NCYPred: A Bidirectional LSTM Network With Attention for Y RNA and Short Non-Coding RNA Classification.

Short non-coding RNAs (sncRNAs) are involved in multiple cellular processes and can be divided into dozens of classes. Among such classes, Y RNAs have been gaining attention, being essential factors for the initiation of DNA replication on vertebrates, as well as potential tumor biomarkers. Homologs have also been described in nematodes and insects, as well as related sequences in bacteria. Methods capable of accurately predicting Y RNA transcripts are lacking. In this work, we developed an attention-based LSTM network and built a classification model able to classify sncRNAs (including Y RNA) directly from nucleotide sequences. A dataset consisting of 45,447 sncRNA sequences, from a wide range of organisms, obtained from Rfam 14.3 was built. Performance evaluation demonstrated that our proposed method, NCYPred (Non-Coding/Y RNA Prediction), can accurately predict Y RNA sequences and their homologs, as well as 11 additional classes, achieving results comparable with state-of-the-art methods. We also demonstrate that applying t-SNE on learned sequence representations could be useful for sequence analysis. Our model is freely available as a web-server (https://www.gpea.uem.br/ncypred/).

Novel arylcarbamate-N-acylhydrazones derivatives as promising BuChE inhibitors: Design, synthesis, molecular modeling and biological evaluation.

A novel series of arylcarbamate-N-acylhydrazones derivatives have been designed and synthesized as potential anti-cholinesterase agents. In vitro studies revealed that these compounds demonstrated selective for butyrylcholinesterase (BuChE) with potent inhibitory activity. The compounds 10a-d, 12b and 12d were the most potent BuChE inhibitors with IC50 values of 0.07-2.07 µM, highlighting the compound 10c (IC50 = 0.07 µM) which showed inhibitory activity 50 times greater than the reference drug donepezil (IC50 = 3.54 µM). The activity data indicates that the position of the carbamate group in the aromatic ring has a greater influence on the inhibitory activity of the derivatives. The enzyme kinetics studies indicate that the compound 10c has a non-competitive inhibition against BuChE with Ki value of 0.097 mM. Molecular modeling studies corroborated the in vitro inhibitory mode of interaction and show that compound 10c is stabilized into hBuChE by strong hydrogen bond interaction with Tyr128, π-π stacking interaction with Trp82 and CH⋯O interactions with His438, Gly121 and Glu197. Based on these data, compound10cwas identified as low-cost promising candidate for a drug prototype for AD treatment.

Synthesis and antifungal activity of new hybrids pyrimido[4,5-d]pyridazinone-N-acylhydrazones.

Paracoccidioidomycosis is an endemic mycosis in Latin America for which there is a high mortality rate and limited treatment options. There are no specific drugs to treat the systemic disease. Thus, there is a need for further studies focused on the development of specific drugs. In this work we synthesized new hybrids pyrimido[4,5-d]pyridazinone-N-acylhydrazone (5a-p) by simple methodologies with good yields. The antifungal activity of compounds was evaluated against P. brasiliensis (Pb18) and Candida spp. Compounds 5a, 5f, 5i, 5 k, 5m and 5n showed significant inhibition against Pb18 with MIC of 0.125 to 64 µg mL-1. Compound 5a is the most promising, showing potent fungicidal profile with MFC of 0.5 µg mL-1, synergic effect with amphotericin B, besides showing no toxicity against HeLa and Vero cells.

Targeting the Homoserine Dehydrogenase of Paracoccidioides Species for Treatment of Systemic Fungal Infections.

This work evaluated new potential inhibitors of the enzyme homoserine dehydrogenase (HSD) of Paracoccidioides brasiliensis, one of the etiological agents of paracoccidioidomycosis. The tertiary structure of the protein bonded to the analogue NAD, and l-homoserine was modeled by homology. The model with the best output was subjected to gradient minimization, redocking, and molecular dynamics simulation. Virtual screening simulations with 187,841 molecules purchasable from the Zinc database were performed. After the screenings, 14 molecules were selected and analyzed by the use of absorption, distribution, metabolism, excretion, and toxicity criteria, resulting in four compounds for in vitro assays. The molecules HS1 and HS2 were promising, exhibiting MICs of 64 and 32 µg · ml-1, respectively, for the Pb18 isolate of P. brasilensis, 64 µg · ml-1 for two isolates of P. lutzii, and also synergy with itraconazole. The application of these molecules to human-pathogenic fungi confirmed that the HSD enzyme may be used as a target for the development of drugs with specific action against paracoccidioidomycosis; moreover, these compounds may serve as leads in the design of new antifungals.

Incidence of hemoglobinopathies in Northwest Paraná, Brazil / Incidência de hemoglobinopatias no noroeste do Paraná - Brasil

Immigrants from many parts of the world settled in Paraná State in Brazil, contributing to the diversified genetic patrimony of its population. This characteristic led us to investigate, for the first time, the incidence of hemoglobinopathies in the population of one city in Paraná. A total of 585 blood samples were collected from individuals living in Umuarama. Hemoglobinopathy tests were carried out using the classical methodology. The results show that 93.17 percent have the normal electrophoretic pattern (AA); 2.73 percent have the beta-thalassemia trait; 2.05 percent have the sickle cell trait (AS); 1.37 percent are heterozygous for alpha-thalassemia; 0.34 percent heterozygous for hemoglobin C (AC); 0.17 percent have both alpha-thalassemia and sickle cell traits and 0.17 percent are heterozygous for alpha and beta-thalassemia. A comparison of these results with other works suggests that the frequency of hemoglobinopathies can significantly vary between cities within the same state. This fact may be attributed to the miscegenation of the population or even to the diverse prevalence of hemoglobinopathies in distinct populations.

O estado do Paraná, no Brasil, recebeu imigrantes de diversas partes do mundo. Este fato atribuiu à sua população um patrimônio genético bastante diversificado. Esta característica nos levou a investigar, pela primeira vez, a incidência de hemoglobinopatias na população que vive em uma de suas cidades. Para isso, foram coletadas amostras de sangue de 585 pessoas residentes em Umuarama-PR. A triagem para hemoglobinopatias foi realizada através da metodologia clássica. Os resultados mostraram que 93,17 por cento apresentaram o padrão eletroforético normal (AA); 2,73 por cento apresentaram o traço beta-talassêmico; 2,05 por cento o traço falciforme (AS); 1,37 por cento heterozigotos para alfa-talassemia; 0,34 por cento heterozigotos para hemoglobina C (AC); 0,17 por cento tiveram a associação entre alfa talassemia e traço falciforme e também 0,17 por cento tiveram a associação entre os traços alfa e beta talassêmicos. A comparação destes resultados com o de outros autores sugere que a freqüência das hemoglobinopatias pode variar significativamente dentro de cidades de um mesmo estado. Este fato pode ser atribuído à miscigenação da população ou também à prevalência distinta de hemoglobinopatias em populações diferenciadas, que foram o alvo de outros estudos.