One book, two language varieties

This paper presents a comparative study of alignment pairs, either contrasting expressions or stylistic variants of the same expression in the European (EP) and the Brazilian (BP) varieties of Portuguese. The alignments were collected semi-automatically using the CLUE-Aligner tool, which allows to record all pairs of paraphrastic units resulting from the alignment task in a database. The corpus used was a children’s literature book Os livros que devoraram o meu pai (The Books that Devoured My Father) by the Portuguese author Afonso Cruz and the Brazilian adaptation of this book. The main goal of the work presented here is to gather equivalent phrasal expressions and different syntactic constructions, which convey the same meaning in EP and BP, and contribute to the optimisation of editorial processes compulsory in the adaptation of texts, but which are suitable for any type of editorial process. This study provides a scientific basis for future work in the area of editing, proofreading and converting text to and from any variety of Portuguese from a computational point of view, namely to be used in a paraphrasing system with a variety adaptation functionality, even in the case of a literary text. We contemplate “challenging” cases, from a literary point of view, looking for alternatives that do not tamper with the imagery richness of the original version .info:eu-repo/semantics/acceptedVersio

Mathematical model of brain tumour with glia-neuron interactions and chemotherapy treatment

Acknowledgements This study was possible by partial financial support from the following Brazilian government agencies: Fundação Araucária, EPSRC-EP/I032606/1 and CNPq, CAPES and Science Without Borders Program Process nos. 17656125, 99999.010583/2013-00 and 245377/2012-3.Peer reviewedPreprin

Identification and Validation of Novel Drug Targets for the Treatment of Plasmodium falciparum Malaria: New Insights

In order to counter the malarial parasite’s striking ability to rapidly develop drug resistance, a constant supply of novel antimalarial drugs and potential drug targets must be available. The so-called Harlow-Knapp effect, or “searching under the lamp post,” in which scientists tend to further explore only the areas that are already well illuminated, significantly limits the availability of novel drugs and drug targets. This chapter summarizes the pool of electron transport chain (ETC) and carbon metabolism antimalarial targets that have been “under the lamp post” in recent years, as well as suggest a promising new avenue for the validation of novel drug targets. The interplay between the pathways crucial for the parasite, such as pyrimidine biosynthesis, aspartate metabolism, and mitochondrial tricarboxylic acid (TCA) cycle, is described in order to create a “road map” of novel antimalarial avenues

New directions in antimalarial target validation

Introduction: Malaria is one of the most prevalent human infections worldwide with over 40% of the world's population living in malaria-endemic areas. In the absence of an effective vaccine, emergence of drug-resistant strains requires urgent drug development. Current methods applied to drug target validation, a crucial step in drug discovery, possess limitations in malaria. These constraints require the development of techniques capable of simplifying the validation of Plasmodial targets. Areas covered: The authors review the current state of the art in techniques used to validate drug targets in malaria, including our contribution - the protein interference assay (PIA) - as an additional tool in rapid in vivo target validation. Expert opinion: Each technique in this review has advantages and disadvantages, implying that future validation efforts should not focus on a single approach, but integrate multiple approaches. PIA is a significant addition to the current toolset of antimalarial validation. Validation of aspartate metabolism as a druggable pathway provided proof of concept of how oligomeric interfaces can be exploited to control specific activity in vivo. PIA has the potential to be applied not only to other enzymes/pathways of the malaria parasite but could, in principle, be extrapolated to other infectious diseases

A novel mechanism of inhibition by phenylthiourea on PvdP, a tyrosinase synthesizing pyoverdine of Pseudomonas aeruginosa

The biosynthesis of pyoverdine, the major siderophore of Pseudomonas aeruginosa, is a well-organized process involving a discrete number of enzyme-catalyzed steps. The final step of this process involves the PvdP tyrosinase, which converts ferribactin into pyoverdine. Thus, inhibition of the PvdP tyrosinase activity provides an attractive strategy to interfere with siderophore synthesis to manage P. aeruginosa infections. Here, we report phenylthiourea as a non-competitive inhibitor of PvdP for which we solved a crystal structure in complex with PvdP. The crystal structure indicates that phenylthiourea binds to an allosteric binding site and thereby interferes with its tyrosinase activity. We further provide proofs that PvdP tyrosinase inhibition by phenylthiourea requires the C-terminal lid region. This provides opportunities to develop inhibitors that target the allosteric site, which seems to be confined to fluorescent pseudomonads, and not the tyrosinase active site. Furthermore, increases the chances to identify PvdP inhibitors that selectively interfere with siderophore synthesis

Molecular target validation of Aspartate Transcarbamoylase from Plasmodium falciparum by Torin 2

Malaria is a tropical disease that kills about half a million people around the world annually. Enzymatic reactions within pyrimidine biosynthesis have been proven to be essential for Plasmodium proliferation. Here we report on the essentiality of the second enzymatic step of the pyrimidine biosynthesis pathway, catalyzed by aspartate transcarbamoylase (ATC). Crystallization experiments using a double mutant ofPlasmodium falciparum ATC (PfATC) revealed the importance of the mutated residues for enzyme catalysis. Subsequently, this mutant was employed in protein interference assays (PIAs), which resulted in inhibition of parasite proliferation when parasites transfected with the double mutant were cultivated in medium lacking an excess of nutrients, including aspartate. Addition of 5 or 10 mg/L of aspartate to the minimal medium restored the parasites' normal growth rate. In vitro and whole-cell assays in the presence of the compound Torin 2 showed inhibition of specific activity and parasite growth, respectively. In silico analyses revealed the potential binding mode of Torin 2 to PfATC. Furthermore, a transgenic ATC-overexpressing cell line exhibited a 10-fold increased tolerance to Torin 2 compared with control cultures. Taken together, our results confirm the antimalarial activity of Torin 2, suggesting PfATC as a target of this drug and a promising target for the development of novel antimalarials.</p

Selection of nature-based solutions to improve comfort in schools during heat waves

Climate change impacts particularly affect vulnerable populations such as children. Therefore, addressing the adaptation of educational buildings is crucial in avoiding these negative effects on school performance. In this paper, three educational buildings, located in Badajoz (Spain), Evora (Portugal) and Porto (Portugal), serve as pilot samples to study the suitability of nature-based solutions (NBS), chosen for each one of three climatic zones. The NBS selected include green roofs, vertical structures with vegetation to shade holes, outdoor trees and free-cooling ventilation. The scenarios of the different NBS implemented in the three models were simulated with the software EnergyPlus, which allows optimising the appropriate decision before renovation operations begin. The results obtained from the simulations suggest energy performance improvements after applying the most adequate NBS selection to each one of the three buildings tested. Particularly, a reduction in radiation on both roofs and facades is required in the case of Evora and Badajoz, where both climate zones have similar features, that is, warm and dry. While in Porto, milder and more humid than the former ones, it is very effective to operate mainly on the roof, complemented by small ventilation operations.The authors gratefully acknowledge the support of this work by the LIFE+ Programme under the responsibility of the Directorate General for the Environment of the European Commission through the agreement LIFE17 CCA/ES/00088, LIFE myBUILDINGisGREEN

addressing vaccine inequity in socially vulnerabilised communities

VacinaMar\u00E9 was a multi-institutional initiative, and funders had no role in the study\u2019s design, the collection, analysis, and interpretation of data, the writing of the manuscript, or the decision to submit the manuscript for publication. Funding Information: The authors thank the Redes da Mar\u00E9 for all their support and the efficient strategies for community engagement and communication during the pandemic. The authors also thank the Presidency of FIOCRUZ for the enthusiastic support in all moments and the Unidade de Apoio ao Diagn\u00F3stico da Covid-19 (UNADIGFIOCRUZ) for supporting the testing diagnosis. The Vacina Mar\u00E9 initiative was funded by Fiocruz and an unrestricted grant from Todos Pela Sa\u00FAde fund. AABS acknowledges funding from CAPES Print (88887.899318/2023-00). OTR acknowledges funding from the END-VOC Project (Horizon 2021\u20132024), funded by the European Union under grant agreement no. 101046314. OTR acknowledges support from the Spanish Ministry of Science and Innovation through the Centro de Excelencia Severo Ochoa 2019\u20132023 programme (CEX2018-000806-S) and from the Generalitat de Catalunya through the Centres de Recerca de Catalunya (CERCA) programme. Funding Information: The authors thank the Redes da Mare for all their support and the efficient strategies for community engagement and communication during the pandemic. The authors also thank the Presidency of FIOCRUZ for the enthusiastic support in all moments and the Unidade de Apoio ao Diagn\u00F3stico da Covid-19 (UNADIGFIOCRUZ) for supporting the testing diagnosis. The Vacina Mar\u00E9 initiative was funded by Fiocruz and an unrestricted grant from Todos Pela Sa\u00FAde fund. AABS acknowledges funding from CAPES Print (88887.899318/2023-00). OTR acknowledges funding from the END-VOC Project (Horizon 2021-2024), funded by the European Union under grant agreement no. 101046314. OTR acknowledges support from the Spanish Ministry of Science and Innovation through the Centro de Excelencia Severo Ochoa 2019-2023 programme (CEX2018-000806-S) and from the Generalitat de Catalunya through the Centres de Recerca de Catalunya (CERCA) programme.publishersversionpublishe

Oligomeric interfaces as a tool in drug discovery:Specific interference with activity of malate dehydrogenase of Plasmodium falciparum in vitro

Malaria remains a major threat to human health, as strains resistant to current therapeutics are discovered. Efforts in finding new drug targets are hampered by the lack of sufficiently specific tools to provide target validation prior to initiating expensive drug discovery projects. Thus, new approaches that can rapidly enable drug target validation are of significant interest. In this manuscript we present the crystal structure of malate dehydrogenase from Plasmodium falciparum (PfMDH) at 2.4 Å resolution and structure-based mutagenic experiments interfering with the inter-oligomeric interactions of the enzyme. We report decreased thermal stability, significantly decreased specific activity and kinetic parameters of PfMDH mutants upon mutagenic disruption of either oligomeric interface. In contrast, stabilization of one of the interfaces resulted in increased thermal stability, increased substrate/cofactor affinity and hyperactivity of the enzyme towards malate production at sub-millimolar substrate concentrations. Furthermore, the presented data show that our designed PfMDH mutant could be used as specific inhibitor of the wild type PfMDH activity, as mutated PfMDH copies were shown to be able to self-incorporate into the native assembly upon introduction in vitro, yielding deactivated mutant:wild-type species. These data provide an insight into the role of oligomeric assembly in regulation of PfMDH activity and reveal that recombinant mutants could be used as probe tool for specific modification of the wild type PfMDH activity, thus offering the potential to validate its druggability in vivo without recourse to complex genetics or initial tool compounds. Such tool compounds often lack specificity between host or pathogen proteins (or are toxic in in vivo trials) and result in difficulties in assessing cause and effect-particularly in cases when the enzymes of interest possess close homologs within the human host. Furthermore, our oligomeric interference approach could be used in the future in order to assess druggability of other challenging human pathogen drug targets

Podridão-do-caule e podridão-dos-ramos da mamoneira causada por Botryodiplodia theobromae Pat.

For several years, the occurrence of stem and branch rot of the Castor-oil plant has been detected in the fields of castor bean of the state of Bahia, Brazil. It was observed that the fungus Botryodiplodia sp. was frequently associated to the symptoms of this disease. It was afterward identified as Lasiodiplodia theobromae (Pat.) Griff & Maubl. (= Botryodiplodia theobromae (Pat.). Pathogenicity studies showed that the fungus B. theobromae was the etiological agent of the "rot of Botryodiplodia". This disease is characterized by the rot, dry and death of the stem and branches of Castor-oil plants with pycnidium formation of the pathogen on the infected tissue.Há vários anos tem-se constatado em municípios produtores de mamona do Estado da Bahia a ocorrência de podridão-do-caule e podridão-dos-ramos da mamoneira. Observou-se que o fungo Botryodiplodia sp. encontrava-se constantemente associado aos sintomas desta doença, sendo posteriormente identificado como Lasiodiplodia theobromae (Pat.) Griff & Maubl. (= Botryodiplodia theobromae Pat.). Estudos de patogenicidade evidenciaram que este fungo era o agente etiológico da podridão-de-botryodiplodia, doença caracterizada pela podridão, seca e morte do caule e dos ramos da mamoneira, com formação de picnídios do patógeno sobre o tecido infectado