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Análise da participação das células neuronais e não-neuronais na Esclerose Lateral Amiotrófica em camundongos transgênicos para SOD1 humana utilizando técnicas de microdissecção a laser e PCR em tempo real; Analysis of neuronal and non-neuronal cells participation in Amyotrophic Lateral Sclerosis in transgenic SOD1 mice by means of laser microdissection and real time PCR

Oliveira, Gabriela Pintar de
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 19/03/2014 PT
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A Esclerose Lateral Amiotrófica (ELA) é a doença neurodegenerativa do neurônio motor que acomete indivíduos adultos e promove a perda progressiva das funções motoras. A evolução é rápida (2 a 5 anos) e culmina na morte por complicações e falência dos músculos respiratórios. Descrições recentes sugerem a contribuição de tipos celulares não neuronais, particularmente o astrócito e a microglia, para a morte do neurônio motor. O camundongo transgênico SOD1G93A, que carrega a SOD1 humana mutada, foi utilizado neste trabalho. Estudos comportamentais apontaram alterações motoras importantes no animal transgênico a partir de 90 dias de vida e permitiram selecionar, então, as idades pré-sintomáticas de 40 dias e 80 dias para os estudos moleculares. A análise da expressão gênica nos animais transgênicos e selvagens destas duas idades foi realizada por microarray utilizando-se a plataforma que contém o genoma completo do camundongo e detectou 492 e 1105 transcritos diferencialmente expressos nos animais de 40 e 80 dias, respectivamente. Estes resultados foram validados por PCR quantitativa (qPCR). As análises bioinformáticas dos resultados identificaram 17 e 11 vias moleculares super-representadas nas idades de 40 dias e 80 dias...

Estudo das variações no número de cópias (CNVs) das regiões subteloméricas em portadores de malformações congênitas e deficiência intelectual; Study of copy number variations (CNVs) of subtelomeric regions in patients with congenital malformations and intellectual disabilities

Novo Filho, Gil Monteiro
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 13/10/2014 PT
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A variação no número de cópias gênicas (CNVs) é a alteração estrutural mais prevalente no genoma humano. Estas alterações estão presentes em alta proporção nos subtelômeros, quando comparados com o resto do genoma. Isso ocorre principalmente porque essas regiões são ricas em genes e porque apresentam sequências repetitivas que as tornam suscetíveis a rearranjos genômicos. Na literatura os rearranjos subteloméricos, como deleções, duplicações e translocações estão associados à etiologia da deficiência intelectual (DI), do atraso no desenvolvimento neuropsicomotor (ADNPM) e das malformações congênitas (MC). Estudos prévios com pacientes com DI revelaram taxas de CNVs patogênicas em regiões subteloméricas variando de 2,4% a 4,8%. Os objetivos desse trabalho foram: investigar a presença das CNVs subteloméricas nos pacientes portadores de malformações congênitas e deficiência intelectual, caracteriza-las quanto a extensão e patogenicidade e sugerir os mecanismos produtores dessas alterações. Foram analisadas 105 amostras de DNA de pacientes com DI/ADNPM associada a MC. Utilizamos a técnica de MLPA (Multiplex Ligation-dependent Probe Amplification) com kits específicos para regiões subteloméricas (P036 e P070). Dentre os pacientes que apresentaram alterações pela técnica de MLPA...

Avaliação de métodos citogenômicos para diagnóstico de pacientes com malformações congênitas e atraso do desenvolvimento neuropsicomotor; Assessment of cytogenomics methods for diagnosis of patients with congenital malformations and developmental delay

Zanardo, Evelin Aline
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 12/12/2014 PT
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O genoma humano é composto por diversos tipos de variações estruturais, como por exemplo, as variações no número de cópias (CNVs), que, mesmo sendo muito pequenas, podem gerar diversas alterações clínicas específicas, como as malformações congênitas e o atraso do desenvolvimento neuropsicomotor (MC/ADNPM). Para a detecção destas alterações existem diferentes técnicas citogenômicas dentre elas a FISH (Fluorescent in situ Hibridization) e a MLPA (Multiplex Ligation-dependent Probe Amplification), que investigam um número limitado de regiões do genoma, como as regiões envolvidas nas síndromes de microdeleções/microduplicações mais comuns e as regiões subteloméricas. Outros métodos como a cariotipagem clássica e o array genômico possibilitam uma análise completa do DNA em uma única reação, aumentando a taxa de detecção de desequilíbrios complexos. Alcançar um diagnóstico inequívoco é fundamental para entender a natureza da doença, fornecendo respostas sobre o prognóstico, sobre os riscos de recorrência e direcionando o paciente à terapia específica, o que pode minimizar o custo financeiro dessas doenças e até mesmo possibilitar a inclusão desses indivíduos na sociedade. O projeto teve como objetivo comparar a capacidade diagnóstica destas tecnologias (FISH...

Microarray expression analysis of meiosis and microsporogenesis in hexaploid bread wheat

Crismani, W.; Baumann, U.; Sutton, T.; Shirley, N.; Webster, T.; Spangenberg, G.; Langridge, P.; Able, J.
Fonte: BioMed Central Ltd. Publicador: BioMed Central Ltd.
Tipo: Artigo de Revista Científica
Publicado em //2006 EN
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Background: Our understanding of the mechanisms that govern the cellular process of meiosis is limited in higher plants with polyploid genomes. Bread wheat is an allohexaploid that behaves as a diploid during meiosis. Chromosome pairing is restricted to homologous chromosomes despite the presence of homoeologues in the nucleus. The importance of wheat as a crop and the extensive use of wild wheat relatives in breeding programs has prompted many years of cytogenetic and genetic research to develop an understanding of the control of chromosome pairing and recombination. The rapid advance of biochemical and molecular information on meiosis in model organisms such as yeast provides new opportunities to investigate the molecular basis of chromosome pairing control in wheat. However, building the link between the model and wheat requires points of data contact. Results: We report here a large-scale transcriptomics study using the Affymetrix wheat GeneChip® aimed at providing this link between wheat and model systems and at identifying early meiotic genes. Analysis of the microarray data identified 1,350 transcripts temporally-regulated during the early stages of meiosis. Expression profiles with annotated transcript functions including chromatin condensation...

Gene expression analysis of multiple gastrointestinal regions reveals activation of common cell regulatory pathways following cytotoxic chemotherapy

Bowen, J.; Gibson, R.; Tsykin, A.; Stringer, A.; Logan, R.; Keefe, D.
Fonte: Wiley-liss Publicador: Wiley-liss
Tipo: Artigo de Revista Científica
Publicado em //2007 EN
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800.778%
Gastrointestinal mucositis involves many changes at the gene level, affecting epithelial/subepithelial interactions and leading to overt damage. The regional specificity and time course of these changes, and how they relate to subsequent mucositis development however remain unknown. The aim of this study was to determine the early time course of gene expression changes along the gastrointestinal tract of the DA rat following chemotherapy. Female DA rats were treated with a single dose of 200 mg/kg irinotecan to induce mucositis, and were killed at short intervals following treatment. Small sections of stomach, jejunum and colon were harvested for analysis of genetic profiles. RNA was hybridised to high density Affymetrix oligonucleotide microarrays. Data analysis was carried out with software package, TimeCourse, freely available through Bioconductor. As early as 1 hr following chemotherapy, expression of hundreds of genes was altered, including those for transcription factors, stress response proteins and protein turnover. These genes are involved in cell proliferation, differentiation and apoptosis along with other cellular processes. At early time points, there was a significant response involving the mitogen-activated protein kinase pathway...

Heterologous microarray experiments used to identify the early gene response to heat stress in a coral reef fish

Kassahn, K.; Caley, M.; Ward, A.; Connolly, A.; Stone, G.; Crozier, R.
Fonte: Blackwell Publishing Ltd Publicador: Blackwell Publishing Ltd
Tipo: Artigo de Revista Científica
Publicado em //2007 EN
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Coral reef fishes are expected to experience rising sea surface temperatures due to climate change. How well tropical reef fishes will respond to these increased temperatures and which genes are important in the response to elevated temperatures is not known. Microarray technology provides a powerful tool for gene discovery studies, but the development of microarrays for individual species can be expensive and time-consuming. In this study, we tested the suitability of a Danio rerio oligonucleotide microarray for application in a species with few genomic resources, the coral reef fish Pomacentrus moluccensis. Results from a comparative genomic hybridization experiment and direct sequence comparisons indicate that for most genes there is considerable sequence similarity between the two species, suggesting that the D. rerio array is useful for genomic studies of P. moluccensis. We employed this heterologous microarray approach to characterize the early transcriptional response to heat stress in P. moluccensis. A total of 111 gene loci, many of which are involved in protein processing, transcription, and cell growth, showed significant changes in transcript abundance following exposure to elevated temperatures. Changes in transcript abundance were validated for a selection of candidate genes using quantitative real-time polymerase chain reaction. This study demonstrates that heterologous microarrays can be successfully employed to study species for which specific microarrays have not yet been developed...

Genome-wide copy number analysis in esophageal adenocarcinoma using high-density single-nucleotide polymorphism arrays

Nancarrow, D.; Handoko, H.; Smithers, B.; Gotley, D.; Drew, P.; Watson, D.; Clouston, A.; Hayward, N.; Whiteman, D.
Fonte: Amer Assoc Cancer Research Publicador: Amer Assoc Cancer Research
Tipo: Artigo de Revista Científica
Publicado em //2008 EN
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We applied whole-genome single-nucleotide polymorphism arrays to define a comprehensive genetic profile of 23 esophageal adenocarcinoma (EAC) primary tumor biopsies based on loss of heterozygosity (LOH) and DNA copy number changes. Alterations were common, averaging 97 (range, 23–208) per tumor. LOH and gains averaged 33 (range, 3–83) and 31 (range, 11–73) per tumor, respectively. Copy neutral LOH events averaged 27 (range, 7–57) per EAC. We noted 126 homozygous deletions (HD) across the EAC panel (range, 0–11 in individual tumors). Frequent HDs within FHIT (17 of 23), WWOX (8 of 23), and DMD (6 of 23) suggest a role for common fragile sites or genomic instability in EAC etiology. HDs were also noted for known tumor suppressor genes (TSG), including CDKN2A, CDKN2B, SMAD4, and GALR1, and identified PDE4D and MGC48628 as potentially novel TSGs. All tumors showed LOH for most of chromosome 17p, suggesting that TSGs other than TP53 may be targeted. Frequent gains were noted around MYC (13 of 23), BCL9 (12 of 23), CTAGE1 (14 of 23), and ZNF217 (12 of 23). Thus, we have confirmed previous reports indicating frequent changes to FHIT, CDKN2A, TP53, and MYC in EAC and identified additional genes of interest. Meta-analysis of previous genome-wide EAC studies together with the data presented here highlighted consistent regions of gain on 8q...

Integrative analysis of RUNX1 downstream pathways and target genes

Michaud, J.; Simpson, K.; Escher, R.; Buchet-Poyau, K.; Beissbarth, T.; Carmichael, C.; Ritchie, M.; Schutz, F.; Cannon, P.; Liu, M.; Shen, X.; Ito, Y.; Raskind, W.; Horwitz, M.; Osato, M.; Turner, D.; Speed, T.; Kavallaris, M.; Smyth, G.; Scott, H.
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
Publicado em //2008 EN
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Background The RUNX1 transcription factor gene is frequently mutated in sporadic myeloid and lymphoid leukemia through translocation, point mutation or amplification. It is also responsible for a familial platelet disorder with predisposition to acute myeloid leukemia (FPD-AML). The disruption of the largely unknown biological pathways controlled by RUNX1 is likely to be responsible for the development of leukemia. We have used multiple microarray platforms and bioinformatic techniques to help identify these biological pathways to aid in the understanding of why RUNX1 mutations lead to leukemia. Results Here we report genes regulated either directly or indirectly by RUNX1 based on the study of gene expression profiles generated from 3 different human and mouse platforms. The platforms used were global gene expression profiling of: 1) cell lines with RUNX1 mutations from FPD-AML patients, 2) over-expression of RUNX1 and CBFβ, and 3) Runx1 knockout mouse embryos using either cDNA or Affymetrix microarrays. We observe that our datasets (lists of differentially expressed genes) significantly correlate with published microarray data from sporadic AML patients with mutations in either RUNX1 or its cofactor, CBFβ. A number of biological processes were identified among the differentially expressed genes and functional assays suggest that heterozygous RUNX1 point mutations in patients with FPD-AML impair cell proliferation...

Analysis of FOXP3+ regulatory T cells that display apparent viral antigen specificity during chronic hepatitis C virus infection

Li, S.; Floess, S.; Hamann, A.; Gaudieri, S.; Lucas, A.; Hellard, M.; Roberts, S.; Paukovic, G.; Plebanski, M.; Loveland, B.; Aitken, C.; Barry, S.; Schofield, L.; Gowans, E.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em //2009 EN
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We reported previously that a proportion of natural CD25+ cells isolated from the PBMC of HCV patients can further upregulate CD25 expression in response to HCV peptide stimulation in vitro, and proposed that virus-specific regulatory T cells (Treg) were primed and expanded during the disease. Here we describe epigenetic analysis of the FOXP3 locus in HCV-responsive natural CD25+ cells and show that these cells are not activated conventional T cells expressing FOXP3, but hard-wired Treg with a stable FOXP3 phenotype and function. Of ~46,000 genes analyzed in genome wide transcription profiling, about 1% were differentially expressed between HCV-responsive Treg, HCV-non-responsive natural CD25+ cells and conventional T cells. Expression profiles, including cell death, activation, proliferation and transcriptional regulation, suggest a survival advantage of HCV-responsive Treg over the other cell populations. Since no Treg-specific activation marker is known, we tested 97 NS3-derived peptides for their ability to elicit CD25 response (assuming it is a surrogate marker), accompanied by high resolution HLA typing of the patients. Some reactive peptides overlapped with previously described effector T cell epitopes. Our data offers new insights into HCV immune evasion and tolerance...

Fine-scale survey of X chromosome copy number variants and indels underlying intellectual disability

Whibley, A.; Plagnol, V.; Tarpey, P.; Abidi, F.; Fullston, T.; Choma, M.; Boucher, C.; Shepherd, L.; Willatt, L.; Parkin, G.; Smith, R.; Futreal, P.; Shaw, M.; Boyle, J.; Licata, A.; Skinner, C.; Stevenson, R.; Turner, G.; Field, M.; Hackett, A.; et al.
Fonte: Univ Chicago Press Publicador: Univ Chicago Press
Tipo: Artigo de Revista Científica
Publicado em //2010 EN
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Copy number variants and indels in 251 families with evidence of X-linked intellectual disability (XLID) were investigated by array comparative genomic hybridization on a high-density oligonucleotide X chromosome array platform. We identified pathogenic copy number variants in 10% of families, with mutations ranging from 2 kb to 11 Mb in size. The challenge of assessing causality was facilitated by prior knowledge of XLID-associated genes and the ability to test for cosegregation of variants with disease through extended pedigrees. Fine-scale analysis of rare variants in XLID families leads us to propose four additional genes, PTCHD1, WDR13, FAAH2, and GSPT2, as candidates for XLID causation and the identification of further deletions and duplications affecting X chromosome genes but without apparent disease consequences. Breakpoints of pathogenic variants were characterized to provide insight into the underlying mutational mechanisms and indicated a predominance of mitotic rather than meiotic events. By effectively bridging the gap between karyotype-level investigations and X chromosome exon resequencing, this study informs discussion of alternative mutational mechanisms, such as noncoding variants and non-X-linked disease, which might explain the shortfall of mutation yield in the well-characterized International Genetics of Learning Disability (IGOLD) cohort...

Analysis of anther transcriptomes to identify genes contributing to meiosis and male gametophyte development in rice

Deveshwar, P.; Bovill, W.; Sharma, R.; Able, J.; Kapoor, S.
Fonte: BioMed Central Ltd. Publicador: BioMed Central Ltd.
Tipo: Artigo de Revista Científica
Publicado em //2011 EN
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Background: In flowering plants, the anther is the site of male gametophyte development. Two major events in the development of the male germline are meiosis and the asymmetric division in the male gametophyte that gives rise to the vegetative and generative cells, and the following mitotic division in the generative cell that produces two sperm cells. Anther transcriptomes have been analyzed in many plant species at progressive stages of development by using microarray and sequence-by synthesis-technologies to identify genes that regulate anther development. Here we report a comprehensive analysis of rice anther transcriptomes at four distinct stages, focusing on identifying regulatory components that contribute to male meiosis and germline development. Further, these transcriptomes have been compared with the transcriptomes of 10 stages of rice vegetative and seed development to identify genes that express specifically during anther development. Results: Transcriptome profiling of four stages of anther development in rice including pre-meiotic (PMA), meiotic (MA), anthers at single-celled (SCP) and tri-nucleate pollen (TPA) revealed about 22,000 genes expressing in at least one of the anther developmental stages, with the highest number in MA (18...

Microarray analysis identifies candidate genes for key roles in coral development

Grasso, L.; Maindonald, J.; Rudd, S.; Hayward, D.; Saint, R.; Miller, D.; Ball, E.
Fonte: BioMed Central Ltd. Publicador: BioMed Central Ltd.
Tipo: Artigo de Revista Científica
Publicado em //2008 EN
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702.0735%
Background: Anthozoan cnidarians are amongst the simplest animals at the tissue level of organization, but are surprisingly complex and vertebrate-like in terms of gene repertoire. As major components of tropical reef ecosystems, the stony corals are anthozoans of particular ecological significance. To better understand the molecular bases of both cnidarian development in general and coral-specific processes such as skeletogenesis and symbiont acquisition, microarray analysis was carried out through the period of early development – when skeletogenesis is initiated, and symbionts are first acquired. Results: Of 5081 unique peptide coding genes, 1084 were differentially expressed (P ≤ 0.05) in comparisons between four different stages of coral development, spanning key developmental transitions. Genes of likely relevance to the processes of settlement, metamorphosis, calcification and interaction with symbionts were characterised further and their spatial expression patterns investigated using whole-mount in situ hybridization. Conclusion: This study is the first large-scale investigation of developmental gene expression for any cnidarian, and has provided candidate genes for key roles in many aspects of coral biology, including calcification...

The bHLH/Per-Arnt-Sim transcription factor SIM2 regulates muscle transcript myomesin2 via a novel, non-canonical E-box sequence

Woods, S.; Farrall, A.; Procko, C.; Whitelaw, M.
Fonte: Oxford Univ Press Publicador: Oxford Univ Press
Tipo: Artigo de Revista Científica
Publicado em //2008 EN
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699.3162%
Despite a growing number of descriptive studies that show Single-minded 2 (Sim2) is not only essential for murine survival, but also upregulated in colon, prostate and pancreatic tumours, there is a lack of direct target genes identified for this basic helix–loop–helix/PAS transcription factor. We have performed a set of microarray experiments aimed at identifying genes that are differentially regulated by SIM2, and successfully verified that the Myomesin2 (Myom2) gene is SIM2-responsive. Although SIM2 has been reported to be a transcription repressor, we find that SIM2 induces transcription of Myom2 and activates the Myom2 promoter sequence when co-expressed with the heterodimeric partner protein, ARNT1, in human embryonic kidney cells. Truncation and mutation of the Myom2 promoter sequence, combined with chromatin immunoprecipitation studies in cells, has lead to the delineation of a non-canonical E-box sequence 5'-AACGTG-3' that is bound by SIM2/ARNT1 heterodimers. Interestingly, in immortalized human myoblasts knock down of Sim2 results in increased levels of Myom2 RNA, suggesting that SIM2 is acting as a repressor in these cells and so its activity is likely to be highly context dependent. This is the first report of a direct SIM2/ARNT1 target gene with accompanying analysis of a functional response element.; Susan Woods...

Array-based gene discovery with three unrelated subjects shows SCARB2/LIMP-2 deficiency causes myoclonus epilepsy and glomerulosclerosis

Berkovic, S.; Dibbens, L.; Oshlack, A.; Silver, J.; Katerelos, M.; Vears, D.; Lullmann-Rauch, R.; Blanz, J.; Zhang, K.; Stankovich, J.; Kalnins, R.; Dowling, J.; Andermann, E.; Andermann, F.; Faldini, E.; D'Hooge, R.; Vadlamudi, L.; Macdonnell, R.; Hodgso
Fonte: Univ Chicago Press Publicador: Univ Chicago Press
Tipo: Artigo de Revista Científica
Publicado em //2008 EN
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697.0806%
Action myoclonus-renal failure syndrome (AMRF) is an autosomal-recessive disorder with the remarkable combination of focal glomerulosclerosis, frequently with glomerular collapse, and progressive myoclonus epilepsy associated with storage material in the brain. Here, we employed a novel combination of molecular strategies to find the responsible gene and show its effects in an animal model. Utilizing only three unrelated affected individuals and their relatives, we used homozygosity mapping with single-nucleotide polymorphism chips to localize AMRF. We then used microarray-expression analysis to prioritize candidates prior to sequencing. The disorder was mapped to 4q13-21, and microarray-expression analysis identified SCARB2/Limp2, which encodes a lysosomal-membrane protein, as the likely candidate. Mutations in SCARB2/Limp2 were found in all three families used for mapping and subsequently confirmed in two other unrelated AMRF families. The mutations were associated with lack of SCARB2 protein. Reanalysis of an existing Limp2 knockout mouse showed intracellular inclusions in cerebral and cerebellar cortex, and the kidneys showed subtle glomerular changes. This study highlights that recessive genes can be identified with a very small number of subjects. The ancestral lysosomal-membrane protein SCARB2/LIMP-2 is responsible for AMRF. The heterogeneous pathology in the kidney and brain suggests that SCARB2/Limp2 has pleiotropic effects that may be relevant to understanding the pathogenesis of other forms of glomerulosclerosis or collapse and myoclonic epilepsies.; Samuel F. Berkovic...

Histological and molecular analysis of Rdg2a barley resistance to leaf stripe

Haegi, A.; Bonardi, V.; Dall'aglio, E.; Glissant, D.; Tumino, G.; Collins, N.; Bulgarelli, D.; Infantio, A.; Stanca, A.; Delledonne, M.; Vale, G.
Fonte: Wiley-Blackwell Publishing Ltd. Publicador: Wiley-Blackwell Publishing Ltd.
Tipo: Artigo de Revista Científica
Publicado em //2008 EN
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Barley (Hordeum vulgare L.) leaf stripe is caused by the seed-borne fungus Pyrenophora graminea. We investigated microscopically and molecularly the reaction of barley embryos to leaf stripe inoculation. In the resistant genotype NIL3876-Rdg2a, fungal growth ceased at the scutellar node of the embryo, while in the susceptible near-isogenic line (NIL) Mirco-rdg2a fungal growth continued past the scutellar node and into the embryo. Pathogen-challenged embryos of resistant and susceptible NILs showed different levels of UV autofluorescence and toluidine blue staining, indicating differential accumulation of phenolic compounds. Suppression subtractive hybridization and cDNA amplified fragment-length polymorphism (AFLP) analyses of embryos identified P. graminea-induced and P. graminea-repressed barley genes. In addition, cDNA-AFLP analysis identified six pathogenicity-associated fungal genes expressed during barley infection but at low to undetectable levels during growth on artificial media. Microarrays representing the entire set of differentially expressed cDNA-AFLP fragments and 100 barley homologues of previously described defence-related genes were used to study gene expression changes at 7 and 14 days after inoculation in the resistant and susceptible NILs. A total of 171 significantly modulated barley genes were identified and assigned to four groups based on timing and genotype dependence of expression. Analysis of the changes in gene expression during the barley resistance response to leaf stripe suggests that the Rdg2a-mediated response includes cell-wall reinforcement...

Whole genome expression array profiling highlights differences in mucosal defense genes in Barrett's esophagus and esophageal adenocarcinoma

Nancarrow, D.; Clouston, A.; Smithers, B.; Gotley, D.; Drew, P.; Watson, D.; Tyagi, S.; Hayward, N.; Whiteman, D.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em //2011 EN
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695.0322%
Esophageal adenocarcinoma (EAC) has become a major concern in Western countries due to rapid rises in incidence coupled with very poor survival rates. One of the key risk factors for the development of this cancer is the presence of Barrett's esophagus (BE), which is believed to form in response to repeated gastro-esophageal reflux. In this study we performed comparative, genome-wide expression profiling (using Illumina whole-genome Beadarrays) on total RNA extracted from esophageal biopsy tissues from individuals with EAC, BE (in the absence of EAC) and those with normal squamous epithelium. We combined these data with publically accessible raw data from three similar studies to investigate key gene and ontology differences between these three tissue states. The results support the deduction that BE is a tissue with enhanced glycoprotein synthesis machinery (DPP4, ATP2A3, AGR2) designed to provide strong mucosal defenses aimed at resisting gastro-esophageal reflux. EAC exhibits the enhanced extracellular matrix remodeling (collagens, IGFBP7, PLAU) effects expected in an aggressive form of cancer, as well as evidence of reduced expression of genes associated with mucosal (MUC6, CA2, TFF1) and xenobiotic (AKR1C2, AKR1B10) defenses. When our results are compared to previous whole-genome expression profiling studies keratin...

Within and between whorls: comparative transcriptional profiling of Aquilegia and Arabidopsis

Voelckel, Claudia; Borevitz, Justin O.; Kramer, Elena M.; Hodges, Scott A.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica Formato: 12 pages
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BACKGROUND The genus Aquilegia is an emerging model system in plant evolutionary biology predominantly because of its wide variation in floral traits and associated floral ecology. The anatomy of the Aquilegia flower is also very distinct. There are two whorls of petaloid organs, the outer whorl of sepals and the second whorl of petals that form nectar spurs, as well as a recently evolved fifth whorl of staminodia inserted between stamens and carpels. METHODOLOGY/PRINCIPAL FINDINGS We designed an oligonucleotide microarray based on EST sequences from a mixed tissue, normalized cDNA library of an A. formosa x A. pubescens F2 population representing 17,246 unigenes. We then used this array to analyze floral gene expression in late pre-anthesis stage floral organs from a natural A. formosa population. In particular, we tested for gene expression patterns specific to each floral whorl and to combinations of whorls that correspond to traditional and modified ABC model groupings. Similar analyses were performed on gene expression data of Arabidopsis thaliana whorls previously obtained using the Ath1 gene chips (data available through The Arabidopsis Information Resource). CONCLUSIONS/SIGNIFICANCE Our comparative gene expression analyses suggest that 1) petaloid sepals and petals of A. formosa share gene expression patterns more than either have organ-specific patterns...

Global Analysis of Genetic, Epigenetic and Transcriptional Polymorphisms in Arabidopsis thaliana Using Whole Genome Tiling Arrays

Zhang, Xu; Shiu, Shinhan; Cal, Andrew; Borevitz, Justin O.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
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695.0322%
Whole genome tiling arrays provide a high resolution platform for profiling of genetic, epigenetic, and gene expression polymorphisms. In this study we surveyed natural genomic variation in cytosine methylation among Arabidopsis thaliana wild accessions Columbia (Col) and Vancouver (Van) by comparing hybridization intensity difference between genomic DNA digested with either methylation-sensitive (HpaII) or -insensitive (MspI) restriction enzyme. Single Feature Polymorphisms (SFPs) were assayed on a full set of 1,683,620 unique features of Arabidopsis Tiling Array 1.0F (Affymetrix), while constitutive and polymorphic CG methylation were assayed on a subset of 54,519 features, which contain a 5'CCGG3' restriction site. 138,552 SFPs (1% FDR) were identified across enzyme treatments, which preferentially accumulated in pericentromeric regions. Our study also demonstrates that at least 8% of all analyzed CCGG sites were constitutively methylated across the two strains, while about 10% of all analyzed CCGG sites were differentially methylated between the two strains. Within euchromatin arms, both constitutive and polymorphic CG methylation accumulated in central regions of genes but under-represented toward the 5' and 3' ends of the coding sequences. Nevertheless...

Reduced Retinal Microvascular Density, Improved Forepaw Reach, Comparative Microarray and Gene Set Enrichment Analysis with c-jun Targeting DNA Enzyme

Chan, Cecilia W. S.; Kaplan, Warren; Parish, Christopher R.; Khachigian, Levon M.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
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Retinal neovascularization is a critical component in the pathogenesis of common ocular disorders that cause blindness, and treatment options are limited. We evaluated the therapeutic effect of a DNA enzyme targeting c-jun mRNA in mice with pre-existing retinal neovascularization. A single injection of Dz13 in a lipid formulation containing N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium methyl-sulfate and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine inhibited c-Jun expression and reduced retinal microvascular density. The DNAzyme inhibited retinal microvascular density as effectively as VEGF-A antibodies. Comparative microarray and gene expression analysis determined that Dz13 suppressed not only c-jun but a range of growth factors and matrix-degrading enzymes. Dz13 in this formulation inhibited microvascular endothelial cell proliferation, migration and tubule formation in vitro. Moreover, animals treated with Dz13 sensed the top of the cage in a modified forepaw reach model, unlike mice given a DNAzyme with scrambled RNA-binding arms that did not affect c-Jun expression. These findings demonstrate reduction of microvascular density and improvement in forepaw reach in mice administered catalytic DNA.; This work was supported by grants from Cancer Institute NSW and the National Health and Medical Research Council (NHMRC). The funders had no role in study design...

Functional transcriptome analysis of the postnatal brain of the Ts1Cje mouse model for Down syndrome reveals global disruption of interferon-related molecular networks

Ling, K.H.; Hewitt, C.A.; Tan, K.L.; Cheah, P.S.; Vidyadaran, S.; Lai, M.I.; Lee, H.C.; Simpson, K.; Hyde, L.; Pritchard, M.A.; Smyth, G.K.; Thomas, T.; Scott, H.S.
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
Publicado em //2014 EN
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BACKGROUND: The Ts1Cje mouse model of Down syndrome (DS) has partial triplication of mouse chromosome 16 (MMU16), which is partially homologous to human chromosome 21. These mice develop various neuropathological features identified in DS individuals. We analysed the effect of partial triplication of the MMU16 segment on global gene expression in the cerebral cortex, cerebellum and hippocampus of Ts1Cje mice at 4 time-points: postnatal day (P)1, P15, P30 and P84. RESULTS: Gene expression profiling identified a total of 317 differentially expressed genes (DEGs), selected from various spatiotemporal comparisons, between Ts1Cje and disomic mice. A total of 201 DEGs were identified from the cerebellum, 129 from the hippocampus and 40 from the cerebral cortex. Of these, only 18 DEGs were identified as common to all three brain regions and 15 were located in the triplicated segment. We validated 8 selected DEGs from the cerebral cortex (Brwd1, Donson, Erdr1, Ifnar1, Itgb8, Itsn1, Mrps6 and Tmem50b), 18 DEGs from the cerebellum (Atp5o, Brwd1, Donson, Dopey2, Erdr1, Hmgn1, Ifnar1, Ifnar2, Ifngr2, Itgb8, Itsn1, Mrps6, Paxbp1, Son, Stat1, Tbata, Tmem50b and Wrb) and 11 DEGs from the hippocampus (Atp5o, Brwd1, Cbr1, Donson, Erdr1, Itgb8, Itsn1...