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- A Simulation Framework to Investigate in vitro Viral Infection Dynamics. [JOURNAL ARTICLE]
- J Comput Sci 2013 May 1; 4(3):127-134.
Virus infection is a complex biological phenomenon for which in vitro experiments provide a uniquely concise view where data is often obtained from a single population of cells, under controlled environmental conditions. Nonetheless, data interpretation and real understanding of viral dynamics is still hampered by the sheer complexity of the various intertwined spatio-temporal processes. In this paper we present a tool to address these issues: a cellular automata model describing critical aspects of in vitro viral infections taking into account spatial characteristics of virus spreading within a culture well. The aim of the model is to understand the key mechanisms of SARS-CoV infection dynamics during the first 24 hours post infection. Using a simulated annealing algorithm we tune free parameters with data from SARS-CoV infection of cultured lung epithelial cells. We also interrogate the model using a Latin Hypercube sensitivity analysis to identify which mechanisms are critical to the observed infection of host cells and the release of measured virus particles.
- Novel Inhibitors of SARS-CoV Entry acting by Three Distinct Mechanisms. [JOURNAL ARTICLE]
- J Virol 2013 May 15.
Severe acute respiratory syndrome (SARS) is an infectious and highly contagious disease that is caused by SARS coronavirus, (SARS-CoV) and for which there are currently no approved treatments. We report the discovery and characterization of small molecule inhibitors of SARS-CoV replication that block viral entry by three different mechanisms. The compounds were discovered by screening a chemical library of compounds for blocking entry of HIV-1 pseudotyped with SARS-CoV surface glycoprotein S (SARS-S), but not with Vesicular Stomatitis Virus surface glycoprotein G (VSV-G). Studies on their mechanisms of action revealed that they act by three distinct mechanisms: a) SSAA09E2 (N-[[4-(4-methylpiperazin-1-yl)phenyl]methyl]-1,2-oxazole-5-carboxamide) acts through a novel mechanism of action, by blocking early interactions of SARS-S with the receptor for SARS-CoV, Angiotensin Converting Enzyme-2 (ACE2); b) SSAA09E1 ([(Z)-1-thiophen-2-ylethylideneamino]thiourea), which acts later by blocking cathepsin L, a host protease required for processing of SARS-S during viral entry and c) SSAA09E3 (N-(9,10-dioxo-9,10-dihydroanthracen-2-yl)benzamide)), which also acts later and does not affect interactions of SARS-S with ACE2 or the enzymatic functions of cathepsin L, but prevents fusion of the viral membrane with the host cellular membrane. Our work demonstrates that there are at least three independent strategies to block SARS-CoV entry, validates these mechanisms of inhibition, and introduces promising leads for the development of SARS therapeutics.
- Species-area relationships and extinction forecasts. [JOURNAL ARTICLE]
- Ann N Y Acad Sci 2013 May 14.
The species-area relationship (SAR) predicts that smaller areas contain fewer species. This is the basis of the SAR method that has been used to forecast large numbers of species committed to extinction every year due to deforestation. The method has a number of issues that must be handled with care to avoid error. These include the functional form of the SAR, the choice of equation parameters, the sampling procedure used, extinction debt, and forest regeneration. Concerns about the accuracy of the SAR technique often cite errors not much larger than the natural scatter of the SAR itself. Such errors do not undermine the credibility of forecasts predicting large numbers of extinctions, although they may be a serious obstacle in other SAR applications. Very large errors can arise from misinterpretation of extinction debt, inappropriate functional form, and ignoring forest regeneration. Major challenges remain to understand better the relationship between sampling protocol and the functional form of SARs and the dynamics of relaxation, especially in continental areas, and to widen the testing of extinction forecasts.
- Joseph Sung: marking the tenth anniversary of SARS. [Journal Article]
- Lancet 2013 Mar 9; 381(9869):797.
- SARS legacy: outbreak reporting is expected and respected. [Journal Article]
- Lancet 2013 Mar 9; 381(9869):779-81.
- Furthering the design and the discovery of small molecule ATP-competitive mTOR inhibitors as an effective cancer treatment. [JOURNAL ARTICLE]
- Expert Opin Drug Discov 2013 May 14.
Introduction: The mammalian target of rapamycin (mTOR) is a serine/threonine kinase, which is the key component of two distinct signaling complexes in cells; these complexes are the mTOR complex 1 (mTORC1) and the mTOR complex 2 (mTORC2). Given the importance of these complexes in cellular growth, survival, motility, proliferation, protein synthesis and transcription, it is not surprising that they are impacted in multiple types of cancer. Studies on a number of ATP-competitive mTOR inhibitors have suggested that these inhibitors have a therapeutic superiority to rapalogs (rapamycin analogs) in a number of cancers. Areas covered: This review provides insight into the binding of mTOR inhibitors with the ATP-binding site, for the benefit of future mTOR inhibitor design and discovery. The authors, furthermore, deduce that a hypothetical binding mode is from docking studies, co-crystal structures and the structure-activity relationships (SARs). The authors also highlight the preclinical and clinical development of hit/lead compounds, and the selectivity for representative mTOR inhibitors. Expert opinion: The structural analysis of mTOR is hampered by its large size and complexity. Further exploration of mTOR inhibitors may therefore require the combination of structure-based drug design (SBDD, based on the mTOR homology models), fragment-based drug design (FBDD) and analog synthesis. Recent studies suggested that the global inhibition of PI3Ks may be harmful to organisms. Therefore, the future discovery of dual mTOR/PI3K inhibitors needs to ensure that inhibitors are both efficacious and have reduced adverse effects.
- [Molecular genetic identification and phylogeny of Daphnia species (Crustacea, Cladocera) from water bodies of Lake Chany basin]. [English Abstract, Journal Article]
- Genetika 2013 Feb; 49(2):235-43.
The data on the molecular genetic identification of Daphnia species from the water bodies of Lake Chany basin are presented. Phylogenetic relationships between these species have been established. The fragments of the mitochondrial DNA 16S and 12S genes were used as genetic markers. According to the data obtained, the water bodies examined were inhabited by five Daphnia species, including Daphnia (Daphnia) galeata Sars, D. (D) longispina O. E Müller, D. (D) curvirostris Eylmann, D. (D) pulex Leydig, and D. (Ctenodaphnia) magna Straus. In addition, a group of longispina-like individuals that form a separate phylogenetic cluster was identified.
- A combination of epitope prediction and molecular docking allows for good identification of MHC class I restricted T-cell epitopes. [JOURNAL ARTICLE]
- Comput Biol Chem 2013 Apr 18.:30-35.
In silico identification of T-cell epitopes is emerging as a new methodology for the study of epitope-based vaccines against viruses and cancer. In order to improve accuracy of prediction, we designed a novel approach, using epitope prediction methods in combination with molecular docking techniques, to identify MHC class I restricted T-cell epitopes. Analysis of the HIV-1 p24 protein and influenza virus matrix protein revealed that the present approach is effective, yielding prediction accuracy of over 80% with respect to experimental data. Subsequently, we applied such a method for prediction of T-cell epitopes in SARS coronavirus (SARS-CoV) S, N and M proteins. Based on available experimental data, the prediction accuracy is up to 90% for S protein. We suggest the use of epitope prediction methods in combination with 3D structural modelling of peptide-MHC-TCR complex to identify MHC class I restricted T-cell epitopes for use in epitope based vaccines like HIV and human cancers, which should provide a valuable step forward for the design of better vaccines and may provide in depth understanding about activation of T-cell epitopes by MHC binding peptides.
- Phages bearing affinity peptides to severe acute respiratory syndromes-associated coronavirus differentiate this virus from other viruses. [JOURNAL ARTICLE]
- J Clin Virol 2013 May 9.
BACKGROUND:Transmission of SARS-associated coronavirus (SARS-CoV) is now well controlled, nevertheless, it is important to develop effective methods to identify this virus from other pathogens.
OBJECTIVES:The purpose of this study was to identify potential ligands and develop a novel diagnostic test to SARS-CoV using phage display technology.
STUDY DESIGN:The SARS-CoV spike 1 (S1) protein containing the receptor binding region (RBD) was used as an immobilized target followed by incubation with a 12-mer phage display random peptide library. After four rounds of biopanning, 10 monoclonal phages with specific binding activity to the S1-RBD protein were obtained and subjected to binding and diagnostic assays.
RESULTS:DNA sequencing showed that two phage displayed peptides HHKTWHPPVMHL (phage-H) and SQWHPRSASYPM (phage-S) that were specific ligands to the S1 protein. Moreover, the selected phage-H and phage-S were capable of differentiating SARS-CoV from other coronaviruses in indirect enzyme-linked immunosorbent assays.
CONCLUSION:The peptides identified in this study are useful reagents for detection of SARS-CoV.
- [Barrier elements of chromatin domains and nuclear envelope]. [English Abstract, Journal Article]
- Genetika 2013 Jan; 49(1):30-6.
The results of investigating the functions of different barrier elements, including insulators and MARs/SARs and the models of their effect, are described. The functions of neDNA (DNA from the nuclear envelopes) as a barrier element that protects the transgene from position-effect variegation and its interaction with insulators are discussed. The possible mechanisms of the functioning of structural and functional units of eukaryotic chromosomes of different species are suggested.