Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 58
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Mol Oncol ; 14(1): 22-41, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31733171

RESUMO

Ultraviolet radiation-induced DNA mutations are a primary environmental driver of melanoma. The reason for this very high level of unrepaired DNA lesions leading to these mutations is still poorly understood. The primary DNA repair mechanism for UV-induced lesions, that is, the nucleotide excision repair pathway, appears intact in most melanomas. We have previously reported a postreplication repair mechanism that is commonly defective in melanoma cell lines. Here we have used a genome-wide approach to identify the components of this postreplication repair mechanism. We have used differential transcript polysome loading to identify transcripts that are associated with UV response, and then functionally assessed these to identify novel components of this repair and cell cycle checkpoint network. We have identified multiple interaction nodes, including global genomic nucleotide excision repair and homologous recombination repair, and previously unexpected MASTL pathway, as components of the response. Finally, we have used bioinformatics to assess the contribution of dysregulated expression of these pathways to the UV signature mutation load of a large melanoma cohort. We show that dysregulation of the pathway, especially the DNA damage repair components, are significant contributors to UV mutation load, and that dysregulation of the MASTL pathway appears to be a significant contributor to high UV signature mutation load.

2.
Front Genet ; 10: 963, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31803221

RESUMO

Simultaneous profiling of biospecimens using different technological platforms enables the study of many data types, encompassing microbial communities, omics, and meta-omics as well as clinical or chemistry variables. Reduction in costs now enables longitudinal or time course studies on the same biological material or system. The overall aim of such studies is to investigate relationships between these longitudinal measures in a holistic manner to further decipher the link between molecular mechanisms and microbial community structures, or host-microbiota interactions. However, analytical frameworks enabling an integrated analysis between microbial communities and other types of biological, clinical, or phenotypic data are still in their infancy. The challenges include few time points that may be unevenly spaced and unmatched between different data types, a small number of unique individual biospecimens, and high individual variability. Those challenges are further exacerbated by the inherent characteristics of microbial communities-derived data (e.g., sparse, compositional). We propose a generic data-driven framework to integrate different types of longitudinal data measured on the same biological specimens with microbial community data and select key temporal features with strong associations within the same sample group. The framework ranges from filtering and modeling to integration using smoothing splines and multivariate dimension reduction methods to address some of the analytical challenges of microbiome-derived data. We illustrate our framework on different types of multi-omics case studies in bioreactor experiments as well as human studies.

3.
Brief Bioinform ; 2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31776547

RESUMO

Microbial communities have been increasingly studied in recent years to investigate their role in ecological habitats. However, microbiome studies are difficult to reproduce or replicate as they may suffer from confounding factors that are unavoidable in practice and originate from biological, technical or computational sources. In this review, we define batch effects as unwanted variation introduced by confounding factors that are not related to any factors of interest. Computational and analytical methods are required to remove or account for batch effects. However, inherent microbiome data characteristics (e.g. sparse, compositional and multivariate) challenge the development and application of batch effect adjustment methods to either account or correct for batch effects. We present commonly encountered sources of batch effects that we illustrate in several case studies. We discuss the limitations of current methods, which often have assumptions that are not met due to the peculiarities of microbiome data. We provide practical guidelines for assessing the efficiency of the methods based on visual and numerical outputs and a thorough tutorial to reproduce the analyses conducted in this review.

4.
Arthritis Rheumatol ; 71(10): 1642-1650, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31038287

RESUMO

OBJECTIVE: HLA alleles affect susceptibility to more than 100 diseases, but the mechanisms that account for these genotype-disease associations are largely unknown. HLA alleles strongly influence predisposition to ankylosing spondylitis (AS) and rheumatoid arthritis (RA). Both AS and RA patients have discrete intestinal and fecal microbiome signatures. Whether these changes are the cause or consequence of the diseases themselves is unclear. To distinguish these possibilities, we examined the effect of HLA-B27 and HLA-DRB1 RA risk alleles on the composition of the intestinal microbiome in healthy individuals. METHODS: Five hundred sixty-eight stool and biopsy samples from 6 intestinal sites were collected from 107 healthy unrelated subjects, and stool samples were collected from 696 twin pairs from the TwinsUK cohort. Microbiome profiling was performed using sequencing of the 16S ribosomal RNA bacterial marker gene. All subjects were genotyped using the Illumina CoreExome SNP microarray, and HLA genotypes were imputed from these data. RESULTS: Associations were observed between the overall microbial composition and both the HLA-B27 genotype and the HLA-DRB1 RA risk allele (P = 0.0002 and P = 0.00001, respectively). These associations were replicated using the stool samples from the TwinsUK cohort (P = 0.023 and P = 0.033, respectively). CONCLUSION: This study shows that the changes in intestinal microbiome composition seen in AS and RA are at least partially due to effects of HLA-B27 and HLA-DRB1 on the gut microbiome. These findings support the hypothesis that HLA alleles operate to cause or increase the risk of these diseases through interaction with the intestinal microbiome and suggest that therapies targeting the microbiome may be effective in preventing or treating these diseases.

5.
Nat Methods ; 16(6): 479-487, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31133762

RESUMO

Single cell RNA-sequencing (scRNA-seq) technology has undergone rapid development in recent years, leading to an explosion in the number of tailored data analysis methods. However, the current lack of gold-standard benchmark datasets makes it difficult for researchers to systematically compare the performance of the many methods available. Here, we generated a realistic benchmark experiment that included single cells and admixtures of cells or RNA to create 'pseudo cells' from up to five distinct cancer cell lines. In total, 14 datasets were generated using both droplet and plate-based scRNA-seq protocols. We compared 3,913 combinations of data analysis methods for tasks ranging from normalization and imputation to clustering, trajectory analysis and data integration. Evaluation revealed pipelines suited to different types of data for different tasks. Our data and analysis provide a comprehensive framework for benchmarking most common scRNA-seq analysis steps.


Assuntos
Adenocarcinoma/genética , Benchmarking , Biologia Computacional/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias Pulmonares/genética , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos , Humanos , Software , Células Tumorais Cultivadas
6.
Water Res ; 158: 106-117, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31022528

RESUMO

Industrial thiocyanate (SCN-) waste streams from gold mining and coal coking have polluted environments worldwide. Modern SCN- bioremediation involves use of complex engineered heterotrophic microbiomes; little attention has been given to the ability of a simple environmental autotrophic microbiome to biodegrade SCN-. Here we present results from a bioreactor experiment inoculated with SCN- -loaded mine tailings, incubated autotrophically, and subjected to a range of environmentally relevant conditions. Genome-resolved metagenomics revealed that SCN- hydrolase-encoding, sulphur-oxidizing autotrophic bacteria mediated SCN- degradation. These microbes supported metabolically-dependent non-SCN--degrading sulphur-oxidizing autotrophs and non-sulphur oxidizing heterotrophs, and "niche" microbiomes developed spatially (planktonic versus sessile) and temporally (across changing environmental parameters). Bioreactor microbiome structures changed significantly with increasing temperature, shifting from Thiobacilli to a novel SCN- hydrolase-encoding gammaproteobacteria. Transformation of carbonyl sulphide (COS), a key intermediate in global biogeochemical sulphur cycling, was mediated by plasmid-hosted CS2 and COS hydrolase genes associated with Thiobacillus, revealing a potential for horizontal transfer of this function. Our work shows that simple native autotrophic microbiomes from mine tailings can be employed for SCN- bioremediation, thus improving the recycling of ore processing waters and reducing the hydrological footprint of mining.


Assuntos
Metagenômica , Tiocianatos , Processos Autotróficos , Reatores Biológicos , Consórcios Microbianos
7.
Ann Rheum Dis ; 78(4): 494-503, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30700427

RESUMO

OBJECTIVES: Certain gut bacterial families, including Bacteroidaceae, Porphyromonadaceae and Prevotellaceae, are increased in people suffering from spondyloarthropathy (SpA), a disease group associated with IL23R signalling variants. To understand the relationship between host interleukin (IL)-23 signalling and gut bacterial dysbiosis in SpA, we inhibited IL-23 in dysbiotic ZAP-70-mutant SKG mice that develop IL-23-dependent SpA-like arthritis, psoriasis-like skin inflammation and Crohn's-like ileitis in response to microbial beta 1,3-glucan (curdlan). METHODS: We treated SKG mice weekly with anti-IL-23 or isotype mAb for 3 weeks, rested them for 3 weeks, then administered curdlan or saline. We collected faecal samples longitudinally, assessed arthritis, spondylitis, psoriasis and ileitis histologically, and analysed the microbiota community profiles using next-generation sequencing. We used multivariate sparse partial least squares discriminant analysis to identify operational taxonomic unit (OTU) signatures best classifying treatment groups and linear regression to develop a predictive model of disease severity. RESULTS: IL-23p19 inhibition in naïve SKG mice decreased Bacteroidaceae, Porphyromonadaceae and Prevotellaceae. Abundance of Clostridiaceae and Lachnospiraceae families concomitantly increased, and curdlan-mediated SpA development decreased. Abundance of Enterobacteriaceae and Porphyromonadaceae family and reduction in Lachnospiraceae Dorea genus OTUs early in disease course were associated with disease severity in affected tissues. CONCLUSIONS: Dysbiosis in SKG mice reflects human SpA and is IL-23p19 dependent. In genetically susceptible hosts, IL-23p19 favours outgrowth of SpA-associated pathobionts and reduces support for homeostatic-inducing microbiota. The relative abundance of specific pathobionts is associated with disease severity.


Assuntos
Bactérias/crescimento & desenvolvimento , Disbiose/microbiologia , Microbioma Gastrointestinal/imunologia , Subunidade p19 da Interleucina-23/imunologia , Espondilartrite/microbiologia , Animais , Disbiose/imunologia , Fezes/microbiologia , Feminino , Homeostase/imunologia , Interações Hospedeiro-Patógeno/imunologia , Subunidade p19 da Interleucina-23/antagonistas & inibidores , Camundongos Mutantes , Índice de Gravidade de Doença , Espondilartrite/induzido quimicamente , Espondilartrite/imunologia , beta-Glucanas
8.
Bioinformatics ; 35(17): 3055-3062, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-30657866

RESUMO

MOTIVATION: In the continuously expanding omics era, novel computational and statistical strategies are needed for data integration and identification of biomarkers and molecular signatures. We present Data Integration Analysis for Biomarker discovery using Latent cOmponents (DIABLO), a multi-omics integrative method that seeks for common information across different data types through the selection of a subset of molecular features, while discriminating between multiple phenotypic groups. RESULTS: Using simulations and benchmark multi-omics studies, we show that DIABLO identifies features with superior biological relevance compared with existing unsupervised integrative methods, while achieving predictive performance comparable to state-of-the-art supervised approaches. DIABLO is versatile, allowing for modular-based analyses and cross-over study designs. In two case studies, DIABLO identified both known and novel multi-omics biomarkers consisting of mRNAs, miRNAs, CpGs, proteins and metabolites. AVAILABILITY AND IMPLEMENTATION: DIABLO is implemented in the mixOmics R Bioconductor package with functions for parameters' choice and visualization to assist in the interpretation of the integrative analyses, along with tutorials on http://mixomics.org and in our Bioconductor vignette. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

10.
Pediatr Diabetes ; 20(2): 166-171, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30556344

RESUMO

BACKGROUND: Stimulated C-peptide measurement after a mixed meal tolerance test (MMTT) is the accepted gold standard for assessing residual beta-cell function in type 1 diabetes (T1D); however, this approach is impractical outside of clinical trials. OBJECTIVE: To develop an improved estimate of residual beta-cell function in children with T1D using commonly measured clinical variables. SUBJECTS/METHODS: A clinical model to predict 90-minute MMTT stimulated C-peptide in children with recent-onset T1D was developed from the combined AbATE, START, and TIDAL placebo subjects (n = 46) 6 months post-recruitment using multiple linear regression. This model was then validated in a clinical cohort (Hvidoere study group, n = 262). RESULTS: A model of estimated C-peptide at 6 months post-diagnosis, which included age, gender, body mass index (BMI), hemoglobin A1c (HbA1c), and insulin dose predicted 90-minute stimulated C-peptide measurements (adjusted R2 = 0.63, P < 0.0001). The predictive value of insulin dose and HbA1c alone (IDAA1c) for 90-minute stimulated C-peptide was significantly lower (R2 = 0.37, P < 0.0001). The slopes of linear regression lines of the estimated and stimulated 90-minute C-peptide levels obtained at 6 and 12 months post diagnosis in the Hvidoere clinical cohort were R2 = 0.36, P < 0.0001 at 6 months and R2 = 0.37, P < 0.0001 at 12 months. CONCLUSIONS: A clinical model including age, gender, BMI, HbA1c, and insulin dose predicts stimulated C-peptide levels in children with recent-onset T1D. Estimated C-peptide is an improved surrogate to monitor residual beta-cell function outside clinical trial settings.


Assuntos
Peptídeo C/metabolismo , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Células Secretoras de Insulina/fisiologia , Modelos Biológicos , Adolescente , Adulto , Idade de Início , Anticorpos Monoclonais Humanizados/uso terapêutico , Criança , Estudos de Coortes , Diabetes Mellitus Tipo 1/epidemiologia , Feminino , Humanos , Secreção de Insulina/fisiologia , Células Secretoras de Insulina/patologia , Masculino , Prognóstico , Indução de Remissão , Resultado do Tratamento , Adulto Jovem
11.
mBio ; 9(5)2018 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-30301852

RESUMO

Cutaneous squamous cell carcinoma (SCC) is the second-most-common cancer in Australia. The majority of SCCs progress from premalignant actinic keratosis (AK) lesions that form on chronically sun-exposed skin. The role of skin microbiota in this progression is not well understood; therefore, we performed a longitudinal microbiome analysis of AKs and SCCs using a cohort of 13 SCC-prone immunocompetent men. The majority of variability in microbial profiles was attributable to subject, followed by time and lesion type. Propionibacterium and Malassezia organisms were relatively more abundant in nonlesional photodamaged skin than in AKs and SCCs. Staphylococcus was most commonly associated with lesional skin, in particular, sequences most closely related to Staphylococcus aureus Of 11 S. aureus-like operational taxonomic units (OTUs), six were significantly associated with SCC lesions across seven subjects, suggesting their specific involvement with AK-to-SCC progression. If a causative link exists between certain S. aureus-like OTUs and SCC etiology, therapeutic approaches specifically targeting these bacteria could be used to reduce SCC.IMPORTANCE Actinic keratosis (AK) and cutaneous squamous cell carcinoma (SCC) are two of the most common dermatologic conditions in Western countries and cause substantial morbidity worldwide. The role of human papillomaviruses under these conditions has been well studied yet remains inconclusive. One PCR-based study has investigated bacteria in the etiology of these conditions; however, no study has investigated the microbiomes of AK and SCC more broadly. We longitudinally profiled the microbiomes of 112 AK lesions, profiled cross sections of 32 spontaneously arising SCC lesions, and compared these to matching nonlesional photodamaged control skin sites. We identified commonly occurring strains of Propionibacterium and Malassezia at higher relative abundances on nonlesional skin than in AK and SCC lesions, and strains of Staphylococcus aureus were relatively more abundant in lesional than nonlesional skin. These findings may aid in the prevention of SCC.


Assuntos
Bactérias/isolamento & purificação , Carcinoma de Células Escamosas/microbiologia , Ceratose Actínica/microbiologia , Microbiota , Neoplasias Cutâneas/microbiologia , Idoso , Idoso de 80 Anos ou mais , Bactérias/genética , Progressão da Doença , Humanos , Imunocompetência , Estudos Longitudinais , Malassezia/isolamento & purificação , Masculino , Pessoa de Meia-Idade , Propionibacterium/isolamento & purificação , RNA Ribossômico 16S/genética , Pele/microbiologia , Pele/patologia , Pele/efeitos da radiação , Staphylococcus aureus/isolamento & purificação
12.
JCI Insight ; 3(5)2018 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-29515040

RESUMO

Autoimmune-mediated destruction of pancreatic islet ß cells results in type 1 diabetes (T1D). Serum islet autoantibodies usually develop in genetically susceptible individuals in early childhood before T1D onset, with multiple islet autoantibodies predicting diabetes development. However, most at-risk children remain islet-antibody negative, and no test currently identifies those likely to seroconvert. We sought a genomic signature predicting seroconversion risk by integrating longitudinal peripheral blood gene expression profiles collected in high-risk children included in the BABYDIET and DIPP cohorts, of whom 50 seroconverted. Subjects were followed for 10 years to determine time of seroconversion. Any cohort effect and the time of seroconversion were corrected to uncover genes differentially expressed (DE) in seroconverting children. Gene expression signatures associated with seroconversion were evident during the first year of life, with 67 DE genes identified in seroconverting children relative to those remaining antibody negative. These genes contribute to T cell-, DC-, and B cell-related immune responses. Near-birth expression of ADCY9, PTCH1, MEX3B, IL15RA, ZNF714, TENM1, and PLEKHA5, along with HLA risk score predicted seroconversion (AUC 0.85). The ubiquitin-proteasome pathway linked DE genes and T1D susceptibility genes. Therefore, a gene expression signature in infancy predicts risk of seroconversion. Ubiquitination may play a mechanistic role in diabetes progression.


Assuntos
Diabetes Mellitus Tipo 1/diagnóstico , Regulação da Expressão Gênica/imunologia , Soroconversão/genética , Transcriptoma/imunologia , Autoanticorpos/sangue , Autoanticorpos/imunologia , Pré-Escolar , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/imunologia , Progressão da Doença , Feminino , Seguimentos , Perfilação da Expressão Gênica/métodos , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Masculino , Prognóstico , Ubiquitinação/genética , Ubiquitinação/imunologia
13.
J Chem Ecol ; 44(3): 215-234, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29479643

RESUMO

Chemical ecology has strong links with metabolomics, the large-scale study of all metabolites detectable in a biological sample. Consequently, chemical ecologists are often challenged by the statistical analyses of such large datasets. This holds especially true when the purpose is to integrate multiple datasets to obtain a holistic view and a better understanding of a biological system under study. The present article provides a comprehensive resource to analyze such complex datasets using multivariate methods. It starts from the necessary pre-treatment of data including data transformations and distance calculations, to the application of both gold standard and novel multivariate methods for the integration of different omics data. We illustrate the process of analysis along with detailed results interpretations for six issues representative of the different types of biological questions encountered by chemical ecologists. We provide the necessary knowledge and tools with reproducible R codes and chemical-ecological datasets to practice and teach multivariate methods.


Assuntos
Bases de Dados de Compostos Químicos , Ecologia/métodos , Guias como Assunto , Modelos Estatísticos , Análise Multivariada
14.
J Rheumatol ; 45(6): 771-778, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29449501

RESUMO

OBJECTIVE: We tested the discriminatory capacity of diffusion-weighted magnetic resonance imaging (DWI) and its potential as an objective measure of treatment response to tumor necrosis factor inhibition in ankylosing spondylitis (AS). METHODS: Three cohorts were studied prospectively: (1) 18 AS patients with Bath Ankylosing Spondylitis Disease Activity Index > 4, and erythrocyte sedimentation rate > 25 and/or C-reactive protein > 10 meeting the modified New York criteria for AS; (2) 20 cases of nonradiographic axial spondyloarthritis (nr-axSpA) as defined by the Assessment of Spondyloarthritis international Society (ASAS) criteria; and (3) 20 non-AS patients with chronic low back pain, aged between 18 and 45 years, who did not meet the imaging arm of the ASAS criteria for axSpA. Group 1 patients were studied prior to and following adalimumab treatment. Patients were assessed by DWI and conventional magnetic resonance imaging (MRI), and standard nonimaging measures. RESULTS: At baseline, in contrast to standard nonimaging measures, DWI apparent diffusion coefficient (ADC) values showed good discriminatory performance [area under the curve (AUC) > 80% for Group 1 or 2 compared with Group 3]. DWI ADC values were significantly lower posttreatment (0.45 ± 0.433 before, 0.154 ± 0.23 after, p = 0.0017), but had modest discriminating capacity comparing pre- and posttreatment measures (AUC = 68%). This performance was similar to the manual Spondyloarthritis Research Consortium of Canada (SPARCC) scoring system. CONCLUSION: DWI is informative for diagnosis of AS and nr-axSpA, and has moderate utility in assessment of disease activity or treatment response, with performance similar to that of the SPARCC MRI score.


Assuntos
Imagem de Difusão por Ressonância Magnética/métodos , Dor Lombar/diagnóstico por imagem , Articulação Sacroilíaca/diagnóstico por imagem , Espondilartrite/diagnóstico por imagem , Espondilite Anquilosante/diagnóstico por imagem , Adulto , Sedimentação Sanguínea , Feminino , Humanos , Dor Lombar/sangue , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Espondilartrite/sangue , Espondilite Anquilosante/sangue , Adulto Jovem
15.
Arthritis Rheumatol ; 70(2): 255-265, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29108111

RESUMO

OBJECTIVE: Endoplasmic reticulum aminopeptidase 1 (ERAP-1) and ERAP-2, encoded on chromosome 5q15, trim endogenous peptides for HLA-mediated presentation to the immune system. Polymorphisms in ERAP1 and/or ERAP2 are strongly associated with several immune-mediated diseases with specific HLA backgrounds, implicating altered peptide handling and presentation as prerequisites for autoreactivity against an arthritogenic peptide. Given the thorough characterization of disease risk-associated polymorphisms that alter ERAP activity, this study aimed instead to interrogate the expression effect of chromosome 5q15 polymorphisms to determine their effect on ERAP isoform and protein expression. METHODS: RNA sequencing and genotyping across chromosome 5q15 were performed to detect genetic variants in ERAP1 and ERAP2 associated with altered total gene and isoform-specific expression. The functional implication of a putative messenger RNA splice-altering variant on ERAP-1 protein levels was validated using mass spectrometry. RESULTS: Polymorphisms associated with ankylosing spondylitis (AS) significantly influenced the transcript and protein expression of ERAP-1 and ERAP-2. Disease risk-associated polymorphisms in and around both genes were also associated with increased gene expression. Furthermore, key risk-associated ERAP1 variants were associated with altered transcript splicing, leading to allele-dependent alternate expression of 2 distinct isoforms and significant differences in the type of ERAP-1 protein produced. CONCLUSION: In accordance with studies demonstrating that polymorphisms that increase aminopeptidase activity predispose to immune disease, the increased risk also attributed to increased expression of ERAP1 and ERAP2 supports the notion of using aminopeptidase inhibition to treat AS and other ERAP-associated conditions.


Assuntos
Aminopeptidases/genética , Doenças do Sistema Imunitário/genética , Antígenos de Histocompatibilidade Menor/genética , Espondilite Anquilosante/genética , Adulto , Aminopeptidases/metabolismo , Cromossomos Humanos Par 5/genética , Feminino , Expressão Gênica , Predisposição Genética para Doença , Variação Genética , Genótipo , Humanos , Masculino , Espectrometria de Massas/métodos , Pessoa de Meia-Idade , Antígenos de Histocompatibilidade Menor/metabolismo , Polimorfismo Genético , Análise de Sequência de RNA/métodos , Adulto Jovem
16.
PLoS Comput Biol ; 13(11): e1005752, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29099853

RESUMO

The advent of high throughput technologies has led to a wealth of publicly available 'omics data coming from different sources, such as transcriptomics, proteomics, metabolomics. Combining such large-scale biological data sets can lead to the discovery of important biological insights, provided that relevant information can be extracted in a holistic manner. Current statistical approaches have been focusing on identifying small subsets of molecules (a 'molecular signature') to explain or predict biological conditions, but mainly for a single type of 'omics. In addition, commonly used methods are univariate and consider each biological feature independently. We introduce mixOmics, an R package dedicated to the multivariate analysis of biological data sets with a specific focus on data exploration, dimension reduction and visualisation. By adopting a systems biology approach, the toolkit provides a wide range of methods that statistically integrate several data sets at once to probe relationships between heterogeneous 'omics data sets. Our recent methods extend Projection to Latent Structure (PLS) models for discriminant analysis, for data integration across multiple 'omics data or across independent studies, and for the identification of molecular signatures. We illustrate our latest mixOmics integrative frameworks for the multivariate analyses of 'omics data available from the package.


Assuntos
Biologia Computacional/métodos , Genômica , Metabolômica , Software , Interpretação Estatística de Dados , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Biologia de Sistemas
17.
Environ Sci Technol ; 51(22): 13353-13362, 2017 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-29064247

RESUMO

Thiocyanate (SCN-) is a contaminant requiring remediation in gold mine tailings and wastewaters globally. Seepage of SCN--contaminated waters into aquifers can occur from unlined or structurally compromised mine tailings storage facilities. A wide variety of microorganisms are known to be capable of biodegrading SCN-; however, little is known regarding the potential of native microbes for in situ SCN- biodegradation, a remediation option that is less costly than engineered approaches. Here we experimentally characterize the principal biogeochemical barrier to SCN- biodegradation for an autotrophic microbial consortium enriched from mine tailings, to arrive at an environmentally realistic assessment of in situ SCN- biodegradation potential. Upon amendment with phosphate, the consortium completely degraded up to ∼10 mM SCN- to ammonium and sulfate, with some evidence of nitrification of the ammonium to nitrate. Although similarly enriched in known SCN--degrading strains of thiobacilli, this consortium differed in its source (mine tailings) and metabolism (autotrophy) from those of previous studies. Our results provide a proof of concept that phosphate limitation may be the principal barrier to in situ SCN- biodegradation in mine tailing waters and also yield new insights into the microbial ecology of in situ SCN- bioremediation involving autotrophic sulfur-oxidizing bacteria.


Assuntos
Biodegradação Ambiental , Ouro , Tiocianatos , Mineração , Fosfatos
18.
Hepatology ; 66(5): 1502-1518, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28498607

RESUMO

Hepatocellular carcinomas (HCCs) exhibit a diversity of molecular phenotypes, raising major challenges in clinical management. HCCs detected by surveillance programs at an early stage are candidates for potentially curative therapies (local ablation, resection, or transplantation). In the long term, transplantation provides the lowest recurrence rates. Treatment allocation is based on tumor number, size, vascular invasion, performance status, functional liver reserve, and the prediction of early (<2 years) recurrence, which reflects the intrinsic aggressiveness of the tumor. Well-differentiated, potentially low-aggressiveness tumors form the heterogeneous molecular class of nonproliferative HCCs, characterized by an approximate 50% ß-catenin mutation rate. To define the clinical, pathological, and molecular features and the outcome of nonproliferative HCCs, we constructed a 1,133-HCC transcriptomic metadata set and validated findings in a publically available 210-HCC RNA sequencing set. We show that nonproliferative HCCs preserve the zonation program that distributes metabolic functions along the portocentral axis in normal liver. More precisely, we identified two well-differentiated, nonproliferation subclasses, namely periportal-type (wild-type ß-catenin) and perivenous-type (mutant ß-catenin), which expressed negatively correlated gene networks. The new periportal-type subclass represented 29% of all HCCs; expressed a hepatocyte nuclear factor 4A-driven gene network, which was down-regulated in mouse hepatocyte nuclear factor 4A knockout mice; were early-stage tumors by Barcelona Clinic Liver Cancer, Cancer of the Liver Italian Program, and tumor-node-metastasis staging systems; had no macrovascular invasion; and showed the lowest metastasis-specific gene expression levels and TP53 mutation rates. Also, we identified an eight-gene periportal-type HCC signature, which was independently associated with the highest 2-year recurrence-free survival by multivariate analyses in two independent cohorts of 247 and 210 patients. CONCLUSION: Well-differentiated HCCs display mutually exclusive periportal or perivenous zonation programs. Among all HCCs, periportal-type tumors have the lowest intrinsic potential for early recurrence after curative resection. (Hepatology 2017;66:1502-1518).


Assuntos
Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Fígado/patologia , Recidiva Local de Neoplasia/patologia , beta Catenina/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/cirurgia , França/epidemiologia , Fator 4 Nuclear de Hepatócito/metabolismo , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/cirurgia , Mutação , Recidiva Local de Neoplasia/genética , Fenótipo , Transcriptoma
19.
BMC Bioinformatics ; 18(1): 128, 2017 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-28241739

RESUMO

BACKGROUND: Molecular signatures identified from high-throughput transcriptomic studies often have poor reliability and fail to reproduce across studies. One solution is to combine independent studies into a single integrative analysis, additionally increasing sample size. However, the different protocols and technological platforms across transcriptomic studies produce unwanted systematic variation that strongly confounds the integrative analysis results. When studies aim to discriminate an outcome of interest, the common approach is a sequential two-step procedure; unwanted systematic variation removal techniques are applied prior to classification methods. RESULTS: To limit the risk of overfitting and over-optimistic results of a two-step procedure, we developed a novel multivariate integration method, MINT, that simultaneously accounts for unwanted systematic variation and identifies predictive gene signatures with greater reproducibility and accuracy. In two biological examples on the classification of three human cell types and four subtypes of breast cancer, we combined high-dimensional microarray and RNA-seq data sets and MINT identified highly reproducible and relevant gene signatures predictive of a given phenotype. MINT led to superior classification and prediction accuracy compared to the existing sequential two-step procedures. CONCLUSIONS: MINT is a powerful approach and the first of its kind to solve the integrative classification framework in a single step by combining multiple independent studies. MINT is computationally fast as part of the mixOmics R CRAN package, available at http://www.mixOmics.org/mixMINT/ and http://cran.r-project.org/web/packages/mixOmics/ .


Assuntos
Análise Multivariada , Perfilação da Expressão Gênica , Humanos , Reprodutibilidade dos Testes , Tamanho da Amostra
20.
Bioinformatics ; 33(12): 1773-1781, 2017 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-28186228

RESUMO

Motivation: Genome-wide association studies are identifying single nucleotide variants (SNVs) linked to various diseases, however the functional effect caused by these variants is often unknown. One potential functional effect, the loss or gain of protein phosphorylation sites, can be induced through variations in key amino acids that disrupt or introduce valid kinase binding patterns. Current methods for predicting the effect of SNVs on phosphorylation operate on the sequence content of reference and variant proteins. However, consideration of the amino acid sequence alone is insufficient for predicting phosphorylation change, as context factors determine kinase-substrate selection. Results: We present here a method for quantifying the effect of SNVs on protein phosphorylation through an integrated system of motif analysis and context-based assessment of kinase targets. By predicting the effect that known variants across the proteome have on phosphorylation, we are able to use this background of proteome-wide variant effects to quantify the significance of novel variants for modifying phosphorylation. We validate our method on a manually curated set of phosphorylation change-causing variants from the primary literature, showing that the method predicts known examples of phosphorylation change at high levels of specificity. We apply our approach to data-sets of variants in phosphorylation site regions, showing that variants causing predicted phosphorylation loss are over-represented among disease-associated variants. Availability and Implementation: The method is freely available as a web-service at the website http://bioinf.scmb.uq.edu.au/phosphopick/snp. Contact: m.boden@uq.edu.au. Supplementary information: Supplementary data are available at Bioinformatics online.


Assuntos
Biologia Computacional/métodos , Fosforilação , Fosfotransferases/metabolismo , Polimorfismo de Nucleotídeo Único , Processamento de Proteína Pós-Traducional/genética , Software , Sequência de Aminoácidos , Humanos , Ligação Proteica
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA