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Single Target (single + target)
Selected AbstractsMembrane-associated guidance cues direct the innervation of forebrain and midbrain by dorsal raphe-derived serotonergic axonsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 3 2005Audrey Petit Abstract Unlike many neurons that extend an axon precisely to a single target, individual dorsal raphe 5-HT neurons project to multiple brain regions and their axon terminals often lack classical synaptic specializations. It is not known how 5-HT axon collaterals select between multiple target fields, or even if 5-HT axons require specific guidance cues to innervate their targets. Nor is it known how these axon collaterals are restrained within specific innervation target regions. To investigate this, we challenged explants of dorsal raphe with co-explants, or cell membrane preparations of ventral midbrain, striatum or cerebral cortex. We provide evidence for membrane-associated cues that promote 5-HT axon growth into each of these three target regions. The axon growth-promoting activity was heat-, protease- and phosphatidylinositol-phospholipase-C (PI-PLC)-sensitive. Interestingly, 5-HT axons specifically lost the ability to grow in heterotypic explants, or membrane carpets, following contact with ventral midbrain or striatal, but not cortical, explants or membranes. This inductive activity associated with striatal and ventral midbrain membranes was sensitive to both high salt extraction and PI-PLC treatment. By contrast, the activity that inhibited 5-HT axon growth onto heterotypic membranes was sensitive only to high salt extraction. These results provide evidence that a glycosylphosphatidylinositol (GPI)-linked membrane protein promotes 5-HT axon growth, and that short-range membrane-bound, as well as GPI-linked, molecules contribute to the guidance of 5-HT axon collaterals. These findings suggest that 5-HT axon collaterals acquire a target-induced growth-inhibitory response to alternative targets, increasing their selectivity for the newly innervated field. [source] Pain Processing: Paradoxes and PredictionsPAIN PRACTICE, Issue 1 2001William J. Martin PhD Abstract: During the last 25 years, there have been substantial advances in our understanding of the physiology and pathophysiology of pain. The development of animal models that more closely mimic clinical pain in humans has helped elucidate the putative mechanisms by which chronic pain develops and is maintained. However, our increased understanding of the neurobiology of pain has not translated into breakthrough treatments for pain management. As such, chronic pain is still primarily managed by drugs whose primary indication does not include pain (eg, antidepressants, anticonvulsants, antiarrhythmics, local anesthetics). These adjuvant analgesics have come into favor despite the fact that the mechanisms through which these drugs provide pain relief remain either largely unknown or are not selective for a single target. Moreover, the efficacy of adjuvant analgesics in animal models of pain is often validated only after case studies or clinical trials have been reported. This retrospective validation of "novel" analgesics in animal models of pain raises a question of the predictive validity of these models. This article reviews the use of several adjuvant and standard analgesics currently used to treat difficult-to-manage pain. What can these drugs teach us about the development of novel pain medicines? Within this context, the use of animal models of pain to predict analgesic efficacy in clinical pain conditions is considered. [source] Insulin resistance at the crossroads of metabolic syndrome: Systemic analysis using microarraysBIOTECHNOLOGY JOURNAL, Issue 9 2010Dr. Eunjung Kim Abstract Recently, it has been suggested that insulin resistance is a better predictor of metabolic syndrome than obesity. Numerous studies have been conducted to identify insulin resistance susceptibility genes in various model systems. This review focuses on recent findings in microarray analyses, which have indicated that (i) in the liver, genes involved in lipid synthesis and gluconeogenesis are increased in an animal model of insulin resistance that leads into liver steatosis and hyperglycemia; (ii) in adipose tissues, genes involved in fatty acid synthesis and adipogenesis are down-regulated both in insulin-resistant humans and in animals; and (iii) in muscle, overall gene expression, including genes involved in fatty acid oxidation and biosynthesis, is either decreased or unresponsive compared to that of insulin-sensitive control human subjects or animals. Considering the multifaceted effects of insulin resistance in various tissues, aiming at multi-targets rather than a single target will be a more promising strategy for the prevention or treatment of insulin resistance. [source] Multicolor in vivo targeted imaging to guide real-time surgery of HER2-positive micrometastases in a two-tumor coincident model of ovarian cancerCANCER SCIENCE, Issue 6 2009Michelle Longmire One of the primary goals of oncological molecular imaging is to accurately identify and characterize malignant tissues in vivo. Currently, molecular imaging relies on targeting a single molecule that while overexpressed in malignancy, is often also expressed at lower levels in normal tissue, resulting in reduced tumor to background ratios. One approach to increasing the specificity of molecular imaging in cancer is to use multiple probes each with distinct fluorescence to target several surface antigens simultaneously, in order to identify tissue expression profiles, rather than relying on the expression of a single target. This next step forward in molecular imaging will rely on characterization of tissue based on fluorescence and therefore will require the ability to simultaneously identify several optical probes each attached to different targeting ligands. We created a novel ,coincident' ovarian cancer mouse model by coinjecting each animal with two distinct cell lines, HER2+/red fluorescent protein (RFP), SKOV3 and HER2,/RFP+ SHIN3-RFP, in order to establish a model of disease in which animals simultaneously bore tumors with two distinct phenotypes (HER2+/RFP,, HER2,/RFP+), which could be utilized for multicolor imaging. The HER2 receptor of the SKOV3 cell line was targeted with a trastuzumab,rhodamine green conjugate to create green tumor implants, whereas the RFP plasmid of the SHIN3 cells created red tumor implants. We demonstrate that real-time in vivo multicolor imaging is feasible and that fluorescence characteristics can then serve to guide the surgical removal of disease. (Cancer Sci 2009; 100: 1099,1104) [source] Indoloquinolizidine,Peptide Hybrids as Multiple Agonists for D1 and D2 Dopamine ReceptorsCHEMMEDCHEM, Issue 9 2009Marc Vendrell Abstract Multiple-specificity ligands are considered promising pharmacological tools that may show higher efficacy in the treatment of diseases for which the modulation of a single target is therapeutically inadequate. We prepared a set of novel ligands for D1 and D2 dopamine receptors by combining two indolo[2,3- a]quinolizidine scaffolds with various tripeptide moieties. The binding and functional properties of these molecules were determined by radioligand binding studies in brain striatum membranes and by intracellular cAMP production assays in cells expressing different dopamine receptor subtypes. Some indoloquinolizidine,peptide hybrids, mainly with the trans configuration, showed dual agonist activity at both D1 and D2 dopamine receptors and may therefore be useful for testing the therapeutic potential of multivalent drugs on these targets. [source] Spatiotemporal expression of chemokines and chemokine receptors in experimental anti-myeloperoxidase antibody-mediated glomerulonephritisCLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 1 2009B. S. Van Der Veen Summary Myeloperoxidase (MPO)-anti-neutrophil cytoplasmic autoantibody (ANCA)-associated necrotizing crescentic glomerulonephritis (NCGN) is characterized by abundant leucocyte infiltration. Chemokines are chemotactic cytokines involved in receptor-mediated recruitment of leucocytes. Our objective was to analyse spatiotemporal gene expression of chemokines and chemokine receptors in anti-MPO-mediated NCGN, to find potential targets for intervening with leucocyte influx. NCGN was induced in mice by co-administration of anti-MPO immunoglobulin (Ig)G and lipopolysaccharide. mRNA expression levels of chemokines and chemokine receptors were analysed in whole kidney lysates as well as in laser microdissected glomeruli and tubulo-interstitial tissue 1 and 7 day(s) after NCGN induction. Several chemokines and chemokine receptors were induced or up-regulated in anti-MPO-mediated NCGN, both on day 1 (chemokines CCL3, 5; CXCL2, 5, 13; receptor CXCR2) and on day 7 (chemokines CCL2, 5, 7, 8, 17, 20; CXCL1, 2, 5, 10; CX3CL1; receptors CCR2, 8; CX3CR1). The expression levels of most chemokines and receptors were higher in glomeruli than in the tubulo-interstitium. Because of the temporal induction of CXCR2 on day 1, we hypothesized CXCR2 as a potential target for treatment in anti-MPO-induced NCGN. Inhibition of CXCR2 using a goat-anti-CXCR2 serum prior to NCGN induction increased glomerular neutrophil influx but did not affect crescent formation and albuminuria. In conclusion, expression levels of various chemokines and chemokine receptors were increased in anti-MPO NCGN, and expressed particularly in glomeruli. These chemokines and receptors may serve as potential targets for treatment. Inhibition of a single target, CXCR2, did not attenuate anti-MPO NCGN. Combinatorial interventions may be necessary to avoid redundancy. [source] Stereotypes of singles: are singles what we think?EUROPEAN JOURNAL OF SOCIAL PSYCHOLOGY, Issue 3 2009Tobias Greitemeyer Four studies examined the accuracy of the single stereotype by comparing perceptions of single and partnered targets with self-ratings and ratings by others of single and partnered participants. Results revealed that single targets were evaluated more negatively than partnered targets in terms of a wide range of personality characteristics, overall well-being, and satisfaction with relationships status. These findings were very robust and not qualified by target sex, participant sex, and participant relationship status. In contrast, self-ratings of single and partnered participants were remarkably similar for all personality characteristics as well as overall well-being, which was corroborated by ratings of participants by others. However, partnered participants were indeed more satisfied with their relationship status than single participants. When all is considered, the single stereotype is largely inaccurate. Copyright © 2008 John Wiley & Sons, Ltd. [source] | |||||||||||||