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Viper venom phospholipase A2 enzymes (vvPLA2s) and phospholipase A2-like (PLA2-like) proteins are two of the principal toxins in viper venom that are responsible for the severe myotoxic and neurotoxic effects caused by snakebite envenoming, among other pathologies. As snakebite envenoming is the deadliest neglected tropical disease, a complete understanding of these proteins’ properties and their mechanisms of action is urgently needed. Therefore, we created a database comprising information on the holo-form, cofactor-bound 3D structure of 217 vvPLA2 and PLA2-like proteins in their physiologic environment, as well as 79 membrane-bound viper species from 24 genera, which we have made available to the scientific community to accelerate the development of new anti-snakebite drugs. In addition, the analysis of the sequenced, 3D structure of the database proteins reveals essential aspects of the anatomy of the proteins, their toxicity mechanisms, and the conserved binding site areas that may anchor universal interspecific inhibitors. Moreover, it pinpoints hypotheses for the molecular origin of the myotoxicity of the PLA2-like proteins. Altogether, this study provides an understanding of the diversity of these toxins and how they are conserved, and it indicates how to develop broad, interspecies, efficient small-molecule inhibitors to target the toxin’s many mechanisms of action.

Since the beginning of the XXI century, Leishmaniasis has been integrated into the World Health Organization’s list of the 20 neglected tropical diseases, being considered a public health issue in more than 88 countries, especially in the tropics, subtropics, and the Mediterranean area. Statistically, this disease presents a world prevalence of 12 million cases worldwide, with this number being expected to increase shortly due to the 350 million people considered at risk and the 2–2.5 million new cases appearing every year. The lack of an appropriate and effective treatment against this disease has intensified the interest of many research groups to pursue the discovery and development of novel treatments in close collaboration with the WHO, which hopes to eradicate it shortly. This paper intends to highlight the quinoline scaffold’s potential for developing novel antileishmanial agents and provide a set of structural guidelines to help the research groups in the medicinal chemistry field perform more direct drug discovery and development programs. Thus, this review paper presents a thorough compilation of the most recent advances in the development of new quinoline-based antileishmanial agents, with a particular focus on structure–activity relationship studies that should be considerably useful for the future of the field.

The membrane-active nature of phospholipase A2-derived peptides makes them potential candidates for antineoplastic and antibacterial therapies. Two short 13-mer C-terminal fragments taken from snake venom Lys49-PLA2 toxins (p-AppK and p-Acl), differing by a leucine/phenylalanine substitution, were synthesized and their bioactivity was evaluated. Their capacity to interfere with the survival of Gram-positive and Gram-negative bacteria as well as with solid and liquid tumors was assessed in vitro. Toxicity to red blood cells was investigated via in silico and in vitro techniques. The mode of action was mainly studied by molecular dynamics simulations and membrane permeabilization assays. Briefly, both peptides have dual activity, i.e., they act against both bacteria, including multidrug-resistant strains and tumor cells. All tested bacteria were susceptible to both peptides, Pseudomonas aeruginosa being the most affected. RAMOS, K562, NB4, and CEM cells were the main leukemic targets of the peptides. In general, p-Acl showed more significant activity, suggesting that phenylalanine confers advantages to the antibacterial and antitumor mechanism, particularly for osteosarcoma lines (HOS and MG63). Peptide-based treatment increased the uptake of a DNA-intercalating dye by bacteria, suggesting membrane damage. Indeed, p-AppK and p-Acl did not disrupt erythrocyte membranes, in agreement with in silico predictions. The latter revealed that the peptides deform the membrane and increase its permeability by facilitating solvent penetration. This phenomenon is expected to catalyze the permeation of solutes that otherwise could not cross the hydrophobic membrane core. In conclusion, the present study highlights the role of a single amino acid substitution present in natural sequences towards the development of dual-action agents. In other words, dissecting and fine-tuning biomembrane remodeling proteins, such as snake venom phospholipase A2 isoforms, is again demonstrated as a valuable source of therapeutic peptides.

(S)-Norcoclaurine is synthesized in vivo through a metabolic pathway that ends with (S)-norcoclaurine synthase (NCS). The former constitutes the scaffold for the biosynthesis of all benzylisoquinoline alkaloids (BIAs), including many drugs such as the opiates morphine and codeine and the semi-synthetic opioids oxycodone, hydrocodone, and hydromorphone. Unfortunately, the only source of complex BIAs is the opium poppy, leaving the drug supply dependent on poppy crops. Therefore, the bioproduction of (S)-norcoclaurine in heterologous hosts, such as bacteria or yeast, is an intense area of research nowadays. The efficiency of (S)-norcoclaurine biosynthesis is strongly dependent on the catalytic efficiency of NCS. Therefore, we identified vital NCS rate-enhancing mutations through the rational transition-state macrodipole stabilization method at the Quantum Mechanics/Molecular Mechanics (QM/MM) level. The results are a step forward for obtaining NCS variants able to biosynthesize (S)-norcoclaurine on a large scale.

Leishmaniasis is one of the most neglected diseases in modern times, mainly affecting people from developing countries of the tropics, subtropics and the Mediterranean basin, with approximately 350 million people considered at risk of developing this disease. The incidence of human leishmaniasis has increased over the past decades due to failing prevention and therapeutic measures—there are no vaccines and chemotherapy, which is problematic. Acridine derivatives constitute an interesting group of nitrogen-containing heterocyclic compounds associated with numerous bioactivities, with emphasis to their antileishmanial potential. The present work builds on computational studies focusing on a specific enzyme of the parasite, S-adenosylmethionine decarboxylase (AdoMet DC), with several 1,2,3,4-tetrahydro-acridines emerging as potential inhibitors, evidencing this scaffold as a promising building block for novel antileishmanial pharmaceuticals. Thus, several 1,2,3,4-tetrahydroacridine derivatives have been synthesized, their activity against Leishmania (Leishmania) infantum promastigotes evaluated and a structure–activity relationship (SAR) study was developed based on the results obtained. Even though the majority of the 1,2,3,4-tetrahydroacridines evaluated presented high levels of toxicity, the structural information gathered in this work allowed its application with another scaffold (quinoline), leading to the obtention of N1,N12-bis(7-chloroquinolin-4-yl)dodecane-1,12-diamine (12) as a promising novel antileishmanial agent (IC50 = 0.60 ± 0.11 μM, EC50 = 11.69 ± 3.96 μM and TI = 19.48).

α-Amylase has been considered an important therapeutic target for the management of type 2 diabetes mellitus (T2DM), decreasing postprandial hyperglycaemia (PPHG). In the present work, a panel of 40 structurally related flavonoids was tested, concerning their ability to inhibit α-amylase activity, using a microanalysis screening system, an inhibitory kinetic analysis and molecular docking calculations. From the obtained results, it was possible to observe that the flavone with a -Cl ion at 3-position of C-ring, an –OH group at 3′- and 4′- positions of B-ring and at 5- and 7- positions of A-ring and the C2 = C3 double bond, was the most active tested flavonoid, through competitive inhibition. In conclusion, some of the tested flavonoids have shown promising inhibition of α-amylase and may be considered as possible alternatives to the modulation of T2DM.

Nowadays, leishmaniasis constitutes a public health issue in more than 88 countries, affecting mainly people from the tropics, subtropics, and the Mediterranean area. Every year, the prevalence of this infectious disease increases, with the appearance of 1.5–2 million new cases of cutaneous leishmaniasis and 500,000 cases of visceral leishmaniasis, endangering approximately 350 million people worldwide. Therefore, the absence of a vaccine or effective treatment makes the discovery and development of new antileishmanial therapies one of the focuses for the scientific community that, in association with WHO, hopes to eradicate this disease shortly. This paper is intended to highlight the relevance of nitrogen- and oxygen-containing tricyclic heterocycles, particularly acridine and xanthene derivatives, for the development of treatments against leishmaniasis. Thus, in this review, a thorough compilation of the most promising antileishmanial acridine and xanthene derivatives is performed from both natural and synthetic origins. Additionally, some structure–activity relationship studies are also depicted and discussed to provide insight into the optimal structural features responsible for these compounds’ antileishmanial activity.

α-Glucosidase inhibitors are described as the most effective in reducing post-prandial hyperglycaemia (PPHG) from all available anti-diabetic drugs used in the management of type 2 diabetes mellitus. As flavonoids are promising modulators of this enzyme’s activity, a panel of 44 flavonoids, organised in five groups, was screened for their inhibitory activity of α-glucosidase, based on in vitro structure–activity relationship studies. Inhibitory kinetic analysis and molecular docking calculations were also applied for selected compounds. A flavonoid with two catechol groups in A- and B-rings, together with a 3-OH group at C-ring, was the most active, presenting an IC50 much lower than the one found for the most widely prescribed α-glucosidase inhibitor, acarbose. The present work suggests that several of the studied flavonoids have the potential to be used as alternatives for the regulation of PPHG.

Background: Glutamine synthetase (GS) is a crucial enzyme to the nitrogen cycle with great commercial and pharmaceutical value. Current inhibitors target the active site, affecting GS activity indiscriminately in all organisms. As the active site is located at the interface between two monomers, the protein-protein interface (PPI) of GSs gains a new role, by providing new targets for enzyme inhibition. Exploring GSs PPI could allow for the development of inhibitors selective for specific organisms. Here we map the PPI of three GSs—human (hsGS), maize (zmGS) and Mycobacterium tuberculosis (mtGS)—and unravel new drugable pockets. Methods: The PPI binding free energy coming from key residues on three GSs from different organisms were mapped by computational alanine scan mutagenesis, applying a multiple dielectric constant MM-PBSA methodology. The most relevant residues for binding are referred as hot-spots. Drugable pockets on GS were detected with the Fpocket software. Results and Conclusions: A total of 23, 19 and 30 hot-spots were identified on hsGS, zmGS and mtGS PPI. Even possessing differences in the hot-spots, hsGS and zmGS PPI are overall very similar. On the other hand, mtGS PPI differs greatly from hsGS and zmGS PPI. A novel drugable pocket was detected on the mtGS PPI. It seems particularly promising for the development of selective anti-tuberculosis drugs given its location on a PPI region that is highly populated with hot-spots and is completely different from the hsGS and zmGS PPIs. Drugs targeting this pockets should be inactive on eukaryotic GS II enzymes.

Research Purpose: The objective of this study is trying to answer the question “Are smart cities human and inclusive?” Methodology: The method used was the systematic literature review. Research was conducted in sources Scopus, Scielo, EBSCO, Web of Science and Google Scholar. The discussion of results has been developed with a synthesis of findings. Findings: We concluded that the issue of human aspects an inclusion in smart cities, is a topic that has been debated directly or indirectly by numerous authors. Vast majority alert to human aspects and inclusion in smart cities. Originality/Value: The importance of smart cities is growing today in our society. That is important to understand how it treats its citizens and guarantees human issues and social inclusion.

The COVID-19 pandemic has brought many challenges to human beings, related to not only health and way of life but also teaching because of the interruption of the standard training at universities imposed by lockdowns. Concerning the latter, the academic community had to reinvent itself, in many ways, to carry on with prepandemic education. This article focuses on the use of modern technology and software to create a virtual, highly interactive classroom where a remote but still hands-on course on molecular bioinformatics can be taught, motivating the university students and helping them learn the course contents without significant compromises imposed by successive lockdowns. We implemented such a virtual hands-on molecular bioinformatics course in the second semester of the 2020/2021 academic year. Furthermore, we compared the learning outcomes with those for the earlier editions of the same course in the pre-COVID-19 era, in which the more traditional teaching method was used where all teaching was delivered with physically present lecturers. The virtual classroom proposed here allowed the students to develop skills close to, although slightly below, those obtained with physically present learning.

Cotton is one of the largest agricultural commodities that generate various sources of foreign exchange and employment worldwide. However, water deficiency is an environmental factor that limits the production of this crop, especially in semi-arid regions. We evaluated pyruvate supplementation to mitigate the effects of water stress on colored cotton. Experiments were conducted in a greenhouse. We studied two forms of pyruvate supplementation (SP1- via seed and foliar and SP2- only via foliar); three conditions of irrigation management of the plants: water restriction in the vegetative phase (VE), flowering (FL), and vegetative and flowering (VE/FL); and additional treatment (total irrigation throughout the crop cycle and without pyruvate supplementation). The experimental design included a randomized block in a 2 × 3 + 1 factorial scheme. The factors resulted in seven treatments with three replications, with a total of 21 experimental units. Gas exchange, enzyme activity, and production of components were evaluated. Water restriction in the vegetative phase does not cause losses in BRS Jade cotton when supplemented with pyruvate. However, in the flowering and vegetative phases plus flowering, it reduces gas exchange and production components and increases the activity of antioxidant enzymes in relation to plants under full irrigation. Supplementation with pyruvate via seed plus foliar (SP1) was better for BRS Jade cotton grown under water restriction.

As estimativas de incidência das Infecções Sexualmente Transmissíveis atingem os diversos públicos e possuem múltiplas etiologias, sintomatologias e complicações que podem ser prevenidas, diagnosticadas e tratadas precocemente através das práticas de educação em saúde na atenção primária. O objetivo do estudo foi descrever a experiência da educação em saúde vivenciada por estudantes na Atenção Primária de acordo com a proposta metodológica de educação defendida por Paulo Freire. Foi notória a boa aceitação da proposta pela população, a qual demonstrou interesse na troca de conhecimentos, participação ativa durante todo o processo e palavras de agradecimento pelo espaço ofertado.

Background/Objectives: According to the World Health Organization, the gold standard for diagnosing COVID-19 is the Reverse Transcription Polymerase Chain Reaction (RT-PCR) test. However, to confirm the diagnosis in patients who have negative results but still show symptoms, imaging tests, especially computed tomography (CT), are used. In this study, using convolutional neural networks, we compared the following topics using manual and automatic lung segmentation methods: (1) the performance of an automatic segmentation of COVID-19 areas using two strategies for data partitioning, CT scans, and slice strategies; (2) the performance of an automatic segmentation method of COVID-19 when there was interobserver agreement between two groups of radiologists; and (3) the performance of the area affected by COVID-19. Methods: Two datasets and two deep neural network architectures are used to evaluate the automatic segmentation of lungs and COVID-19 areas. The performance of the U-Net architecture is compared with the performance of a new architecture proposed by the research group. Results: With automatic lung segmentation, the Dice metrics for the segmentation of the COVID-19 area were 73.01 ± 9.47% and 84.66 ± 5.41% for the CT-scan strategy and slice strategy, respectively. With manual lung segmentation, the Dice metrics for the automatic segmentation of COVID-19 were 74.47 ± 9.94% and 85.35 ± 5.41% for the CT-scan and the slice strategy, respectively. Conclusions: The main conclusions were as follows: COVID-19 segmentation was slightly better for the slice strategy than for the CT-scan strategy; a comparison of the performance of the automatic COVID-19 segmentation and the interobserver agreement, in a group of 7 CT scans, revealed that there was no statistically significant difference between any metric. [ABSTRACT FROM AUTHOR]

O uso de águas salinas na agricultura irrigada vem se tornando uma realidade em diversas regiões do mundo, entretanto, dependendo do nível de tolerância da cultura ocorrem limitações no crescimento e desenvolvimento. Dessa forma, o uso das estratégias que minimizem o estresse salino nas culturas é fundamental, nesta perspectiva, o ácido salicílico pode atuar como antioxidante e contribuir na tolerância das plantas ao estresse salino. Neste sentido, objetivou-se avaliar os efeitos da aplicação foliar de ácido salicílico na fisiologia e nos componentes de produção do algodoeiro naturalmente colorido cv. BRS Jade cultivado sob estresse salino. As plantas foram conduzidas em lisímetros sob condições de céu aberto, no Centro de Ciências e Tecnologia Agroalimentar pertencente à Universidade Federal de Campina Grande, Pombal-PB. O delineamento utilizado foi em blocos casualizados, em esquema fatorial 5 × 5, sendo cinco níveis de condutividade elétrica da água de irrigação - CEa (0,3; 1,8; 3,3; 4,8 e 6,3 dS m-1) e cinco concentrações de ácido salicílico - AS (0; 1,5; 3,0, 4,5 e 6,0 mM) com três repetições. A irrigação com água a partir de 0,3 dS m-1 reduziu as trocas gasosas, a síntese de pigmentos fotossintéticos e o número de capulhos do algodoeiro cv. BRS Jade. A irrigação com água a partir de 0,3 dS m-1 induziu o fechamento estomático e diminuiu a transpiração, a taxa de assimilação de CO2, os teores de pigmentos fotossintéticos e os componentes de produção do algodoeiro cv. BRS Jade. As concentrações de ácido salicílico de 2,6 e 2,7 mM proporcionaram aumento na taxa de assimilação de CO2 e condutância estomática, respectivamente, das plantas de algodão. A aplicação foliar de ácido salicílico não amenizou os efeitos do estresse salino sobre as trocas gasosas, a síntese de pigmentos fotossintéticos e os componentes de produção do algodoeiro.

ABSTRACT: Water scarcity associated with irregular rainfall in the semi-arid region of Northeastern Brazil stands out as a limiting factor for agricultural production. Thus, the use of waters with high concentration of salts is an alternative to expand irrigated agriculture in this region. In this context, this study evaluated the water status, intercellular electrolyte leakage, photosynthetic pigments, and gas exchange of ‘BRS SC1’ sour passion fruit as a function of irrigation with water of different levels of salinity and potassium doses. The experiment was carried out in pots adapted as drainage lysimeters under field conditions at the Experimental Farm of the Federal University of Campina Grande in São Domingos - PB, Brazil. The experimental design was randomized blocks, in a 5 × 4 factorial scheme, whose treatments were obtained by combining two factors: five levels of electrical conductivity of irrigation water - ECw (0.3, 1.1, 1.9, 2.7, and 3.5 dS m-1), associated with four potassium doses (60, 80, 100, and 120% of the recommendation), with three replicates. Water with electrical conductivity greater than 0.3 dS m-1 reduced the relative water content, chlorophyll a and chlorophyll b contents, CO2 assimilation rate, and instantaneous water use efficiency of ‘BRS SC1’ sour passion fruit plants. The estimated potassium dose of 85% of the recommendation (equivalent to 293 g per plant per year) mitigated the deleterious effects of salt stress on stomatal conductance, transpiration, internal CO2 concentration, and instantaneous carboxylation efficiency of passion fruit ‘BRS SC1’.

Verificar se a implementação da assistência interprofissional durante a reabilitação cardiovascular contribuiu para a redução do tempo de internação dos pacientes submetidos à cirurgia cardíaca. Estudo observacional, transversal, a partir de consulta em prontuários em um hospital de referência no centro oeste brasileiro, durante o mês de janeiro de 2020. Os dados foram armazenados no programa Epi Info 7.2, por meio de dupla digitação. As análises foram realizadas a partir da estatística descritiva, obtendo frequência simples e percentual para as variáveis nominais, e mínima, máxima e média para as variáveis contínuas. Foram acessados 42 prontuários de pacientes submetidos à cirurgia cardiovascular, previamente à implementação da assistência interprofissional, e 50 prontuários de pacientes submetidos à intervenção cirúrgica em questão, após a implementação da assistência interprofissional. Em síntese, houve impacto positivo da implementação da assistência interprofissional para a redução do tempo de internação dos pacientes submetidos à cirúrgica cardiovascular.