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At least 289 records · Page 16Linked to original sources
PubMed2006

Identification of target genes in their native cellular context: an analysis of EWS/FLI in Ewing's sarcoma.

Ewing's sarcoma is the second most common tumor of bone in children and young adults, and requires highly intensive chemotherapy along with surgery and/or radiation for successful treatment. Because these therapies are associated with significant short- and long-term side effects, new therapeutic approaches are needed. Most cases of Ewing's sarcoma contain somatic translocations between chromosomes 11 and 22 that result in the t(11;22)(q24;q12). This translocation encodes the EWS/FLI fusion protein. EWS/FLI formation appears to be the critical oncogenic event in the development of Ewing's sarcoma. It is hoped that an in-depth understanding of the mechanism that EWS/FLI uses to cause oncogenic transformation will result in new therapies for this disease. Unfortunately, this hope has not been realized. One difficulty has been the lack of an appropriate model system in which to study the fusion oncoprotein. We recently described and validated the use of retroviral RNA interference approaches to study EWS/FLI in Ewing's sarcoma cell lines. We now put this model into a historical context, and describe the benefits (both perceived and observed) of this model over previous approaches using heterologous cell types.

Animals↗
PubMed2000

Cloning of human early B-cell factor and identification of target genes suggest a conserved role in B-cell development in man and mouse.

Early B-cell factor (EBF) is a helix-loop-helix transcription factor suggested to be essential for B-cell development in the mouse. Several genetic targets for EBF have been identified in mice, among these the surrogate light chain lambda5 and the signal-transducing molecules Igalpha (mb-1) and Igbeta (B29). This article reports cloning of the human homologue of EBF, hEBF. This protein has 93% sequence and 98.8% amino acid homology with mouse EBF. The encoded protein binds DNA and is expressed in cells of the B lineage, but not in cell populations representing T lymphocytes or myeloid cells. It is also shown that EBF-binding sites are functionally conserved in the human mb-1 and B29 promoters because hEBF interacts with these in the electrophoretic mobility shift assay (EMSA) and have the ability to increase the activity of reporter constructs under the control of these promoters in nonlymphoid HeLa cells. A third genetic target for hEBF is the promoter of the human surrogate light chain 14.1. This promoter contains 5 independent binding sites capable of interacting with hEBF in the EMSA, and the activity of the promoter was induced 24-fold in co-transfection experiments. These findings suggest that the human homologue of mouse EBF displays conserved biochemical features as well as genetic targets, indicating that this protein also has an important role in human B-cell development. (Blood. 2000;96:1457-1464)

Amino Acid Sequence↗
PubMed1988

Expression of HIV in lymph node cells of LAS patients. Immunohistology, in situ hybridization, and identification of target cells.

Monoclonal antibodies (MAb) anti-HIV core and envelope proteins and in situ hybridization, using cDNA HIV probe, were employed to determine which lymph node cells in LAS patients express viral antigens and viral nucleic acids. The results have been correlated with the histologic phases of LAS and with the germinal center lysis detected using DRC-1 MAb directed against follicular dendritic reticulum cells (FDRC). Viral antigens occasionally were detected on high endothelial cells of paracortical venules and frequently on germinal center FDR accessory cells; this last finding correlates well with the extent of FDRC lysis and of CD4+ and CD8+ lymphocyte infiltration in germinal centers. HIV replication, detected by in situ hybridization, was observed in mononucleated cells present in T and B areas and, in one case, in flat endothelium.

AIDS-Related Complex↗
PubMed1985

Identification of target proteins participating in a lectin-dependent macrophage-mediated cytotoxic reaction.

Membrane proteins of mouse macrophages and mammary tumor cells having affinity to Sarcophaga lectin were isolated by affinity chromatography. The electrophoretic profiles and antigenicities of lectin-binding proteins from macrophages and tumor cells were different. Antibody raised against tumor cell lectin-binding proteins inhibited both the binding of the lectin to tumor cells and the lectin-dependent macrophage-mediated cytotoxic reaction. However, it did not inhibit the binding of the lectin to macrophages. It was suggested that the same lectin molecule transmitted different stimuli to macrophages and tumor cells via different receptor proteins.

Animals↗
PubMed1980

Identification of target antigen for antibody-dependent cellular cytotoxicity on cells carrying Epstein-Barr virus genome.

The target antigen for antibody-dependent-cellular cytotoxicity (ADCC) on Epstein-Barr virus-(EBV) carrying lymphoblastoid cells expressing EBV-specific membrane antigen (MA) were examined with human serum antibody and adult human peripheral lymphocytes as effector cells. These studies confirmed that anti-MA-positive but not MA-negative sera were reactive in the ADCC. The ADCC reaction was positive with cells in which the MA consisted of late (LMA) and early (EMA) components. These included 1) MA-positive cells prepared by EBV antigen-adsorption, 2) cells carrying de novo-synthesized MA without adsorbed MA, and 3) EBV-producer cells expressing MA spontaneously. In all these preparations, the target cells were lysed roughly in parallel with the frequency of MA-positive cells. Inhibition of LMA synthesis in EBV-superinfected cells by phosphonoacetate (PA) reduced ADCC sensitivity significantly and to a far greater extent than MA synthesis as measured by immunofluorescence. This suggests that a target for ADCC is the PA-sensitive LMA. No ADCC reaction occurred with the cell preparation comprised of a high percentage of MA-positive cells induced by 5-iodo-2'-deoxyuridine, which is believed to be EMA only. These results strongly suggest that the target antigen for ADCC in EBV-positive cells is a late MA but not early MA.

Adsorption↗
PubMed1993

Stroke rehabilitation: identification of target groups and planning data.

In order to ascertain the need for late stroke rehabilitation in South-West Stockholm (SWS) and explore the conditions for experimental stroke outcome research, we followed a population-based, systematic sample of incident stroke patients, hospitalized during the period 1987-1988, using computer files and a telephone interview. The annual incidence of first-ever or recurrent transitory ischaemic attack (TIA) or acute stroke during the period was 2.83 per 1000. In December 1989, approximately 3% of these incident patients declared subjective residual dysfunction, were living at home and were considered potential candidates for rehabilitation. The estimated prevalence of home-bound individuals with residual dysfunction due to stroke was 0.74 per 1000 (95% CI 0.51-1.04). The average duration of hospitalization for these patients was 95.2 days. Approximately 3/4 of them were interested in further conventional rehabilitation. The group not interested in this therapy were mainly females and were older. They scored lower in personal ADL and mental activity, but similarly in motor function. We concluded that the prevalence need for rehabilitation after stroke in the SWS community amounted to at least 1/1000. Early rehabilitation in the community, linked to post-acute stroke care with reduction of hospital stay would be functionally and socially advantageous and cost-effective for more than 25% of the incident stroke cases. Stroke rehabilitation and clinical follow-up are closely related processes that should be evaluated simultaneously.

Activities of Daily Living↗
PubMed1998

Visualization of enteroviral replication in myocardial tissue by ultrastructural in situ hybridization: identification of target cells and cytopathic effects.

In humans as well as in various murine models, enteroviruses are capable of inducing a severe acute and chronic myocarditis, which is characterized by myocytotoxic alterations and interstitial mononuclear infiltrates. With regard to the pathogenesis of enteroviral myocarditis, coxsackievirus B3 (CVB3)-infected immunocompetent A.CA/SnJ (H-2f) mice were used as a model to trace viral plus- and minus-strand RNA during acute and chronic organ infection by ultrastructural in situ hybridization techniques. For electron microscopic detection of enteroviral RNA in myocardial tissue, a pre-embedding hybridization technique was developed and optimized for excellent conservation of structural integrity and RNA retention. Herein, we demonstrate how the virus gains access to the myocardium during viremia involving infection of the capillary endothelial cells. In myocytes, viral replication was found to be closely associated with the generation of vesicular regions and lysis of myofibrils, resulting in complete destruction of the internal architecture of the cell. In the course of acute infection, the direct cell-to-cell spread of the virus from one myocyte to the other was found to be related with filaments of the cytoskeleton. The observation of prominent cytopathic alterations in close spatial association with viral replication before the development of the reactive cellular immune response strongly implies that the loss of host cell integrity is a direct consequence of acute viral replication. In addition to myocytes, non-heart muscle cells were found to be infected during acute as well as chronic disease. Viral replication observed in myocardial fibroblasts and immune cells such as B lymphocytes proved to be associated with minor cytopathic effects. The technique of electron microscopic in situ hybridization established for the detection of viral RNA within myocardial tissue provides a powerful tool for the elucidation of molecular and structural interrelationships in organ pathology.

Animals↗
PubMed2005

How will RNAi facilitate drug development?

Development of effective drugs for treatment of human disease relies on identification of therapeutic molecular targets. The identification of targets to treat human disease has previously relied on genetic screens in model organisms, and less robust or lower throughput approaches in mammalian systems. RNA interference (RNAi) makes possible, for the first time, the use of large-scale functional genomics approaches for target identification in human cells. This remarkable breakthrough has the potential to influence every facet of the drug discovery process, and is poised to revolutionize drug development. Reports of RNAi screens for the identification of novel genes implicated in apoptosis, cell division, and drug resistance support the enormous promise of this technology. Here, we discuss the potential impact of RNAi screens on target identification and validation and consider issues that warrant caution when interpreting RNAi screening results.

Animals↗
PubMed1997

Tactile pattern perception by two fingers: temporal interference and response competition.

The identification of a spatial pattern (target) presented to one fingerpad may be interfered with by the presentation of a second pattern (nontarget) to either the same fingerpad or a second fingerpad. A portion of the interference appears to be due to masking and a portion to response competition. In the present study, vibrotactile spatial patterns were designed to extend over two fingerpads. Target and nontarget patterns were presented to the same two fingerpads with a temporal separation between the two patterns. The function relating target identification to the temporal separation between the target and nontarget was very similar to the functions obtained with one-finger patterns in temporal masking studies. Subsequent measurements showed that a substantial portion of the interference resulted from response competition. Pattern categorization was better when patterns were presented to two fingers on opposite hands than to two fingers on the same hand; however, there was more interference for patterns presented bilaterally than for patterns presented ipsilaterally. The results supported the conclusion that similar processes are involved in the perception of sequences of spatial patterns whether the patterns are presented to one or to two fingers.

Adult↗
PubMed2003

Timing modulation of a 40-MHz laser-pulse train for target ranging and identification.

We have demonstrated a target ranging and identification technique based on the timing modulation of a mode-locked laser coupled with fast incoherent detection. The range-to-target and the target-depth information have been determined with a resolution of better than 25 cm at single-pulse signal-to-noise ratios below 0.1. Our modeling results suggest that laser average power requirements remain a challenge, with upwards of 100 W likely needed for extension of this technique to ranges over 10 km, but improvements in overall system throughput would allow realization of its potential.

Journal Article↗
PubMed2003

Target Explorer: An automated tool for the identification of new target genes for a specified set of transcription factors.

With the increasing number of eukaryotic genomes available, high-throughput automated tools for identification of regulatory DNA sequences are becoming increasingly feasible. Several computational approaches for the prediction of regulatory elements were recently developed. Here we combine the prediction of clusters of binding sites for transcription factors with context information taken from genome annotations. Target Explorer automates the entire process from the creation of a customized library of binding sites for known transcription factors through the prediction and annotation of putative target genes that are potentially regulated by these factors. It was specifically designed for the well-annotated Drosophila melanogaster genome, but most options can be used for sequences from other genomes as well. Target Explorer is available at http://trantor.bioc.columbia.edu/Target_Explorer/

Animals↗
PubMed2005

The effect of target contrast on the attentional blink.

In this set of five rapid serial visual presentation experiments, observers identified one or two target letters that were embedded in a stream of distractors. Target contrasts were varied, and their effects on the attentional blink (AB) were examined. Target identification improved when its contrast was increased. But whereas an increase in the first target's (T1) contrast facilitated its identification, the recovery of the second target (T2) was paradoxically hampered (Experiments 2 and 5). Similarly, identification of the target suffered when the preceding singleton's contrast was increased (Experiment 1). The AB was eliminated by inserting a blank after a low-contrast, but not a high-contrast, T1 (Experiment 5). Increasing T2's contrast attenuated the blink (Experiment 3) and compensated the larger AB caused by a high-contrast T1 (Experiment 4). In all, these results showed that attention continued to be engaged as long as the target's contrast prolonged its perceptibility. When the high-contrast target was T1, a larger AB was produced; when it was T2, there was protection from substitution masking.

Attention↗
PubMed1982

A time-course analysis of attentional tuning of the auditory evoked response.

This study examined the time course of attentional tuning of the N1 and P3 components of the auditory evoked potential. Human subjects were presented with two concurrent sequences of pure tone stimuli, one sequence delivered to each ear. They were instructed to listen to the tones in one ear and count randomly-embedded target stimuli, identified by pitch, while ignoring concurrent and physically equivalent stimuli in the other ear. Attention was then allocated to other ear-pitch combinations in subsequent runs. The rate of stimulation was rapid, an average of three stimuli per second per channel, to maximize N1 differences between channels. Evoked potentials were sampled at various times during each experimental run, to determine the time course of amplitude change in each auditory channel, as the subject tuned his neural response to the selected stimuli. The results indicated that N1 took 30-45 s to emerge as significantly larger in the attended channel, whereas P3 was instantly larger in the attended channel upon presenting the first rare stimulus of a run. The N1 effect disappeared for standard stimuli after about 7 min of stimulation, despite a continuously high rate of target identification. However, for the rare target stimuli, N1 and P3 remained at a higher level in the attended channel throughout the typical 15 min run. The study concludes that neural selectivity proceeds in a "top-down" manner, with the longer-latency P3 component showing a selective response sooner than N1. In addition, there is evidence that the selectivity of N1 tuning increases over time, with the continued focussing of attention.

Attention↗
PubMed1999

Is attentional selection to different levels of hierarchical structure based on spatial frequency?

Target identification is faster when the target level (global or local) is the same as that on the previous trial, presumably because attention is directed to the appropriate level. L. C. Robertson (1996) found that eliminating low spatial frequencies by contrast balancing eliminated this level repetition effect and concluded that attentional selection between different levels of structure is based on spatial frequency. In contrast, M. R. Lamb and E. W. Yund (1996a) found no effect of contrast balancing on the level repetition effect and thus concluded that attentional selection is not based on spatial frequency. In this study, the authors identified the procedural difference between the 2 studies responsible for this difference in results and replicated both findings. The data show that spatial frequency is not a necessary basis for attentional selection between global and local forms. Although it remains possible that spatial frequency is the basis of attentional selection under some circumstances, the data supporting this proposition are not yet compelling.

Adult↗
PubMed2000

Gene-target recognition among members of the myc superfamily and implications for oncogenesis.

Myc and Mad family proteins regulate multiple biological processes through their capacity to influence gene expression directly. Here we show that the basic regions of Myc and Mad proteins are not functionally equivalent in oncogenesis, have separable E-box-binding activities and engage both common and distinct gene targets. Our data support the view that the opposing biological actions of Myc and Mxi1 extend beyond reciprocal regulation of common gene targets. Identification of differentially regulated gene targets provides a framework for understanding the mechanism through which the Myc superfamily governs the growth, proliferation and survival of normal and neoplastic cells.

3T3 Cells↗