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1.
NPJ Microgravity ; 9(1): 21, 2023 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-36941263

RESUMO

Spaceflight presents a multifaceted environment for plants, combining the effects on growth of many stressors and factors including altered gravity, the influence of experiment hardware, and increased radiation exposure. To help understand the plant response to this complex suite of factors this study compared transcriptomic analysis of 15 Arabidopsis thaliana spaceflight experiments deposited in the National Aeronautics and Space Administration's GeneLab data repository. These data were reanalyzed for genes showing significant differential expression in spaceflight versus ground controls using a single common computational pipeline for either the microarray or the RNA-seq datasets. Such a standardized approach to analysis should greatly increase the robustness of comparisons made between datasets. This analysis was coupled with extensive cross-referencing to a curated matrix of metadata associated with these experiments. Our study reveals that factors such as analysis type (i.e., microarray versus RNA-seq) or environmental and hardware conditions have important confounding effects on comparisons seeking to define plant reactions to spaceflight. The metadata matrix allows selection of studies with high similarity scores, i.e., that share multiple elements of experimental design, such as plant age or flight hardware. Comparisons between these studies then helps reduce the complexity in drawing conclusions arising from comparisons made between experiments with very different designs.

2.
iScience ; 24(4): 102361, 2021 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-33870146

RESUMO

With the development of transcriptomic technologies, we are able to quantify precise changes in gene expression profiles from astronauts and other organisms exposed to spaceflight. Members of NASA GeneLab and GeneLab-associated analysis working groups (AWGs) have developed a consensus pipeline for analyzing short-read RNA-sequencing data from spaceflight-associated experiments. The pipeline includes quality control, read trimming, mapping, and gene quantification steps, culminating in the detection of differentially expressed genes. This data analysis pipeline and the results of its execution using data submitted to GeneLab are now all publicly available through the GeneLab database. We present here the full details and rationale for the construction of this pipeline in order to promote transparency, reproducibility, and reusability of pipeline data; to provide a template for data processing of future spaceflight-relevant datasets; and to encourage cross-analysis of data from other databases with the data available in GeneLab.

3.
iScience ; 23(12): 101733, 2020 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-33376967

RESUMO

To understand the physiological changes that occur in response to spaceflight, mice are transported to the International Space Station (ISS) and housed for variable periods of time before euthanasia on-orbit or return to Earth. Sample collection under such difficult conditions introduces confounding factors that need to be identified and addressed. We found large changes in the transcriptome of mouse tissues dissected and preserved on-orbit compared with tissues from mice euthanized on-orbit, preserved, and dissected after return to Earth. Changes due to preservation method eclipsed those between flight and ground samples, making it difficult to identify spaceflight-specific changes. Follow-on experiments to interrogate the roles of euthanasia methods, tissue and carcass preservation protocols, and library preparation methods suggested that differences due to preservation protocols are exacerbated when coupled with polyA selection. This has important implications for the interpretation of existing datasets and the design of future experiments.

5.
Sci Rep ; 9(1): 19195, 2019 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-31844325

RESUMO

Spaceflight has several detrimental effects on the physiology of astronauts, many of which are recapitulated in rodent models. Mouse studies performed on the Space Shuttle showed disruption of lipid metabolism in liver. However, given that these animals were not sacrificed on-orbit and instead returned live to earth, it is unclear if these disruptions were solely induced by space stressors (e.g. microgravity, space radiation) or in part explained by the stress of return to Earth. In this work we analyzed three liver datasets from two different strains of mice (C57BL/6 (Jackson) & BALB/c (Taconic)) flown aboard the International Space Station (ISS). Notably, these animals were sacrificed on-orbit and exposed to varying spaceflight durations (i.e. 21, 37, and 42 days vs 13 days for the Shuttle mice). Oil Red O (ORO) staining showed abnormal lipid accumulation in all space-flown mice compared to ground controls regardless of strain or exposure duration. Similarly, transcriptomic analysis by RNA-sequencing revealed several pathways that were affected in both strains related to increased lipid metabolism, fatty acid metabolism, lipid and fatty acid processing, lipid catabolic processing, and lipid localization. In addition, key upstream regulators were predicted to be commonly regulated across all conditions including Glucagon (GCG) and Insulin (INS). Moreover, quantitative proteomic analysis showed that a number of lipid related proteins were changed in the livers during spaceflight. Taken together, these data indicate that activation of lipotoxic pathways are the result of space stressors alone and this activation occurs in various genetic backgrounds during spaceflight exposures of weeks to months. If similar responses occur in humans, a prolonged change of these pathways may result in the development of liver disease and should be investigated further.

6.
Bioinformatics ; 35(10): 1753-1759, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30329036

RESUMO

MOTIVATION: To curate and organize expensive spaceflight experiments conducted aboard space stations and maximize the scientific return of investment, while democratizing access to vast amounts of spaceflight related omics data generated from several model organisms. RESULTS: The GeneLab Data System (GLDS) is an open access database containing fully coordinated and curated 'omics' (genomics, transcriptomics, proteomics, metabolomics) data, detailed metadata and radiation dosimetry for a variety of model organisms. GLDS is supported by an integrated data system allowing federated search across several public bioinformatics repositories. Archived datasets can be queried using full-text search (e.g. keywords, Boolean and wildcards) and results can be sorted in multifactorial manner using assistive filters. GLDS also provides a collaborative platform built on GenomeSpace for sharing files and analyses with collaborators. It currently houses 172 datasets and supports standard guidelines for submission of datasets, MIAME (for microarray), ENCODE Consortium Guidelines (for RNA-seq) and MIAPE Guidelines (for proteomics). AVAILABILITY AND IMPLEMENTATION: https://genelab.nasa.gov/.


Assuntos
Voo Espacial , Biologia Computacional , Bases de Dados Factuais , Genômica
7.
PLoS One ; 13(7): e0199621, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30044882

RESUMO

Translating fundamental biological discoveries from NASA Space Biology program into health risk from space flights has been an ongoing challenge. We propose to use NASA GeneLab database to gain new knowledge on potential systemic responses to space. Unbiased systems biology analysis of transcriptomic data from seven different rodent datasets reveals for the first time the existence of potential "master regulators" coordinating a systemic response to microgravity and/or space radiation with TGF-ß1 being the most common regulator. We hypothesized the space environment leads to the release of biomolecules circulating inside the blood stream. Through datamining we identified 13 candidate microRNAs (miRNA) which are common in all studies and directly interact with TGF-ß1 that can be potential circulating factors impacting space biology. This study exemplifies the utility of the GeneLab data repository to aid in the process of performing novel hypothesis-based research.


Assuntos
Regulação da Expressão Gênica , MicroRNAs/genética , Voo Espacial , Transcriptoma , Fator de Crescimento Transformador beta1/metabolismo , Animais , Biomarcadores , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes , Humanos , Camundongos , Ratos , Medição de Risco , Fator de Crescimento Transformador beta1/farmacologia , Ausência de Peso
8.
Eur J Pharmacol ; 649(1-3): 349-53, 2010 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-20868661

RESUMO

Airway hyperresponsiveness and inflammation characterize the airways of individuals with asthma and chronic obstructive pulmonary disease (COPD). Hence, therapeutic approaches that attenuate such manifestations may offer promise in the management of these diseases. In the present study, we investigated whether a novel long-acting cholinergic antagonist, aclidinium bromide, modulates airway function and leukocyte trafficking in an Aspergillus fumigatus (Af)-induced murine model of asthma. Nebulized aclidinium (1 mg/ml) administration completely abrogated increases in methacholine-induced lung resistance in Af-exposed mice. Parallel assessment of dynamic compliance showed that aclidinium also completely restores methacholine-mediated decreases in naïve and Af-exposed mice. As evidenced by differential cell counts within bronchoalveolar lavage fluid, aclidinium also diminished (51±4%) Af-induced airway eosinophil numbers with no significant change in other immune cell types. Further assessment of cytokine and total protein levels in bronchoalveolar lavage fluid showed that aclidinium had little effect on IL-4 or IL-6 levels in either Af-exposed or naïve mice but markedly decreased total protein levels in bronchoalveolar lavage fluid. These data suggest that aclidinium, a selective muscarinic antagonist, not only acts as a bronchodilator but could also act as an anti-inflammatory agent with potential clinical benefits in the treatment of COPD and asthma.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Antagonistas Colinérgicos/uso terapêutico , Inflamação/prevenção & controle , Eosinofilia Pulmonar/prevenção & controle , Hipersensibilidade Respiratória/tratamento farmacológico , Sistema Respiratório/efeitos dos fármacos , Tropanos/uso terapêutico , Animais , Antígenos de Fungos/imunologia , Asma/tratamento farmacológico , Bronquite/prevenção & controle , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Contagem de Células , Citocinas/análise , Feminino , Leucócitos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Hipersensibilidade Respiratória/imunologia , Hipersensibilidade Respiratória/fisiopatologia , Sistema Respiratório/imunologia , Sistema Respiratório/fisiopatologia
9.
Am J Physiol Lung Cell Mol Physiol ; 299(1): L25-35, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20382746

RESUMO

Severe asthma is characterized by increased airway smooth muscle (ASM) mass due, in part, to ASM cell growth and contractile protein expression associated with increased protein synthesis. Little is known regarding the combined effects of mitogens and interferons on ASM cytosolic protein synthesis. We demonstrate that human ASM mitogens including PDGF, EGF, and thrombin stimulate protein synthesis. Surprisingly, pleiotropic cytokines IFN-beta and IFN-gamma, which inhibit ASM proliferation, also increased cytosolic protein content in ASM cells. Thus IFN-beta alone significantly increased protein synthesis by 1.62 +/- 0.09-fold that was further enhanced by EGF to 2.52 +/- 0.17-fold. IFN-gamma alone also stimulated protein synthesis by 1.91 +/- 0.15-fold; treatment of cells with PDGF, EGF, and thrombin in the presence of IFN-gamma stimulated protein synthesis by 2.24 +/- 0.3-, 1.25 +/- 0.17-, and 2.67 +/- 0.34-fold, respectively, compared with growth factors alone. The mammalian target of rapamycin (mTOR)/S6 kinase 1 (S6K1) inhibition with rapamycin inhibited IFN- and EGF-induced protein synthesis, suggesting that IFN-induced protein synthesis is modulated by mTOR/S6K1 activation. Furthermore, overexpression of tumor suppressor protein tuberous sclerosis complex 2 (TSC2), which is an upstream negative regulator of mTOR/S6K1 signaling, also inhibited mitogen-induced protein synthesis in ASM cells. IFN-beta and IFN-gamma stimulated miR143/145 microRNA expression and increased SM alpha-actin accumulation but had little effect on ASM cell size. In contrast, EGF increased ASM cell size but had little effect on miR143/145 expression. Our data demonstrate that both IFNs and mitogens stimulate protein synthesis but have differential effects on cell size and contractile protein expression and suggest that combined effects of IFNs and mitogens may contribute to ASM cell growth, contractile protein expression, and ASM remodeling in asthma.


Assuntos
Interferons/farmacologia , Mitógenos/farmacologia , Músculo Liso/metabolismo , Biossíntese de Proteínas/efeitos dos fármacos , Sistema Respiratório/metabolismo , Animais , Asma/patologia , Asma/fisiopatologia , Células Cultivadas , Fator de Crescimento Epidérmico/farmacologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Músculo Liso/citologia , Fator de Crescimento Derivado de Plaquetas/farmacologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Sistema Respiratório/anatomia & histologia , Proteínas Quinases S6 Ribossômicas/genética , Proteínas Quinases S6 Ribossômicas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR , Trombina/farmacologia
10.
Exp Lung Res ; 36(2): 75-84, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20205598

RESUMO

Evidence suggests inhibition of leukocyte trafficking mitigates, in part, ozone-induced inflammation. In the present study, the authors postulated that inhibition of myristoylated alanine-rich C kinase substrate (MARCKS), an 82-kDa protein with multiple biological roles, could inhibit ozone-induced leukocyte trafficking and cytokine secretions. BALB/c mice (n = 5/cohort) were exposed to ozone (100 ppb) or forced air (FA) for 4 hours. MARCKS-inhibiting peptides, MANS, BIO-11000, BIO-11006, or scrambled control peptide RNS, were intratracheally administered prior to ozone exposure. Ozone selectively enhanced bronchoalveolar lavage (BAL) levels of killer cells (KCs; 6 +/- 0.9-fold), interleukin-6 (IL-6; 12.7 +/- 1.9-fold), and tumor necrosis factor (TNF; 2.1 +/- 0.5-fold) as compared to cohorts exposed to FA. Additionally, ozone increased BAL neutrophils by 21% +/- 2% with no significant (P > .05) changes in other cell types. MANS, BIO-11000, and BIO-11006 significantly reduced ozone-induced KC secretion by 66% +/- 14%, 47% +/- 15%, and 71.1% +/- 14%, and IL-6 secretion by 69% +/- 12%, 40% +/- 7%, and 86.1% +/- 11%, respectively. Ozone-mediated increases in BAL neutrophils were reduced by MANS (86% +/- 7%) and BIO-11006 (84% +/- 2.5%), but not BIO-11000. These studies identify for the first time the novel potential of MARCKS protein inhibitors in abrogating ozone-induced increases in neutrophils, cytokines, and chemokines in BAL fluid. BIO-11006 is being developed as a treatment for chronic obstructive pulmonary disorder (COPD) and is currently being evaluated in a phase 2 clinical study.


Assuntos
Bronquite/tratamento farmacológico , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Proteínas de Membrana/antagonistas & inibidores , Infiltração de Neutrófilos/efeitos dos fármacos , Peptídeos/uso terapêutico , Animais , Bronquite/induzido quimicamente , Bronquite/imunologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/metabolismo , Avaliação Pré-Clínica de Medicamentos , Camundongos , Camundongos Endogâmicos BALB C , Substrato Quinase C Rico em Alanina Miristoilada , Peptídeos/farmacologia
11.
Cancer Cell ; 12(2): 131-44, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17692805

RESUMO

Activation of NF-kappaB has been noted in many tumor types, however only rarely has this been linked to an underlying genetic mutation. An integrated analysis of high-density oligonucleotide array CGH and gene expression profiling data from 155 multiple myeloma samples identified a promiscuous array of abnormalities contributing to the dysregulation of NF-kappaB in approximately 20% of patients. We report mutations in ten genes causing the inactivation of TRAF2, TRAF3, CYLD, cIAP1/cIAP2 and activation of NFKB1, NFKB2, CD40, LTBR, TACI, and NIK that result primarily in constitutive activation of the noncanonical NF-kappaB pathway, with the single most common abnormality being inactivation of TRAF3. These results highlight the critical importance of the NF-kappaB pathway in the pathogenesis of multiple myeloma.


Assuntos
Regulação Neoplásica da Expressão Gênica , Mieloma Múltiplo/genética , Mutação/genética , NF-kappa B/genética , Proteínas de Neoplasias/metabolismo , Adenoviridae , Proteína 3 com Repetições IAP de Baculovírus , Antígenos CD40/genética , Antígenos CD40/metabolismo , Células Cultivadas , Enzima Desubiquitinante CYLD , Ativação Enzimática , Imunofluorescência , Deleção de Genes , Perfilação da Expressão Gênica , Humanos , Immunoblotting , Técnicas Imunoenzimáticas , Hibridização in Situ Fluorescente , Proteínas Inibidoras de Apoptose/genética , Proteínas Inibidoras de Apoptose/metabolismo , Receptor beta de Linfotoxina/genética , Receptor beta de Linfotoxina/metabolismo , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , NF-kappa B/metabolismo , Subunidade p50 de NF-kappa B/genética , Subunidade p50 de NF-kappa B/metabolismo , Subunidade p52 de NF-kappa B/genética , Subunidade p52 de NF-kappa B/metabolismo , Proteínas de Neoplasias/genética , Hibridização de Ácido Nucleico , Plasmídeos , Reação em Cadeia da Polimerase , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Fator 2 Associado a Receptor de TNF/genética , Fator 2 Associado a Receptor de TNF/metabolismo , Fator 3 Associado a Receptor de TNF/genética , Fator 3 Associado a Receptor de TNF/metabolismo , Transfecção , Proteína Transmembrana Ativadora e Interagente do CAML/genética , Proteína Transmembrana Ativadora e Interagente do CAML/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina-Proteína Ligases , Quinase Induzida por NF-kappaB
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