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Apresenta����o realizada na sess��o O meu P��ster num minuto da 12�� Confer��ncia Luso-Brasileira de Ci��ncia Aberta, formato h��brido, de 13 a 15 de outubro de 2021.

Tauopathies are neurodegenerative disorders with increasing incidence and still without cure. The extensive time required for development and approval of novel therapeutics highlights the need for testing and repurposing known safe molecules. Since doxycycline impacts α-synuclein aggregation and toxicity, herein we tested its effect on tau. We found that doxycycline reduces amyloid aggregation of the different isoforms of tau protein in a dose-dependent manner, remodeling the resultant species. Furthermore, doxycycline interacts with tau microtubule-binding domain preventing its aggregation. In a cell free system doxycycline also prevents tau seeding and in cell culture reduces toxicity of tau aggregates. Overall, our results expand the spectrum of action of doxycycline against aggregation-prone proteins, opening novel perspectives for its repurposing as a disease-modifying drug for tauopathies.

Clinical psychological science is a field committed to reducing the negative impact of psychiatric illness through innovative research and psychological treatments. Unfortunately, the impact of racial injustices that pervade American society and permeate our academic institutions is felt not only by the individuals who work in our departments as faculty, staff, and students, but also by those who seek our services as mental health providers. Representing the collective work of numerous graduate students and postdoctoral trainees from multiple institutions, this call to action instantiates the need for prompt and consistent efforts towards dismantling institutionalized racism and inequity in clinical science. Specifically, we articulate the multiple roles our field plays in perpetuating racial oppression and outline concrete demands and recommendations for structural reform in the following key areas: (1) the mental health needs of Black, Indigenous, and People of Color (BIPOC) students, (2) clinical training and supervision, (3) curriculum and pedagogical approaches, (4) research and methods, and (5) the recruitment, retention, and success of graduate students and faculty.

Background: Over the last few years, microdeletions of the 22q11.2 region responsible for DiGeorge syndrome, or velocardiofacial syndrome, have been increasingly related to neuropsychiatric disorders including schizophrenia and bipolar disorders. These signs seem to be related to certain genes located in the hemideleted region as the proline dehydrogenase (PRODH) and the catecholo-methyltransferase (COMT) genes. The PRODH or proline oxidase deficiency is responsible for hyperprolinemia type 1 (HPI) also causing psychiatric manifestations. Case Report: We describe a 17 year old boy with previous mild psychomotor and speech delay, mild cognitive impairment, and obsessive behaviours who started his adolescent psychiatric care presenting irritablemood and aggressive behaviour with schizophrenia symptoms that scored a “severely ill” level PANSS assessment. Symptoms got worse when he was treated with valproic acid and plasma aminoacids showing increase in alanine and proline, suggested a mitochondrial involvement of the proline metabolic pathway. Results: Mild dysmorphia suggested a possible 22q11.2 deletion genetically confirmed involving both the PRODH and COMT regions. HPI that can present with psychiatric features is however a recessive disorder and therefore the symptoms could not be solely explained by this genetic deletion. Additional investigations also showed disclosed a p.L289m (c.1865 T > A) mutation in the PRODH gene. Discussion: We believe that the association of this mutation together with the 22q11.2 deletion would lead to a decrease of functional protein. Although it may be difficult to diagnosis chromosomal abnormalities in patients with no clear malformations and mild dysmorphic features as in this patient we emphasize need to investigate the aetiology in patients with psychiatric symptoms, especially if they have other systemic manifestations such as developmental delay or psychotic symptoms, as it may be important in the management of the patients.

A hiperglicinémia não cetótica é um erro inato da degradação da glicina, resultando na sua excessiva acumulação nos tecidos corporais, designadamente no sistema nervoso central. Trata-se de uma doença muito grave e uma das terapêuticas recentemente propostas consiste na associação do dextrometorfano com o benzoato de sódio em altas doses. Admite-se a possibilidade de o dextrometorfano bloquear o complexo-canal receptor de N-metil-D-aspartato, implicado na toxicidade da hiperglicinémia ao nível do cérebro e de o benzoato reduzir os níveis de glicina, pela sua conjugação e eliminação como hipurato. Relatamos dois casos clínicos de crianças com hiperglicinémia não cetótita, actualmente com mais de 15 meses de idade, as quais foram medicadas com dextrometorfano e benzoato de sódio desde as primeiras semanas após o parto. Não obstante se ter verificado sobrevivência para além do período neonatal e aquisição de autonomia respiratória, a evolução neurológica, até à data, não tem sido satisfatória, porventura devido ao atraso no início da terapêutica., Portuguese Journal of Pediatrics, Vol 31 No 3 (2000)

Item does not contain fulltext Currently, six inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature are known. The "Primary 3-methylglutaconic aciduria," 3-methylglutaconyl-CoA hydratase deficiency or AUH defect, is a disorder of leucine catabolism. For all other subtypes, also denoted "Secondary 3-methylglutaconic acidurias" (TAZ defect or Barth syndrome, SERAC1 defect or MEGDEL syndrome, OPA3 defect or Costeff syndrome, DNAJC19 defect or DCMA syndrome, TMEM70 defect, "not otherwise specified (NOS) 3-MGA-uria"), the origin of 3-methylglutaconic aciduria remains enigmatic but is hypothesized to be independent from leucine catabolism. Here we show the results of leucine loading test in 21 patients with different inborn errors of metabolism who present with 3-methylglutaconic aciduria. After leucine loading urinary 3-methylglutaconic acid levels increased only in the patients with an AUH defect. This strongly supports the hypothesis that 3-methylglutaconic aciduria is independent from leucine breakdown in other inborn errors of metabolism with 3-methylglutaconic aciduria and also provides a simple test to discriminate between primary and secondary 3-methylglutaconic aciduria in regular patient care.

Dye sensitized solar cells (DSCs) are governed by light absorption, charge injection, electron transport and recombination and electrolyte diffusion. One way to improve the efficiency of these devices is by the design of highly ordered nanostructured semiconductor materials.The advantages can be two-fold: Firstly charge transport within the metal-oxide can be enhanced and hence thicker films can be employed and secondly, the complete permeation with a solid-state hole-transport medium of the sensitized metal-oxide can be facilitated. Nanostructured materials should promote vectorial electron diffusion and have as few recombination sights as possible so as to further enhance electron lifetimes and electron collection efficiencies. These materials should also have a high surface area so as to allow for efficient dye-loading and hence light absorption. Highly ordered TiO2 nanostructured films were prepared by reactive sputtering and their charge transport characteristics evaluated in DSCs. These were compared to DSCs employing mesoporous TiO2 films prepared by doctor blade technique using commercial paste. Charge transport characteristics were evaluated by impedance spectroscopy (IS), incident photon to current conversion efficiencies (IPCE) and current-voltage (iV) curves under simulated AM1.5G irradiation. Film morphology and structural properties were evaluated by scanning electron microscopy (SEM) and X-ray diffraction (XRD), respectively.

Perylene monoimides or monoanhydrides are being intensively investigated as sensitizers in DSSCs. Keeping only one acceptor group, i.e. imide or anhydride, and introducing a donor group in the 9-position (such as diarylamine) proved to be important in order to obtain a favorable orbital partitioning strength and dipole moment of perylene compounds for DSSCs [1]. One way to control optical and electrochemical properties of perylenes dyes is achieved by functionalizing periand bay positions of perylene core with different substituents. In a simplified view, the peri groups coarsely tune the spectroscopic and electrochemical properties whereas the bay functional groups provide an additional fine tuning [2,3]. Here we report the design and synthesis of new perylene dyes (Figure 1) comprising: (1) a 4-alkoxyphenylamino moiety in the 9-position as a strong donating group, (2) a cyanoacrylic acid as electron acceptor and anchoring group and (3) a triple bond as short and rigid linker between perylene core and the acceptor group [4]. The photophysical properties (i.e. absorption and emission spectra, absorption extinction coefficients, fluorescence quantum yields and lifetime measurements) and electrochemical properties of the new perylene dyes were investigated and all results will be presented and discussed.

Dye sensitized solar cells (DSC’s) have received considerable attention once this technology offers economic and environmental advantages over conventional photovoltaic (PV) devices. A DSC photoanode typically consists of a nanocrystalline porous TiO2 film, endowed with a large adsorptive surface area. Dye molecules that capture photons during device operation are attached to the film nanoparticles. The effective loading of the dye in the TiO2 electrode is of paramount relevance for controlling and optimizing solar cell parameters. In particular, the cell shortcircuit current density (Jsc) is directly proportional to the light harvesting ability of the photoanode, which in turn is strictly dependent on the dye concentration on the TiO2 adsorptive surface. In addition, the dye adsorption behavior affects the cell open circuit voltage (Voc). Relatively few methods are known today for quantitative evaluation of the total dye adsorbed in the film. In this context microprobe techniques come out as suitable tools to evaluate the dye distribution and dye depth profile in sensitized films. Electron Probe Microanalysis (EPMA) and Ion Beam Analytical (IBA) techniques using a micro-ion beam were used to quantify and to study the distribution of the ruthenium organometallic (N719) dye in TiO2 films, making use of their different penetration depth and beam sizes. Two different types of films were prepared and sensitized, mesoporous nanoparticles and 1D nanostructured TiO2 films (about 4 ìm thickness). The high sensitive analytical techniques used allowed to assess dye surface distribution and depth profile, by means of Ru signal, despite the low concentration of this element. X-ray mapping by EPMA/WDS technique made possible to visualise the dye distribution in sample cross-section. PIXE maps of Ru and Ti indicated an homogeneous surface distribution. The assessment of ruthenium depth profile by RBS showed that some films have homogeneous Ru depth distribution while others presented up to half of the Ru concentration in the top layer (2 ìm thickness) when compared to the lower one. Dye load evaluation in different TiO2 films by two different techniques (ìPIXE and EPMA/WDS) provided similar results of Ru/Ti. The assessment of the dye distribution and quantification across an oxide semiconductor film by microprobe techniques can lead to a better understanding of the device performance.

A síndrome de Smith-Lemli-Opitz (SLOS) é uma síndrome polimalformativa de transmissão autossómica recessiva causada por um défice metabólico da biossíntese do colesterol, que se caracteriza por dismorfias craniofaciais, anomalias congénitas de vários órgãos (salientando-se as do esqueleto e do aparelho urogenital), restrição de crescimento intra-uterino (RCIU), alterações comportamentais e atraso mental. É causada por mutações no gene DHCR7, que codifica para a enzima 7-dehidrocolesterol reductase, responsável pelo último passo da via metabólica da síntese do colesterol. A SLOS caracteriza-se por níveis diminuídos de colesterol e concentrações altas do seu precursor, 7-dehidrocolesterol, no sangue e tecidos. Procedeu-se a uma análise comparativa dos fenótipo e genótipo de quinze casos de SLOS de origem portuguesa, e são tecidas considerações quanto às dificuldades e limitações inerentes ao diagnóstico, e ao facto de esta doença hereditária do metabolismo dever ser considerada no diagnóstico diferencial das situações de (i) hipocolesterolémia, (ii) RCIU e (iii) síndromes polimalformativas,(especialmente quando crianças com atraso de crescimento apresentam simultaneamente sindactilia do segundo e terceiro dedos do pé e microcefalia e/ou narinas antevertidas entre outras anomalias).

A Dislipidemia Familiar Combinada (FCHL) é uma doença poligénica caracterizada por hiperlipidemia simples ou combinada, variabilidade intra-individual e intra-familiar do perfil lipídico, ApoB elevada (> 120 mg/dL) e risco elevado de doença cardiovascular (DCV). A sua causa é desconhecida mas alterações nos genes LPL, APOAIV, APOAV, APOCIII e USF1 parecem contribuir para o seu fenótipo. O objectivo deste estudo é caracterizar bioquímica e molecularmente doentes com diagnóstico clínico de FCHL. Todos os exões e promotor dos genes LPL, APOAIV, APOAV, APOCIII e regiões do gene USF1 (s1,s2) de 41 doentes foram amplificados por PCR e sequenciados. O colesterol total (CT), c-LDL, c-HDL, sdLDL, trigliceridos (TG), apoB e apoCIII foram determinados num aparelho automatizado. Em alguns doentes as sdLDL foram também analisadas por electroforese de lipoproteínas. A ApoAIV e ApoAV foram quantificadas por ELISA. Foram encontradas alterações genéticas em 37 doentes, 3 não descritas (APOAIV Q359_E362, APOAV D332fsX336 e APOCIII 3269C>A). O índex com a alteração Q359_E362del apresentou valores normais de apo AIV (15.5 mg/dL) e o índex com a alteração D332fsX336 apresentou valores baixos de apo AV (74.5 ng/mL). Os doentes estudados apresentam valores elevados de CT (285 ± 83 mg/dL), c-LDL (189 ± 85 mg/dL), TG (310 ± 253 mg/dL), e apo CIII (15 ± 4 mg/dL) e valores reduzidos de c-HDL (45 ± 11 mg/dL), sem medicação. Os valores de apoAIV (17,5 ± 10,4 mg/dL) e apoAV (150 ± 135 ng/mL) encontram-se, na maioria dos casos, no intervalo normal assim como os valores de sdLDL (35 ± 18 mg/dL), no entanto alguns casos apresentam valores acima do cut-off para DCV (35 mg/dL). A análise de sdLDL por electroforese foi realizada em 11 doentes, 9 dos quais apresentaram um perfil aterogénico. O valor médio de ApoB destes doentes era de 94 ± 43 mg/dL, mas aproximadamente 70% dos doentes estavam medicados com terapêutica hipolimiante (estatinas e/ou fibratos). Cerca de 30% dos doentes apresentavam DCV prematura. Os resultados obtidos parecem indicar que alterações nos genes estudados influenciam o fenótipo da FCHL. Os níveis séricos de apo CIII encontram-se alterados nesta dislipidemia. Doentes com FCHL, apesar de estarem medicados, apresentam valores elevados de sdLDL, evidenciando o seu elevado risco cardiovascular. A caracterização bioquímica complementa a identificação genética e permite uma melhor avaliação do risco cardiovascular do doente bem como a escolha de uma terapêutica adequada.

Resumo: As doenças do ciclo da ureia são o resultado do défice enzimático de uma das enzimas que compõem a via metabólica de excreção do azoto. Com a excepção do défice na transcarbamilase da ornitina, que está ligado ao cromossoma X, todas as doenças são autossómicas recessivas. A apresentação clínica destas doenças pode ocorrer no período neonatal, durante a infância ou mesmo na adolescência ou idade adulta. A hiperamoniemia, as alterações urinárias e plasmáticas dos aminoácidos e ácidos orgânicos, constituem os principais marcadores bioquímicos das doenças do ciclo da ureia. O tratamento nutricional baseia-se na implementação de uma dieta restrita em proteína natural e suplementada com uma mistura de aminoácidos essenciais. O aporte proteico tem de ser constantemente ajustado em função do controlo metabólico, da avaliação antropométrica e da medicação usada para explorar as vias alternativas de excreção do azoto. A monitorização do estado nutricional assume uma importância crucial no seguimento destes doentes, de modo a melhor aferir as suas reais necessidades, prevenindo a insuficiência proteica, a qual poderá afectar negativamente o crescimento e desenvolvimento.

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