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- Supplemental Data - Genetics of Growth Hormone Deficiency: Insights from a Cohort of 203 PatientsPublication . Ribeiro, Ana Cláudia Batista JordãoSupplemental Table S1. Genes selected for variant analysis. Supplemental Table S2. Characteristics of 172 GH deficiency patients studied by exome sequencing of 184 genes (only P, LP and VUS variants are presented).
- Influência do Sistema Estrutural na Resistência Sísmica dos EdifíciosPublication . Carvalho, Gabrielly Cristina de Souza; Andrade, Jorge Miguel de AlmeidaA ação sísmica além de ser uma realidade global que assola inúmeras regiões todo ano, é também responsável por uma parte marcante da história e do desenvolvimento de Portugal, como foi o caso do sismo de 1755, moldando assim, a forma como a sociedade lida com os desafios sísmicos e impulsionando o desenvolvimento de uma abordagem mais ativa em termos de prevenção tanto para garantir a estabilidade das estruturas como para preservar a vida humana. Este trabalho tem como objetivo principal a elaboração de um documento de aplicação prática sobre a influência dos sistemas de contraventamento em estruturas metálicas quando sujeitas a ações horizontais, mais especificamente no caso da ação sísmica. Deste modo considerou-se os procedimentos descritos no Eurocódigo 8 [3], tanto para a definição da ação sísmica, como para a verificação da capacidade dos elementos estruturais. Com este intuito foram considerados vários casos de estudo baseados no dimensionamento de pórticos idênticos, mas com diferentes sistemas resistentes a ações horizontais, contraventamento em X, V ou V invertido e com ligações viga-pilar resistentes a momentos. Para a análise dos diversos casos de estudo foram realizadas simulações numéricas, tanto estáticas como dinâmicas. De modo a otimizar o processo de dimensionamento dos elementos estruturais recorreu-se à utilização do programa de cálculo automático TRICALC, sendo, deste modo, apresentados modelos estruturais mais eficientes para cada situação estudada. No final são apresentadas algumas conclusões que podem vir a ser consideradas como base para a escolha de um sistema estrutural eficiente para uma dada situação de projeto.
- Insect-based chitin and chitosan from whole body sources and rearing by-products: extraction, physicochemical, structural and bioactivity characterisationPublication . Navarro, Pedro; Ribeiro, José Carlos Reis ; Luís, Ângelo Filipe Santos ; Domingues, Fernanda; Anjos, Ofélia; Cunha, LuisFractionation of edible insects and their rearing by-products can lead to expanded industrial applications and extraction of value-added products. The main goal of this study was to extract chitin and synthesise chitosan from three different insect sources – Tenebrio molitor larvae, adult Acheta domesticus and A. domesticus rearing by-products (legs and wings). Furthermore, the physicochemical, structural, and bioactive properties of insectderived chitin and chitosan were characterised and compared to commercial crustacean-based samples. Chitin was isolated from defatted sources through chemical hydrolysis followed by decolourisation and was deacetylated with a strong alkaline solution to synthesise chitosan. Notably, A. domesticus rearing by-products yielded the highest chitin and chitosan content. Chitin and chitosan derived from insects exhibited physicochemical and structural characteristics consistent with the α-polymorphic form, similar to the commercial samples. Differences were found in surface morphology, with insect-derived samples presenting large and irregular flakes and porosity, while the crustacean-derived samples presented irregularly arranged fibres and a more regular and smoother surface. As for antioxidant activity, although all chitosan samples demonstrated poor DPPH radical scavenging activity, this study showed for the first time that insect-derived chitosan presents lipid peroxidation inhibition ability. All chitosan samples presented antimicrobial activity against different pathogenic bacteria, with K. pneumoniae being the most susceptible strain. Nevertheless, there is potential for enhancement of the biological properties through modifications on the molecular weight and deacetylation degree. This research introduces the potential of cricketrearing by-products as sustainable sources of chitosan with functional bioactive properties.
- As tensões entre as perspetivas informativa e política da comunicação de risco e de crise: A comunicação das organizações públicas portuguesas sobre os incêndios florestaisPublication . Toniolo, Bianca Persici; Gonçalves, Gisela Marques PereiraOs incêndios florestais em Portugal fazem parte de problema global associado às mudanças climáticas que, nos últimos anos, têm aumentado a intensidade e a frequência de desastres naturais em todo o mundo. A comunicação de desastres naturais, contudo, envolve tensões entre dois propósitos distintos da comunicação das organizações públicas: a proteção da população versus a preservação da reputação. Nesse sentido, investigámos qual perspetiva – informativa ou política (Frandsen & Johansen, 2020d) – prevaleceu, ao nível da mensagem, na comunicação de risco e crise das organizações públicas nacionais portuguesas implicadas diretamente no enfrentamento aos incêndios florestais em 2017, 2018 e 2019. Para isso, desenvolvemos um modelo original a que denominámos Modelo Loop, composto por um loop de 12 meses com seis fases cronologicamente delimitadas que se repetem infinitamente: (1) Prevenção; (2) Preparação; (3) Alerta; (4) Socorro; (5) Recuperação; e (6) Avaliação. O nosso estudo empírico adotou uma abordagem que combinou métodos quantitativos e qualitativos na análise dos dados. Analisámos o conteúdo (Bardin, 2014) de 1.151 mensagens emitidas por 10 organizações públicas conforme 10 variáveis do Modelo Loop. Também verificámos a presença ou a ausência dos 13 fatores que formam o Indicador da Qualidade Informativa em Incêndios Florestais (IQI-IF), um indicador agregado de análise multivariada que nos permitiu avaliar objetivamente a qualidade informativa, relacionada com a perspetiva informativa da comunicação de risco e crise, das mensagens emitidas em cada fase do Modelo Loop. A nossa principal conclusão foi que a comunicação dos incêndios florestais oscilou entre as perspetivas informativa e política, com marcada predominância da perspetiva informativa, exceto na fase Prevenção, que apresentou o IQI-IF negativo nos três anos analisados.
- Thyroid modulating activity of UV-B filter octylmethoxycinnamate on vascular systemPublication . Lorigo, Margarida Ferreira; Oliveira, Maria Elisa Cairrão Rodrigues; Granadeiro, Luiza Augusta Tereza Gil Breitenfeld; Antunes, Carla Patrícia QuintaneiroEvery day, an extensive and varied range of emerging contaminants encounter humans. Exposure to these endocrine-disrupting chemicals (EDCs) is not without risks and has even been associated with adverse effects on multiple human systems, including the cardiovascular system. Due to the fundamental role of thyroid hormones (TH) in vascular homeostasis, EDCs capable of disturbing thyroid homeostasis (thyroid disruptive chemicals, TDCs) may increase the risk of cardiovascular disease (CVD). However, the mechanisms underlying thyroid disruption associated with the progression or development of CVD are not fully understood. Endocrine disruption is one of the biggest concerns and, therefore, one of the most extensive research forces. Endocrine disruption comprises a diverse set of target organs, processes, and modes of action (MoA), with multiple interactions and complex actions. Periods of development, such as pregnancy, are susceptible to endocrine disruption and constitute a priority area of research. Pregnant women often use various personal care products containing UV filters. The UV-B filters are designed to protect humans against the biological effects of UV radiation. However, their use has been questioned, and some concerns of toxicity to human health have emerged, demonstrating an EDC role for some UV filters. Octylmethoxycinnamate (OMC) is one of the most used UV-B filters worldwide. However, the OMC is also an EDC that affects human health and the environment, and its use remains under intense controversy. The scientific community has given special importance to the environmental and severe effects on coral reefs and aquatic species, which led to OMC being withdrawn from the market in different countries since 2018. On the contrary, the endocrine-disrupting effects in humans have been neglected despite in vitro studies having proven effects at the estrogenic level and non-consensual effects concerning (anti)thyroid and (anti)androgenic activities. Based on the above, it is worrying that the effects of a UV filter widely used worldwide are practically unknown on human health. Within the scope of my MSc dissertation, we demonstrated that OMC acts as a rapid vasodilator of the human umbilical artery (HUA). Although this vasorelaxation has a short-term beneficial effect on the vascular system, also observed with other EDCs, in the long term, all EDCs studied impaired the main vasorelaxation mechanisms of HUA through different MoA. In the case of OMC, only one study evaluated its short-term effects on human vasculature, and the effects of its long-term exposure on human health were not known until this research. Therefore, the main objective of this doctoral thesis was to understand whether exposure to the OMC UV filter impairs human vascular function in the presence of thyroid disorders. We hypothesize that exposure to OMC has adverse effects on the human vasculature, altering the expression of different receptors involved in thyroid functions. To achieve our objective and answer our research hypothesis, various in silico (molecular docking), ex vivo, in vitro (HUA and human umbilical artery smooth muscle cells, HUASMC), and in vivo (zebrafish) approaches were outlined. The first research work analysed the effects of long-term exposure to OMC on HUA vascular homeostasis. Potential changes in the vascular responses of proteins and channels involved in contractile processes were the focus of the research. The effects of 24- hour exposure to OMC (1, 10, and 50 μmol/L) were evaluated on HUA contractile responses to serotonin (5-HT) and potassium chloride (KCl). The data showed that exposure to OMC altered HUA vascular homeostasis; therefore, its MoA was explored in more detail by studying the activity of cyclic guanosine 3’,5’–monophosphate (cGMP) and Ca2+ channels (two pathways involved in its relaxation and contraction, respectively). Prolonged exposure to OMC impaired the main vasorelaxant mechanism of HUA. Interference in the nitric oxide (NO)/soluble guanyl cyclase (sGC)/cGMP/protein kinase G (PKG) signaling pathway and modulation of L-Type voltage-operated Ca2+ channels, BKCa1.1 potassium channels (α subunit), and PKG were the MoA implicated in the decrease in the contractile response. This work demonstrated that OMC could compromise vascular homeostasis in pregnant women and may have a role in the induction of hypertensive diseases of pregnancy. The HUA is regulated mainly by local mediators (5-HT and histamine, His). Membrane receptors, such as G protein-coupled receptors, GPCR induce the effects of these mediators which, when altered, compromises maternal-foetal health. Elevated levels of 5-HT and His increased HUA reactivity/sensitivity to these vasoactive agents, increasing vascular resistance and inducing preeclampsia (PE) and gestational hypertension. On the other hand, it has been demonstrated that EDCs can activate membrane receptors and alter signal transduction. Based on the above and considering the results obtained in the first study, our second research work deepened knowledge about the effects of prolonged exposure to OMC on vascular homeostasis, evaluating the modulation of receptors involved in the contractile processes of HUA. In this work, the research focused on the activity and expression of different 5-HT and His receptors. Thus, the effects of 24-hour exposure to OMC (1, 10 and 50 μmol/L) were evaluated on the contractile responses of HUA to 5-HT and His, using different specific agonists and antagonists, namely 5-HT2A receptor agonist (AMHT), 5-HT7 receptor agonist (AS19), 5- HT1B/1D receptor agonist (L69), H1 receptor agonist (BHI), H2 receptor agonist (dimaprit) and H2 receptor antagonist (cimetidine). Our results demonstrated that exposure to OMC increased HUA reactivity to the vasoactive agents under study. Consequently, and in line with previous research, our results denote a potential role for OMC in the development of hypertensive diseases of pregnancy, such as PE or gestational hypertension. In the third research work, the effects of short- and long-term exposure to OMC were evaluated on the vasculature of pregnant women with hypothyroidism. Although it has been suggested that OMC is a TDC due to its action on thyroid hormone receptor (TR), its disruptive effects on thyroid pathologies during pregnancy have never been evaluated. Therefore, in this study, we assessed the disruptive vascular effects of OMC in hypothyroidism conditions. Computational simulations using molecular docking allowed the correlation of vascular changes with the action of OMC on TRα. Our results indicated that OMC alters the contractility patterns of HUA contracted with 5-HT, His, and KCl, possibly due to interference with 5-HT and His receptors and/or involvement of Ca2+ channels (as shown in two previous investigations, in the absence of thyroid pathologies). Molecular docking analysis confirmed OMC competition with the endogenous hormone T3 for binding to the active centre of TRα, supporting the observed vascular changes. Taken together, our data demonstrate that exposure to OMC alters the vascular reactivity of pregnant women with thyroid pathologies and, thus, may be related to an increased risk and development of cardiovascular diseases. In the fourth research work, developing zebrafish embryos were used as a model to study the effects of OMC exposure in conditions of thyroid pathologies. This work aimed to unravel whether and how the response to OMC exposure is altered by developmental hypothyroidism and hyperthyroidism simulated conditions in zebrafish developing embryos and impair their normal development. For this purpose, developmental hypothyroidism and hyperthyroidism were induced through exogenous exposure to PTU (propylthiouracil, an anti-thyroid drug) or T3 (triiodothyronine endogenous hormone), respectively. Then, embryos were exposed during 120h to OMC isolated and in binary mixture with PTU or T3. In hypo- or hyperthyroidism developmental conditions, exposure to OMC impaired the embryonic development of zebrafish through the induction of several malformations. Pericardial and yolk sac oedema, yolk sac delayed absorption, noninflation of the swim bladder, notochord curvature, and lack of pigmentation were the most prevalent malformations. Furthermore, exposure to OMC under these conditions impairs the behaviour of larvae. Altered transcription of genes related with the HPT axis found proves the TDC action of the OMC. Our findings highlight a modified OMC response in the presence of thyroid pathologies, with harmful effects in development period more sensitive to endocrine disruption, which is in line with research work III. Lastly, the fifth research work was based on the study of the molecular interactions of the OMC in the HPT axis and their implications for humans and zebrafish. This in silico research aimed to reveal the different modes of interaction of the OMC at different levels of the HPT axis, comparing it to the PTU and T3. Our results demonstrated an action of OMC at different levels on the HPT axis, with different actions depending on the target. Molecular docking analysis revealed favourable binding to the corticotrophin-releasing hormone (CRH) receptor and the TH transporter protein, transthyretin (TTR). Furthermore, competition with T3 (inverse agonist activity) was observed for TRα and TRβ. Overall, the action of OMC appears to lead to a decrease in TH, which may promote hypothyroidism. This investigation proves that the OMC acts as a TDC and offers new insights about its disruptive action on the HPT axis, capable of supporting previous investigations. In summary, this doctoral thesis analysed the effects of prolonged exposure to OMC on human vasculature for the first time. Our mechanistic and integrative in silico, ex vivo, in vitro and in vivo approaches demonstrate that OMC impairs vascular homeostasis in pregnant women with and without thyroid pathologies, acting through different molecular initiating events (MIEs) and key events (Kes). Consequently, exposure to OMC can induce the development of cardiovascular diseases. Complementation with in vivo studies made it possible to prove the action of OMC on the HPT axis since the response to OMC was altered in the presence of both thyroid pathologies. In silico studies compared its thyroid modulatory activity to that of the endogenous hormone T3 and the antithyroid drug PTU, which revealed interference at different levels in the HPT axis. Considering the agonist and antagonist actions as an endocrine disruptor, we conclude that prolonged exposure to OMC triggers pathophysiological mechanisms capable of inducing vascular changes with implications for human thyroid health.
- Nucleic acid based nanosystem for Human Papillomavirus related lesionsPublication . Nunes, Jéssica Lopes; Cruz, Carla Patrícia Alves Freire Madeira; Oliveira, Paula Alexandra Martins deHuman Papillomaviruses (HPVs) are among the most common sexually transmitted infectious agents. The infectious virus particles (virions) invade and replicate in dividing cells, hijack their host cellular process, and new virions are released in terminally differentiated cells, in the uppermost layers of the epithelium. The immune system usually clears the virus, but on some occasions the infection remains and can induce proliferation alterations, leading to the development of warts. Although, high-risk HPVs, namely HPV16 and HPV18, can also cause malignant transformations, being considered etiological agents of cervical or head and neck cancers. Currently, there are HPV screening and vaccination programs that contributed for a reduction in the infections prevalence by up to 85% for the genotypes covered by the vaccines, and a 50% reduction in the number of high grade lesions related to this virus, particularly in countries with high vaccination rates (≥50%). Although, they are still limited in some countries, as well as in men, which together with the prophylactic nature contribute for HPV remaining a worldwide health issue. Adding to this, the available therapeutic approaches have limited efficacy and cause several side effects, with a great impact on patients’ quality of life. Therefore, there is still investigation for the development of new treatment options for HPV-related cancers. In the pursuit of new therapeutic options, nanoparticles are being proposed as efficient delivery method. Many of them take advantage of passive targeting, which facilitates nanoparticles deposition in tumor cells, owing to some characteristics of the tumor milieu, such as the enhanced permeability of the vasculature. Although, this permeability varies between individuals, and internalization by other organs can occur, reducing the therapeutic efficacy and inducing nonspecific effects. Thus, targeting strategies are being employed to enhance the nanoparticles selectivity towards cancer cells, reducing potential off-target effects. To achieve this, biorecognition molecules are attached to the nanoparticles surface. For instance, nucleic acids can be used, such as the internalizing RNA previously developed by Magalhães et al., 2012, that shown promising results as a strategy for the development and enhancement of novel RNA-based transfection methods. On the other hand, DNA aptamers are also a promising approach due to their high selectivity towards a specific target that can be a protein or a whole cell. Particularly, G-quadruplex aptamers are emerging, due to their increased stability and higher negative charge density comparingly to duplex DNA, favoring the interactions with cationic proteins. The most well-known and used example is AS1411 with nucleolin as target, a protein that is overexpressed in cancer cells surface. To achieve better structural or antiproliferative results, derivatives of AS1411 were more recently proposed. Thus, in this thesis, new nanotherapeutic approaches for HPV-related cancers were investigated and functionalization with different targeting moieties (AS1411 and derivatives or an internalizing RNA) was tested. The nanosystems were developed for a more selective delivery of different small molecules, including the drugs imiquimod or dexamethasone and the potential therapeutic molecule C8 (10-(8-(4-iodobenzamide) octyl)-3,6-bis (dimethylamine) acridinium iodide). Firstly, the targeting capacity of AS1411 derivatives (namely AT11, AT11-Bo and AT11-L0) was investigated and these sequences were used for a more selective delivery of Zn(II) phthalocyanine (ZnPc) derivatives. The supramolecular aggregates composed by the aptamers and ZnPc derivatives were more cytotoxic in HPV cancer cells (HeLa cells), relatively to the non-malignant NHDF cells (<40% versus ~80%). These findings support the development of new strategies using these sequences for an improved anticancer effect of the therapeutic molecules. Then, different nanosystems were tested in HPV-integrated cervical, namely HeLa (HPV18+), CaSki (HPV16+ and HPV18+) and SiHa (HPV16+), or head and neck UPCI-SCC-154 (HPV16+) cancer cell lines and, in the final part of the work, in HPV16 transgenic mice. At first, gold nanoparticles functionalized with AS1411, with a known improved cancer cells uptake, were tested as a potential drug delivery system of imiquimod or C8. The obtained drug delivery systems were produced, characterized, evaluated and incorporated in a gel formulation, prepared based on the universal placebo formulation. As proposed, the AS1411-functionalized gold nanoparticles were indeed capable of improving the selectivity (decreasing the therapeutic molecules cytotoxicity in the non-malignant cells, NHDF cells; cell viabilities >60%) and to potentiate their anticancer effect, especially in HeLa cells (cell viabilities <30%). Additionally, when in a formulation, the C8 ligand was able to permeate and be retained in ex vivo porcine vaginal tissues. To achieve higher biocompatibility, the work was further moved to lipid nanoparticles, aiming to improve the potential clinical applicability of the produced drug delivery systems. First, liposomes produced by the thin film hydration method were obtained and functionalized with a promising internalizing RNA. The RNA was firstly biophysically characterized to analyze the effect of intermolecular interactions with C8 or dexamethasone, in which it was observed that these molecules do not induce alterations in its structure and thermal stability. Then, the produced liposomes were also characterized and biologically evaluated. Overall, the liposomes improved the selectivity of the used therapeutic molecules towards the tongue cancer cell line, UPCI-SCC-154 (~13/37% versus >85%). Although, this production method resulted in low amounts of liposomal suspension (<1 mL of suspension at <1 mg/mL of lipids, per batch). For this reason, we changed to the ethanol injection method, which resulted in larger volumes of liposomal suspension (~10 mL of suspension at 3.56 mg/mL of lipids) and faster (from ~3 days to ~1 h up to the obtention of the functionalized liposomes), being more compatible with a bulk manufacturing process. Thus, liposomes were produced and functionalized by a post-insertion method with AT11 and were used to deliver imiquimod or C8. The obtained liposomes shown to be cancer-selective and with an effective anticancer effect in the UPCI-SCC-154 cell line, reducing the viability, proliferation, migration, invasion and inducing cancer cells death. The AT11-functionalized liposomes with C8 were then incorporated in gel formulations, prepared based on the universal placebo, with or without essential oils (Thymus vulgaris or Origanum vulgare). The formulations presented suitable features for application (including high viscosities, 968-1318 mPa.s, and osmolality <1200 mOsmol/kg), the essential oils potentiate the anticancer effect in cervical cancer cell lines (HeLa, SiHa and CaSki) and after application in healthy or HPV16 transgenic mice, it was confirmed that the produced formulation was safe and with potential therapeutic effect in HPV-associated lesions. Overall, different nanotherapeutic strategies were proposed to enhance drug delivery towards HPV-related cervical and head and neck cancers, which highlight the great potential of nanomedicine in cancer treatment. While there is still considerable progress to be made, this work provides valuable insights into potential new targeting moieties and therapeutic molecules.
- Equações diferenciais biharmónicas evolutivas com crescimento não standardPublication . Panni, Willian dos Santos; Duque, José Carlos Matos; Ferreira, JorgeNeste trabalho, investiga-se uma equação diferencial evolutiva com o operador p(x)- biharmónico. Especificamente, estuda-se o problema de encontrar uma função u = u(x; t) que satisfaz: [...]
- Genetic Polymorphisms of NRF2-KEAP1 in Breast Cancer: a marker for prognosis and treatmentPublication . Almeida, Micaela Carina Pereira; Granadeiro, Luiza Augusta Tereza Gil Breitenfeld; Patrício, Ana Cristina Monteiro Ramalhinho Tavares; Oliveira, António José Polónia Rodrigues deBreast cancer remains the oncological disease with the greatest impact on morbidity and mortality in women worldwide. Prolonged exposure to estrogens is considered one of the main risk factors for breast cancer. This carcinogenic process is potentiated by genetic alterations in lowpenetrance genes in the estrogen biosynthetic and metabolic pathways. Phase II enzymes responsible for estrogens detoxification, are regulated by the NRF2- KEAP1 (nuclear factor erythroid 2-related factor 2 - kelch-like ECH-associated protein 1) complex. The value of this complex in estrogen detoxification led us to the aim of this thesis, which is to validate the NRF2-KEAP1 complex as a marker for breast cancer prognosis and therapy. Thus, we studied the influence of genetic polymorphisms, in low penetrance genes of the estrogen metabolic pathway in breast cancer development. The genotype of Val432Leu, C677T and null polymorphisms, respectively of CYP1B1, MTHFR, GSTM1 and GSTT1 genes, were assessed in women with hormone-dependent breast cancer. It was verified that carriers of the null genotype of GSTT1, alone or in association with the null genotype of GSTM1, as well as carriers of Val432 of CYP1B1 and the null polymorphism of GSTT1 or GSTM1, and carriers of the null genotype of GSTT1 and the T allele of the C677T polymorphism, were diagnosed with breast cancer at the age of 50 or over. The results indicate that polymorphisms that contribute to inefficient estrogen detoxification may predispose women to developing hormone-dependent breast cancer at a later age. In order to assess the clinical influence of the NRF2 rs35652124, rs6706649, rs6721961 polymorphisms and the KEAP1 rs1048290 polymorphism in breast cancer cases with a "present" GSTM1 genotype, a technique was optimised which made it possible to distinguish heterozygous from present genotypes. Heterozygous GSTM1 cases cumulatively carriers of the NRF2 and/or KEAP1 polymorphisms were associated with HER2+ (epidermal growth factor receptor 2 positive) breast cancers. There are several studies correlating NRF2 polymorphisms and its expression with breast cancer prognosis. After a systematic review with meta-analysis, it was found that patients with NRF2 over-expression had lower overall survival and shorter disease-free survival. Subsequently, the genotypes of the aforementioned KEAP1 and NRF2 polymorphisms were assessed in blood, tumour’s benign surrounding tissue and tumour tissue. There was a trend towards the loss of heterozygosity in the benign surrounding tissue and a greater variability of genotypes in histological grade 2. The acquisition of somatic mutations and their different distribution are probably the result of a more active and heterogeneous microenvironment. Polymorphisms that compromise the availability of NRF2 in the nucleus impair estrogen detoxification and may predispose to the development of postmenopausal breast cancer. High levels of NRF2 in the nucleus promote high detoxification, protecting both healthy and tumour cells. It is therefore pertinent to carry out further studies in benign and tumour tissue, in different subgroups of participants, in order to understand the role of the complex in the development and progression of breast cancer.
- Uma Introdução à Filosofia da MatemáticaPublication . Castro, Eduardo Jorge de SousaEste livro é um manual para um primeiro curso de Filosofia da Matemática. Pode ser usado ao nível de uma graduação ou de uma pós -graduação, de Filosofia ou de Matemática. Restantes académicos e investigadores, bem como professores do ensino não -universitário, podem também encontrar aqui uma referência e uma orientação para o seu trabalho e investigação. O livro apenas pressupõe conhecimentos de matemática e de filosofia, de nível pré -universitário.
- Characterization of Elite Rink Hockey Players, Match and Training DemandsPublication . Ferraz, António Leopoldo Lopes; Travassos, Bruno Filipe Rama; Santos, João Alberto Valente dos; Mendes, Pedro Alexandre DuarteThis work aimed to provide valuable insights into the characteristics of players, training, and game demands in rink hockey, applying the knowledge developed towards a more suitable method for monitoring training and competition to enhance player performance. To achieve this, six studies were conducted with specific objectives: (1) to understand the evolutionary trends in the characterization of players and game performance in men's rink hockey; (2) to characterize the body composition and grip strength of elite male rink hockey players and establish the relationship between ethnicity in body composition and grip strength; (3) to understand the applicability of monitoring systems for physical performance analysis in team sports over the last decade in order to develop knowledge for load monitoring in rink hockey; (4) to understand the dynamics of external and internal load throughout the 2-week training period and competition week of a rink hockey International Championship; (5) to propose a new approach to characterize and classify the physiological and biomechanical specificity of training tasks in relation to elite competition - a quadrant-based classification system; (6) to apply the quadrant-based classification system to characterize and classify load demands, considering the physiological and biomechanical requirements of training and games according to positional dimensions. Overall, the results obtained in the six studies of this thesis promoted a proposal for practical applicability from player profiling to training and game monitoring. Study 1 revealed that the literature on rink hockey is scarce and generally presents a holistic approach to physiological and functional demands, cardiorespiratory adaptations, training characteristics, anthropometry, body composition, conditional profile, game characterization, and injuries in rink hockey. However, most studies are conducted on young athletes, with few studies on elite athletes. Thus, it was essential to conduct research toward characterizing elite athletes and the physical demands of training and competition. Study 2 described that given the characteristics of the sport and its neuromuscular adaptation, elite rink hockey players show a specific anthropometric profile considering percentile values of fat and characteristic grip strength for this sport, with ethnicity, right thigh circumference, and right calf circumference being the variables that best describe fat percentile, while age, distal circumference of the right thigh, and ethnicity better describe grip strength. Considering that monitoring through positional analysis technology in rink hockey is almost non-existent, Study 3 sought to understand how research using indoor positioning systems could contribute to a better understanding of the demands of rink hockey. It was found that most studies have focused on performance analysis, load management, injury development process, and nutrition. Still, in Study 3, it was proposed that integrated analysis of kinematic and mechanical variables should be studied alongside their correlation or association with internal load variables to understand athletes' performance improvement strategies better. In this logic, Study 4 observed in a preparation for an international competition that training demands do not match those of the competition. High-intensity impacts followed by decelerations characterize the metrics that most impact athletes' subjective perception of effort during competition, which are underexplored during training, particularly high-intensity impacts. Therefore, in Studies 5 and 6, a proposal was developed to characterize physiological and biomechanical demands in training and competition situations, providing coaching staff with a methodological tool to optimize microcycle planning. In Study 5, it was found that no exercise category analysed has the physiological and biomechanical demands of the game. While the game is characterized by high physiological and biomechanical demands, most exercises have low physiological and biomechanical demands, except for exercises performed in midcourt and full court, which have high physiological and medium biomechanical demands. Still, in Study 5, no category of exercises with simultaneous high biomechanical and low physiological demands was found. Finally, in study 6, a misalignment between the specific demands of different positions was observed when comparing the game with the training sessions of the microcycle. That is, although the game is characterized by high physiological and biomechanical efforts, advanced players tend to achieve a lower physiological and biomechanical profile than defender-midfielder players. These differences are not considered throughout the microcycle. Finally, this approach used in Studies 5 and 6 allows us to assume that the integrated variables that best characterize the physiological demands in rink hockey are average heart rate, maximum heart rate, and distances skated at high intensity. In turn, those that best integrate biomechanical demands are high-intensity impacts, decelerations, and accelerations. In summary, the results suggest that training does not meet the demands of the game, compromising athletes' appropriate response capacity, particularly considering the game's biomechanical demands. This is because there is a failure to replicate these demands in training in terms of training structure and player individualization, mainly due to the absence of exercises that promote high-intensity impacts associated with decelerations and accelerations. The quadrant-based classification system proposal presented in studies 5 and 6 offers coaching staff a methodology to analyse and adjust training structure and player specificity, thus promoting an environment that better replicates competition demands.