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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    Machine learning 21 (1995), S. 151-175 
    ISSN: 0885-6125
    Keywords: domain knowledge ; change of representation ; theory revision ; protein structure prediction ; homology modeling ; amino acid properties
    Source: Springer Online Journal Archives 1860-2000
    Topics: Computer Science
    Notes: Abstract Predicting the fold, or approximate 3D structure, of a protein from its amino acid sequence is an important problem in biology. The homology modeling approach uses a protein database to identify fold-class relationships by sequence similarity. The main limitation of this method is that some proteins with similar structures appear to have very different sequences, which we call the “hidden-homology problem.” As in other real-world domains for machine learning, this difficulty may be caused by a low-level representation. Learning in such domains can be improved by using domain knowledge to search for representations that better match the inductive bias of a preferred algorithm. In this domain, knowledge of amino acid properties can be used to construct higher-level representations of protein sequences. In one experiment using a 179-protein data set, the accuracy of fold-class prediction was increased from 77.7% to 81.0%. The search results are analyzed to refine the grouping of small residues suggested by Dayhoff. Finally, an extension to the representation incorporates sequential context directly into the representation, which can express finer relationships among the amino acids. The methods developed in this domain are generalized into a framework that suggests several systematic roles for domain knowledge in machine learning. Knowledge may define both a space of alternative representations, as well as a strategy for searching this space. The search results may be summarized to extract feedback for revising the domain knowledge.
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    Machine learning 21 (1995), S. 151-175 
    ISSN: 0885-6125
    Keywords: domain knowledge ; change of representation ; theory revision ; protein structure prediction ; homology modeling ; amino acid properties
    Source: Springer Online Journal Archives 1860-2000
    Topics: Computer Science
    Notes: Abstract Predicting the fold, or approximate 3D structure, of a protein from its amino acid sequence is an important problem in biology. The homology modeling approach uses a protein database to identify fold-class relationships by sequence similarity. The main limitation of this method is that some proteins with similar structures appear to have very different sequences, which we call the “hidden-homology problem.” As in other real-world domains for machine learning, this difficulty may be caused by a low-level representation. Learning in such domains can be improved by using domain knowledge to search for representations that better match the inductive bias of a preferred algorithm. In this domain, knowledge of amino acid properties can be used to construct higher-level representations of protein sequences. In one experiment using a 179-protein data set, the accuracy of fold-class prediction was increased from 77.7% to 81.0%. The search results are analyzed to refine the grouping of small residues suggested by Dayhoff. Finally, an extension to the representation incorporates sequential context directly into the representation, which can express finer relationships among the amino acids. The methods developed in this domain are generalized into a framework that suggests several systematic roles for domain knowledge in machine learning. Knowledge may define both a space of alternative representations, as well as a strategy for searching this space. The search results may be summarized to extract feedback for revising the domain knowledge.
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  • 3
    Electronic Resource
    Electronic Resource
    Copenhagen : International Union of Crystallography (IUCr)
    Acta crystallographica 56 (2000), S. 722-734 
    ISSN: 1399-0047
    Source: Crystallography Journals Online : IUCR Backfile Archive 1948-2001
    Topics: Chemistry and Pharmacology , Geosciences , Physics
    Notes: TEXTAL is an automated system for building protein structures from electron-density maps. It uses pattern recognition to select regions in a database of previously determined structures that are similar to regions in a map of unknown structure. Rotation-invariant numerical values, called features, of the electron density are extracted from spherical regions in an unknown map and compared with features extracted around regions in maps generated from a database of known structures. Those regions in the database that match best provide the local coordinates of atoms and these are accumulated to form a model of the unknown structure. Similarity between the regions in the database and an uninterpreted region is determined firstly by evaluating the numerical difference in feature values and secondly by calculating the electron-density correlation coefficient for those regions with similar feature values. TEXTAL has been successful at building protein structures for a wide range of test electron-density maps and can automatically model entire protein structures in a few hours on a workstation. Models built by TEXTAL from test electron-density maps of known protein structures were accurate to within 0.6–0.7 Å root-mean-square deviation, assuming prior knowledge of Cα positions. The system represents a new approach to protein structure determination and has the potential to greatly reduce the time required to interpret electron-density maps in order to build accurate protein models.
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  • 4
    Electronic Resource
    Electronic Resource
    Springer
    Autonomous agents and multi-agent systems 3 (2000), S. 219-257 
    ISSN: 1573-7454
    Keywords: emotions ; emotional agents ; social agents ; believable agents ; life-like agents
    Source: Springer Online Journal Archives 1860-2000
    Topics: Computer Science
    Notes: Abstract Emotions are an important aspect of human intelligence and have been shown to play a significant role in the human decision-making process. Researchers in areas such as cognitive science, philosophy, and artificial intelligence have proposed a variety of models of emotions. Most of the previous models focus on an agent's reactive behavior, for which they often generate emotions according to static rules or pre-determined domain knowledge. However, throughout the history of research on emotions, memory and experience have been emphasized to have a major influence on the emotional process. In this paper, we propose a new computational model of emotions that can be incorporated into intelligent agents and other complex, interactive programs. The model uses a fuzzy-logic representation to map events and observations to emotional states. The model also includes several inductive learning algorithms for learning patterns of events, associations among objects, and expectations. We demonstrate empirically through a computer simulation of a pet that the adaptive components of the model are crucial to users' assessments of the believability of the agent's interactions.
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  • 5
    ISSN: 1432-2145
    Keywords: cDNA clones ; Pistil S-allele-associated proteins ; Gametophytic self-incompatibility ; Nicotiana alata
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary In order to study the extent and nature of differences among various S-allele-associated proteins in N. alata, we carried out comparative studies of seven such proteins. We first isolated and sequenced cDNA clones for the Sz-, SF11-, S1-, and Sa-alleles, and then we compared the deduced amino acid sequences both of these four S-proteins and of three previously published S2-, S3-, and S6-proteins. This comparison revealed (1) an average homology of 53.8% among the seven proteins and (2) two homology classes, with Sz and SF11 in one class and S1, S2, S3, and S6 in the other class. There are 60 conserved residues, including 9 cysteines. Of the 144 variable residues, 50 were identified as hypervariable based on a calculation of their Similarity Indices. Although conserved, variable, and hypervariable residues are dispersed throughout the protein, some are clustered to form five conserved, five hypervariable, and a number of variable regions. Those variable sites which contain residues conserved within one class of S-proteins but different between classes might provide a clue to the evolutionary relationship of these two classes of S-proteins. The hypervariable residues, which account for sequence variability, may contribute to allelic specificity.
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  • 6
    ISSN: 1432-2145
    Keywords: cDNA sequence ; S-allele-associated proteins ; Petunia inflata ; Self-incompatibility
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary We have identified three alleles of the S-locus controlling self-incompatibility and their associated pistil proteins in Petunia inflata, a species that displays monofactorial gametophytic self-incompatibility. These S-allele-associated proteins (S-proteins) are pistil specific, and their levels are developmentally regulated. The amino-terminal sequences determined for the three S-proteins are highly conserved and show considerable homology to those of S-proteins from Petunia hybrida, Nicotiana alata and Lycopersicon peruvianum, three other species of the Solanaceae that also exhibit gametophytic self-incompatibility. cDNA clones encoding the three S-proteins were isolated and sequenced. Comparison of their deduced amino acid sequences reveals an average homology of 75.6%, with conserved and variable residue interspersed throughout the protein. Of the 137 conserved residues, 53 are also conserved in the N. alata S-proteins studies so far; of the 64 variable residues, 29 were identified as hypervariable based on calculation of the Similarity Index. There is only one hypervariable region of significant length, and it consists of eight consecutive hypervariable residues. This region correspond approximately to the hypervariable region HV2 identified in N. alata S-proteins. Of the two classes of N. alata S-proteins previously identified, one class exhibits greater homology to the three P. inflata S-proteins reported here than to the other class of N. alata S-proteins.
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  • 7
    Publication Date: 2015-10-05
    Description: Peptidoglycan (PG), a complex polymer composed of saccharide chains cross-linked by short peptides, is a critical component of the bacterial cell wall. PG synthesis has been extensively studied in model organisms but remains poorly understood in mycobacteria, a genus that includes the important human pathogen Mycobacterium tuberculosis (Mtb). The principle PG synthetic enzymes have similar and, at times, overlapping functions. To determine how these are functionally organized, we carried out whole-genome transposon mutagenesis screens in Mtb strains deleted for ponA1, ponA2, and ldtB, major PG synthetic enzymes. We identified distinct factors required to sustain bacterial growth in the absence of each of these enzymes. We find that even the homologs PonA1 and PonA2 have unique sets of genetic interactions, suggesting there are distinct PG synthesis pathways in Mtb. Either PonA1 or PonA2 is required for growth of Mtb, but both genetically interact with LdtB, which has its own distinct genetic network. We further provide evidence that each interaction network is differentially susceptible to antibiotics. Thus, Mtb uses alternative pathways to produce PG, each with its own biochemical characteristics and vulnerabilities.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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  • 8
    Publication Date: 2016-07-18
    Description: The rising incidence of antimicrobial resistance (AMR) makes it imperative to understand the underlying mechanisms.Mycobacterium tuberculosis(Mtb) is the single leading cause of death from a bacterial pathogen and estimated to be the leading cause of death from AMR. A pyrido-benzimidazole, 14, was reported to have potent bactericidal activity against Mtb. Here, we isolated multiple Mtb clones resistant to 14. Each had mutations in the putative DNA-binding and dimerization domains ofrv2887, a gene encoding a transcriptional repressor of the MarR family. The mutations in Rv2887 led to markedly increased expression ofrv0560c.We characterized Rv0560c as anS-adenosyl-L-methionine-dependent methyltransferase thatN-methylates 14, abolishing its mycobactericidal activity. An Mtb strain lackingrv0560cbecame resistant to 14 by mutating decaprenylphosphoryl-β-d-ribose 2-oxidase (DprE1), an essential enzyme in arabinogalactan synthesis; 14 proved to be a nanomolar inhibitor of DprE1, and methylation of 14 by Rv0560c abrogated this activity. Thus, 14 joins a growing list of DprE1 inhibitors that are potently mycobactericidal. Bacterial methylation of an antibacterial agent, 14, catalyzed by Rv0560c of Mtb, is a previously unreported mechanism of AMR.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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  • 9
    Publication Date: 2017-03-06
    Description: The glyoxylate shunt is a metabolic pathway of bacteria, fungi, and plants used to assimilate even-chain fatty acids (FAs) and has been implicated in persistence ofMycobacterium tuberculosis(Mtb). Recent work, however, showed that the first enzyme of the glyoxylate shunt, isocitrate lyase (ICL), may mediate survival ofMtbduring the acute and chronic phases of infection in mice through physiologic functions apart from fatty acid metabolism. Here, we report that malate synthase (MS), the second enzyme of the glyoxylate shunt, is essential for in vitro growth and survival ofMtbon even-chain fatty acids, in part, for a previously unrecognized activity: mitigating the toxicity of glyoxylate excess arising from metabolism of even-chain fatty acids. Metabolomic profiling revealed that MS-deficientMtbcultured on fatty acids accumulated high levels of the ICL aldehyde endproduct, glyoxylate, and increased levels of acetyl phosphate, acetoacetyl coenzyme A (acetoacetyl-CoA), butyryl CoA, acetoacetate, and β-hydroxybutyrate. These changes were indicative of a glyoxylate-induced state of oxaloacetate deficiency, acetate overload, and ketoacidosis. Reduction of intrabacterial glyoxylate levels using a chemical inhibitor of ICL restored growth of MS-deficientMtb, despite inhibiting entry of carbon into the glyoxylate shunt. In vivo depletion of MS resulted in sterilization ofMtbin both the acute and chronic phases of mouse infection. This work thus identifies glyoxylate detoxification as an essential physiologic function ofMtbmalate synthase and advances its validation as a target for drug development.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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  • 10
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