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Abstract Thiosemicarbazones are promising classes of compounds with antitumor activity. For this study, six 2,4-dihydroxy-benzylidene-thiosemicarbazones compounds were synthesized. These compounds were submitted to different assays in silico, in vitro and in vivo to evaluate the toxicological, antioxidant and antitumor effects. The in silico results were evaluated by the SwissADME and pkCSM platforms and showed that all compounds had good oral bioavailability profiles. The in vitro and in vivo toxicity assays showed that the compounds showed low cytotoxicity against different normal cells and did not promote hemolytic effects. The single dose acute toxicity test (2000 mg/kg) showed that none of the compounds were toxic to mice. In in vitro antioxidant activity assays, the compounds showed moderate to low activity, with PB17 standing out for the ABTS radical capture assay. The in vivo antioxidant activity highlighted the compounds 1, 6 and 8 that promoted a significant increase in the concentration of liver antioxidant enzymes. Finally, all compounds showed promising antitumor activity against different cell lines, especially MCF-7 and DU145 lines, in addition, they inhibited the growth of sarcoma 180 at concentrations lower than 50 mg/kg. These results showed that the evaluated compounds can be considered as potential antitumor agents.

The dataset provided in this paper refers to an experimental campaign conducted in Laboratory of Fluid Dynamics (LTDF) of the Free University of Bozen-Bolzano at NOI Techpark aiming to understand the movement of granular material in fluids of low viscosity and density exhibited in debris flows.One experimental test was performed consisting of 31 repetitions. In detail, a three-litre volume of granular material (d = 1.8mm) was suddenly released from an upstream reservoir in a 1.5 m long acrylic chute tilted at 19 degrees and stopped in the outlet area by a vertical barrier.This vertical barrier used is adjacent to the side wall of the chute, with two vertical gaps and a width equal to twice the size of the particles used (s = 2d).The instrumentation included two high-speed cameras (300fps) and one spotlight. Camera 1 (C1) was located upstream at the lock gate location and Camera 2 was placed at downstream part of the chute, focusing on the vertical barrier site. A Particle Tracking Velocimetry (PTV) was applied to the set of images captured by the camera placed in the downstream area of the chute in a region of interest (ROI) of 4000 pixel width and 300 pixel height.Firstly, the raw data concerns to the particles coordinates (x,z), their along-chute and wall-normal trajectories and particle tag, detected with the PTV algorithm for the 31 repetitions held.The previous data was submitted to filtering processes where we converted particle trajectories into maps of these mean quantities by binning and constructing a data ensemble. To remove some detected outliers, a refinement of ensemble data was subsequently applied [1].All of the solutions computed to build the pointed dataset were performed by means of Matlab algorithms.This dataset allows researchers to characterize the behaviour of granular processes that may occur in inclined channels partially or fully obstructed.

The persistence of random walker can quantify the kinetics of transport limited reactions and predict the time to reach a target, but is challenging for non-stationary random processes with a large number of degrees of freedom. The authors introduce a method to determine the persistence exponent of random processes with general non-stationary dynamics.

In the therapeutic arsenal to treat moderate to severe psoriasis, the new agents are secukinumab and ustekinumab, which are fully human monoclonal antibodies, directed against IL-17A and IL-12/23, respectively, which have been shown to be effective and safe in several studies. Their side effects are rare, and the most frequently reported side effects were infection, especially nasopharyngitis, headache, pruritus, high blood pressure, and low back pain. Unlike the side effects, the paradoxical reaction can be defined by the appearance or exacerbation of a pathological condition that usually responds to a certain class of drug. The appearance of this reaction in patients using anti-interleukins is poorly described; however, as they are new drugs, they may be more common than the literature reports. We describe a case of a paradoxical reaction, with the appearance of atopic dermatitis, after using secukinumab to treat psoriasis.

Objectives: Recurrent urinary tract infections (rUTIs) occur frequently after kidney transplantation (KT), however their optimal management remains undefined. This study aimed to identify risk factors for rUTI and to validate a protocol for UTI and rUTI treatment after KT. Methods: This retrospective cohort study involved patients undergoing KT between January 2013 and July 2016. Patients were followed-up from day of KT until graft loss, death or end of follow-up (31 December 2018). We analysed all episodes of symptomatic UTI. The main outcome measure was rUTI after KT. Analysis was done per episode in a multilevel approach; patient features were considered in the distal level and UTI features in the proximal level. Univariate and multivariate analyses were performed by Cox regression. A propensity score was used to adjust the risk of patients with carbapenem-resistant Enterobacteriaceae. Results: During the study period, 787 patients underwent KT, of whom 152 (19.3%) developed 356 UTI episodes. The most common micro-organisms wereEscherichia coli (165/356; 46.3%) and Klebsiella pneumoniae (101/356; 28.4%). Multidrug-resistant micro-organisms were isolated in 161 UTIs (45.2%). Risk factors for rUTI were diabetic nephropathy as the cause of end-stage renal disease (P = 0.02), UTI in first 180 days after KT (P = 0.04), anatomic alteration of the urinary tract at UTI diagnosis (P = 0.004) and length of time to effective therapy (P = 0.002); UTI treatment duration according to institutional protocol (P = 0.04) was the only protective factor identified. Conclusion: Appropriate therapy duration has an impact on rUTI prevention after KT.

Abstract Extracytoplasmic function (ECF) sigma factors are key transcriptional regulators that prokaryotes have evolved to respond to environmental challenges. Streptomyces tsukubaensis harbours 42 ECFs to reprogram stress-responsive gene expression. Among them, SigG1 features a minimal conserved ECF σ2–σ4 architecture and an additional C-terminal extension that encodes a SnoaL_2 domain, which is characteristic for ECF σ factors of group ECF56. Although proteins with such domain organisation are widely found among Actinobacteria, the functional role of ECFs with a fused SnoaL_2 domain remains unknown. Our results show that in addition to predicted self-regulatory intramolecular amino acid interactions between the SnoaL_2 domain and the ECF core, SigG1 activity is controlled by the cognate anti-sigma protein RsfG, encoded by a co-transcribed sigG1-neighbouring gene. Characterisation of ∆sigG1 and ∆rsfG strains combined with RNA-seq and ChIP-seq experiments, suggests the involvement of SigG1 in the morphological differentiation programme of S. tsukubaensis. SigG1 regulates the expression of alanine dehydrogenase, ald and the WhiB-like regulator, wblC required for differentiation, in addition to iron and copper trafficking systems. Overall, our work establishes a model in which the activity of a σ factor of group ECF56, regulates morphogenesis and metal-ions homeostasis during development to ensure the timely progression of multicellular differentiation.

Abstract Introduction In canine visceral leishmaniasis (CVL), lymphopenia, and the disorganization of lymphoid organs such as spleen and lymph nodes have been demonstrated. However, the involvement of thymus in CVL has not been evaluated so far. Herein, we investigated whether the thymus can be colonized by Leishmania infantum in naturally infected dogs. Methods Thymus were obtained from 16 of 58 dogs and samples of this organ were submitted to immunohistochemistry for laminin and fibronectin detection, histopathology, in situ hybridization and polymerase chain reaction (PCR) targeting the gene ITS‐1 for Leishmania and sequenced. Samples of spleen, skin and popliteal lymph nodes were collected and submitted to immunohistochemistry and parasitological culture followed by multilocus enzyme electrophoresis. Results L. infantum was identified in all dogs. DNA and amastigote forms of Leishmania were detected in the thymus from 16 dogs by PCR and in eight by immunohistochemistry. Besides thymus, parasites were detected in spleen, lymph nodes, and skin. A granulomatous or pyogranulomatous thymitis was observed in eight dogs associated to intact amastigotes forms of this parasite. Fibronectin deposition in thymus was higher in dogs with more clinical signs. Conclusions These results demonstrate that the thymus of dogs can be parasitized by L. infantum, which may generate inflammatory reactions leading to alterations in thymic microarchitecture.

Abstract Background The renal Doppler resistive index (renal RI) is a noninvasive tool that has been used to assess renal perfusion in the intensive care unit (ICU) setting. However, many parameters have been described as influential on the values of renal RI. Therefore, we proposed this study to evaluate the variables that could impact renal RI in critically ill patients. Methods A prospective observational study was performed in a 14-bed medical–surgical adult ICU. All consecutive patients admitted to the ICU during the study period were evaluated for eligibility. Renal RI was performed daily until the third day after ICU admission, death, or renal replacement therapy (RRT) requirement. Clinical and blood test data were collected throughout this period. Acute kidney injury (AKI) reversibility was categorized as transient (normalization of renal function within 3 days of AKI onset) or persistent (non-resolution of AKI within 3 days of onset or need for RRT). A linear mixed model was applied to evaluate the factors that could influence renal RI. Results Eighty-three consecutive patients were included. Of these, 65% were male and 50.6% were medical admissions. Mean SAPS 3 was 47 ± 16. Renal RI was significantly different between no-AKI (0.64 ± 0.06), transient AKI (0.64 ± 0.07), and persistent AKI groups (0.70 ± 0.08, p

A nautical chart is a cartographic document specifically designed to meet the requirements of safe maritime navigation. Nautical charts are not only important for navigation but are used for environmental studies, economic aspects, urban and tourist developments among others. The objective of this text was to analyze and evaluate the relevance of four documentary languages for the indexing of nautical charts. A sample of different nautical charts was taken, the keywords in this sample representing each document were extracted. Four documentary languages were selected identifying the relevance of each vocabulary in relation to each keyword. No selected vocabulary could represent at least 50 % of the selected key words, nor do they represent all the typologies of nautical charts. It allows to infer that the controlled vocabularies surveyed do not offer enough specific terms for the exhaustive thematic description of nautical charts.

The deep-sea constitutes a true unexplored frontier and a potential source of innovative drug scaffolds. Here, we present the genome sequence of two novel marine actinobacterial strains, MA3_2.13 and S07_1.15, isolated from deep-sea samples (sediments and sponge) and collected at Madeira archipelago (NE Atlantic Ocean; Portugal). The de novo assembly of both genomes was achieved using a hybrid strategy that combines short-reads (Illumina) and long-reads (PacBio) sequencing data. Phylogenetic analyses showed that strain MA3_2.13 is a new species of the Streptomyces genus, whereas strain S07_1.15 is closely related to the type strain of Streptomyces xinghaiensis. In silico analysis revealed that the total length of predicted biosynthetic gene clusters (BGCs) accounted for a high percentage of the MA3_2.13 genome, with several potential new metabolites identified. Strain S07_1.15 had, with a few exceptions, a predicted metabolic profile similar to S. xinghaiensis. In this work, we implemented a straightforward approach for generating high-quality genomes of new bacterial isolates and analyse in silico their potential to produce novel NPs. The inclusion of these in silico dereplication steps allows to minimize the rediscovery rates of traditional natural products screening methodologies and expedite the drug discovery process.

The oxidative stress response is a key mechanism that microorganisms have to adapt to changeling environmental conditions. Adaptation is achieved by a fine-tuned molecular response that extends its influence to primary and secondary metabolism. In the past, the role of the intracellular redox status in the biosynthesis of tacrolimus in Streptomyces tsukubaensis has been briefly acknowledged. Here, we investigate the impact of the oxidative stress response on tacrolimus biosynthesis in S. tsukubaensis. Physiological characterization of S. tsukubaensis showed that the onset of tacrolimus biosynthesis coincided with the induction of catalase activity. In addition, tacrolimus displays antioxidant properties and thus a controlled redox environment would be beneficial for its biosynthesis. In addition, S. tsukubaensis ∆ahpC strain, a strain defective in the H2O2-scavenging enzyme AhpC, showed increased production of tacrolimus. Proteomic and transcriptomic studies revealed that the tacrolimus over-production phenotype was correlated with a metabolic rewiring leading to increased availability of tacrolimus biosynthetic precursors. Altogether, our results suggest that the carbon source, mainly used for cell growth, can trigger the production of tacrolimus by modulating the oxidative metabolism to favour a low oxidizing intracellular environment and redirecting the metabolic flux towards the increase availability of biosynthetic precursors.

Cancer frequency and prevalence have been increasing in the past decades, with devastating impacts on patients and their families. Despite the great advances in targeted approaches, there is still a lack of methods to predict individual patient responses, and therefore treatments are tailored according to average response rates. “Omics” approaches are used for patient stratification and choice of therapeutic options towards a more precise medicine. These methods, however, do not consider all genetic and non-genetic dynamic interactions that occur upon drug treatment. Therefore, the need to directly challenge patient cells in a personalized manner remains. The present review addresses the state of the art of patient-derived in vitro and in vivo models, from organoids to mouse and zebrafish Avatars. The predictive power of each model based on the retrospective correlation with the patient clinical outcome will be considered. Finally, the review is focused on the emerging zebrafish Avatars and their unique characteristics allowing a fast analysis of local and systemic effects of drug treatments at the single-cell level. We also address the technical challenges that the field has yet to overcome.

Resumo Este artigo discute o sentido atual das políticas de avaliaçãona e da escola ao apresentar a investigação realizada por pesquisadores brasileiros e portugueses, com a participação de vinte escolas públicas, nas cidades de São Paulo e Campinas (Brasil) e do Porto (Portugal). Referenciando-se na Avaliação Institucional Participativa e na Qualidade Negociada, a pesquisa se junta aos profissionais das escolas e de setores da administração educacional, com a formação de grupos de estudo em cada uma das universidades. O artigo aborda criticamente a função expertise da pesquisa que frequentemente legitima avaliações centradas nos produtos, portando credibilidade aos testes padronizados, à proliferação de uma avaliocracia, com consequente alteração de procedimentos de inspeção e direção escolares, além de mudanças na gestão dos sistemas educativos, corrompendo/deformando o conceito de autonomia escolar, favorecendo a proliferação de escolas administradas por concessão, o estímulo ao cheque-ensino, bem como o aumento e naturalização das desigualdades escolares e uma dada representação da sociedade do conhecimento, que refuncionaliza a formação profissional para as classes populares, recriando a dualidade do ensino. Em contraponto, a pesquisa argumenta as possibilidades de um circuito virtuoso do ensino, da pesquisa e da extensão como método na relação com escolas públicas, partindo de uma concepção de Qualidade Negociada que, em conjunto com profissionais e comunidade, em cada escola, inicia processos deautoavaliação, com intencionalidade de transformação e com a possibilidade de desenvolvimento de novas relações dentro e fora da escola, reforçando a aprendizagem estratégica da competência coletiva dos atores sociais em prol da escola pública de qualidade social.

Environmental stress in newly-emerged adult insects can have dramatic consequences on their life traits (e.g., dispersion, survival and reproduction) as adults. For instance, insects sublethally exposed to environmental stressors (e.g., insecticides) can gain fitness benefits as a result of hormesis (i.e., benefits of low doses of compounds that would be toxic at higher doses). Here, we experimentally tested whether sublethal exposure to the insecticide imidacloprid would hormetically affect the sexual fitness of newly-emerged adults of the Neotropical brown stink bug Euschistus heros (Hemiptera: Heteroptera: Pentatomidae), which is the most abundant and prevalent insect pest in Neotropical soybean fields. We evaluated the sexual fitness of four couple combinations: unexposed couples, exposed females, exposed males, and exposed couples. Sublethal exposure to dry residues (i.e., contact) of imidacloprid (at 1% of recommended field rate) did not affect insect survival, but led to higher mating frequencies when at least one member of the couple was exposed. However, the average mating duration was shortened when only females were exposed to imidacloprid. Moreover, exposed males showed higher locomotory (walking) activity, lower respiration rates and induced higher fecundity rates when mated to unexposed females. Although the reproductive tracts of exposed males did not differ morphometrically from unexposed males, their accessory glands exhibited positive reactions for acidic and basic contents. Our findings suggest that males of the Neotropical brown stink bug hormetically increase their sexual fitness when cued by impending insecticidal stress in early adulthood.

After the report of a second case of canine visceral leishmaniasis (CVL) in São Bento da Lagoa, Itaipuaçu, in the municipality of Maricá, Rio de Janeiro State, an epidemiological survey was carried out, through active search, totaling 145 dogs. Indirect immunofluorescence assay (IFA), enzyme-linked immunosorbent assay (ELISA), and rapid chromatographic immunoassay based on dual-path platform (DPP(r)) were used to perform the serological examinations. The parasitological diagnosis of cutaneous fragments was performed by parasitological culture, histopathology, and immunohistochemistry. In the serological assessment, 21 dogs were seropositive by IFA, 17 by ELISA, and 11 by DPP(r), with sensitivity of 66.7%, 66.7% and 50%, and specificity of 87.2%, 90.2% and 94%, respectively for each technique. The immunohistochemistry of bone marrow using the cell-block technique presented the best results, with six positive dogs found, three of which tested negative by the other parasitological techniques. Leishmania sp. was isolated by parasitological culture in three dogs. The detection of autochthonous Leishmania infantum in Itaipuaçu, and the high prevalence of seropositive dogs confirm the circulation of this parasite in the study area and alert for the risk of expansion in the State of Rio de Janeiro.

Resumo: Recentemente assistiu-se à emergência de infeções na comunidade por Staphylococcus aureus meticilina-resistente (MRSA) em indivíduos sem fatores de risco. O MRSA associado à comunidade (CA-MRSA) parece ser mais virulento, causando desde infeções superficiais da pele e tecidos moles até fasceíte necrosante e, raramente, pneumonia.O CA-MRSA foi inicialmente identificado na Austrália no início da década de 80 e, após cerca de duas décadas, surgiu nos EUA e em vários países da Europa, Ásia e América do Sul. Não existe informação disponível acerca da prevalência em Portugal.Os autores reportam o primeiro caso de infeção por CA-MRSA em Portugal, num adulto jovem com pneumonia necrotizante grave complicada por empiema bilateral e insuficiência respiratória. Abstract: Methicillin-resistant Staphylococcus aureus (MRSA) has recently emerged as a cause of community-acquired infections among individuals without risk factors. Community-associated MRSA (CA-MRSA) appears to be more virulent, causing superficial mild skin and soft tissue infections to severe necrotizing fasciitis, and in rare cases, pneumonia.Community-associated MRSA was first reported in Australia in the early 80s, after almost two decades in the USA, and then in several countries in Europe, Asia and South America. No data exists in Portugal.We report the first case of CA-MRSA infection in Portugal, in a young adult with severe necrotizing pneumonia, complicated with bilateral empyema and respiratory failure. Palavras-chave: comunidade associada, MRSA, Staphylococcus aureus, pneumonia necrosante, empiema, Keywords: Community-associated, MRSA, Staphylococcus aureus, Necrotizing pneumonia, Empyema

Se proponen cuatro indicadores para evaluar la calidad de la estructura sistemática del tesauro, considerando que las especificaciones incluidas en las normas para su diseño y desarrollo, así como los principios de la teoría de la clasificación son los requisitos de calidad que deben alcanzar las características inherentes de los tesauros. Las características que no cumplen con dichos requisitos se consideran no conformidades. Se proponen cuatro indicadores para medir las no conformidades, que fueron probados en tres tesauros en español (DeCS, Spines y Tesauro de la Unesco). Los resultados, que constituyen no conformidades, fueron: 1) Porcentaje de términos preferentes que representan más de un concepto: 10,8 % para DeCS, 7,3 % Spines y 10,9 % Unesco. 2) Porcentaje de términos preferentes que carecen de relación jerárquica: 0 DeCS, 1,4 % Spines y 1,1 % Unesco. 3) Porcentaje de términos preferentes con dos o más términos genéricos: 53,8 % DeCS, 14,9 % Spines, 0 Unesco. 4) Porcentaje de términos preferentes con un solo término específico: 13,5 % DeCS, 3,5 % Spines, 10,3 % Unesco. Se concluye que estos indicadores cumplen con los criterios de un buen indicador y pueden ser útiles para la evaluación de la calidad de la estructura sistemática del tesauro durante el proceso de diseño y desarrollo.