A malária tem moldado o genoma humano há milhares de anos e continua a representar um desafio significativo para a saúde pública, sobretudo na África Subsariana. O desenvolvimento de imunidade parasitária e clínica na população das áreas endémicas propicia o aparecimento de infeções submicroscópicas e assintomáticas por Plasmodium, as quais favorecem a transmissão em regiões endémicas. Esta tese teve como objetivo geral estimar a carga das infeções submicroscópicas por P. falciparum na transmissão da malária na Guiné-Bissau. A partir da análise de um conjunto de 601 amostras de sangue seco em papel filtro, 98 oriundas de indivíduos positivos à microscopia óptica e 503 de indivíduos negativos, a frequência, distribuição étnico-geográfica e morbilidade das infeções submicroscópicas foram estimadas, assim como os fatores independentes associados a elas. Separadamente, foi avaliada a contribuição de fatores do hospedeiro e do parasita, tais como o traço falciforme e a deleções dos genes pfhrp2 e pfhrp3 no desenvolvimento de infeções submicroscópicas. Finalmente, a diversidade genética de parasitas oriundos de infeções submicroscópicas vs microscópicas e de hospedeiros com traço falciforme vs sem traço falciforme foi avaliada através da análise de regiões genómicas microssatélites. Infeções submicroscópicas por P. falciparum foram detetadas em 20.3% da amostra e em 21.4% das grávidas, ambas com microscopia negativa. Estas infeções apresentaram associação significativa com grupos étnicos. O traço falciforme foi identificado em 32.0% da amostra, maioritariamente das regiões insulares e seus grupos étnicos. Os portadores de traço falciforme até os 24 anos de idade apresentaram maior prevalência e risco de infeção microscópica por P. falciparum do que não-portadores. Portadores menores de cinco anos de idade infetados com P. falciparum apresentaram menor parasitemia e maiores níveis de hemoglobina do que não-portadores. Os resultados evidenciam a necessidade de métodos de diagnósticos mais sensíveis e estratégias direcionadas para a vigilância da malária em contextos de pré-eliminação. O papel do traço falciforme destaca-se como relevante para intervenções ao nível do hospedeiro. São necessários mais estudos sobre a frequência e relevância das deleções nos genes pfhrp2/pfhrp3 nos parasitas da Guiné-Bissau, assim como sobre a diversidade genética parasitária e estrutura populacional dos parasitas das infeções submicroscópicas. A integração de infeções submicroscópicas aos dados nacionais é crucial para reavaliar a epidemiologia da malária e orientar estratégias para interromper a transmissão residual. menores de cinco anos de idade infetados com P. falciparum apresentaram menor parasitemia e maiores níveis de hemoglobina do que não-portadores. Os resultados evidenciam a necessidade de métodos de diagnósticos mais sensíveis e estratégias direcionadas para a vigilância da malária em contextos de pré-eliminação. O papel do traço falciforme destaca-se como relevante para intervenções ao nível do hospedeiro. São necessários mais estudos sobre a frequência e relevância das deleções nos genes pfhrp2/pfhrp3 nos parasitas da Guiné-Bissau, assim como sobre a diversidade genética parasitária e estrutura populacional dos parasitas das infeções submicroscópicas. A integração de infeções submicroscópicas aos dados nacionais é crucial para reavaliar a epidemiologia da malária e orientar estratégias para interromper a transmissão residual.

This thesis investigates how firms navigate the decision to pursue, maintain, or exit sustainability certification, such as B Corp. Using a mixed-methods approach, combining quantitative analysis of B Lab’s Exit Survey with 25 interviews and secondary data, it identifies key drivers of (dis)engagement: perceived lack of value, operational constraints, and identity misalignment. Framed through Institutional and Organizational Identity Theory, the study reconceptualizes certification as a non-linear journey shaped by both external pressures and internal convictions. Findings offer practical insights for firms and certifying bodies, and highlight the legitimacy of alternative, authenticity-based approaches to demonstrating sustainability commitment.

At the moment, tax reform is a hot topic in Portugal. Promoting the competitiveness of the Portuguese economy and stepping up the fight against tax fraud and tax evasion have been elected as the two hallmarks of an ongoing tax reform, the complete details of which should be known by the end of this year.

Sepsis is an immune dysregulation syndrome triggered by infection, characterized by host self-damage due to immune imbalances. This study focuses on dynamic changes of mitochondrial symbiotic function in host cells during sepsis and systematically investigates dysregulation of mitochondrial communication modes and the intrinsic link between mitochondrial DNA (mtDNA) release and immune dysregulation. We demonstrate that during early-stage LPS treatment, mitochondria actively remodel by extruding flagella-like extensions (termed mitoFLARE). These structures, nanotubes mediating long-distance transport, form through glycosylated TRAK1 binding FHL2 to drive actin network formation, thereby shifting mitochondrial communication from direct fusion to nanotube-mediated transport. This helps maintain dynamic exchange within the inner mitochondrial membrane under LPS treatment. However, as inflammation progresses, deteriorated mitochondrial quality control disrupts the MICOS-SAM complex, abrogates inner-outer membrane anchoring, and suppresses mitoFLARE functions. All these ultimately enhance endoplasmic reticulum-mitochondrial contacts to promote outer membrane rupture and result in mtDNA release into the cytoplasm to activate cGAS-STING signaling, further triggering immune dysregulation and inflammatory storm, culminating in programmed cell death and organ dysfunction. This study elucidates the pivotal role of dysregulated mitochondrial-host symbiosis in sepsis progression and provides important insights into the underlying mechanisms of sepsis-associated immune imbalances, laying a theoretical foundation for targeted therapy development.

INTRODUCTION AND OBJECTIVES: The gap junction alpha-4 (GJA4) gene, which encodes connexin37, regulates endothelial function and influences inflammation, platelet adhesion, and thrombus formation in vascular endothelial cells, which may favour atherosclerosis and cardiovascular (CV) events. The main objective is to assess whether the GJA4 rs618675 T>C variant is a risk factor for the onset of CV events in an asymptomatic Portuguese population. METHODS: 1421 individuals without CV disease (52.2±8.3 years, 73.6% male) were followed up during a mean of 7.3±6.0 years, and CV events were recorded. GJA4 rs618675 T>C was genotyped by real-time PCR (TaqMan), and four genetic models were created. We analysed traditional, biochemical and clinical risk factors. We performed bivariate analysis and adjusted logistic regression with respective OR. Kaplan-Meier estimated event-free survival and Cox regression, adjusted for confounding, evaluated the association between four genetic models and CV events (HR). RESULTS: Wild TT genotype, TC, and CC were 50.6%, 39.2%, and 10.1% in the CV events group and 66.2%, 30.4% and 3.4% in the non-events group (p=0.001). After logistic regression, the codominant model (CCvsTT and CTvsTT) showed an OR of 3.9 (p=0.002). Kaplan-Meier showed 87.6% event-free time for TT and 64.8% for CC (p=0.005). Adjusted Cox regression identified the codominant model as the best predictor (HR=2.8; p=0.008), together with male gender (HR=2.1; p=0.020), age (HR=1.1; p=0.001), hypertension (HR=1.9; p=0.014), smoking (HR=1.9; p=0.010), and leucocytosis (HR=1.2; p=0.003). CONCLUSION: We have demonstrated that the CC variant of GJA4 is significantly associated with CV events. Further investigations into this biomarker may improve CV risk prediction, leading to better primary prevention.

The exact solution for the evolution over time of all the molecular species intervening in the MichaelisMenten/Briggs-Haldane enzyme mechanism is deduced applying a new method inserting a Guessed Solution. Common approximations like quasi-steady-state, instantaneous equilibrium between substrate and complex and irreversible product formation are avoided. The Guessed Solution consists in a negative time exponential multiplied by an infinite summation. In this summation each term is a Modified Bessel Function of 1st Kind multiplied by a corresponding constant coefficient. The analytical solution is reached without ambiguity and, therefore prove to be unique.

Sanitàriamente o território está dividido em 16 delegacias: Goa, Salcete, Bardez, Vasco da Gama (Mormugão), Porto, Bicholim, Pondá, Perném, Sanguém, Satari, Quepém, Sanguém, Canócona, Diu, Damão e Praganã dirigidas por um médico delegado de saúde. As delegacias de Salcete, Bardez, Praganã e Diu envolvem ainda na sua área, respectivamente, as subdelegacias de Cuncolim. Nerul, Noroli, Canoel e Gogolá e Brancavará, dirigidas por um médico subdelegado de saúde e directamente dependentes dos delegados de saúde. Espalhados por todo o território e subordinados aos delegados de saúde existem 11 postos a cargo de enfermeiros. Grande número de delegacias (Fig. 1) têm residência para o pessoal e está aprovado superiormente o programa que manda se construam duas anualmente até ficarem servidas na totalidade. Estabelecimentos de assistência, de categoria variável conforme o meio (Figs. 2 e 3), encontram-se dispersos pelo território. Todas elas estão dotadas de transportes automóveis para a deslocação dos médicos (Fig. 4) e os postos de motocicletas ou bicicletas para deslocação dos enfermeiros. Além disso as delegacias das regiões mineiras e das cidades de Diu, Damão, Margão. Vasco da Gama, Mapuçá e Pangim possuem ainda automóveis-ambulâncias para transporte de doentes (Fig.5).

At the 2025 ESPCR (European Society for Pigment Cell Research) meeting in Erlangen, a workshop on “Pigment Cell Models: Sensitivity, Innovation, and the Challenges of Cell Culture” brought together researchers to discuss technical, methodological, and reproducibility issues in culturing melanocytes, keratinocytes, fibroblasts, and melanoma cells. The discussion between experts in the field highlighted key and recurrent pitfalls affecting experimental outcomes, including low-density seeding, temperature fluctuations, over-passaging, and mycoplasma contamination, as well as sources of variability arising from media composition, batch effects, and environmental conditions. Importantly, the workshop distinguished between practices supported by evidence and consensus-based guidance derived from collective expert experience. Species- and donor-specific differences, especially between human, mouse, and zebrafish melanocyte models, were identified as additional major determinants of experimental variability. Emerging systems, including human and mouse pluripotent stem cell (PSC)-derived melanocytes, as well as avian and zebrafish melanoma lines, were discussed for their complementary mechanistic and translational value. Overall, the workshop concluded that transparent documentation, explicit reporting standards, and shared best practices are essential to improve reproducibility and further advance pigment cell research.

INTRODUCTION: Central Precocious Puberty (CPP) is rare in boys, and idiopathic forms are particularly uncommon. This study characterizes the genetic architecture of idiopathic CPP (ICPP) in a national cohort of boys. DESIGN AND METHODS: We conducted a retrospective and prospective study of boys with ICPP recorded in the Portuguese national registry over the past 2 decades. Clinical, laboratory and demographic characteristics of the patients were reviewed. Whole exome sequencing (WES) was performed to identify pathogenic variants. RESULTS: Of 736 children with CPP, 8.2% were males. Total CPP cases in boys increased significantly over time (p<0.001), particularly during COVID-19. While secondary CPP remained stable (p=0.198), idiopathic forms increased by 19.1%/year (p<0.001), with change points in 2011 and 2021. WES identified pathogenic MKRN3 variants in 13.3% (2/15) boys, including a novel variant (p.Asp267Asn). MKRN3-positive patients presented with later-onset puberty, though sample size limits definitive conclusions. WES also detected a clinically significant TP53 variant as an incidental finding. CONCLUSIONS: ICPP incidence in Portuguese boys increased significantly over two decades, with acceleration during the pandemic. While genetic causes (primarily MKRN3 variants) were identified in 13.3% of cases, the substantial proportion of unexplained cases and temporal clustering indicate important roles for environmental and epigenetic factors.