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91.
Worth AP 《Alternatives to laboratory animals : ATLA》2002,30(Z2):133-137
This paper introduces the basic concepts of quantitative structure-activity relationship (QSAR), expert system and integrated testing strategy, and explains how the analogy between QSARs and prediction models leads naturally to criteria for the validation of QSARs. ECVAM's in-house research programme on QSAR modelling and integrated testing is summarised, along with plans for the validation of QSAR models and expert system rulebases at the European Union level. 相似文献
92.
Worth CL Bickerton GR Schreyer A Forman JR Cheng TM Lee S Gong S Burke DF Blundell TL 《Journal of bioinformatics and computational biology》2007,5(6):1297-1318
The prediction of the effects of nonsynonymous single nucleotide polymorphisms (nsSNPs) on function depends critically on exploiting all information available on the three-dimensional structures of proteins. We describe software and databases for the analysis of nsSNPs that allow a user to move from SNP to sequence to structure to function. In both structure prediction and the analysis of the effects of nsSNPs, we exploit information about protein evolution, in particular, that derived from investigations on the relation of sequence to structure gained from the study of amino acid substitutions in divergent evolution. The techniques developed in our laboratory have allowed fast and automated sequence-structure homology recognition to identify templates and to perform comparative modeling; as well as simple, robust, and generally applicable algorithms to assess the likely impact of amino acid substitutions on structure and interactions. We describe our strategy for approaching the relationship between SNPs and disease, and the results of benchmarking our approach -- human proteins of known structure and recognized mutation. 相似文献
93.
Kaiwan Gan Peter Alexander James M. Coxon A. John McKinnon Gillian H. Worth 《Biopolymers》1997,41(4):367-379
A multiple regression analysis has established a nonlinear relationship between the backbone dihedral angles and the Cα coordinates obtained from the x-ray crystal structures of 14 proteins. The regression equations have been applied to predict specific dihedral angles of each residue in the backbone of 24 proteins. Overall this method (Nonlinear Regression Distance Torsion) predicts values of ϕ and ψ within a ±45° window of those found in the x-ray structure with an accuracy of 94 and 91% and within a ±30° window of 88 and 81%. Two methods for the assignment of motif from Cα coordinates are reported. For the first method, motif is assigned from the dihedral angles predicted using the regression equations. By the second method, motif of the ith residue is assigned from the distance Cαi-1 to Cαi+2 (v6) and torsional angle Cαi-1, Cαi, Cαi+1, Cαi+2 (v13). For the 24 proteins, 23.7% of the residues by the former method and 19.6% by the latter method are assigned differently than in the Protein Data Bank. © 1997 John Wiley & Sons, Inc. 相似文献
94.
David F Burke Catherine L Worth Eva-Maria Priego Tammy Cheng Luc J Smink John A Todd Tom L Blundell 《BMC bioinformatics》2007,8(1):301
Background
Genome-wide association studies of common diseases for common, low penetrance causal variants are underway. A proportion of these will alter protein sequences, the most common of which is the non-synonymous single nucleotide polymorphism (nsSNP). It would be an advantage if the functional effects of an nsSNP on protein structure and function could be predicted, both for the final identification process of a causal variant in a disease-associated chromosome region, and in further functional analyses of the nsSNP and its disease-associated protein. 相似文献95.
Batrachotoxin (BTX) in the low concentration range of 19-190 nM blocks axoplasmic transport in the desheathed cat peroneal nerve in vitro. When the level of Na+ in the incubation medium was reduced to 10 mM, the blocking effect of BTX was much diminished, and in an Na+-free medium BTX had no effect on transport at all. The blocking action of BTX with Na+ present was inhibited by increasing the concentration of Ca2+ in the experimental medium. Relatively small increases were effective with a maximum protection seen when the Ca2+ concentrations were 7-10 mM. The results support the view that an increase in axonal Na+ is inhibitory to the transport mechanism. The results are discussed on the basis of the recently developed transport filament model of axoplasmic transport which takes into account an obligatory role for Ca2+ in transport and its axonal regulation. The possible relation of intraaxonal Na+ concentration to the Ca2+ level is also discussed. 相似文献
96.
Burkholderia pseudomallei is the causative agent of melioidosis and is a major mediator of sepsis in its endemic areas. Because of the low LD50 via aerosols and resistance to multiple antibiotics, it is considered a Tier 1 select agent by the CDC and APHIS. B. pseudomallei is an encapsulated bacterium that can infect, multiply, and persist within a variety of host cell types. In vivo studies suggest that macrophages and neutrophils are important for controlling B. pseudomallei infections, however few details are known regarding how neutrophils respond to these bacteria. Our goal is to describe the capacity of human neutrophils to control highly virulent B. pseudomallei compared to the relatively avirulent, acapsular B. thailandensis using in vitro analyses. B. thailandensis was more readily phagocytosed than B. pseudomallei, but both displayed similar rates of persistence within neutrophils, indicating they possess similar inherent abilities to escape neutrophil clearance. Serum opsonization studies showed that both were resistant to direct killing by complement, although B. thailandensis acquired significantly more C3 on its surface than B. pseudomallei, whose polysaccharide capsule significantly decreased the levels of complement deposition on the bacterial surface. Both Burkholderia species showed significantly enhanced uptake and killing by neutrophils after critical levels of C3 were deposited. Serum-opsonized Burkholderia induced a significant respiratory burst by neutrophils compared to unopsonized bacteria, and neutrophil killing was prevented by inhibiting NADPH-oxidase. In summary, neutrophils can efficiently kill B. pseudomallei and B. thailandensis that possess a critical threshold of complement deposition, and the relative differences in their ability to resist surface opsonization may contribute to the distinct virulence phenotypes observed in vivo. 相似文献
97.
98.
99.
Taira K Nakamura S Nakano K Maehara D Okamoto K Arimoto S Loakes D Worth L Schaaper RM Seio K Sekine M Negishi K Negishi T 《Mutation research》2008,640(1-2):107-112
The MutS-based mismatch repair (MMR) system has been conserved from prokaryotes to humans, and plays important roles in maintaining the high fidelity of genomic DNA. MutS protein recognizes several different types of modified base pairs, including methylated guanine-containing base pairs. Here, we looked at the relationship between recognition and the effects of methylating versus ethylating agents on mutagenesis, using a MutS-deficient strain of E. coli. We find that while methylating agents induce mutations more effectively in a MutS-deficient strain than in wild-type, this genetic background does not affect mutagenicity by ethylating agents. Thus, the role of E. coli MMR with methylation-induced mutagenesis appears to be greater than ethylation-induced mutagenesis. To further understand this difference an early step of repair was examined with these alkylating agents. A comparison of binding affinities of MutS with O6-alkylated guanine base paired with thymine, which could lead to transition mutations, versus cytosine which could not, was tested. Moreover, we compared binding of MutS to oligoduplexes containing different base pairs; namely, O6-MeG:T, O6-MeG:C, O6-EtG:T, O6-EtG:C, G:T and G:C. Dissociation constants (Kd), which reflect the strength of binding, followed the order G:T- > O6-MeG:T- > O6-EtG:T- = O6-EtG:C- ≥ O6-MeG:C- > G:C. These results suggest that a thymine base paired with O6-methyl guanine is specifically recognized by MutS and therefore should be removed more efficiently than a thymine opposite O6-ethylated guanine. Taken together, the data suggest that in E. coli, the MMR system plays a more significant role in repair of methylation-induced lesions than those caused by ethylation. 相似文献
100.