A mechanistic perspective on pex1 and pex6, two aaa+ proteins of the peroxisomal protein import machinery

In contrast to many protein translocases that use ATP or GTP hydrolysis as the driving force to transport proteins across biological membranes, the peroxisomal matrix protein import machinery relies on a regulated self-assembly mechanism for this purpose and uses ATP hydrolysis only to reset its components. The ATP-dependent protein complex in charge of resetting this machinery—the Receptor Export Module (REM)—comprises two members of the “ATPases Associated with diverse cellular Activities” (AAA+) family, PEX1 and PEX6, and a membrane protein that anchors the ATPases to the organelle membrane. In recent years, a large amount of data on the structure/function of the REM complex has become available. Here, we discuss the main findings and their mechanistic implications.This work was financed by FEDER—Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020—Operacional Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by Portuguese funds through FCT—Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Ensino Superior in the framework of the project PTDC/BEX-BCM/2311/2014 (POCI-01-0145-FEDER-016613) and the project “Institute for Research and Innovation in Health Sciences” (POCI-01-0145-FEDER-007274). This work is a result of the project NORTE-01-0145-FEDER-000008—Porto Neurosciences and Neurologic Disease Research Initiative at I3S, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (FEDER). A.B.-B., A.G.P., M.J.F., T.F. and T.A.R. are supported by Fundação para a Ciência e Tecnologia, Programa Operacional Potencial Humano do QREN, and Fundo Social Europeu

Atividades de estudo e investigação para a construção de modelos de pirâmides tringulares

Neste artigo, os autores têm como objetivo fazer uma reflexão a respeito da razão de ser do ensino de planificação de superfícies de sólidos geométricos, para construção de modelos, partindo de um estudo matemático já realizado a fim de propor Atividades de Estudo e Investigação – AEI, no sentido de Chevallard. Este estudo, prioritariamente de cunho teórico, foca no significado que alunos do ensino básico poderão construir, especificamente, na construção do modelo para uma pirâmide triangular a partir da planificação de sua superfície. Para o desenvolvimento dessa reflexão, utilizamos o software Geogebra como ferramenta para a construção do modelo, por permitir a manipulação da construção geométrica realizada e levantar conjecturas e, ainda, a produção de modelos de diversos tipos. Por outro lado, possibilita ao professor ampliar discussões a respeito de planificações, tanto para outros conteúdos, como é o caso da medida de volumes, quanto para outros tipos de sólidos

Um modelo epistemológico de referência para o estudo da planificação de superfícies de pirâmides triangulares

Retomamos neste artigo um anteriormente publicado no sentido de ampliar as discussões lá propostas analisando a situação a partir de outro referencial. Trata-se da apresentação de um Modelo Epistemológico de Referência (MER) para a construção, no Geogebra, de planificações de superfícies de pirâmides triangulares de altura determinada, verificando condições e restrições para a referida construção. Tal MER pode justificar organizações didáticas que promovam Atividades de Estudo e Pesquisa (PEP) desenvolvidas a partir de questionamentos realizados durante a atividade que conduzirão a resolução do problema proposto. Um dos objetivos do estudo é proporcionar uma razão de ser para o trabalho com a representação plana de sólidos geométricos

As Operações com Números Racionais e seus Significados a partir da Concepção Parte-todo

We present a reflection regarding operations with fractional numbers focusing on the part-all conception through some activities that can contribute to teaching practices at the elementary school level. A brief characterization of the all-part conception is provided along with descriptions of activities involving the four basic operations based on the use of flat figures, although other conceptions may emerge during the solution. We limit our considerations to this conception because it is the most frequent, in textbooks as well as teacher practice, although it is not used to justify operational rules of fractional numbers. Key-words: Fractions. Fractional Numbers. Operations.Neste artigo, apresentamos uma reflexão a respeito das operações com números fracionários focalizando a concepção parte-todo por meio de algumas atividades que possam contribuir para a prática docente na escola básica. O estudo explicita uma breve caracterização da concepção parte-todo e atividades envolvendo as quatro operações fundamentais tratadas em figuras planas, embora outras concepções possam ser mobilizadas durante a solução. Restringimos nossas considerações a essa concepção visto ser a mais freqüente, tanto em livros didáticos, quanto na prática do professor, embora não seja utilizada para justificar as regras operatórias dos números fracionários. Palavras-chave: Frações. Números Fracionários. Operações

Comparison Between Maximum Inspiratory Pressure Measured By A Digital Manometer And By An Electronic Inspiratory Muscle Training Device

To compare maximum inspiratory pressure (MIP) measured by a digital manometer and by an inspiratory muscle training (IMT) device and to evaluate hemodynamic changes after measurements. Methods: The sample included male and female individuals older than 18 years admitted to an intensive care unit who were hemodynamically stable, not being treated with vasoactive drugs or sedated, intubated or tracheostomized, and who were in the process of being weaned from mechanical ventilation. MIP was measured by both devices on three different occasions, with an occlusion time of 20 seconds and a 5-minute interval between measurements. The following parameters were assessed: respiratory rate, mean arterial pressure, and respiratory rate before and after each measurement by each device. The statistical analysis was made in the Statistical Analysis System and the R Project for Statistical Computing V. 3.1.2 softwares, using the ANOVA and the Wilcoxon tests. Results: Fifty-eight patients were included in the study. The mean value obtained for MIP was -46.22 centimeters of water (cmH(2)O) in the digital manometer and -13.15 cmH(2)O (p<0.001) in the IMT device. Heart rate showed a significant increase (p<0.0001) both before and after all measurements in both devices. Mean arterial pressure showed a statistically significant difference only before and after the first measurement by the digital manometer and before and after the second measurement by the IMT device (p<0.001). The respiratory rate oscillated significantly before and after the three measurements by both devices (p<0.0001). The hemodynamic parameters remained within reference values after MIP measurements. Conclusions: The digital manometer recorded a higher MIP than that measured by the IMT device. The hemodynamic parameter values oscillated in both devices, but they remained within the normal range and were not clinically significant.2

Benefícios dos Ativadores Seletivos dos Recetores de Vitamina D em Doentes Transplantados Renais

Severe chronic kidney disease may lead to disturbances, such as hyperphosphatemia, increased secretion of fibroblast growth factor -23 (FGF -23) and vitamin D deficiency. These may increase plasmatic levels of parathyroid hormone, and decrease plasmatic levels of calcium. Altogether, these may contribute to the development of secondary hyperparathyroidism, and to abnormalities in mineral metabolism. Kidney transplantation is the best option to improve longevity and quality of life in end -stage chronic kidney disease patients. Vitamin D deficiency has been associated with cardiovascular disease, which is the leading cause of death in chronic kidney disease. Therefore, diagnosing this deficiency may be pivotal for minimizing mortality in chronic kidney disease, because pharmacological treatments for this deficiency may be prescribed. Calcitriol is indicated for the treatment of vitamin D deficiency, both in chronic kidney disease and in kidney transplanted patients. However, calcitriol may increase the plasmatic levels of calcium and phosphorous, which can lead to vascular calcifications, that have been associated with cardiovascular mortality. Selective vitamin D receptor activators are indicated for the treatment of vitamin D deficiency in chronic kidney disease. These have the advantage of being associated with lower increases of plasmatic levels of calcium and phosphorous. These drugs also seem to have additional effects that may minimise patient morbidity and mortality, especially due to potentially reducing cardiovascular events. Unfortunately, there are few studies about the use of these drugs in kidney transplanted patients. Here we present a review about the physiology of vitamin D, the consequences of its deficiency in chronic kidney disease and in kidney transplanted patients, and about the diagnosis and treatment of this deficiency. Finally, we discuss the new line of research about the efficacy and safety of selective vitamin D receptor activators in kidney transplanted patients

mTOR pathway in papillary thyroid carcinoma: Different contributions of mTORC1 and mTORC2 complexes for tumor behavior and SLC5A5 mRNA expression

The mammalian target of rapamycin (mTOR) pathway is overactivated in thyroid cancer (TC). We previously demonstrated that phospho-mTOR expression is associated with tumor aggressiveness, therapy resistance, and lower mRNA expression of SLC5A5 in papillary thyroid carcinoma (PTC), while phospho-S6 (mTORC1 effector) expression was associated with less aggressive clinicopathological features. The distinct behavior of the two markers led us to hypothesize that mTOR activation may be contributing to a preferential activation of the mTORC2 complex. To approach this question, we performed immunohistochemistry for phospho-AKT Ser473 (mTORC2 effector) in a series of 182 PTCs previously characterized for phospho-mTOR and phospho-S6 expression. We evaluated the impact of each mTOR complex on SLC5A5 mRNA expression by treating cell lines with RAD001 (mTORC1 blocker) and Torin2 (mTORC1 and mTORC2 blocker). Phospho-AKT Ser473 expression was positively correlated with phospho-mTOR expression. Nuclear expression of phospho-AKT Ser473 was significantly associated with the presence of distant metastases. Treatment of cell lines with RAD001 did not increase SLC5A5 mRNA levels, whereas Torin2 caused a ~6 fold increase in SLC5A5 mRNA expression in the TPC1 cell line. In PTC, phospho-mTOR activation may lead to the activation of the mTORC2 complex. Its downstream effector, phospho-AKT Ser473, may be implicated in distant metastization, therapy resistance, and downregulation of SLC5A5 mRNA expression.Acknowledgments: This study was supported by FCT (“Portuguese Foundation for Science and Technology”) through PhD grants to Catarina Tavares (SFRH/BD/87887/2012), Ana Pestana (SFRH/BD/110617/2015), and Rui Batista (SFRH/BD/111321/2015) and by a CNPq PhD grant (“National Counsel of Technological and Scientific Development”, Brazil), Science without Borders, Process n# 237322/2012-9 for Luciana Ferreira. Miguel Melo received a grant from Genzyme for the research project “Molecular biomarkers of prognosis and response to therapy in differentiated thyroid carcinomas”. Further funding was obtained from FEDER—Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020—Operational Program for Competitiveness and Internationalization (POCI), Portugal 2020, and by Portuguese funds through FCT—Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Inovação in the framework of the project "Institute for Research and Innovation in Health Sciences” (POCI-01-0145-FEDER-007274), and by the project “Advancing cancer research: from basic acknowledgement to application”; NORTE-01-0145-FEDER-000029; “Projetos Estruturados de I&D&I, funded by Norte 2020-Programa Operacional Regional do Norte. This work was also financed by Sociedade Portuguesa de Endocrinologia Diabetes e Metabolismo through a grant “Prof. E. Limbert Sociedade Portuguesa de Endocrinologia Diabetes e Metabolismo/Sanofi-Genzyme in thyroid pathology”

In vivo activity of Sapindus saponaria against azole-susceptible and -resistant human vaginal Candida species

<p>Abstract</p> <p>Background</p> <p>Study of <it>in vivo </it>antifungal activity of the hydroalcoholic extract (HE) and n-BuOH extract (BUTE) of <it>Sapindus saponaria </it>against azole-susceptible and -resistant human vaginal <it>Candida </it>spp.</p> <p>Methods</p> <p>The <it>in vitro </it>antifungal activity of HE, BUTE, fluconazole (FLU), and itraconazole (ITRA) was determined by the broth microdilution method. We obtained values of minimal inhibitory concentration (MIC) and minimum fungicide concentration (MFC) for 46 strains of <it>C. albicans </it>and 10 of <it>C. glabrata </it>isolated from patients with vulvovaginal candidiasis (VVC). VVC was induced in hyperestrogenic Wistar rats with azole-susceptible <it>C. albicans </it>(SCA), azole-resistant <it>C. albicans </it>(RCA), and azole-resistant <it>C. glabrata </it>(RCG). The rats were treated intravaginally with 0.1 mL of HE or BUTE at concentrations of 1%, 2.5% and 5%; 100 μg/mL of FLU (treatment positive control); or distilled water (negative control) at 1, 24, and 48 h after induction of the infection, and the progress of VVC was monitored by culturing and scanning electron microscopy (SEM). The toxicity was evaluated in cervical cells of the HeLa cell line.</p> <p>Results</p> <p>The extracts showed <it>in vitro </it>inhibitory and fungicidal activity against all the isolates, and the MIC and MFC values for the <it>C. glabrata </it>isolates were slightly higher. <it>In vivo</it>, the SCA, RCA, and RCG infections were eliminated by 21 days post-infection, with up to 5% HE and BUTE, comparable to the activity of FLU. No cytotoxic action was observed for either extract.</p> <p>Conclusions</p> <p>Our results demonstrated that HE and BUTE from <it>S. saponaria </it>show inhibitory and fungicidal activity <it>in vitro</it>, in addition to <it>in vivo </it>activity against azole-resistant vaginal isolates of <it>C. glabrata </it>and azole-susceptible and resistant isolates of <it>C. albicans</it>. Also considering the lack of cytotoxicity and the low concentrations of the extracts necessary to eliminate the infection <it>in vivo</it>, HE and BUTE show promise for continued studies with purified antifungal substances in VVC yeast isolates.</p