ABSTRACT
Life-threatening RNA viruses emerge regularly, and often in an unpredictable manner. Yet, the very few drugs available against known RNA viruses have sometimes required decades of research for development. Can we generate preparedness for outbreaks of the, as yet, unknown viruses? The VIZIER (VIral enZymes InvolvEd in Replication) (http://www.vizier-europe.org/) project has been set-up to develop the scientific foundations for countering this challenge to society. VIZIER studies the most conserved viral enzymes (that of the replication machinery, or replicases) that constitute attractive targets for drug-design. The aim of VIZIER is to determine as many replicase crystal structures as possible from a carefully selected list of viruses in order to comprehensively cover the diversity of the RNA virus universe, and generate critical knowledge that could be efficiently utilized to jump-start research on any emerging RNA virus. VIZIER is a multidisciplinary project involving (i) bioinformatics to define functional domains, (ii) viral genomics to increase the number of characterized viral genomes and prepare defined targets, (iii) proteomics to express, purify, and characterize targets, (iv) structural biology to solve their crystal structures, and (v) pre-lead discovery to propose active scaffolds of antiviral molecules.
Subject(s)
Antiviral Agents/pharmacology , Computational Biology , Crystallography , Drug Design , Genomics , Proteomics , RNA Viruses/drug effects , RNA-Dependent RNA Polymerase , Virus Replication/drug effects , Antiviral Agents/chemistry , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , International Cooperation , Models, Molecular , RNA Viruses/enzymology , RNA Viruses/pathogenicity , RNA Viruses/physiology , RNA, Viral/biosynthesis , RNA-Dependent RNA Polymerase/antagonists & inhibitors , RNA-Dependent RNA Polymerase/chemistry , RNA-Dependent RNA Polymerase/genetics , RNA-Dependent RNA Polymerase/metabolismABSTRACT
Modifications of the previously described adaptive algorithm of automatic annotating A4 have been considered, which make it possible to improve the quality of prediction. First, the direct use of the so-called basis statistics eta refines the quality of prediction compared with the previously proposed statistics gamma. Second, the quality is improved if not all similar sequences found but only part of them are used. This decreases the noising of the data, which in turn improves the quality of prognosis.
Subject(s)
Algorithms , Databases, Nucleic Acid , Databases, Protein , Sequence Analysis, DNA , Animals , Humans , Predictive Value of Tests , Sequence Analysis, DNA/methodsABSTRACT
MOTIVATION: It is common knowledge that the avalanche of data arriving from the sequencing projects cannot be annotated either experimentally or manually by experts. The need for a reliable and convenient tool for automated sequence annotation is broadly recognized. RESULTS: Here, we describe the Adaptive Algorithm of Automated Annotation (A(4)) based on a statistical approach to this problem. The mathematical model relates a set of homologous sequences and descriptions of their functional properties, and calculates the probabilities of transferring a sequence description onto its homologue. The proposed model is adaptive, its parameters (distribution characteristics, transference probabilities, thresholds, etc.) are dynamic, i.e. are generated individually for the sequences and various functional properties (words of the description). The proposed technique significantly outperforms the widely used test for frequency threshold, which is a special case of our model realized for the simplest set of parameters. The prediction technique has been realized as a computer program and tested on a random sequence sampling from SWISS-PROT. AVAILABILITY: The automated annotation program based on the proposed algorithm is available through the Web browser at http://www.genebee.msu.su/services/annot/basic.html.
Subject(s)
Algorithms , Computational Biology , Computer Simulation , Databases, Protein/statistics & numerical data , SoftwareABSTRACT
A network server providing biopolymer structure databank retrieval as well as some other biocomputing procedures for Internet users is described. Its basic procedures consist in looking for sequence and 3D homologies (similarities). Found homologies are used for constructing multiple alignment, for predicting RNA and protein secondary structures as well as for constructing phylogenetic trees. Alongside traditional methods of sequence homology retrieval, a "matrix-free" (correlation) method is proposed. A similar procedure is used to locate protein 3D similarities. For novel procedures algorithm ideas and their possible applications are discussed. The service ideology is based on the interaction of server and client programs. The client program (GeneBee for IBM PC) can be used to form queries to the server as well as to manipulate a treatment result. In the absence of the client program the interaction with the server can be in the text mode. The E-mail and WWW addresses for the server are as follows: SERVE/INDY.GENEBEE.MSU.SU and WWW.GENEBEE.MSU.SU.
Subject(s)
Biopolymers/chemistry , Computer Communication Networks , Information Systems , Amino Acid Sequence , Molecular Sequence Data , Nucleic Acid Conformation , Protein Folding , Protein Structure, Secondary , Sequence Homology, Amino AcidABSTRACT
A novel algorithm for construction of complete maps of local similarity for two biopolymer sequences is described. The algorithm is much faster than the related Altschul-Erickson procedure, it is implemented as the Dot-Helix module within the GeneBee package. Performance of the algorithm is exemplified with the analysis of the polyproteins of two poliovirus type 3 strains and its effectivity is compared to the Staden method. Possible applications of the algorithm are briefly discussed.
Subject(s)
Algorithms , Biopolymers , Models, Chemical , Amino Acid Sequence , Mathematics , Molecular Sequence Data , Peptide Mapping , Poliovirus/genetics , Software , Viral Proteins/chemistry , Viral Proteins/geneticsABSTRACT
A novel algorithm for multiple alignment of biological sequences is suggested. At the first step the DotHelix procedure is employed for construction of motifs, i.e. continuous fragments of local similarity of various "thickness" and strength, and then these motifs are concatenated into chains consistent with the order of letters in the sequences. The algorithm is implemented in the MA-Tools program of the GeneBee package. An example illustrating the effectivity of the algorithm is presented.
Subject(s)
Algorithms , Biopolymers , Sequence Alignment/methods , Amino Acid Sequence , Animals , Carboxypeptidases/chemistry , Evaluation Studies as Topic , Humans , Mathematics , Molecular Sequence Data , Proteins/chemistry , Sequence Alignment/statistics & numerical data , SoftwareABSTRACT
A mathematical description of random orientation of centrioles with respect to the plane has been suggested for two modes of experimental procedure: a) all the centrioles in a given volume are taken into account; b) all the centrioles crossing an ultrathin section are accounted. In the former case the function of distribution does not depend on the length of the centrioles. Histograms of the distribution of centriolar length projections on the plane of the section have been obtained. These histograms are compared with those obtained for centrioles in mitotic pig kidney embryo cells (PE-cells). Tables of credible occurrence intervals for "nearly perpendicular" (the angle is tipped to the substrate plane by over 74 degrees) and for "nearly parallel" (the angle is tipped to the substrate plane by less than 12 degrees) centrioles in different samplings are adduced.
Subject(s)
Centrioles/ultrastructure , Anaphase , Animals , Cells, Cultured , Culture Techniques , Metaphase , Models, Biological , Stochastic ProcessesABSTRACT
Methods for estimation of randomness of mutual overlaps of cells, their parts, and intracellular structures are developed. Two methods are proposed: a "method of areas" based on the estimation of the area of overlaps of randomly located figures, and a "method of contours" based on the evaluation of the number of intersections of linear structures located randomly. Examples are given as applied to cells and cellular nuclei, in particular during contact inhibition of cellular movement.
Subject(s)
Cells, Cultured/cytology , Probability , Stochastic Processes , Animals , Cell Communication , Cell Movement , Cell Nucleus/ultrastructure , Cytological Techniques , Humans , MathematicsABSTRACT
Heterotopic transplantation of marrow fragments results in the formation of new bone marrow organs. The amount of hemopoietic cells populating these organs is connected nonlinearly with the volume of the grafted tissue or with the number of transplanted marrow cells. Statistical analysis points out that the number of the populating cells depends on the radius of the initial bone marrow transplant. Thus, the previous data on the radiosensitivity of the microenvironmental transfering stromal cells and on their concentration obtained by measuring the size of the heterotopic bone marrow organs have turned out incorrect.
Subject(s)
Bone Marrow Transplantation , Hematopoietic Stem Cell Transplantation , Animals , Bone Marrow/radiation effects , Cell Count , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/radiation effects , Mice , Mice, Inbred C57BL , Mice, Inbred CBAABSTRACT
The firing rate in type "B" preganglionic sympathetic fibers during strong pressor reactions varied in different fibers from 0 to 80/sec. With an increase of the pressor reaction, the maximum of the density of frequency distribution shifts from 30--40 to 50--60/sec, previously "silent" fibers becoming involved.
