Transthyretin is not necessary for thyroid hormone metabolism in conditions of increased hormone demand

Thyroid hormones circulate in blood mainly bound to plasma proteins. Transthyretin is the major thyroxine plasma carrier in mice. Studies in transthyretin-null mice revealed that the absence of transthyretin results in euthyroid hypothyroxinemia and normal thyroid hormone tissue distribution, with the exception of the choroid plexus in the brain. Therefore, transthyretin does not influence normal thyroid hormone homeostasis under standard laboratory conditions. To investigate if transthyretin has a buffer/storage role we challenged transthyretin-null and wild-type mice with conditions of increased hormone demand: (i) exposure to cold, which elicits thermogenesis, a process that requires thyroid hormones; and (ii) thyroidectomy, which abolishes thyroid hormone synthesis and secretion and induces severe hypothyroidism. Transthyretin-null mice responded as the wild-type both to changes induced by stressful events, namely in body weight, food intake and thyroid hormone tissue content, and in the mRNA levels of genes whose expression is altered in such conditions. These results clearly exclude a role for transthyretin in thyroid hormone homeostasis even under conditions of increased hormone demand.POCTI/NSE/37315/2001, from Fundação para a Ciência e Tecnologia (Portugal) and FEDER; J C S is a recipient of a PhD fellowship from Fundação para a Ciência e Tecnologia (Portugal

Magnetic/plasmonic MnFe2O4/Au nanoparticles covered with lipid bilayers for applications in thermotherapy

In this work, three different types of magnetic/plasmonic nanoparticles were prepared: core-shell nanoparticles with a manganese ferrite core and a gold shell; plasmonic gold nanoparticles decorated with magnetic nanoparticles of manganese ferrite; and magnetic nanoparticles of manganese ferrite decorated with plasmonic gold nanoparticles. The structural, spectroscopic and magnetic properties of these nanoparticles were evaluated. In order to further develop applications in cancer therapy, the prepared mixed nanoparticles were covered with a lipid bilayer. The local heating capability of these nanosystems was tested through the quenching of rhodamine fluorescence incorporated in the lipid layer.Financial support by the Portuguese Foundation for Science and Technology (FCT) in the framework of the Strategic Funding UID/FIS/04650/2013. A.R.O Rodrigues thanks the FCT for SFRH/BD/90949/2012 PhD grant and funding to MAP-Fis Doctoral Program.info:eu-repo/semantics/publishedVersio

Synthesis of benzoazole ionic liquids and evaluation of their antimicrobial activity

A new class of chemicals composed not of molecules but ions, an organic cation and an organic or inorganic anion, has recently attracted attention. When these new kind of salts are in the liquid state below 100 oC, they are named ionic liquids (ILs). In this work, the synthesis of ionic liquids obtained from a 2-mercaptobenzimidazole, 2-mercaptobenzoxazole or 2-mercaptobenzothiazole anion and 1-alkyl-3-methylimidazolium or choline cation are described. The antimicrobial activity against several Gram-positive and Gram-negative bacteria and a yeast was also evaluated

Glucosylpolyphenols as Inhibitors of Aβ-Induced Fyn Kinase Activation and Tau Phosphorylation: Synthesis, Membrane Permeability, and Exploratory Target Assessment within the Scope of Type 2 Diabetes and Alzheimer's Disease

Despite the rapidly increasing number of patients suffering from type 2 diabetes, Alzheimer's disease, and diabetes-induced dementia, there are no disease-modifying therapies that are able to prevent or block disease progress. In this work, we investigate the potential of nature-inspired glucosylpolyphenols against relevant targets, including islet amyloid polypeptide, glucosidases, and cholinesterases. Moreover, with the premise of Fyn kinase as a paradigm-shifting target in Alzheimer's drug discovery, we explore glucosylpolyphenols as blockers of Aβ-induced Fyn kinase activation while looking into downstream effects leading to Tau hyperphosphorylation. Several compounds inhibit Aβ-induced Fyn kinase activation and decrease pTau levels at 10 μM concentration, particularly the per-O-methylated glucosylacetophloroglucinol and the 4-glucosylcatechol dibenzoate, the latter inhibiting also butyrylcholinesterase and β-glucosidase. Both compounds are nontoxic with ideal pharmacokinetic properties for further development. This work ultimately highlights the multitarget nature, fine structural tuning capacity, and valuable therapeutic significance of glucosylpolyphenols in the context of these metabolic and neurodegenerative disorders.European Commission GA 612347Fundação para a Ciência e a Tecnologia SFRH/BD/93170/2013, SFRH/BD/116614/2016, PD/BD/142847/2018, SFRH/BD/145600/2019, CEECIND/03414/2018, CEECIND/02300/2017, UIDB/00100/2020, UIDB/04046/2020, UIDB/04378/2020, IF/00780/2015Gobierno de España CTQ2016-78703-PJunta de Andalucía FQM13

A busca ativa de tuberculose pulmonar em Teresópolis, RJ, Brasil: a procura de sintomáticos respiratórios na emergência do Hospital das Clínicas de Teresópolis Costantino Ottaviano, Fundação Educacional Serra dos Órgãos

The aim of the present study was to investigate the detection percentage of tuberculosis among patients that are respiratory symptomatic (TB suspects). In this work, we present the preliminary results of research carried out at "Hospital das Clínicas de Teresópolis Costantino Ottaviano da Fundação Educacional Serra dos Órgãos (FESO)" from November 2003 to April 2004. Among the 40 respiratory symptomatic individuals identified and referred to the Tuberculosis Control Program in Teresópolis, two (5.0%) were characterized as smear-positive. These results confirm reports in the literature and underscore the need for and importance of this strategy.Investigar o percentual de detecção de tuberculose entre sintomáticos respiratórios é o objetivo do presente estudo. Nesta nota prévia, apresentam-se os resultados preliminares da pesquisa desenvolvida no Hospital das Clinicas de Teresópolis Costantino Ottaviano da Fundação Educacional Serra dos Órgãos (FESO), de novembro de 2003 a abril de 2004. Dos 40 sintomáticos respiratórios identificados e encaminhados ao Programa de Controle da Tuberculose do município de Teresópolis, dois (5.0%) foram caracterizados como bacilíferos. Esses resultados corroboram com os relatos da literatura e confirmam a necessidade e importância desta estratégia

Differential Temporal Dynamics of Axial and Appendicular Ataxia in SCA3

Background: Disease severity in spinocerebellar ataxia type 3 (SCA3) is commonly defined by the Scale for the Assessment and Rating of Ataxia (SARA) sum score, but little is known about the contributions and progression patterns of individual items. Objectives: To investigate the temporal dynamics of SARA item scores in SCA3 patients and evaluate if clinical and demographic factors are differentially associated with evolution of axial and appendicular ataxia. Methods: In a prospective, multinational cohort study involving 11 European and 2 US sites, SARA scores were determined longitudinally in 223 SCA3 patients with a follow-up assessment after 1 year. Results: An increase in SARA score from 10 to 20 points was mainly driven by axial and speech items, with a markedly smaller contribution of appendicular items. Finger chase and nose-finger test scores not only showed the lowest variability at baseline, but also the least deterioration at follow-up. Compared with the full set of SARA items, omission of both tests would result in lower sample size requirements for therapeutic trials. Sex was associated with change in SARA sum score and appendicular, but not axial, subscore, with a significantly faster progression in men. Despite considerable interindividual variability, the average annual progression rate of SARA score was approximately three times higher in subjects with a disease duration over 10 years than in those within 10 years from onset. Conclusion: Our findings provide evidence for a difference in temporal dynamics between axial and appendicular ataxia in SCA3 patients, which will help inform the design of clinical trials and development of new (etiology-specific) outcome measures. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.Funding agencies: This publication is an outcome of ESMI, an EU Joint Programme — Neurodegenerative Disease Research (JPND) Project (www.jpnd.eu). The project is supported through the following funding organizations under the aegis of JPND: Germany, Federal Ministry of Education and Research (BMBF; funding codes 01ED1602A/B); Netherlands, The Netherlands Organization for Health Research and Development; Portugal, Foundation for Science and Technology and Regional Fund for Science and Technology of the Azores; United Kingdom, Medical Research Council. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 643417. At the United States sites this work was in part supported by the National Ataxia Foundation.Spinocerebellar ataxia type 3Natural historyScale for the Assessment and Rating of AtaxiaDisease progressio

Estratégia institucional para a gestão dos dados de investigação: estudo e recomendações

O presente relatório apresenta o estudo e as recomendações para o desenvolvimento de uma estratégia institucional na Universidade do Minho para a gestão de dados de investigação. O relatório foi preparado pelo grupo de trabalho nomeado pelo Senhor Reitor da UMinho a 12 de abril de 2017 no despacho nº RT-27/2017. O Grupo iniciou os seus trabalhos no mês de maio com o mandato de “produzir um estudo e recomendações que sustentem a formulação de uma estratégia institucional relativa aos dados de investigação, incluindo a identificação de políticas, infraestruturas e serviços para a gestão dos dados de investigação na UMinho”. A metodologia adotada passou pela realização de duas reuniões presenciais, correspondendo às duas fases do trabalho – inicialmente diagnóstico e posteriormente desenho de soluções e formulação de recomendações –, e pela redação deste documento, de forma assíncrona e não presencial. O relatório reflete a metodologia adotada e encontra-se estruturado em duas partes: 1ª) estudo e análise e 2ª) recomendações. Para a primeira parte, o grupo de trabalho tomou como base o estudo realizado em 2014 pelos Serviços de Documentação da UMinho (SDUM) que fornece informação relevante sobre os dados gerados no âmbito da investigação realizada na UMinho e sobre as práticas de gestão desses dados. Esta parte do estudo foi complementada com a análise dos primeiros resultados do programa de diagnóstico iniciado pelos SDUM e aplicado a seis comunidades piloto no primeiro semestre de 2017 com o intuito de caracterizar os processos de gestão dos dados e avaliar papéis e responsabilidade associados. Neste relatório analisam-se ainda as políticas para dados dos financiadores de ciência e inovação, com particular enfoque para os requisitos dos dados de investigação abertos no Horizonte 2020 e princípios FAIR para a gestão de dados. Reflete-se ainda sobre a Política Nacional de Ciência Aberta e o desenvolvimento de estratégias institucionais nas universidades. A secção prospetiva do presente relatório apresenta recomendações estruturadas em cinco tópicos: 1) Política, 2) Infraestrutura e sistemas para dados, 3) Serviços e ferramentas de apoio à gestão dos dados, 4) Capacitação e 5) Questões legais, de proteção de dados e de propriedade intelectual. O relatório desenvolve os componentes e detalhes das seguintes recomendações: 1. Definição de uma política institucional da Universidade do Minho relativa à gestão e partilha dos dados de investigação. 2. Disponibilização de uma infraestrutura de sistemas e serviços integrados a disponibilizar à comunidade da UMinho para a gestão de dados ao longo do ciclo de vida da investigação. 3. Criação de ferramentas de apoio à gestão de dados que assegurem a interligação e utilização dos componentes da infraestrutura institucional de dados. 4. Desenvolvimento de ações e programas integrados que promovam e valorizem as competências dos investigadores em matéria de gestão e partilha de dados de investigação. 5. Disponibilização e reforço de serviços de apoio e consultoria no domínio da proteção de dados, licenciamento e reutilização de dados e propriedade intelectual

Immunophenotype of Gastric Tumors Unveils a Pleiotropic Role of Regulatory T Cells in Tumor Development.

Gastric cancer (GC) patients display increased regulatory T cell (Tregs) numbers in peripheral blood and among tumor-infiltrating lymphocytes. Nevertheless, the role of Tregs in GC progression remains controversial. Here, we sought to explore the impact of Tregs in GCs with distinct histology, and whether Tregs can directly influence tumor cell behavior and GC development. We performed a comprehensive immunophenotyping of 82 human GC cases, through an integrated analysis of multispectral immunofluorescence detection of T cells markers and patient clinicopathological data. Moreover, we developed 3D in vitro co-cultures with Tregs and tumor cells that were followed by high-throughput and light-sheet imaging, and their biological features studied with conventional/imaging flow cytometry and Western blotting. We showed that Tregs located at the tumor nest were frequent in intestinal-type GCs but did not associate with increased levels of effector T cells. Our in vitro results suggested that Tregs preferentially infiltrated intestinal-type GC spheroids, induced the expression of IL2Rα and activation of MAPK signaling pathway in tumor cells, and promoted spheroid growth. Accumulation of Tregs in intestinal-type GCs was increased at early stages of the stomach wall invasion and in the absence of vascular and perineural invasion. In this study, we proposed a non-immunosuppressive mechanism through which Tregs might directly modulate GC cells and thereby promote tumor growth. Our findings hold insightful implications for therapeutic strategies targeting intestinal-type GCs and other tumors with similar immune context

Individual common variants exert weak effects on the risk for autism spectrum disorders.

While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest