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2.
Nat Commun ; 10(1): 1313, 2019 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-30899020

RESUMO

Individual cells in clonal populations often respond differently to environmental changes; for binary phenotypes, such as cell death, this can be measured as a fractional response. These types of responses have been attributed to cell-intrinsic stochastic processes and variable abundances of biochemical constituents, such as proteins, but the influence of organelles is still under investigation. We use the response to TNF-related apoptosis inducing ligand (TRAIL) and a new statistical framework for determining parameter influence on cell-to-cell variability through the inference of variance explained, DEPICTIVE, to demonstrate that variable mitochondria abundance correlates with cell survival and determines the fractional cell death response. By quantitative data analysis and modeling we attribute this effect to variable effective concentrations at the mitochondria surface of the pro-apoptotic proteins Bax/Bak. Further, our study suggests that inhibitors of anti-apoptotic Bcl-2 family proteins, used in cancer treatment, may increase the diversity of cellular responses, enhancing resistance to treatment.


Assuntos
Apoptose/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Mitocôndrias/efeitos dos fármacos , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Proteína Killer-Antagonista Homóloga a bcl-2/genética , Proteína X Associada a bcl-2/genética , Anexina A5/química , Biomarcadores/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Corantes Fluorescentes/química , Variação Genética , Células HeLa , Humanos , Células Jurkat , Mitocôndrias/genética , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Modelos Genéticos , Compostos Orgânicos/química , Proteína Killer-Antagonista Homóloga a bcl-2/metabolismo , Proteína X Associada a bcl-2/metabolismo
3.
Nat Commun ; 9(1): 4979, 2018 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-30478272

RESUMO

There has been recent progress in predicting whether common verbal descriptors such as "fishy", "floral" or "fruity" apply to the smell of odorous molecules. However, accurate predictions have been achieved only for a small number of descriptors. Here, we show that applying natural-language semantic representations on a small set of general olfactory perceptual descriptors allows for the accurate inference of perceptual ratings for mono-molecular odorants over a large and potentially arbitrary set of descriptors. This is noteworthy given that the prevailing view is that humans' capacity to identify or characterize odors by name is poor. We successfully apply our semantics-based approach to predict perceptual ratings with an accuracy higher than 0.5 for up to 70 olfactory perceptual descriptors, a ten-fold increase in the number of descriptors from previous attempts. These results imply that the semantic distance between descriptors defines the equivalent of an odorwheel.

4.
Dis Model Mech ; 10(4): 349-352, 2017 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-28381596

RESUMO

Cancer therapeutics currently have the lowest clinical trial success rate of all major diseases. Partly as a result of the paucity of successful anti-cancer drugs, cancer will soon be the leading cause of mortality in developed countries. As a disease embedded in the fundamentals of our biology, cancer presents difficult challenges that would benefit from uniting experts from a broad cross-section of related and unrelated fields. Combining extant approaches with novel ones could help in tackling this challenging health problem, enabling the development of therapeutics to stop disease progression and prolong patient lives. This goal provided the inspiration for a recent workshop titled 'Rethinking Cancer', which brought together a group of cancer scientists who work in the academic and pharmaceutical sectors of Europe, America and Asia. In this Editorial, we discuss the main themes emerging from the workshop, with the aim of providing a snapshot of key challenges faced by the cancer research community today. We also outline potential strategies for addressing some of these challenges, from understanding the basic evolution of cancer and improving its early detection to streamlining the thorny process of moving promising drug targets into clinical trials.


Assuntos
Pesquisa Biomédica , Neoplasias/patologia , Animais , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Genômica , Humanos , Biologia de Sistemas
5.
Science ; 355(6327): 820-826, 2017 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-28219971

RESUMO

It is still not possible to predict whether a given molecule will have a perceived odor or what olfactory percept it will produce. We therefore organized the crowd-sourced DREAM Olfaction Prediction Challenge. Using a large olfactory psychophysical data set, teams developed machine-learning algorithms to predict sensory attributes of molecules based on their chemoinformatic features. The resulting models accurately predicted odor intensity and pleasantness and also successfully predicted 8 among 19 rated semantic descriptors ("garlic," "fish," "sweet," "fruit," "burnt," "spices," "flower," and "sour"). Regularized linear models performed nearly as well as random forest-based ones, with a predictive accuracy that closely approaches a key theoretical limit. These models help to predict the perceptual qualities of virtually any molecule with high accuracy and also reverse-engineer the smell of a molecule.


Assuntos
Odorantes , Percepção Olfatória , Olfato , Adulto , Conjuntos de Dados como Assunto , Humanos , Masculino , Modelos Biológicos
6.
Nat Rev Genet ; 17(8): 470-86, 2016 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-27418159

RESUMO

The generation of large-scale biomedical data is creating unprecedented opportunities for basic and translational science. Typically, the data producers perform initial analyses, but it is very likely that the most informative methods may reside with other groups. Crowdsourcing the analysis of complex and massive data has emerged as a framework to find robust methodologies. When the crowdsourcing is done in the form of collaborative scientific competitions, known as Challenges, the validation of the methods is inherently addressed. Challenges also encourage open innovation, create collaborative communities to solve diverse and important biomedical problems, and foster the creation and dissemination of well-curated data repositories.


Assuntos
Pesquisa Biomédica/organização & administração , Crowdsourcing , Pesquisa Médica Translacional/organização & administração , Animais , Comportamento Cooperativo , Humanos , Comunicação Interdisciplinar , Inovação Organizacional
8.
Comput Biol Chem ; 59 Pt B: 113-22, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26278972

RESUMO

To better understand how enzyme localization affects enzyme activity we studied the cellular localization of the glycosyltransferase MurG, an enzyme necessary for cell wall synthesis at the spore during sporulation in the bacterium Bacillus subtilis. During sporulation MurG was gradually enriched to the membrane at the forespore and point mutations in a MurG helical domain disrupting its localization to the membrane caused severe sporulation defects, but did not affect localization nor caused detectable defects during exponential growth. We found that this localization is dependent on the phospholipid cardiolipin, as in strains where the cardiolipin-synthesizing genes were deleted, MurG levels were diminished at the forespore. Furthermore, in this cardiolipin-less strain, MurG localization during sporulation was rescued by external addition of purified cardiolipin. These results support localization as a critical factor in the regulation of proper enzyme function and catalysis.


Assuntos
Bacillus subtilis/citologia , Bacillus subtilis/enzimologia , Proteínas da Membrana Bacteriana Externa/análise , Proteínas da Membrana Bacteriana Externa/metabolismo , N-Acetilglucosaminiltransferases/análise , N-Acetilglucosaminiltransferases/metabolismo , Proteínas da Membrana Bacteriana Externa/química , Biocatálise , Cardiolipinas/metabolismo , Cardiolipinas/farmacologia , Biologia Computacional , Escherichia coli/química , Escherichia coli/citologia , Escherichia coli/metabolismo , N-Acetilglucosaminiltransferases/química , Transporte Proteico , Esporos Bacterianos/citologia , Esporos Bacterianos/enzimologia , Esporos Bacterianos/metabolismo
9.
PLoS Comput Biol ; 11(5): e1004096, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-26020786

RESUMO

Whole-cell models that explicitly represent all cellular components at the molecular level have the potential to predict phenotype from genotype. However, even for simple bacteria, whole-cell models will contain thousands of parameters, many of which are poorly characterized or unknown. New algorithms are needed to estimate these parameters and enable researchers to build increasingly comprehensive models. We organized the Dialogue for Reverse Engineering Assessments and Methods (DREAM) 8 Whole-Cell Parameter Estimation Challenge to develop new parameter estimation algorithms for whole-cell models. We asked participants to identify a subset of parameters of a whole-cell model given the model's structure and in silico "experimental" data. Here we describe the challenge, the best performing methods, and new insights into the identifiability of whole-cell models. We also describe several valuable lessons we learned toward improving future challenges. Going forward, we believe that collaborative efforts supported by inexpensive cloud computing have the potential to solve whole-cell model parameter estimation.


Assuntos
Células/metabolismo , Modelos Biológicos , Algoritmos , Bactérias/genética , Bactérias/metabolismo , Bioengenharia , Computação em Nuvem , Biologia Computacional , Simulação por Computador , Estudos de Associação Genética/estatística & dados numéricos , Mutação , Mycoplasma genitalium/genética , Mycoplasma genitalium/metabolismo
10.
Rev Panam Salud Publica ; 37(2): 69-75, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25915010

RESUMO

OBJECTIVE: To evaluate the prevalence of soil-transmitted helminth infections, anemia, and malnutrition among children in the Paucartambo province of Cusco region, Peru, in light of demographic, socio-economic, and epidemiologic contextual factors. METHODS: Children from three to twelve years old from six communities in Huancarani district in the highlands of Peru were evaluated for helminth infections, anemia, and nutritional status. Data collected included demographic variables, socioeconomic status, exposures, complete blood counts, and direct and sedimentation stool tests. RESULTS: Of 240 children analyzed, 113 (47%) were infected with one or more parasites. Giardia (27.5%) and Fasciola (9.6%) were the most commonly identified organisms. Eosinophilia was encountered in 21% of the children. Anemia (48.8%) was associated with age (3-4 vs 5-12 years old; odds ratio (OR): 5.86; 95% confidence interval (CI): 2.81-12.21). Underweight (10%) was associated with male sex (OR: 5.97; CI: 1.12-31.72), higher eosinophil count (OR: 4.67; CI: 1.31-16.68) and education of the mother (OR: 0.6; CI: 0.4-0.9). Stunting (31.3%) was associated with education of the mother (OR: 0.83; CI: 0.72-0.95); wasting (2.7%) was associated with higher eosinophil count (OR: 2.75; CI: 1.04-7.25). CONCLUSIONS: Anemia and malnutrition remain significant problems in the Peruvian highlands. These findings suggest that demographic factors, socio-economic status, and possibly parasitic infections intertwine to cause these health problems.


Assuntos
Anemia/epidemiologia , Helmintíase/epidemiologia , Enteropatias Parasitárias/epidemiologia , Desnutrição/epidemiologia , Albendazol/uso terapêutico , Anemia/etiologia , Anti-Helmínticos/uso terapêutico , Criança , Pré-Escolar , Estudos Transversais , Escolaridade , Doenças Endêmicas , Eosinofilia/epidemiologia , Feminino , Transtornos do Crescimento/epidemiologia , Helmintíase/prevenção & controle , Helmintíase/transmissão , Humanos , Enteropatias Parasitárias/prevenção & controle , Enteropatias Parasitárias/transmissão , Masculino , Peru/epidemiologia , Prevalência , População Rural , Determinantes Sociais da Saúde , Fatores Socioeconômicos , Solo/parasitologia , Abastecimento de Água
11.
Rev. panam. salud pública ; 37(2): 69-75, Feb. 2015. ilus, tab
Artigo em Inglês | LILACS | ID: lil-744911

RESUMO

Objective. To evaluate the prevalence of soil-transmitted helminth infections, anemia, and malnutrition among children in the Paucartambo province of Cusco region, Peru, in light of demographic, socio-economic, and epidemiologic contextual factors. Methods. Children from three to twelve years old from six communities in Huancarani district in the highlands of Peru were evaluated for helminth infections, anemia, and nutritional status. Data collected included demographic variables, socioeconomic status, exposures, complete blood counts, and direct and sedimentation stool tests. Results. Of 240 children analyzed, 113 (47%) were infected with one or more parasites. Giardia (27.5%) and Fasciola (9.6%) were the most commonly identified organisms. Eosinophilia was encountered in 21% of the children. Anemia (48.8%) was associated with age (3-4 vs 5-12 years old; odds ratio (OR): 5.86; 95% confidence interval (CI): 2.81-12.21). Underweight (10%) was associated with male sex (OR: 5.97; CI: 1.12-31.72), higher eosinophil count (OR: 4.67; CI: 1.31-16.68) and education of the mother (OR: 0.6; CI: 0.4-0.9). Stunting (31.3%) was associated with education of the mother (OR: 0.83; CI: 0.72-0.95); wasting (2.7%) was associated with higher eosinophil count (OR: 2.75; CI: 1.04-7.25). Conclusions. Anemia and malnutrition remain significant problems in the Peruvian highlands. These findings suggest that demographic factors, socio-economic status, and possibly parasitic infections intertwine to cause these health problems.


Objetivo. Evaluar la prevalencia de geohelmintiasis, anemia y desnutrición en los niños de la provincia de Paucartambo (departamento de Cusco, Perú), teniendo en cuenta los factores contextuales demográficos, socioeconómicos y epidemiológicos. Métodos. Se determinó la presencia de helmintiasis y anemia y el estado nutricional de niños de 3 a 12 años de edad de seis comunidades del distrito de Huancarani, en la sierra peruana. Se documentaron las variables demográficas, el nivel socioeconómico, la exposición, los hemogramas y pruebas de observación directa y de sedimentación de parásitos en materia fecal. Resultados. De los 240 niños estudiados, 113 (47%) estaban infectados por uno o más parásitos. Los organismos encontrados con mayor frecuencia fueron de los géneros Giardia (27,5%) y Fasciola (9,6%). El 21% de los niños presentaban eosinofilia. La anemia (48,8%) se asoció con la edad (3-4 años frente a 5-12 años; razón de posibilidades [OR]: 5,86; intervalo de confianza [IC] de 95%: 2,81-12,21). El peso inferior al normal (10%) se asoció con el sexo masculino (OR: 5,97; IC: 1,12-31,72), con un recuento de eosinófilos más alto (OR: 4,67; IC: 1,31-16,68) y con el nivel educativo de la madre (OR: 0,6; IC: 0,4-0,9). El retraso del crecimiento (31,3%) se asoció con el nivel educativo de la madre (OR: 0,83; IC: 0,72-0,95), y la emaciación (2,7%) se asoció con un recuento de eosinófilos más alto (OR: 2,75; IC: 1,04-7,25). Conclusiones. La anemia y la desnutrición siguen siendo problemas importantes en la sierra peruana. Estos resultados sugieren que estas enfermedades se deben a una interacción de los factores demográficos, el nivel socioeconómico y, posiblemente, las parasitosis.


Assuntos
Enteropatias Parasitárias/complicações , Enteropatias Parasitárias/prevenção & controle , Enteropatias Parasitárias/transmissão , Enteropatias Parasitárias/epidemiologia , Peru/epidemiologia
12.
F1000Res ; 4: 1030, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-27134723

RESUMO

UNLABELLED: DREAM challenges are community competitions designed to advance computational methods and address fundamental questions in system biology and translational medicine. Each challenge asks participants to develop and apply computational methods to either predict unobserved outcomes or to identify unknown model parameters given a set of training data. Computational methods are evaluated using an automated scoring metric, scores are posted to a public leaderboard, and methods are published to facilitate community discussions on how to build improved methods. By engaging participants from a wide range of science and engineering backgrounds, DREAM challenges can comparatively evaluate a wide range of statistical, machine learning, and biophysical methods. Here, we describe DREAMTools, a Python package for evaluating DREAM challenge scoring metrics. DREAMTools provides a command line interface that enables researchers to test new methods on past challenges, as well as a framework for scoring new challenges. As of March 2016, DREAMTools includes more than 80% of completed DREAM challenges. DREAMTools complements the data, metadata, and software tools available at the DREAM website http://dreamchallenges.org and on the Synapse platform at https://www.synapse.org. AVAILABILITY:   DREAMTools is a Python package. Releases and documentation are available at http://pypi.python.org/pypi/dreamtools. The source code is available at http://github.com/dreamtools/dreamtools.

13.
Bioinformatics ; 31(4): 484-91, 2015 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-25294919

RESUMO

MOTIVATION: Animal models are important tools in drug discovery and for understanding human biology in general. However, many drugs that initially show promising results in rodents fail in later stages of clinical trials. Understanding the commonalities and differences between human and rat cell signaling networks can lead to better experimental designs, improved allocation of resources and ultimately better drugs. RESULTS: The sbv IMPROVER Species-Specific Network Inference challenge was designed to use the power of the crowds to build two species-specific cell signaling networks given phosphoproteomics, transcriptomics and cytokine data generated from NHBE and NRBE cells exposed to various stimuli. A common literature-inspired reference network with 220 nodes and 501 edges was also provided as prior knowledge from which challenge participants could add or remove edges but not nodes. Such a large network inference challenge not based on synthetic simulations but on real data presented unique difficulties in scoring and interpreting the results. Because any prior knowledge about the networks was already provided to the participants for reference, novel ways for scoring and aggregating the results were developed. Two human and rat consensus networks were obtained by combining all the inferred networks. Further analysis showed that major signaling pathways were conserved between the two species with only isolated components diverging, as in the case of ribosomal S6 kinase RPS6KA1. Overall, the consensus between inferred edges was relatively high with the exception of the downstream targets of transcription factors, which seemed more difficult to predict. CONTACT: ebilal@us.ibm.com or gustavo@us.ibm.com. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Algoritmos , Crowdsourcing , Citocinas/metabolismo , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Fosfoproteínas/metabolismo , Software , Biologia de Sistemas/métodos , Animais , Brônquios/citologia , Brônquios/metabolismo , Comunicação Celular , Células Cultivadas , Bases de Dados Factuais , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Regulação da Expressão Gênica , Humanos , Modelos Animais , Análise de Sequência com Séries de Oligonucleotídeos , Fosforilação , Ratos , Transdução de Sinais , Especificidade da Espécie
14.
Bioinformatics ; 31(4): 453-61, 2015 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-24994890

RESUMO

MOTIVATION: Animal models are widely used in biomedical research for reasons ranging from practical to ethical. An important issue is whether rodent models are predictive of human biology. This has been addressed recently in the framework of a series of challenges designed by the systems biology verification for Industrial Methodology for Process Verification in Research (sbv IMPROVER) initiative. In particular, one of the sub-challenges was devoted to the prediction of protein phosphorylation responses in human bronchial epithelial cells, exposed to a number of different chemical stimuli, given the responses in rat bronchial epithelial cells. Participating teams were asked to make inter-species predictions on the basis of available training examples, comprising transcriptomics and phosphoproteomics data. RESULTS: Here, the two best performing teams present their data-driven approaches and computational methods. In addition, post hoc analyses of the datasets and challenge results were performed by the participants and challenge organizers. The challenge outcome indicates that successful prediction of protein phosphorylation status in human based on rat phosphorylation levels is feasible. However, within the limitations of the computational tools used, the inclusion of gene expression data does not improve the prediction quality. The post hoc analysis of time-specific measurements sheds light on the signaling pathways in both species. AVAILABILITY AND IMPLEMENTATION: A detailed description of the dataset, challenge design and outcome is available at www.sbvimprover.com. The code used by team IGB is provided under http://github.com/uci-igb/improver2013. Implementations of the algorithms applied by team AMG are available at http://bhanot.biomaps.rutgers.edu/wiki/AMG-sc2-code.zip. CONTACT: meikelbiehl@gmail.com.


Assuntos
Brônquios/metabolismo , Células Epiteliais/metabolismo , Perfilação da Expressão Gênica , Fosfoproteínas/metabolismo , Software , Biologia de Sistemas/métodos , Algoritmos , Animais , Brônquios/citologia , Células Cultivadas , Bases de Dados Factuais , Células Epiteliais/citologia , Regulação da Expressão Gênica , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Fosforilação , Ratos , Especificidade da Espécie , Pesquisa Médica Translacional
15.
Bioinformatics ; 31(4): 462-70, 2015 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-25061067

RESUMO

MOTIVATION: Using gene expression to infer changes in protein phosphorylation levels induced in cells by various stimuli is an outstanding problem. The intra-species protein phosphorylation challenge organized by the IMPROVER consortium provided the framework to identify the best approaches to address this issue. RESULTS: Rat lung epithelial cells were treated with 52 stimuli, and gene expression and phosphorylation levels were measured. Competing teams used gene expression data from 26 stimuli to develop protein phosphorylation prediction models and were ranked based on prediction performance for the remaining 26 stimuli. Three teams were tied in first place in this challenge achieving a balanced accuracy of about 70%, indicating that gene expression is only moderately predictive of protein phosphorylation. In spite of the similar performance, the approaches used by these three teams, described in detail in this article, were different, with the average number of predictor genes per phosphoprotein used by the teams ranging from 3 to 124. However, a significant overlap of gene signatures between teams was observed for the majority of the proteins considered, while Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were enriched in the union of the predictor genes of the three teams for multiple proteins. AVAILABILITY AND IMPLEMENTATION: Gene expression and protein phosphorylation data are available from ArrayExpress (E-MTAB-2091). Software implementation of the approach of Teams 49 and 75 are available at http://bioinformaticsprb.med.wayne.edu and http://people.cs.clemson.edu/∼luofeng/sbv.rar, respectively. CONTACT: gyanbhanot@gmail.com or luofeng@clemson.edu or atarca@med.wayne.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Células Epiteliais/metabolismo , Perfilação da Expressão Gênica , Pulmão/metabolismo , Fosfoproteínas/metabolismo , Software , Biologia de Sistemas/métodos , Algoritmos , Animais , Células Cultivadas , Bases de Dados Factuais , Células Epiteliais/citologia , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Pulmão/citologia , Análise de Sequência com Séries de Oligonucleotídeos , Fosforilação , Ratos , Especificidade da Espécie , Pesquisa Médica Translacional
16.
Bioinformatics ; 31(4): 471-83, 2015 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-25236459

RESUMO

MOTIVATION: Inferring how humans respond to external cues such as drugs, chemicals, viruses or hormones is an essential question in biomedicine. Very often, however, this question cannot be addressed because it is not possible to perform experiments in humans. A reasonable alternative consists of generating responses in animal models and 'translating' those results to humans. The limitations of such translation, however, are far from clear, and systematic assessments of its actual potential are urgently needed. sbv IMPROVER (systems biology verification for Industrial Methodology for PROcess VErification in Research) was designed as a series of challenges to address translatability between humans and rodents. This collaborative crowd-sourcing initiative invited scientists from around the world to apply their own computational methodologies on a multilayer systems biology dataset composed of phosphoproteomics, transcriptomics and cytokine data derived from normal human and rat bronchial epithelial cells exposed in parallel to 52 different stimuli under identical conditions. Our aim was to understand the limits of species-to-species translatability at different levels of biological organization: signaling, transcriptional and release of secreted factors (such as cytokines). Participating teams submitted 49 different solutions across the sub-challenges, two-thirds of which were statistically significantly better than random. Additionally, similar computational methods were found to range widely in their performance within the same challenge, and no single method emerged as a clear winner across all sub-challenges. Finally, computational methods were able to effectively translate some specific stimuli and biological processes in the lung epithelial system, such as DNA synthesis, cytoskeleton and extracellular matrix, translation, immune/inflammation and growth factor/proliferation pathways, better than the expected response similarity between species. CONTACT: pmeyerr@us.ibm.com or Julia.Hoeng@pmi.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Algoritmos , Citocinas/metabolismo , Perfilação da Expressão Gênica , Modelos Animais , Fosfoproteínas/metabolismo , Software , Biologia de Sistemas/métodos , Animais , Brônquios/citologia , Brônquios/metabolismo , Células Cultivadas , Bases de Dados Factuais , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Fosforilação , Ratos , Especificidade da Espécie , Pesquisa Médica Translacional
17.
Bioinformatics ; 31(4): 501-8, 2015 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-25150249

RESUMO

MOTIVATION: Experiments in animal models are often conducted to infer how humans will respond to stimuli by assuming that the same biological pathways will be affected in both organisms. The limitations of this assumption were tested in the IMPROVER Species Translation Challenge, where 52 stimuli were applied to both human and rat cells and perturbed pathways were identified. In the Inter-species Pathway Perturbation Prediction sub-challenge, multiple teams proposed methods to use rat transcription data from 26 stimuli to predict human gene set and pathway activity under the same perturbations. Submissions were evaluated using three performance metrics on data from the remaining 26 stimuli. RESULTS: We present two approaches, ranked second in this challenge, that do not rely on sequence-based orthology between rat and human genes to translate pathway perturbation state but instead identify transcriptional response orthologs across a set of training conditions. The translation from rat to human accomplished by these so-called direct methods is not dependent on the particular analysis method used to identify perturbed gene sets. In contrast, machine learning-based methods require performing a pathway analysis initially and then mapping the pathway activity between organisms. Unlike most machine learning approaches, direct methods can be used to predict the activation of a human pathway for a new (test) stimuli, even when that pathway was never activated by a training stimuli. AVAILABILITY: Gene expression data are available from ArrayExpress (accession E-MTAB-2091), while software implementations are available from http://bioinformaticsprb.med.wayne.edu?p=50 and http://goo.gl/hJny3h. CONTACT: christoph.hafemeister@nyu.edu or atarca@med.wayne.edu. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Algoritmos , Inteligência Artificial , Citocinas/metabolismo , Perfilação da Expressão Gênica/métodos , Fosfoproteínas/metabolismo , Software , Biologia de Sistemas/métodos , Animais , Brônquios/citologia , Brônquios/metabolismo , Células Cultivadas , Bases de Dados Factuais , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Regulação da Expressão Gênica , Humanos , Modelos Animais , Análise de Sequência com Séries de Oligonucleotídeos , Fosforilação , Ratos , Transdução de Sinais , Especificidade da Espécie , Pesquisa Médica Translacional
18.
Bioinformatics ; 31(4): 492-500, 2015 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-25152231

RESUMO

MOTIVATION: Translating findings in rodent models to human models has been a cornerstone of modern biology and drug development. However, in many cases, a naive 'extrapolation' between the two species has not succeeded. As a result, clinical trials of new drugs sometimes fail even after considerable success in the mouse or rat stage of development. In addition to in vitro studies, inter-species translation requires analytical tools that can predict the enriched gene sets in human cells under various stimuli from corresponding measurements in animals. Such tools can improve our understanding of the underlying biology and optimize the allocation of resources for drug development. RESULTS: We developed an algorithm to predict differential gene set enrichment as part of the sbv IMPROVER (systems biology verification in Industrial Methodology for Process Verification in Research) Species Translation Challenge, which focused on phosphoproteomic and transcriptomic measurements of normal human bronchial epithelial (NHBE) primary cells under various stimuli and corresponding measurements in rat (NRBE) primary cells. We find that gene sets exhibit a higher inter-species correlation compared with individual genes, and are potentially more suited for direct prediction. Furthermore, in contrast to a similar cross-species response in protein phosphorylation states 5 and 25 min after exposure to stimuli, gene set enrichment 6 h after exposure is significantly different in NHBE cells compared with NRBE cells. In spite of this difference, we were able to develop a robust algorithm to predict gene set activation in NHBE with high accuracy using simple analytical methods. AVAILABILITY AND IMPLEMENTATION: Implementation of all algorithms is available as source code (in Matlab) at http://bhanot.biomaps.rutgers.edu/wiki/codes_SC3_Predicting_GeneSets.zip, along with the relevant data used in the analysis. Gene sets, gene expression and protein phosphorylation data are available on request. CONTACT: hormoz@kitp.ucsb.edu.


Assuntos
Algoritmos , Perfilação da Expressão Gênica/métodos , Redes Reguladoras de Genes , Proteômica/métodos , Biologia de Sistemas/métodos , Animais , Brônquios/citologia , Brônquios/metabolismo , Células Cultivadas , Citocinas/metabolismo , Interpretação Estatística de Dados , Bases de Dados Factuais , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Regulação da Expressão Gênica , Humanos , Camundongos , Fosfoproteínas/metabolismo , Fosforilação , Ratos , Transdução de Sinais , Especificidade da Espécie
19.
J Travel Med ; 22(1): 26-30, 2015 Jan-Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25156197

RESUMO

BACKGROUND: Travelers receive medical advice from a variety of sources, including travel agencies. The aim of this study is to describe the quality of pre-travel advice provided by travel agencies in Cuzco to travelers interested in visiting malaria and yellow fever endemic areas. METHODS: Trained medical students posed as tourists and visited travel agencies in Cuzco requesting travel advice for a trip to the southern Amazon of Peru, recording advice regarding risk and prevention of malaria and yellow fever. RESULTS: A total of 163 registered travel agencies were included in the study. The mean proposed tour duration was 6.8 days (±1.4 days) with a median time to departure of 3 days and a median tour cost of 805 US dollars (USD) [interquartile range (IQR) 580-1,095]. Overall, 45% employees failed to mention the risk for any illness. Eighteen percent of the employees acknowledged risk of malaria and 53% risk of yellow fever. However, 36% denied malaria risk and 2% denied risk of yellow fever in the region. The price of tours from travel agencies that did not mention any health risk was significantly lower [1,009.6 ± 500.5 vs 783.9 ± 402 USD, t (152) = 3, p < 0.01] compared with the price from agencies that did mention health risks. Almost all who acknowledged malaria (97%) and/or yellow fever (100%) were able to provide at least one recommendation for prevention. However, advice was not always accurate or spontaneously volunteered. Only 7% of the employees provided both correct scheduling and location information for administration of the yellow fever vaccine. CONCLUSIONS: The majority of registered travel agencies in Cuzco did not provide sufficient and accurate information regarding risk and prevention of malaria and yellow fever to travelers inquiring about trips to the southern Amazon of Peru.


Assuntos
Antimaláricos/uso terapêutico , Malária/prevenção & controle , Viagem , Vacina contra Febre Amarela/uso terapêutico , Febre Amarela/prevenção & controle , Estudos Transversais , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Malária/epidemiologia , Peru , Fatores de Risco , Inquéritos e Questionários , Febre Amarela/epidemiologia
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