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Search Results: 1 - 10 of 19274 matches for " Richard Lathrop "
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Heterogeneous Biomedical Database Integration Using a Hybrid Strategy: A p53 Cancer Research Database
Vadim Y. Bichutskiy,Richard Colman,Rainer K. Brachmann,Richard H. Lathrop
Cancer Informatics , 2006,
Abstract: Complex problems in life science research give rise to multidisciplinary collaboration, and hence, to the need for heterogeneous database integration. The tumor suppressor p53 is mutated in close to 50% of human cancers, and a small drug-like molecule with the ability to restore native function to cancerous p53 mutants is a long-held medical goal of cancer treatment. The Cancer Research DataBase (CRDB) was designed in support of a project to find such small molecules. As a cancer informatics project, the CRDB involved small molecule data, computational docking results, functional assays, and protein structure data. As an example of the hybrid strategy for data integration, it combined the mediation and data warehousing approaches. This paper uses the CRDB to illustrate the hybrid strategy as a viable approach to heterogeneous data integration in biomedicine, and provides a design method for those considering similar systems. More efficient data sharing implies increased productivity, and, hopefully, improved chances of success in cancer research. (Code and database schemas are freely downloadable, http://www.igb.uci.edu/research/research.html.)
Directed DNA Shuffling of Retrovirus and Retrotransposon Integrase Protein Domains
Xiaojie Qi, Edwin Vargas, Liza Larsen, Whitney Knapp, G. Wesley Hatfield, Richard Lathrop, Suzanne Sandmeyer
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0063957
Abstract: Chimeric proteins are used to study protein domain functions and to recombine protein domains for novel or optimal functions. We used a library of chimeric integrase proteins to study DNA integration specificity. The library was constructed using a directed shuffling method that we adapted from fusion PCR. This method easily and accurately shuffles multiple DNA gene sequences simultaneously at specific base-pair positions, such as protein domain boundaries. It produced all 27 properly-ordered combinations of the amino-terminal, catalytic core, and carboxyl-terminal domains of the integrase gene from human immunodeficiency virus, prototype foamy virus, and Saccharomyces cerevisiae retrotransposon Ty3. Retrotransposons can display dramatic position-specific integration specificity compared to retroviruses. The yeast retrotransposon Ty3 integrase interacts with RNA polymerase III transcription factors to target integration at the transcription initiation site. In vitro assays of the native and chimeric proteins showed that human immunodeficiency virus integrase was active with heterologous substrates, whereas prototype foamy virus and Ty3 integrases were not. This observation was consistent with a lower substrate specificity for human immunodeficiency virus integrase than for other retrovirus integrases. All eight chimeras containing the Ty3 integrase carboxyl-terminal domain, a candidate targeting domain, failed to target strand transfer in the presence of the targeting protein, suggesting that multiple domains of the Ty3 integrase cooperate in this function.
Revista chilena de derecho , 2009, DOI: 10.4067/S0718-34372009000100005
Abstract: abstract: this article reviews the legal situation of older adults in chile and analyses a type of age discrimination: the mistreatment against older people; specially, the situation in nursing homes and long-term care institutions. describes the concept, types and risk factors of the abuse against older adults, and proposes some legal solutions that have been introduced in several countries to protect them. finally, this article draws some conclusions to contribute to the incipient chilean debate regarding protection older people.
Fabiola Lathrop
Revista Chilena de Derecho : Publicado por la Facultad de Derecho Universidad Católica de Chile , 2009,
Abstract: Resumen: Este artículo examina la situación jurídica de los adultos mayores en Chile y analiza un tipo de discriminación por edad: el maltrato contra las personas ancianas, en especial, la situación en los hogares e instituciones de larga estadía. Describe el concepto, los tipos y los factores de riesgo del abuso contra los adultos mayores, y propone algunas soluciones legales introducidas en varios países para protegerlos. Finalmente, se esbozan algunas conclusiones con el objeto de contribuir al incipiente debate chileno sobre la protección de las personas ancianas. Abstract: This article reviews the legal situation of older adults in Chile and analyses a type of age discrimination: the mistreatment against older people; specially, the situation in nursing homes and long-term care institutions. Describes the concept, types and risk factors of the abuse against older adults, and proposes some legal solutions that have been introduced in several countries to protect them. Finally, this article draws some conclusions to contribute to the incipient Chilean debate regarding protection older people.
ISCB Public Policy Statement on Open Access to Scientific and Technical Research Literature
Richard H. Lathrop,Burkhard Rost,ISCB Membership ,ISCB Executive Committee,ISCB Board of Directors,ISCB Public Affairs Committee
PLOS Computational Biology , 2011, DOI: 10.1371/journal.pcbi.1002014
Predicting Positive p53 Cancer Rescue Regions Using Most Informative Positive (MIP) Active Learning
Samuel A. Danziger,Roberta Baronio,Lydia Ho,Linda Hall,Kirsty Salmon,G. Wesley Hatfield,Peter Kaiser ,Richard H. Lathrop
PLOS Computational Biology , 2009, DOI: 10.1371/journal.pcbi.1000498
Abstract: Many protein engineering problems involve finding mutations that produce proteins with a particular function. Computational active learning is an attractive approach to discover desired biological activities. Traditional active learning techniques have been optimized to iteratively improve classifier accuracy, not to quickly discover biologically significant results. We report here a novel active learning technique, Most Informative Positive (MIP), which is tailored to biological problems because it seeks novel and informative positive results. MIP active learning differs from traditional active learning methods in two ways: (1) it preferentially seeks Positive (functionally active) examples; and (2) it may be effectively extended to select gene regions suitable for high throughput combinatorial mutagenesis. We applied MIP to discover mutations in the tumor suppressor protein p53 that reactivate mutated p53 found in human cancers. This is an important biomedical goal because p53 mutants have been implicated in half of all human cancers, and restoring active p53 in tumors leads to tumor regression. MIP found Positive (cancer rescue) p53 mutants in silico using 33% fewer experiments than traditional non-MIP active learning, with only a minor decrease in classifier accuracy. Applying MIP to in vivo experimentation yielded immediate Positive results. Ten different p53 mutations found in human cancers were paired in silico with all possible single amino acid rescue mutations, from which MIP was used to select a Positive Region predicted to be enriched for p53 cancer rescue mutants. In vivo assays showed that the predicted Positive Region: (1) had significantly more (p<0.01) new strong cancer rescue mutants than control regions (Negative, and non-MIP active learning); (2) had slightly more new strong cancer rescue mutants than an Expert region selected for purely biological considerations; and (3) rescued for the first time the previously unrescuable p53 cancer mutant P152L.
Ensemble-Based Computational Approach Discriminates Functional Activity of p53 Cancer and Rescue Mutants
?zlem Demir,Roberta Baronio,Faezeh Salehi,Christopher D. Wassman,Linda Hall,G. Wesley Hatfield,Richard Chamberlin,Peter Kaiser,Richard H. Lathrop,Rommie E. Amaro
PLOS Computational Biology , 2011, DOI: 10.1371/journal.pcbi.1002238
Abstract: The tumor suppressor protein p53 can lose its function upon single-point missense mutations in the core DNA-binding domain (“cancer mutants”). Activity can be restored by second-site suppressor mutations (“rescue mutants”). This paper relates the functional activity of p53 cancer and rescue mutants to their overall molecular dynamics (MD), without focusing on local structural details. A novel global measure of protein flexibility for the p53 core DNA-binding domain, the number of clusters at a certain RMSD cutoff, was computed by clustering over 0.7 μs of explicitly solvated all-atom MD simulations. For wild-type p53 and a sample of p53 cancer or rescue mutants, the number of clusters was a good predictor of in vivo p53 functional activity in cell-based assays. This number-of-clusters (NOC) metric was strongly correlated (r2 = 0.77) with reported values of experimentally measured ΔΔG protein thermodynamic stability. Interpreting the number of clusters as a measure of protein flexibility: (i) p53 cancer mutants were more flexible than wild-type protein, (ii) second-site rescue mutations decreased the flexibility of cancer mutants, and (iii) negative controls of non-rescue second-site mutants did not. This new method reflects the overall stability of the p53 core domain and can discriminate which second-site mutations restore activity to p53 cancer mutants.
Lathrop Gómez,Fabiola;
Ius et Praxis , 2011, DOI: 10.4067/S0718-00122011000200002
Abstract: this text presents some doctrine and jurisprudence considerations regarding declarative action in the chilean property law system intended to point out the failures of this right regarding possession in the protection and legal system, and particularly the court's interpretative work regarding this subject.
Lathrop Gómez,Fabiola;
Ius et Praxis , 2010, DOI: 10.4067/S0718-00122010000200006
Abstract: the present article sustains that the preference towards the mother of the legal attribution of physical custody container] in the article 225 of the chilean civil code, is unconstitutional, since is based in an arbitrary discrimination, unjust, not reasonable and disproportionate, that violates the principie of legal and material equality the chilean case is analyzed in the light of international human rights treaties and comparative law.
BARCIA LEHMANN, RODRIGO(2011). Fundamentos del Derecho de Familia y de la Infancia
Revista de Derecho (Coquimbo) , 2012,
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