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Likely Targets (likely + target)
Selected AbstractsSELECTION IN HETEROGENEOUS ENVIRONMENTS MAINTAINS THE GENE ARRANGEMENT POLYMORPHISM OF DROSOPHILA PSEUDOOBSCURAEVOLUTION, Issue 12 2008Stephen W. Schaeffer Chromosomal rearrangements may play an important role in how populations adapt to a local environment. The gene arrangement polymorphism on the third chromosome of Drosophila pseudoobscura is a model system to help determine the role that inversions play in the evolution of this species. The gene arrangements are the likely target of strong selection because they form classical clines across diverse geographic habitats, they cycle in frequency over seasons, and they form stable equilibria in population cages. A numerical approach was developed to estimate the fitness sets for 15 gene arrangement karyotypes in six niches based on a model of selection,migration balance. Gene arrangement frequencies in the six different niches were able to reach a stable meta-population equilibrium that matched the observed gene arrangement frequencies when recursions used the estimated fitnesses with a variety of initial inversion frequencies. These analyses show that a complex pattern of selection is operating in the six niches to maintain the D. pseudoobscura gene arrangement polymorphism. Models of local adaptation predict that the new inversion mutations were able to invade populations because they held combinations of two to 13 local adaptation loci together. [source] Lipophilic regulator of a developmental switch in Caenorhabditis elegansAGING CELL, Issue 6 2004Matthew S. Gill In Caenorhabditis elegans, the decision to develop into a reproductive adult or arrest as a dauer larva is influenced by multiple pathways including insulin-like and transforming growth factor , (TGF,)-like signalling pathways. It has been proposed that lipophilic hormones act downstream of these pathways to regulate dauer formation. One likely target for such a hormone is DAF-12, an orphan nuclear hormone receptor that mediates these developmental decisions and also influences adult lifespan. In order to find lipophilic hormones we have generated lipophilic extracts from mass cultures of C. elegans and shown that they rescue the dauer constitutive phenotype of class 1 daf-2 insulin signalling mutants and the TGF, signalling mutant daf-7. These extracts are also able to rescue the lethal dauer phenotype of daf-9 mutants, which lack a P450 steroid hydroxylase thought to be involved in the synthesis of the DAF-12 ligand; extracts, however, have no effect on a DAF-12 ligand binding domain mutant that is predicted to be ligand insensitive. The production of this hormone appears to be DAF-9 dependent as extracts from a daf-9;daf-12 double mutant do not exhibit this activity. Preliminary fractionation of the lipophilic extracts shows that the activity is hydrophobic with some polar properties, consistent with a small lipophilic hormone. We propose that the dauer rescuing activity is a hormone synthesized by DAF-9 that acts through DAF-12. [source] COPS3 amplification and clinical outcome in osteosarcomaCANCER, Issue 9 2007Taiqiang Yan MD Abstract BACKGROUND. Amplification of several genes that map to a region of chromosome 17p11.2, including COPS3, was observed in high-grade osteosarcoma. These genes were also shown to be overexpressed and may be involved in osteosarcoma tumorigenesis. COPS3 encodes a subunit of the COP9 signalosome implicated in the ubiquitination and ultimately degradation of the P53 tumor suppressor. To determine the relation between COPS3 amplification, P53 mutation, and patient outcome in osteosarcoma, tumors from a large cohort of patients with high-grade osteosarcoma and long-term clinical follow-up were examined. METHODS. Quantitative real-time polymerase chain reaction (PCR) was performed to detect copy number changes for COPS3, as well as additional genes (NCOR1, TOM1L2, and PMP22) from the 17p11.2 amplicon, in 155 osteosarcomas from a prospective collection of tumors with corresponding clinical data. Univariate and multivariate analyses were performed to assess differences in survival between groups. RESULTS. Amplification of COPS3, detected in 31% of the osteosarcomas, was strongly associated with large tumor size (P = .0009), but was not associated with age at diagnosis, site, sex, and tumor necrosis. COPS3 amplification was significantly correlated with a shorter time to metastasis with an estimated hazard ratio (HR) of 1.61 (95% confidence interval [CI], 1.02,2.55) in univariate analysis (log-rank test, P = .042). However, in an a priori multivariate Cox model including the other clinical parameters, the HR for COPS3 amplification decreased to 1.32 (95% CI, 0.82,2.13, P = .25), mainly due to the strong correlation with tumor size. COPS3 amplification and P53 mutation frequently occurred in the same tumors, suggesting that these are not mutually exclusive events in osteosarcoma. Although not statistically significant, patients whose tumors exhibited both molecular alterations tended to be more likely to develop metastasis compared with patients with either COPS3 amplification or P53 mutation alone. CONCLUSIONS. COPS3 is the likely target of the 17p11.2 amplicon. COPS3 may function as an oncogene in osteosarcoma, and an increased copy number may lead to an unfavorable prognosis. Cancer 2007. © 2007 American Cancer Society. [source] ITCH is a putative target for a novel 20q11.22 amplification detected in anaplastic thyroid carcinoma cells by array-based comparative genomic hybridizationCANCER SCIENCE, Issue 10 2008Takaya Ishihara Anaplastic thyroid carcinoma (ATC) is one of the most virulent of all human malignancies, with a mean survival time among patients of less than 1 year after diagnosis. To date, however, cytogenetic information on this disease has been very limited. During the course of a program to screen a panel of ATC cell lines for genomic copy-number aberrations using array-based comparative genomic hybridization, we identified a high-level amplification of the ITCH gene, which is mapped to 20q11.22 and belongs to the homologous to the E6-associated protein carboxylterminus ubiquitin ligase family. The expression of ITCH was increased in 4 of 14 ATC cell lines (28.6%), including 8305C in which there was a copy-number amplification of this gene, and six of seven primary cases (85.7%). Among the primary thyroid tumors, a considerable number of ITCH high expressers was found in ATC (40/45, 88.9%), papillary thyroid carcinoma (25/25, 100%), and papillary microcarcinoma (25/25, 100%). Furthermore, knockdown of ITCH by specific small interfering RNA significantly inhibited the growth of ITCH-overexpressing cells, whereas ectopic overexpression of ITCH promoted growth of ATC cell lines with relatively weak expression. These observations indicate ITCH to be the most likely target for 20q11.22 amplification and to play a crucial role in the progression of thyroid carcinoma. (Cancer Sci 2008; 99: 1940,1949) [source] Seed-based systematic discovery of specific transcription factor target genesFEBS JOURNAL, Issue 12 2008Ralf Mrowka Reliable prediction of specific transcription factor target genes is a major challenge in systems biology and functional genomics. Current sequence-based methods yield many false predictions, due to the short and degenerated DNA-binding motifs. Here, we describe a new systematic genome-wide approach, the seed-distribution-distance method, that searches large-scale genome-wide expression data for genes that are similarly expressed as known targets. This method is used to identify genes that are likely targets, allowing sequence-based methods to focus on a subset of genes, giving rise to fewer false-positive predictions. We show by cross-validation that this method is robust in recovering specific target genes. Furthermore, this method identifies genes with typical functions and binding motifs of the seed. The method is illustrated by predicting novel targets of the transcription factor nuclear factor kappaB (NF-,B). Among the new targets is optineurin, which plays a key role in the pathogenesis of acquired blindness caused by adult-onset primary open-angle glaucoma. We show experimentally that the optineurin gene and other predicted genes are targets of NF-,B. Thus, our data provide a missing link in the signalling of NF-,B and the damping function of optineurin in signalling feedback of NF-,B. We present a robust and reliable method to enhance the genome-wide prediction of specific transcription factor target genes that exploits the vast amount of expression information available in public databases today. [source] Griefing in virtual worlds: causes, casualties and coping strategiesINFORMATION SYSTEMS JOURNAL, Issue 6 2009Thomas Chesney Abstract A virtual world is a computer-simulated three-dimensional environment. They are increasingly being used for social and commercial interaction, in addition to their original use for game playing. This paper studies negative behaviour, or ,griefing', inside one virtual world through a series of observations and focus groups with users. Data were collected to identify griefing behaviours and their impact, examine why griefing happens and who the likely targets and perpetrators are, and suggest strategies for coping with it. Findings show that griefing behaviour is common. It is defined as unacceptable, persistent behaviour and is typically targeted at inexperienced residents by those with more knowledge of the virtual world. Community and individual coping strategies are identified and discussed. [source] Increase in song frequency decreases spermatophore size: correlative evidence of a macroevolutionary trade-off in katydids (Orthoptera: Tettigoniidae)JOURNAL OF EVOLUTIONARY BIOLOGY, Issue 3 2007R. C. DEL CASTILLO Abstract In many katydids, the male feeds his mate with a large gelatinous spermatophore. Males of most species also produce elaborate calling songs. We predicted a negative relationship between spermatophore size and call frequency because of trade-offs between these two costly traits. Our comparative analysis controlling phylogeny and body size supported this prediction. Although call frequency is expected to decrease with increasing body size, after controlling for phylogeny, both variables were not related. Finally, given that song frequency and spermatophore size are likely targets of sexual selection, we examined the relationship between these variables and sexual size dimorphism (SSD) which can be influenced by sexual selection on body size. We found that only female body size was positively related to SSD, suggesting that natural and/or sexual selection on female body size may be stronger than sexual selection on male and spermatophore size. [source] Gene expression microarray analysis and genome databases facilitate the characterization of a chromosome 22 derived homogenously staining regionMOLECULAR CARCINOGENESIS, Issue 1 2004Suzanna L. Arcand Abstract Karyotype and fluorescence in situ hybridization (FISH) analyses previously identified a homogenously staining region (HSR) derived from chromosome 22 in OV90, an epithelial ovarian cancer (EOC) cell line. Affymetrix® expression microarrays in combination with the UniGene and Human Genome Browser databases were used to identify the candidate genes comprising the amplicon of the HSR, based on comparison of expression profiles of OV90, EOC cell lines lacking HSRs and primary cultures of normal ovarian surface epithelial (NOSE) cells. A group of probe sets displaying a minimum 3-fold overexpression with a high reliability score (P-call) in OV90 were identified which represented genes that mapped within a 1,2 Mb interval on chromosome 22. A large number of probe sets, some of which represent the same genes, displayed no evidence of overexpression and/or low reliability scores (A-call). An investigation of the probe set sequences with the Affymetrix® and Sanger Institute Chromosome 22 Group databases revealed that some of the probe sets displaying discordant results for the same gene were complementary to intronic sequences and/or the antisense strand. Microarray results were validated by RT-PCR. Genomic analysis suggests that the HSR was derived from the amplification of a 1.1 Mb interval defined by the chromosomal map positions of ZNF74 and Hs.372662, at 22q11.21. The deduced amplicon is derived from a complex region of chromosome 22 that harbors low-copy repeats (LCRs). The amplicon contains 18 genes as likely targets for gene amplification. This study illustrates that large-scale expression microarray analysis in combination with genome databases is sufficient for deducing target genes associated with amplicons and stresses the importance of investigating probe set design before engaging in validation studies. © 2004 Wiley-Liss, Inc. [source] Detection and analysis of mammary gland stem cells,THE JOURNAL OF PATHOLOGY, Issue 2 2009J Stingl Abstract Emerging evidence from a variety of tissue types, including the mammary gland, suggests that normal stem and progenitor cells are the likely targets for malignant transformation, and that these transformed cells can function as cancer stem cells that drive tumour growth. In order to develop therapies that target these cancer stem cells, it is essential to determine the molecular mechanisms that regulate the growth and differentiation of these cells and their normal counterparts. To this end, a number of quantitative robust clonal assays have been developed that can detect the presence of human and mouse mammary stem and progenitor cells. These assays, when used in conjunction with cell-sorting strategies, have permitted the prospective isolation and characterization of a variety of cell types, including stem cells. Evidence to date indicates that these stem cells exhibit properties of basal mammary cells, possess extensive self-renewal properties, and are capable of generating a large number of phenotypically-distinct progenitor cells, many of which display characteristics of luminal cells. This review article will focus on the assays used to detect mammary stem and progenitor cells, some of the properties of these cells and their progeny and how they relate to the cancer stem cells that drive breast tumour growth. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Global analysis of siRNA-mediated transcriptional gene silencingBIOESSAYS, Issue 12 2005Harsh H. Kavi The RNAi machinery is not only involved with post-transcriptional degradation of messenger RNAs, but also used for targeting of chromatin changes associated with transcriptional silencing. Two recent papers determine the global patterns of gene expression and chromatin modifications produced by the RNAi machinery in fission yeast.(9, 10) The major sites include the outer centromere repeats, the mating-type locus and subtelomeric regions. By comparison, studies of Arabidopsis heterochromatin also implicate transposons as a major target for silencing. Analyses of siRNA libraries from Drosophila, nematodes and Arabidopsis indicate that major repeats at centromeres, telomeres and transposable elements are likely targets of RNAi. Also, intergenic regions are implicated as targets in Arabidopsis. BioEssays 27:1209,1212, 2005. © 2005 Wiley Periodicals, Inc. [source] | |||||||||||||