A Simulated Intermediate State for Folding and Aggregation Provides Insights into ΔN6 β2-Microglobulin Amyloidogenic Behavior

A major component of ex vivo amyloid plaques of patients with dialysis-related amyloidosis (DRA) is a cleaved variant of β2-microglobulin (ΔN6) lacking the first six N-terminal residues. Here we perform a computational study on ΔN6, which provides clues to understand the amyloidogenicity of the full-length β2-microglobulin. Contrary to the wild-type form, ΔN6 is able to efficiently nucleate fibrillogenesis in vitro at physiological pH. This behavior is enhanced by a mild acidification of the medium such as that occurring in the synovial fluid of DRA patients. Results reported in this work, based on molecular simulations, indicate that deletion of the N-terminal hexapeptide triggers the formation of an intermediate state for folding and aggregation with an unstructured strand A and a native-like core. Strand A plays a pivotal role in aggregation by acting as a sticky hook in dimer assembly. This study further predicts that the detachment of strand A from the core is maximized at pH 6.2 resulting into higher aggregation efficiency. The structural mapping of the dimerization interface suggests that Tyr10, His13, Phe30 and His84 are hot-spot residues in ΔN6 amyloidogenesis

Development of computational thinking using board games: A systematic literature review based on empirical studies

El Pensamiento Computacional (PC) ha sido destacado como una competencia clave del siglo XXI. La literatura ha señalado el uso de actividades desconectadas, incluidos los juegos de mesa (JM), como estrategia para promover el desarrollo del Pensamiento Computacional. Recientemente, los nuevos juegos de mesa modernos (JMM), denominados eurojuegos, han despertado el interés de los investigadores, que han destacado su diseño y mecánica únicos. Para investigar el impacto del uso de JMM en el desarrollo del PC, se estructuró una revisión sistemática de la literatura (RSL) utilizando el protocolo PRISMA como referencia. El enfoque se centró en el análisis de estudios empíricos basados en el uso de juegos de mesa en entornos escolares para promover las habilidades de PC. Este artículo se abre con la presentación de varios conceptos esenciales, entre los que se incluyen el PC y los eurojuegos, y a continuación se presentan los resultados de la RSL, centrándose en los artículos analizados, los marcos teóricos que sustentan los estudios, los contextos y métodos de investigación, los instrumentos de recogida de datos y los resultados comunicados por los autores. De los 85 artículos, se analizaron 11 estudios publicados entre 2011 y 2021. Los resultados sugieren que las mecánicas de juego, típicas de los eurojuegos, revelan el potencial para promover el PC. Sin embargo, el uso de estos recursos requiere una mayor exploración.Computational Thinking (CT) has been highlighted as a key competence of the 21st century. The literature has pointed to the use of unplugged activities, including board games (BG), as a strategy to promote the development of Computational Thinking. Recently, new modern board games (MBG), referred to as Eurogames, have aroused the interest of researchers who have underlined their unique design and mechanics. To investigate the impact of the use of MBG on CT development, a systematic literature review (SLR) was structured using the PRISMA protocol as a reference. The focus was centred on the analysis of empirical studies based on the use of board games in school settings to promote CT skills. This paper opens with the presentation of several essential concepts, among which CT and Eurogames are included, followed by the results of the SLR, focusing on the analysed articles, the theoretical frameworks supporting the studies, the research contexts and methods, the data collection instruments and the results reported by the authors. Out of 85 articles, 11 studies published between 2011 and 2021 were analysed. The results suggest that game mechanics, typical of Eurogames, reveal the potential to promote CT. However, the use of these resources requires further exploration

o contributo da tarefa de planificação para a escrita de textos coerentes na fase inicial da escrita compositiva

Esta dissertação, desenvolvida no âmbito da unidade curricular Estágio III, do curso de Mestrado em Educação Pré-escolar e Ensino do 1.º Ciclo do Ensino Básico, é um estudo sobre o contributo da planificação para o desenvolvimento da escrita compositiva. Com o trabalho desenvolvido, que avalia a influência da planificação textual sobre a coerência de textos produzidos por alunos de uma turma do 2.º ano do 1.º Ciclo do Ensino Básico, este estudo contribui com evidências de que a tarefa de planificação ajuda a estimular a produção de textos com sentido e facilita a organização e estruturação das ideias em situações de escrita compositiva. De forma a contextualizar a questão orientadora da investigação - qual o contributo da planificação para o desenvolvimento de produções textuais escritas por crianças do 2.º ano de escolaridade, em fase inicial da escrita compositiva? –, são introduzidas, no capítulo 1, questões relativas ao ensino da escrita e sua dimensão processual, com particular incidência na fase de planificação. O mesmo capítulo apresenta ainda as principais particularidades da sequência narrativa, bem como a coerência referida neste estudo como processo fundamental de um texto e indicador de qualidade de produções escritas por alunos. O capítulo 2 descreve a fundamentação metodológica e explicita a intervenção didática seguindo-se, no capítulo 3, a apresentação e análise dos dados recolhidos. No final deste estudo sistematizam-se considerações finais relativas à questão de investigação inicial e apresenta-se uma síntese dos resultados a que se chegou e implicações no ensino da escrita compositiva.This dissertation, developed within Estágio III course of the Master's degree in Preschool Education and First Cycle of the Primary School is a research on the contribution of the planning task for the development of the compositional writing. With the experimental work conducted that assesses the influence of the textual planning over the coherence of the texts produced by the students of a Second Year class of the Primary School, this study contributes with evidence that the planning task stimulates the conception of meaningful texts and facilitates the organization and structuring of the ideas in situations of compositional writing. In order to contextualise the general issue of the investigation - what is the contribution of the planning task on the development of written textual productions by children of the Second Year of the Primary School in the full emerging phase of compositional writing? - on Chapter 1, questions regarding the teaching of writing and its procedural dimension, with special focus on the planning task, are introduced. The same chapter integrates the main details of the narrative sequence, being this kind of text highlighted as an emerging textual format in the first years of school. At last, the coherence is referred on this chapter as an essential process of a text working on this investigation as an quality indicator of the written productions by the students. Chapter 2 is dedicated to the methodological foundation and explicitation of the didactic intervention followed on chapter 3 by the presentation and analysis of the data collected. In the end of this study some final considerations regarding the initial question of the investigation are systematized, conducting a synthesis of the verified results and implications on the teaching of the compositional writing

Nos bastidores da Corte: o Rei e a Casa Real na crise da monarquia 1889-1908

O tema desta tese surgiu na sequência da inexistência de estudos acerca daquela que foi uma das mais antigas e duradouras instituições portuguesas, acerca da qual pouco se sabia durante a monarquia constitucional.Efectivamente, para a idade Média e Idade Moderna existiam já alguns estudos que, directa ou indirectamente trataram a questão da Casa Real Portuguesa, embora o mesmo não sucedesse para a época posterior

Nos bastidores da Corte. O Rei e a Casa Real na crise da Monarquia 1889-1908

Tese apresentada para cumprimentos dos requisitos necessários à obtenção do graus de Doutor em História, especialidade História Contemporâne

Concise total synthesis of (+)-gliocladins B and C

The first total synthesis of (+)-gliocladin B is described. Our concise and enantioselective synthesis takes advantage of a new regioselective Friedel–Crafts-based strategy to provide an efficient multigram-scale access to the C3-(3′-indolyl)hexahydropyrroloindole substructure, a molecular foundation present in a significant subset of epipolythiodiketopiperazine natural alkaloids. Our first-generation solution to (+)-gliocladin B involved the stereoselective formation of (+)-12-deoxybionectin A, a plausible biosynthetic precursor. Our synthesis clarified the C15 stereochemistry of (+)-gliocladin B and allowed its full structure confirmation. Further studies of a versatile dihydroxylated diketopiperazine provided a concise and efficient synthesis of (+)-gliocladin B as well as access to (+)-gliocladin C.National Institute of General Medical Sciences (U.S.) (GM089732)Amgen Inc.National Science Foundation (U.S.) (CHE-0946721

Bioactivities of centaurium erythraea (Gentianaceae) decoctions: antioxidant activity, enzyme inhibition and docking studies

Centaurium erythraea is recommended for the treatment of gastrointestinal disorders and to reduce hypercholesterolemia in ethno-medicinal practice. To perform a top-down study that could give some insight into the molecular basis of these bioactivities, decoctions from C. erythraea leaves were prepared and the compounds were identified by liquid chromatography-high resolution tandemmassspectrometry(LC–MS/MS).Secoiridoidsglycosides,likegentiopicrosideandsweroside, and several xanthones, such as di-hydroxy-dimethoxyxanthone, were identified. Following some of the bioactivities previously ascribed to C. erythraea, we have studied its antioxidant capacity and the ability to inhibit acetylcholinesterase (AChE) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR). Significant antioxidant activities were observed, following three assays: free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH) reduction; lipoperoxidation; and NO radical scavengingcapacity. TheAChEandHMGRinhibitoryactivitiesforthedecoctionwerealsomeasured (56% at 500 µg/mL and 48% at 10 µg/mL, respectively). Molecular docking studies indicated that xanthones are better AChE inhibitors than gentiopicroside, while this compound exhibits a better shape complementarity with the HMGR active site than xanthones. To the extent of our knowledge, thisisthefirstreportonAChEandHMGRactivitiesbyC.erythraeadecoctions,inatop-downanalysis, complemented with in silico molecular docking, which aims to understand, at the molecular level, some of the biological effects ascribed to infusions from this plant.info:eu-repo/semantics/publishedVersio

Improvement of conventional anti-cancer drugs as new tools against multidrug resistant tumors

Multidrug resistance (MDR) is the dominant cause of the failure of cancer chemotherapy. The design of antitumor drugs that are able to evade MDR is rapidly evolving, showing that this area of biomedical research attracts great interest in the scientific community. The current review explores promising recent approaches that have been developed with the aim of circumventing or overcoming MDR. Encouraging results have been obtained in the investigation of the MDR-modulating properties of various classes of natural compounds and their analogues. Inhibition of P-gp or downregulation of its expression have proven to be the main mechanisms by which MDR can be surmounted. The use of hybrid molecules that are able to simultaneously interact with two or more cancer cell targets is currently being explored as a means to circumvent drug resistance. This strategy is based on the design of hybrid compounds that are obtained either by merging the structural features of separate drugs, or by conjugating two drugs or pharmacophores via cleavable/non-cleavable linkers. The approach is highly promising due to the pharmacokinetic and pharmacodynamic advantages that can be achieved over the independent administration of the two individual components. However, it should be stressed that the task of obtaining successful multivalent drugs is a very challenging one. The conjugation of anticancer agents with nitric oxide (NO) donors has recently been developed, creating a particular class of hybrid that can combat tumor drug resistance. Appropriate NO donors have been shown to reverse drug resistance via nitration of ABC transporters and by interfering with a number of metabolic enzymes and signaling pathways. In fact, hybrid compounds that are produced by covalently attaching NO-donors and antitumor drugs have been shown to elicit a synergistic cytotoxic effect in a variety of drug resistant cancer cell lines. Another strategy to circumvent MDR is based on nanocarrier-mediated transport and the controlled release of chemotherapeutic drugs and P-gp inhibitors. Their pharmacokinetics are governed by the nanoparticle or polymer carrier and make use of the enhanced permeation and retention (EPR) effect, which can increase selective delivery to cancer cells. These systems are usually internalized by cancer cells via endocytosis and accumulate in endosomes and lysosomes, thus preventing rapid efflux. Other modalities to combat MDR are described in this review, including the pharmaco-modulation of acridine, which is a well-known scaffold in the development of bioactive compounds, the use of natural compounds as means to reverse MDR, and the conjugation of anticancer drugs with carriers that target specific tumor-cell components. Finally, the outstanding potential of in silico structure-based methods as a means to evaluate the ability of antitumor drugs to interact with drug transporters is also highlighted in this review. Structure-based design methods, which utilize 3D structural data of proteins and their complexes with ligands, are the most effective of the in silico methods available, as they provide a prediction regarding the interaction between transport proteins and their substrates and inhibitors. The recently resolved X-ray structure of human P-gp can help predict the interaction sites of designed compounds, providing insight into their binding mode and directing possible rational modifications to prevent them from becoming P-gp drug substrates. In summary, although major efforts were invested in the search for new tools to combat drug resistant tumors, they all require further implementation and methodological development. Further investigation and progress in the abovementioned strategies will provide significant advances in the rational combat against cancer MDR

A novel combinatory treatment against a CDDP-resistant non-small cell lung cancer based on a Ruthenium(II)-cyclopentadienyl compound

The therapeutic approach to many solid tumors, including non-small cell lung cancer (NSCLC), is mainly based on the use of platinum-containing anticancer agents and is often characterized by acquired or intrinsic resistance to the drug. Therefore, the search for safer and more effective drugs is still an open challenge. Two organometallic ruthenium(II)-cyclopentadienyl compounds [Ru(eta(5)-C5H4CHO)(Me(2)bipy)(PPh3)]+ (RT150) and [Ru(eta(5)-C5H4CH2OH)(Me(2)bipy)(PPh3)][CF3SO3] (RT151) were tested against a panel of cisplatinresistant NSCLC cell lines and xenografts. They were more effective than cisplatin in inducing oxidative stress and DNA damage, affecting the cell cycle and causing apoptosis. Importantly, they were found to be inhibitors of drug efflux transporters. Due to this property, the compounds significantly increased the retention and cytotoxicity of cisplatin within NSCLC cells. Notably, they did not display high toxicity in vitro against nontransformed cells (red blood cells, fibroblasts, bronchial epithelial cells, cardiomyocytes, and endothelial cells). Both compounds induced vasorelaxation and reduced endothelial cell migration, suggesting potential antiangiogenic properties. RT151 confirmed its efficacy against NSCLC xenografts resistant to cisplatin. Either alone or combined with low doses of cisplatin, RT151 showed a good biodistribution profile in the liver, kidney, spleen, lung, and tumor. Hematochemical analysis and post-mortem organ pathology confirmed the safety of the compound in vivo, also when combined with cisplatin. To sum up, we have confirmed the effectiveness of a novel class of drugs against cisplatin-resistant NSCLC. Additionally, the compounds have a good biocompatibility and safety profile

Designing new antitubercular isoniazid derivatives with improved reactivity and membrane trafficking abilities

Funding Information: We acknowledge Diogo Vila Vi?osa for valuable discussions. We acknowledge financial support from Funda??o para a Ci?ncia e a Tecnologia, Portugal through projects PTDC/MED-QUI/29036/2017, PTDC/BIA-MIC-30692/2017, UIDB/00100/2020, UIDP/00100/2020, UIDB/04046/2020, UIDP/04046/2020, and UID/Multi/04413/2020, and Grants CEECIND/02300/2017 and DL57/CEECIND/0256/2017. Contributions from JRK, CMB, and DCG supported in part by a grant from the National Science Foundation, USA (MCB 1616059). Funding Information: We acknowledge Diogo Vila Viçosa for valuable discussions. We acknowledge financial support from Fundação para a Ciência e a Tecnologia , Portugal through projects PTDC/MED-QUI/29036/2017 , PTDC/BIA-MIC-30692/2017 , UIDB/00100/2020 , UIDP/00100/2020 , UIDB/04046/2020 , UIDP/04046/2020 , and UID/Multi/04413/2020 , and Grants CEECIND/02300/2017 and DL57/CEECIND/0256/2017 . Contributions from JRK, CMB, and DCG supported in part by a grant from the National Science Foundation , USA ( MCB 1616059 ). Publisher Copyright: © 2021 The AuthorsIsoniazid (INH) is one of the two most effective first-line antitubercular drugs and is still used at the present time as a scaffold for developing new compounds to fight TB. In a previous study, we have observed that an INH derivative, an hydrazide N′-substituted with a C10acyl chain, was able to counterbalance its smaller reactivity with a higher membrane permeability. This resulted in an improved performance against the most prevalent Mycobacterium tuberculosis (Mtb) resistant strain (S315T), compared to INH. In this work, we have designed two new series of INH derivatives (alkyl hydrazides and hydrazones) with promising in silico properties, namely membrane permeabilities and spontaneous IN* radical formation. The kinetics, cytotoxicity, and biological activity evaluations confirmed the in silico predictions regarding the very high reactivity of the alkyl hydrazides. The hydrazones, on the other hand, showed very similar behavior compared to INH, particularly in biological tests that take longer to complete, indicating that these compounds are being hydrolyzed back to INH. Despite their improved membrane permeabilities, the reactivities of these two series are too high, impairing their overall performance. Nevertheless, the systematic data gathered about these compounds have showed us the need to find a balance between lipophilicity and reactivity, which is paramount to devise better INH-based derivatives aimed at circumventing Mtb resistance.publishersversionpublishe