Vitamin D and autoimmunity in the Portuguese population

A vitamina D é única entre as vitaminas pois trata-se de uma verdadeira hormona, à qual tem sido atribuída grande importância na homeostasia do sistema imune, para lá do seu reconhecido papel no metabolismo fosfocálcico. A ampla expressão do seu recetor (VDR), e os numerosos locais de ligação deste em todo o genoma, dão suporte a essa hipótese. Alguns polimorfismos do gene do VDR têm sido associados com doenças autoimunes. Na população portuguesa, demonstramos que o polimorfismo Fok I do VDR está associado à esclerose múltipla (EM), e à gravidade da doença no lúpus eritematoso sistémico (LES). Os baixos níveis séricos de vitamina D também estão associados com um risco aumentado de desenvolver doenças autoimunes como o LES, a EM e a artrite reumatoide. A insuficiência de vitamina D é muito comum em Portugal, podendo afetar entre os 60% e os 95% da população em função da estação do ano e do índice de massa corporal. O desenvolvimento de estratégias para o rastreio da deficiência de vitamina D é crucial, particularmente em grupos de risco. Não existem ainda, no entanto, evidências suficientes que possibilitem emitir recomendações claras e bem fundamentadas para a suplementação de vitamina D como medida preventiva de doenças crónicas, tendo em conta os riscos e benefícios inerentes.Vitamin D is unique among vitamins, as it represents a real hormone to which great impor tance in the homeostasis of the immune system has been ascribed, beyond its known role in phosphocalcic metabolism. The wide expression of its receptor (VDR), and the numerous binding sites for this receptor along the genome suppor t this hypothesis. Some well known VDR polymorphisms have been associated with autoimmune disease susceptibility. In the Por tuguese population, we have shown that the VDR Fok I polymorphism is associated with multiple sclerosis (MS), and with disease severity in systemic lupus er y thematosus (SLE). Low vitamin D serum levels are also associated with an increased risk of developing autoimmune diseases such as SLE, MS and rheumatoid ar thritis. Vitamin D insuf ficiency is ex tremely common in Por tugal, and can af fect 60% to 85% of the population, depending on the season of the year and body-mass index. The development of screening strategies for vitamin D deficiency is needed, par ticularly for high-risk individuals. However, sufficient evidences are not yet available to make it possible to provide clear and well founded recommendations for the use of vitamin D supplementation in the prevention of chronic disease, taking into account the inherent risks and benefits.info:eu-repo/semantics/publishedVersio

Usefulness of genetic characterization of narcolepsy and hypersomnia on phenotype definition: a study in Portuguese patients

The determination of human leukocyte antigen (HLA) class II genotype is widely used to confirm the diagnosis of narcolepsy with or without cataplexy. The HLA genotyping is reliable, easy to perform and reassures the clinician. It is also less invasive than other methodologies and is in accordance with the autoimmune hypothesis for the origin of narcolepsy. AIM. To assess the usefulness of genetic markers (HLA) in the differential diagnosis between different sleep disorders and their relevance in the context of our population

A perspectiva arquipelágica: Açores

"[…]. Dada a inexistência de um catálogo nacional ou regional de espécies ameaçadas, e considerando que muitas das espécies endémicas dos Açores, raras e sujeitas a várias ameaças, não se encontram abrangidas por directivas e convenções internacionais, nem foram alvo de avaliação por nenhum tipo de critérios (IUCN ou outros), houve necessidade de uma definição de prioridades em termos de acções de conservação baseada numa fundamentação tanto quanto possível clara e objectiva. Nesse sentido, a lista agora apresentada permite-nos realizar uma análise de prioridades para os Açores. Com base nos mesmos critérios e pontuações já referidos em capítulos anteriores, organizou-se o Top 100 dos Açores, listagem que permitirá a prioritização de esforços e recursos (humanos, financeiros ou outros) a nível regional de forma objectiva, previamente acordada entre os intervenientes (gestores e cientistas). Pretende-se assim diminuir a subjectividade que, mais frequentemente do que é em geral admitido, está inerente à atribuição de recursos para a conservação do nosso património natural." [da Introdução

Fine mapping and conditional analysis identify a new mutation in the autoimmunity susceptibility gene BLK that leads to reduced half-life of the BLK protein

OBJECTIVES: To perform fine mapping of the autoimmunity susceptibility gene BLK and identify functional variants involved in systemic lupus erythematosus (SLE). METHODS: Genotyping of 1163 European SLE patients and 1482 controls and imputation were performed covering the BLK gene with 158 single-nucleotide polymorphisms. Logistic regression analysis was done using PLINK and conditional analyses using GENABEL's test score. Transfections of BLK constructs on HEK293 cells containing the novel mutation or the wild type form were analysed for their effect on protein half-life using a protein stability assay, cycloheximide and western blot. CHiP-qPCR for detection of nuclear factor κ B (NFkB) binding. RESULTS: Fine mapping of BLK identified two independent genetic effects with functional consequences: one represented by two tightly linked associated haplotype blocks significantly enriched for NFκB-binding sites and numerous putative regulatory variants whose risk alleles correlated with low BLK mRNA levels. Binding of NFkBp50 and p65 to an associated 1.2 Kb haplotype segment was confirmed. A second independent genetic effect was represented by an Ala71Thr, low-frequency missense substitution with an OR=2.31 (95% CI 1.38 to 3.86). The 71Thr decreased BLK protein half-life. CONCLUSIONS: These results show that rare and common regulatory variants in BLK are involved in disease susceptibility and both, albeit independently, lead to reduced levels of BLK protein

HFE variants and the expression of iron-related proteins in breast cancer-associated lymphocytes and macrophages

Disponível em: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5264664/The association of HFE (High Iron FE) major variants with breast cancer risk and behavior has been a matter of discussion for a long time. However, their impact on the expression of iron-related proteins in the breast cancer tissue has never been addressed. In the present study, hepcidin, ferroportin 1, transferrin receptor 1 (TfR1), and ferritin expressions, as well as tissue iron deposition were evaluated in a collection of samples from breast cancers patients and analyzed according to the patients’ HFE genotype. Within the group of patients with invasive carcinoma, those carrying the p.Cys282Tyr variant in heterozygosity presented a higher expression of hepcidin in lymphocytes and macrophages than wild-type or p.His63Asp carriers. An increased expression of TfR1 was also observed in all the cell types analyzed but only in p.Cys282Tyr/p.His63Asp compound heterozygous patients. A differential impact of the two HFE variants was further noticed with the observation of a significantly higher percentage of p.Cys282Tyr heterozygous patients presenting tissue iron deposition in comparison to p.His63Asp heterozygous. In the present cohort, no significant associations were found between HFE variants and classical clinicopathological markers of breast cancer behavior and prognosis. Although limited by a low sampling size, our results provide a new possible explanation for the previously reported impact of HFE major variants on breast cancer progression, i.e., not by influencing systemic iron homeostasis but rather by differentially modulating the local cellular expression of iron-related proteins and tissue iron deposition.OM is a recipient of the PhD grant SFRH/BD/2011/78184 from Fundação para a Ciência e Tecnologia (FCT). The authors also acknowledge financial support from ICBAS/AI&NSUMIB and by national funds through FCT and Ministério da Educação e Ciência (MEC) and when applicable co-funded by FEDER funds within the partnership agreement PT2020 related with the research unit number 4293.info:eu-repo/semantics/publishedVersio

Local iron homeostasis in the breast ductal carcinoma microenvironment

Abstract BACKGROUND: While the deregulation of iron homeostasis in breast epithelial cells is acknowledged, iron-related alterations in stromal inflammatory cells from the tumor microenvironment have not been explored. METHODS: Immunohistochemistry for hepcidin, ferroportin 1 (FPN1), transferrin receptor 1 (TFR1) and ferritin (FT) was performed in primary breast tissues and axillary lymph nodes in order to dissect the iron-profiles of epithelial cells, lymphocytes and macrophages. Furthermore, breast carcinoma core biopsies frozen in optimum cutting temperature (OCT) compound were subjected to imaging flow cytometry to confirm FPN1 expression in the cell types previously evaluated and determine its cellular localization. RESULTS: We confirm previous results by showing that breast cancer epithelial cells present an 'iron-utilization phenotype' with an increased expression of hepcidin and TFR1, and decreased expression of FT. On the other hand, lymphocytes and macrophages infiltrating primary tumors and from metastized lymph nodes display an 'iron-donor' phenotype, with increased expression of FPN1 and FT, concomitant with an activation profile reflected by a higher expression of TFR1 and hepcidin. A higher percentage of breast carcinomas, compared to control mastectomy samples, present iron accumulation in stromal inflammatory cells, suggesting that these cells may constitute an effective tissue iron reservoir. Additionally, not only the deregulated expression of iron-related proteins in epithelial cells, but also on lymphocytes and macrophages, are associated with clinicopathological markers of breast cancer poor prognosis, such as negative hormone receptor status and tumor size. CONCLUSIONS: The present results reinforce the importance of analyzing the tumor microenvironment in breast cancer, extending the contribution of immune cells to local iron homeostasis in the tumor microenvironment context.info:eu-repo/semantics/publishedVersio

Práticas artísticas no ensino básico e secundário

Sobre a Matéria-Prima, há novidades e perigos. O tempo vivido na Europa e no contexto global tem vindo a acentuar a urgência das prioridades quantificadas, com um discurso dominante onde há menos política (pessoas) e mais representação económica (coisas). O correlato entre pessoas e coisas é, como sabemos, o dinheiro, ou trabalho reificado. A crise europeia, em torno da dívida soberana e dos maiores orçamentos do mundo, da capacidade da sua gestão na linguagem dura dos mercados e das taxas de juro veio modificar os objetivos imediatos da Europa, que em 2000 eram ambiciosos — “a sociedade mais competitiva do mundo em 2010” — para uma estratégia de emergência, agora chamada horizonte 2020. Este é o panorama ideal para colocar o ensino artístico em risco. Os fóruns internacionais passaram a valorizar os resultados da educação em rankings e sondagens de aproveitamento, cuja principal estratégia e preocupação é a mensurabilidade e comparabilidade, como são exemplo os relatórios PISA: avaliam-se em todos os países, as competências em Ciências, Matemática e Língua Materna. A matéria-prima de amanhã corre riscos de desaparecer gradualmente, pelos cortes de carga horária, pela concepção extracurricular da educação artística, pela sua perceção menorizada em função das concepções competitivas da sociedade contemporânea globalizada.info:eu-repo/semantics/publishedVersio

Nodal signaling regulates germ cell development and establishment of seminiferous cords in the human fetal testis

Summary: Disruption of human fetal testis development is widely accepted to underlie testicular germ cell cancer (TGCC) origin and additional disorders within testicular dysgenesis syndrome (TDS). However, the mechanisms for the development of testicular dysgenesis in humans are unclear. We used ex vivo culture and xenograft approaches to investigate the importance of Nodal and Activin signaling in human fetal testis development. Inhibition of Nodal, and to some extent Activin, signaling disrupted seminiferous cord formation, abolished AMH expression, reduced androgen secretion, and decreased gonocyte numbers. Subsequent xenografting of testicular tissue rescued the disruptive effects on seminiferous cords and somatic cells but not germ cell effects. Stimulation of Nodal signaling increased the number of germ cells expressing pluripotency factors, and these persisted after xenografting. Our findings suggest a key role for Nodal signaling in the regulation of gonocyte differentiation and early human testis development with implications for the understanding of TGCC and TDS origin. : Jørgensen et al. determine the role of Nodal signaling in human fetal testis development using ex vivo culture and xenografting approaches. They provide insights into the involvement of Nodal signaling in seminiferous cord formation and the regulation of pluripotency factor expression in fetal gonocytes, with implications for the development of testicular cancer. Keywords: Nodal, Activin, human fetal testis, testicular germ cell cancer, testicular dysgenesis syndrome, ex vivo culture, xenografting, testicular development, gonocytes, pluripotency factor

Fitting the integrated Spectral Energy Distributions of Galaxies

Fitting the spectral energy distributions (SEDs) of galaxies is an almost universally used technique that has matured significantly in the last decade. Model predictions and fitting procedures have improved significantly over this time, attempting to keep up with the vastly increased volume and quality of available data. We review here the field of SED fitting, describing the modelling of ultraviolet to infrared galaxy SEDs, the creation of multiwavelength data sets, and the methods used to fit model SEDs to observed galaxy data sets. We touch upon the achievements and challenges in the major ingredients of SED fitting, with a special emphasis on describing the interplay between the quality of the available data, the quality of the available models, and the best fitting technique to use in order to obtain a realistic measurement as well as realistic uncertainties. We conclude that SED fitting can be used effectively to derive a range of physical properties of galaxies, such as redshift, stellar masses, star formation rates, dust masses, and metallicities, with care taken not to over-interpret the available data. Yet there still exist many issues such as estimating the age of the oldest stars in a galaxy, finer details ofdust properties and dust-star geometry, and the influences of poorly understood, luminous stellar types and phases. The challenge for the coming years will be to improve both the models and the observational data sets to resolve these uncertainties. The present review will be made available on an interactive, moderated web page (sedfitting.org), where the community can access and change the text. The intention is to expand the text and keep it up to date over the coming years.Comment: 54 pages, 26 figures, Accepted for publication in Astrophysics & Space Scienc

Transancestral mapping and genetic load in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (∼50% of these regions have multiple independent associations); these include 24 novel SLE regions (P<5 × 10-8), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE