Predicted enhanced human propensity of current avian-like H1N1 swine influenza virus from China

Influenza A virus (IAV) subtypes against which little or no pre-existing immunity exists in humans represent a serious threat to global public health. Monitoring of IAV in animal hosts is essential for early and rapid detection of potential pandemic IAV strains to prevent their spread. Recently, the increased pandemic potential of the avian-like swine H1N1 IAV A/swine/Guangdong/104/2013 has been suggested. The virus is infectious in humans and the general population seems to lack neutralizing antibodies against this virus. Here we present an in silico analysis that shows a strong human propensity of this swine virus further confirming its pandemic potential. We suggest mutations which would further enhance its human propensity. We also propose conserved antigenic determinants which could serve as a component of a prepandemic vaccine. The bioinformatics tool, which can be used to further monitor the evolution of swine influenza viruses towards a pandemic virus, are described here and are made publically available (http://www.vin.bg.ac.rs/180/tools/iav-mon.php; http://www.biomedprotection.com/iav-mon.php)

Ibuprofen, a traditional drug that may impact the course of COVID-19 new effective formulation in nebulizable solution

The traditional formulation of ibuprofen is poorly soluble in water, so the administered dose must be 10 times higher than the dose required for a therapeutic effect. The development of a hydrosoluble form of ibuprofen can be a strategy to reach a high concentration in the lungs by using modern inhalation devices. Therefore, the development of an inhalable formulation with high bioavailability in the lungs was the leitmotiv of our investigation. The hypertonic ibuprofen solution to be nebulized (NIH) presents great relevant characteristics: bactericidal, virucidal, mucolytic and has a known anti-inflammatory property. Bactericidal and virucidal effects are related to the physico-chemical properties of Na-ibuprofenate as an amphipathic molecule. It has the capability to insert into the bilayer membranes destabilizing the structure, altering its biological properties and avoiding the duplication or infection. Our preliminary results indicate that the presence of this high ionic strength solution reduces 10 times the amount of ibuprofen necessary to kill bacteria, but also the time to kill 1x106 bacteria, from 4 h (in its absence) to only three minutes (in its presence). That was observed using Pseudomona aeruginosa, methicillin-resistant Staphylococcus aureus and Burkholderia cepacia. Also, ?in vitro´´ ibuprofen demonstrated virucidal activity against the so-called enveloped virus, a family that includes coronavirus strain (2019-nCoV). We observed too, the markedly reduced local inflammation in the airways after administering NIH lays on its ability to inhibit the enzyme cyclooxygenase and to markedly diminish reactive oxygen species (ROS). Other investigators also showed the importance of actin in the rapid spread of virus infection. Furthermore, reorganization of the actin filaments is a key step in lung inflammation induced by systemic inflammatory responses caused by SARS-CoV-2. These findings suggest that the interaction between actin proteins and S1 is involved in the 2019-nCoV infection and pathogenesis.Consequently, the possibility of interfering in this interaction could represent a valid hypothesis for the development of promising therapeutic and prevention strategies. In conclusion, we consider that treating people with COVID-19 with NIH may be beneficial and an opportunity to contribute for the current global health emergency.publishedVersionFil: García Canclini, Néstor. Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina. Instituto de Investigaciones en Ciencias de la Salud; Argentina.Fil: García Canclini, Néstor. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas; Argentina.Fil: Porta, Daniela Josefina. Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina. Instituto de Investigaciones en Ciencias de la Salud; Argentina.Fil: Porta, Daniela Josefina. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas; Argentina.Fil: Muñoz, Sonia Edith. Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina. Instituto de Investigaciones en Ciencias de la Salud; Argentina; Argentina.Fil: Muñoz, Sonia Edith. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas; Argentina.Fil: Alasino, Roxana Valeria. Ministerio de Ciencia y Tecnología de Córdoba. Centro de Excelencia en Productos y Procesos de Córdoba; Argentina.Fil: Beltramo, Dante MiguelIcon. Ministerio de Ciencia y Tecnología de Córdoba. Centro de Excelencia en Productos y Procesos de Córdoba; Argentina

Biological Effects of a De Novo Designed Myxoma Virus Peptide Analogue: Evaluation of Cytotoxicity on Tumor Cells

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EL_PSSM-RT:DNA-binding residue prediction by integrating ensemble learning with PSSM Relation Transformation

Background: Prediction of DNA-binding residue is important for understanding the protein-DNA recognition mechanism. Many computational methods have been proposed for the prediction, but most of them do not consider the relationships of evolutionary information between residues. Results: In this paper, we first propose a novel residue encoding method, referred to as the Position Specific Score Matrix (PSSM) Relation Transformation (PSSM-RT), to encode residues by utilizing the relationships of evolutionary information between residues. PDNA-62 and PDNA-224 are used to evaluate PSSM-RT and two existing PSSM encoding methods by five-fold cross-validation. Performance evaluations indicate that PSSM-RT is more effective than previous methods. This validates the point that the relationship of evolutionary information between residues is indeed useful in DNA-binding residue prediction. An ensemble learning classifier (EL_PSSM-RT) is also proposed by combining ensemble learning model and PSSM-RT to better handle the imbalance between binding and non-binding residues in datasets. EL_PSSM-RT is evaluated by five-fold cross-validation using PDNA-62 and PDNA-224 as well as two independent datasets TS-72 and TS-61. Performance comparisons with existing predictors on the four datasets demonstrate that EL_PSSM-RT is the best-performing method among all the predicting methods with improvement between 0.02-0.07 for MCC, 4.18-21.47% for ST and 0.013-0.131 for AUC. Furthermore, we analyze the importance of the pair-relationships extracted by PSSM-RT and the results validates the usefulness of PSSM-RT for encoding DNA-binding residues. Conclusions: We propose a novel prediction method for the prediction of DNA-binding residue with the inclusion of relationship of evolutionary information and ensemble learning. Performance evaluation shows that the relationship of evolutionary information between residues is indeed useful in DNA-binding residue prediction and ensemble learning can be used to address the data imbalance issue between binding and non-binding residues. A web service of EL_PSSM-RT ( http://hlt.hitsz.edu.cn:8080/PSSM-RT_SVM/ ) is provided for free access to the biological research community

Impact of DNA methylation on trophoblast function

The influence of epigenetics is evident in many fields of medicine today. This is also true in placentology, where versatile epigenetic mechanisms that regulate expression of genes have shown to have important influence on trophoblast implantation and placentation. Such gene regulation can be established in different ways and on different molecular levels, the most common being the DNA methylation. DNA methylation has been shown today as an important predictive component in assessing clinical prognosis of certain malignant tumors; in addition, it opens up new possibilities for non-invasive prenatal diagnosis utilizing cell-free fetal DNA methods. By using a well known demethylating agent 5-azacytidine in pregnant rat model, we have been able to change gene expression and, consequently, the processes of trophoblast differentiation and placental development. In this review, we describe how changes in gene methylation effect trophoblast development and placentation and offer our perspective on use of trophoblast epigenetic research for better understanding of not only placenta development but cancer cell growth and invasion as well

Comparative analysis of the ATRX promoter and 5' regulatory region reveals conserved regulatory elements which are linked to roles in neurodevelopment, alpha-globin regulation and testicular function

BACKGROUND ATRX is a tightly-regulated multifunctional protein with crucial roles in mammalian development. Mutations in the ATRX gene cause ATR-X syndrome, an X-linked recessive developmental disorder resulting in severe mental retardation and mild alpha-thalassemia with facial, skeletal and genital abnormalities. Although ubiquitously expressed the clinical features of the syndrome indicate that ATRX is not likely to be a global regulator of gene expression but involved in regulating specific target genes. The regulation of ATRX expression is not well understood and this is reflected by the current lack of identified upstream regulators. The availability of genomic data from a range of species and the very highly conserved 5' regulatory regions of the ATRX gene has allowed us to investigate putative transcription factor binding sites (TFBSs) in evolutionarily conserved regions of the mammalian ATRX promoter. RESULTS We identified 12 highly conserved TFBSs of key gene regulators involved in biologically relevant processes such as neural and testis development and alpha-globin regulation. CONCLUSIONS Our results reveal potentially important regulatory elements in the ATRX gene which may lead to the identification of upstream regulators of ATRX and aid in the understanding of the molecular mechanisms that underlie ATR-X syndrome.This work was supported by Department of Zoology research grants

DisProt: intrinsic protein disorder annotation in 2020

The Database of Protein Disorder (DisProt, URL: https://disprot.org) provides manually curated annotations of intrinsically disordered proteins from the literature. Here we report recent developments with DisProt (version 8), including the doubling of protein entries, a new disorder ontology, improvements of the annotation format and a completely new website. The website includes a redesigned graphical interface, a better search engine, a clearer API for programmatic access and a new annotation interface that integrates text mining technologies. The new entry format provides a greater flexibility, simplifies maintenance and allows the capture of more information from the literature. The new disorder ontology has been formalized and made interoperable by adopting the OWL format, as well as its structure and term definitions have been improved. The new annotation interface has made the curation process faster and more effective. We recently showed that new DisProt annotations can be effectively used to train and validate disorder predictors. We believe the growth of DisProt will accelerate, contributing to the improvement of function and disorder predictors and therefore to illuminate the ‘dark’ proteome

Acquisition of Human-Type Receptor Binding Specificity by New H5N1 Influenza Virus Sublineages during Their Emergence in Birds in Egypt

Highly pathogenic avian influenza A virus subtype H5N1 is currently widespread in Asia, Europe, and Africa, with 60% mortality in humans. In particular, since 2009 Egypt has unexpectedly had the highest number of human cases of H5N1 virus infection, with more than 50% of the cases worldwide, but the basis for this high incidence has not been elucidated. A change in receptor binding affinity of the viral hemagglutinin (HA) from α2,3- to α2,6-linked sialic acid (SA) is thought to be necessary for H5N1 virus to become pandemic. In this study, we conducted a phylogenetic analysis of H5N1 viruses isolated between 2006 and 2009 in Egypt. The phylogenetic results showed that recent human isolates clustered disproportionally into several new H5 sublineages suggesting that their HAs have changed their receptor specificity. Using reverse genetics, we found that these H5 sublineages have acquired an enhanced binding affinity for α2,6 SA in combination with residual affinity for α2,3 SA, and identified the amino acid mutations that produced this new receptor specificity. Recombinant H5N1 viruses with a single mutation at HA residue 192 or a double mutation at HA residues 129 and 151 had increased attachment to and infectivity in the human lower respiratory tract but not in the larynx. These findings correlated with enhanced virulence of the mutant viruses in mice. Interestingly, these H5 viruses, with increased affinity to α2,6 SA, emerged during viral diversification in bird populations and subsequently spread to humans. Our findings suggested that emergence of new H5 sublineages with α2,6 SA specificity caused a subsequent increase in human H5N1 influenza virus infections in Egypt, and provided data for understanding the virus's pandemic potential