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91.
Zhang N Hodge D Rogers TJ Oppenheim JJ 《The Journal of biological chemistry》2003,278(15):12729-12736
Heterologous desensitization of chemokine receptors by opioids has been considered to contribute to their immunosuppressive effects. Previous studies show that Met-enkephalin, an endogenous opioid, down-regulates chemotaxis of selected chemokine receptors via phosphorylation. In the present study, we further investigated the molecular mechanism of such cross-regulation. Our data showed that preincubation with Met-enkephalin inhibited both MIP-1 alpha-mediated chemotaxis and Ca(2+) flux of monocytes in a dose-dependent manner. The inhibitory effects were maximal using nanomolar concentrations of activating chemokines, a concentration found in physiological conditions. A decrease both in chemokine receptor affinity and in coupling efficiency between receptors and G protein were observed, which directly contributed to the desensitization effects. However, comparing with chemokines such as MIP-1 alpha and MCP-1, opioids did not elicit a calcium flux, failed to induce MIP-1 alpha receptors internalization, and mediated a less potent heterologous desensitization. We hypothesized that these differences might originate from the involvement of different protein kinase C (PKC) isotypes. In our studies, opioid-mediated down-regulation of MIP-1 alpha receptors could be blocked by the general PKC inhibitor calphostin C, but not by the calcium-dependent classic PKC inhibitor Go6976. Western blotting analysis and immunofluorescent staining further showed that only calcium-independent PKCs were activated upon opioid stimulation. Thus, opioids achieve desensitization of chemokine receptors via a unique pathway, involving only calcium-independent PKC isotypes. 相似文献
92.
One hitherto intractable problem in studying mast seeding (synchronous intermittent heavy flowering by a population of perennial plants) is determining the relative roles of weather, plant reserves, and evolutionary selective pressures such as predator satiation. We parameterize a mechanistic resource-based model for mast seeding in Chionochloa pallens (Poaceae) using a long-term individually structured data set. Each plant's energy reserves were reconstructed using annual inputs (growing degree days), outputs (flowering), and a novel regression technique. This allowed the estimation of the parameters that control internal plant resource dynamics, and thereby allowed different models for masting to be tested against each other. Models based only on plant size, season degree days, and/or climatic cues (warm January temperatures) fail to reproduce the pattern of autocovariation in individual flowering and the high levels of flowering synchrony seen in the field. This shows that resource-matching or simple cue-based models cannot account for this example of mast seeding. In contrast, the resource-based model pulsed by a simple climate cue accurately describes both individual-level and population-level aspects of the data. The fitted resource-based model, in the absence of environmental forcing, has chaotic (but often statistically periodic) dynamics. Environmental forcing synchronizes individual reproduction, and the models predict highly variable seed production in close agreement with the data. An evolutionary model shows that the chaotic internal resource dynamics, as predicted by the fitted model, is selectively advantageous provided that adult mortality is low and seeds survive for more than 1 yr, both of which are true for C. pallens. Highly variable masting and chaotic dynamics appear to be advantageous in this case because they reduce seed losses to specialist seed predators, while balancing the costs of missed reproductive events. 相似文献
93.
94.
Background
Existing cut-offs for fasting plasma glucose (FPG) and post-load glucose (2hPG) criteria are not equivalent in the diagnosis of diabetes and glucose intolerance. Adjusting cut-offs of single measurements have not helped so we undertook this project to see if they could be complementary. 相似文献95.
96.
It has been suggested that recombination may be mutagenic, which, if true, would inflate intraspecies diversity and interspecies silent divergence in regions of high recombination. Here, we test this hypothesis comparing human/orangutan genome-wide non-coding divergence (K) to that in the pseudoautosomal genes which were reported to recombine much more frequently than the rest of the genome. We demonstrate that, compared to the average human/orangutan non-coding divergence (K=3%), the substitution rate is significantly elevated in the introns of SHOX (K=5.7%), PPP2R3L (K=8.7%) and ASMT (K=6.5%) genes located in the human and orangutan Xp/Yp pseudoautosomal region (p-PAR), where recombination is over 20-fold higher than the genomic average. On the other hand, human/orangutan non-coding divergence at the Xp/Yp pseudoautosomal boundary (K=3.5%) and in the SYBL1 gene (K=2.7%), located in the human Xq/Yq pseudoautosomal region (q-PAR), where recombination is known to be less frequent than in p-PAR, was not significantly higher than the genome average. The data are consistent with the hypothesis that recombination may be mutagenic. 相似文献
97.
Mast cells: an unexpected finding in the modulation of cutaneous wound repair by charged beads 总被引:2,自引:0,他引:2
Sasaki A Mueller RV Xi G Sipe R Buck D Hollinger J 《Plastic and reconstructive surgery》2003,111(4):1446-1453
Increased numbers of mast cells are affiliated with a broad spectrum of pathologic skin conditions, including ulcers, atopic dermatitis, neurofibromatosis, hemangiomas, keloids, and hypertrophic scars. It has been proposed that mast cells play a primary pathophysiologic role in these disorders and that their presence represents not merely a secondary event. While investigating their recent hypothesis that positively charged cross-linked diethylaminoethyl dextran (CLDD) beads potentiate cutaneous wound healing, the authors serendipitously observed increased numbers of mast cells in the deep dermis of wounds treated with CLDD beads. The authors propose that mast cells may play an important role in the modulation of healing seen with CLDD beads. Incisional wounds were studied in 30 Sprague-Dawley rats partitioned into two groups that were killed 7 or 14 days after wounding. The wounds were treated with positively, negatively, or neutrally charged CLDD beads. Physiologic saline served as a control. At the designated times after incisional wounding, biopsy specimens were tested for wound breaking strength or processed for histologic testing, fixed in 4% paraformaldehyde, and stained with Giemsa and Goldner-Masson trichrome. Mast cells were counted under light microscopy in a blinded fashion and were expressed as the number of cells per millimeter squared. Significant increases in the number of mast cells were observed in the deep dermis of incisional wounds after implantation with positively or negatively charged CLDD beads. In contrast, neutrally charged beads had no effect on mast cell numbers. At 7 days, the incisions treated with positively charged beads averaged 2.1 times more mast cells compared with those treated with physiologic saline or neutrally charged beads, whereas the incisions treated with negatively charged beads displayed 3.2 times more mast cells. By day 14, the incisions treated with positively charged beads averaged 2.5 times more mast cells than those wounds treated with saline or neutrally charged beads; the incisions treated with negatively charged CLDD beads had 3.4 times more mast cells. The 7-day tensiometric data indicated that wounds treated with negatively charged CLDD beads had increased breaking strength compared with wounds treated with neutrally charged beads or saline (1.8 and 1.7 times, respectively; p = 0.01 and p = 0.02). Wounds treated with positively charged beads also showed increased breaking strength compared with wounds treated with neutrally charged beads or saline (1.5 and 1.4 times greater); however, this did not reach statistical significance. There was no apparent difference in breaking strength when neutrally charged beads were compared with those treated with saline. At 14 days, there was no statistically significant difference in wound breaking strength between different treatments. These findings are clinically germane to the assessment of proposed therapeutic applications of CLDD beads for a variety of impaired wound-healing states. Furthermore, if increased mast cell populations are intimately linked to hypertrophic scar and keloid formation, the results of the authors' study suggest that CLDD bead therapy of cutaneous wounds may lead to pathologic wound healing in humans. 相似文献
98.
Dave KR Syal AR Katyare SS 《Zeitschrift für Naturforschung. C, Journal of biosciences》2000,55(1-2):100-108
The substrate saturation and temperature-dependent kinetic properties of soluble and membrane-bound forms of acetylcholinestarase (AChE) from brain and butyrylcholinesterase (BChE) from heart and liver were examined. In simultaneous studies these parameters were also measured for AChE in erythrocyte membranes and for BChE in the serum from rat and humans. For both soluble and membrane-bound forms of the enzyme from the three tissues, two components were discernible. In the brain, Km of component I (high affinity) and component II (low affinity) was somewhat higher in membrane-bound form than that of the soluble form components, while the Vmax values were significantly higher by about five fold. In the heart, Km of component II was lower in membrane-bound form than in the soluble form, while Vmax for both the components was about four to six fold higher in the membrane-bound form. In the liver, Vmax was marginally higher for the two components of the membrane-bound enzyme; the Km only of component I was higher by a factor of 2. In the rat erythrocyte membranes three components of AChE were present showing increasing values of Km and Vmax. In contrast, in the human erythrocyte membranes only two components could be detected; the one corresponding to component II of rat erythrocyte membranes was absent. In the rat serum two components of BChE were present while the human serum was found to possess three components. Component I of the human serum was missing in the rat serum. Temperature kinetics studies revealed that the Arrhenius plots were biphasic for most of the systems except for human serum. Membrane binding of the enzyme resulted in decreased energy of activation with shift in phase transition temperature (Tt) to near physiological temperature. 相似文献
99.
John Ambler Emma Baker Lyndon Brown Paul Butler Dave Farr Karen Dunnet Darren Le Grand Diana Janus Darryl Jones Keith Menear Mark Mercer Garrick Smith Mark Talbot Morris Tweed 《Bioorganic & medicinal chemistry letters》1998,8(24):189-3588
The chemical optimisation of CGH1668 1 is described employing an in vivo model of absorption to determine the influence on bioavailability of single point modifications to five key molecular templates. The discovery of an orally bioavailable and selective thrombin inhibitor, 24, highlights the utility of this approach. 相似文献
100.
Charles H. Cohan Jake T. Neumann Kunjan R. Dave Aleksey Alekseyenko Marc Binkert Kenneth Stransky Hung Wen Lin Carol A. Barnes Clinton B. Wright Miguel A. Perez-Pinzon 《PloS one》2015,10(5)
Cardiopulmonary arrest is a leading cause of death and disability in the United States that usually occurs in the aged population. Cardiac arrest (CA) induces global ischemia, disrupting global cerebral circulation that results in ischemic brain injury and leads to cognitive impairments in survivors. Ischemia-induced neuronal damage in the hippocampus following CA can result in the impairment of cognitive function including spatial memory. In the present study, we used a model of asphyxial CA (ACA) in nine month old male Fischer 344 rats to investigate cognitive and synaptic deficits following mild global cerebral ischemia. These experiments were performed with the goals of 1) establishing a model of CA in nine month old middle-aged rats; and 2) to test the hypothesis that learning and memory deficits develop following mild global cerebral ischemia in middle-aged rats. To test this hypothesis, spatial memory assays (Barnes circular platform maze and contextual fear conditioning) and field recordings (long-term potentiation and paired-pulse facilitation) were performed. We show that following ACA in nine month old middle-aged rats, there is significant impairment in spatial memory formation, paired-pulse facilitation n dysfunction, and a reduction in the number of non-compromised hippocampal Cornu Ammonis 1 and subiculum neurons. In conclusion, nine month old animals undergoing cardiac arrest have impaired survival, deficits in spatial memory formation, and synaptic dysfunction. 相似文献