunais criminais de Porto, Coimbra e Lisboa ao ‘Questionário de Análise da Tomada de Decisões Judiciais’, desenvolvido por Castro-Rodrigues e Sacau. No terceiro, procedemos à análise de conteúdo de entrevistas a juízes e juízas que agregavam as temáticas surgidas nos estudos anteriores, permitindo a sua exploração de forma mais aprofundada. Globalmente, os resultados mostraram que os/as juízes/as apresentam diferenças nas suas escolhas com base na sua abordagem à interpretação da lei, e detetaram uma série de ‘áreas sensíveis’ passíveis de maior discórdia e subjetivação, entre as quais, as regras da experiência, as situações que diminuem ou aumentam a gravidade dos atos, a avaliação de arrependimento e da postura dos/as arguidos/as em tribunal, as considerações respeitantes a aspetos sociais e psicológicos de quem delinquiu, assim como situações que podem estar na base da criminalidade, quer enquanto causa, quer enquanto motivação. Vários destes elementos substanciam-se em áreas do sentenciar onde as avaliações e considerações efetuadas demonstram lacunas em termos sociais e psicológicos, o que apela à necessidade de formação intencional e de apoio técnico nestas matérias.This research intends to analyse the reality of sentencing by judges in Portugal, as social agents acting in real professional context, with the intention of better understanding how judicial discretion is implemented. Research in the social sciences areas, has presented difficulties in finding a consensual decision making model that fully addresses and explains the sentencing process, and such research also has demonstrated the existence of several influences over the decision-making process. Such influences, which frequently are associated to discrimination and sentence disparities, may relate to different elements of the sentencing process, namely the judge, the defendant and even the context of the court. For the purpose of exploring this decisional process we developed three studies, two qualitative and one quantitative. In the first we carried out a content analysis of 93 sentence pronouncements, looking at the content beyond the reading of the sentence. In the second we analysed the responses of 49 judges from the criminal courts of Porto, Lisbon and Coimbra to the “Judicial Decision-Making Analysis Questionnaire”, developed by Castro-Rodrigues e Sacau. In the third, we analysed the judges’ answers to an interview that aimed to aggregate and explore the themes that arose from the first two studies. On the whole, the results demonstrated that judges differ considerably in their choices based on the way they approach the interpretation of law, and revealed a number of ‘sensitive themes’ prone to disagreement and subjectivity, such as, the rules of experience, the circunstances that mitigate and aggravate the seriousness of the offense, the assessment of defendant’s repentance and behavior in court, the considerations regarding social and psychological aspects of the defendant, as well as situations that might be in the basis of criminality, either as a cause, or as a motivation. Several of these elements substantiate sentencing areas where the considerations and judgements reveal some gaps in terms of social and psychological knowledge, which call for more intentional training and technical support on those themes.Ce travail veut analyser les sentences rendues par des juges, dans le contexte portugais, tandis que des agentes sociaux en actuation effective et en situation réelle, cherchant meilleur comprendre comme la discrétionairité technique de qui fait les jugements, se concrétise. La recherche en sciences sociales, a montrée des difficultés pour trouver un modèle de prise de décision capable d’épuiser le processus sententielle ou de l'expliquer de façon consensuelle, et en même temps ont démontre l'existence d'une série d'influences auxquelles ce processus est sujet. Ces influences, souvent associées à des phénomènes de discrimination et disparités sententielles, peuvent être associées à plusieurs aspects du processus, notamment à ceux qui prononcent le jugement, ceux qui sont jugés et au propre contexte du tribunal. Avec l’objectif d’explorer ce procès de décisions, on a réalisé trois études, deux qualitatives et une quantitative. Dans la première, on a fait une analyse du contenu de 93 moments de lecture des décisions de justice, spécifiquement dans ce qui concerne les contenus verbalises qui sont au-delà de la lecture de ce type de document. Dans la deuxième, on a analysé les réponses des 49 juges des tribunaux criminels de Porto, Coimbra et Lisbonne au “Questionnaire d'Analyse de Prise de Décisions Judiciaires”, élaboré par Castro-Rodrigues et Sacau. Dans la troisième étude, on a analysé les réponses des entrevues aux juges qui visait à agréger et explorer de façon plus approfondie les thématiques qu’on a trouvé dans les deux études précédentes. Généralement les résultats ont démontré que les juges présentent des différences dans l’interprétation de la loi et ont aussi montré une série de “matières sensibles” passibles d’une plus grande discorde et subjectivité parmi lesquelles les règles de l’expérience, les situations qui atténuent ou font grandir l’importance des actions, l’évaluation du regret et l’attitude des accusés, au tribunal, les considérations dans ce qui concerne à leurs problèmes sociaux et psychologiques si bien que d’autres problèmes qui peuvent être la cause ou la motivation de leurs crimes. Plusieurs de ces éléments à l'appui certains domaines du processus sententielle où les considérations et les évaluations effectuées montrent lacunes en termes des savoirs sociaux et psychologiques, ce qui en rend nécessaire la formation et le support des techniques spécialisés

Burnout in Portuguese physiotherapists during COVID-19 pandemic

This study described the burnout experienced by physiotherapists during the COVID-19 pandemic and analysed the role of possible factors of this occupational phenomenon. Cross-sectional study based on a web-based survey applied to physiotherapists living in Portugal. The survey included sociodemographic, health status and clinical practice questions. The Copenhagen Burnout Inventory (personal, work- and patient-related burnout), the Resilience Scale, the Depression Anxiety and Stress Scales and the Satisfaction with Life Scale were used. A total of 511 physiotherapists (median 33 years old, 82% females) completed the survey. The participants worked mainly in private practice (50%) and wards (35%). During COVID-19, 52% were working directly with patients, but only 18% were working with COVID-19 patients. Personal (42%), work- (42%) and patient-related burnout (25%) was observed. Three significant models explained personal- (R2 = 51%), work- (R2 = 31%) and patient-related burnout (R2 = 16%). Lower levels of resilience and higher levels of depression and stress were significantly associated with personal, work- and patient-related burnout. Being female and working directly with patients were additionally associated with both personal and work-related burnout. Having health problems and working with COVID-19 patients were only associated with personal burnout. More than 40% of physiotherapists experienced personal and work-related burnout and 25% patient-related burnout, with resilience, depression and stress having a relevant role in the three burnout dimensions. Early detection and management strategies need to be implemented to address physiotherapists' physical and psychological fatigue and exhaustion.info:eu-repo/semantics/publishedVersio

Pharmacological inhibition of acetylcholinesterase improves the locomotion defective phenotype of a SCA3 C. elegans model.

Inhibition of acetylcholinesterase (AChE) is a common used treatment option for Alzheimer’s disease. However, there has been limited research on the potential use of AChE inhibitors for the treatment of Machado-Joseph disease (MJD)/Spinocerebellar Ataxia 3 (SCA3), in spite of the positive results using AChE inhibitors in patients with other inherited ataxias. MJD/SCA3, the most common form of dominant Spinocerebellar Ataxia worldwide, is caused by an expansion of the polyglutamine tract within the ataxin-3 protein, and is characterized by motor impairments. Our study shows that administration of the AChE inhibitor neostigmine is beneficial in treating the locomotion defective phenotype of a SCA3/MJD model of C. elegans and highlights the potential contribution of AChE enzymes to mutant ataxin-3-mediated toxicity

Combined therapy with m-TOR-dependent and -independent autophagy inducers causes neurotoxicity in a mouse model of Machado-Joseph disease

A major pathological hallmark in several neurodegenerative disorders, like polyglutamine disorders (polyQ), including Machado-Joseph disease (MJD), is the formation of protein aggregates. MJD is caused by a CAG repeat expansion in the ATXN3 gene, resulting in an abnormal protein, which is prone to misfolding and forms cytoplasmic and nuclear aggregates within neurons, ultimately inducing neurodegeneration. Treatment of proteinopathies with drugs that up-regulate autophagy has shown promising results in models of polyQ diseases. Temsirolimus (CCI-779) inhibits the mammalian target of rapamycin (m-TOR), while lithium chloride (LiCl) acts by inhibiting inositol monophosphatase, both being able to induce autophagy. We have previously shown that chronic treatment with LiCl (10.4 mg/kg) had limited effects in a transgenic MJD mouse model. Also, others have shown that CCI-779 had mild positive effects in a different mouse model of the disease. It has been suggested that the combination of mTOR-dependent and -independent autophagy inducers could be a more effective therapeutic approach. To further explore this avenue toward therapy, we treated CMVMJD135 transgenic mice with a conjugation of CCI-779 and LiCl, both at concentrations known to induce autophagy and not to be toxic. Surprisingly, this combined treatment proved to be deleterious to both wild-type (wt) and transgenic animals, failing to rescue their neurological symptoms and actually exerting neurotoxic effects. These results highlight the possible dangers of manipulating autophagy in the nervous system and suggest that a better understanding of the potential disruption in the autophagy pathway in MJD is required before successful long-term autophagy modulating therapies can be developed.Fundação para a Ciência e Tecnologia through the projects [FEDER/FCT, POCI/SAU-MMO/60412/2004], [PTDC/SAU-GMG/64076/2006]. This work was supported by Fundação para a Ciência e Tecnologi