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51.
There is increasing interest in the role of the brain angiotensin AT4 receptor subtype in cognitive processing. This receptor subtype is activated by angiotensin IV (AngIV), is heavily distributed in the mammalian hippocampus, neocortex, and cerebellum, and has been linked with a learning and memory function. The present investigation utilized intracerebroventricular (i.c.v.)-infused scopolamine hydrobromide (scop), a muscarinic receptor antagonist, to disrupt acquisition of the circular water maze task of spatial memory. All animals received 2 days of training trials (five trials/day) using a visible platform in an effort to preclude subsequent confounding by scopolamine-induced sensory and/or motor impairments. In the first experiment, i.c.v.-infused scopolamine (70 nmol) was followed by 0, 10, 100, or 1000 pmol i.c.v. doses of Nle(1)-AngIV in separate groups of rats. Results indicated that each dose of Nle(1)-AngIV improved the poor acquisition of this task induced by scopolamine treatment. However, the 100- and 1000-pmol doses were most effective with respect to latency and distance to find the submerged pedestal. A second experiment demonstrated that treatment with a specific AT4 receptor antagonist, Nle(1), Leual(3)-AngIV (1000 pmol), blocked the ability of Nle(1)-AngIV (100 pmol) to improve the performance of scopolamine-compromised rats. These results support the notion that hippocampal AT4 receptors are involved in spatial memory processing, and that activation of these binding sites can overcome the disruption of spatial memory accompanying treatment with a muscarinic receptor antagonist. 相似文献
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Dendritic cell maturation and subsequent enhanced T-cell stimulation induced with the novel synthetic immune response modifier R-848. 总被引:7,自引:0,他引:7
C L Ahonen S J Gibson R M Smith L K Pederson J M Lindh M A Tomai J P Vasilakos 《Cellular immunology》1999,197(1):62-72
Agents that enhance dendritic cell maturation can enhance T-cell activation and therefore may improve the efficiency of vaccines or improve cellular immunotherapy. Previously, we demonstrated that a novel low-molecular-weight synthetic immune response modifier, R-848, induces IL-12 and IFN-alpha secretion from monocytes and macrophages. Here we report that R-848 induces the maturation of human monocyte-derived dendritic cells. Characteristic of dendritic cell maturation, R-848 treatment induces cell surface expression of CD83 and increases cell surface expression of CD80, CD86, CD40, and HLA-DR. Additionally, R-848 induces cytokine (IL-6, IL-12, TNF-alpha, IFN-alpha) and chemokine (IL-8, MIP-1alpha, MCP-1) secretion from dendritic cells. Most significantly, R-848 enhances dendritic cell antigen presenting function, as measured by increased T-cell proliferation and T-cell cytokine secretion in both allogeneic and autologous T-cell systems. Consequently, low-molecular-weight synthetic molecules such as R-848 and its derivatives may be useful as vaccine adjuvants or as ex vivo stimulators of dendritic cells for cellular immunotherapy. 相似文献
53.
Genetic Characterization of a Cell Envelope-Associated Proteinase from Lactobacillus helveticus CNRZ32
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Jeffrey A. Pederson Gerald J. Mileski Bart C. Weimer James L. Steele 《Journal of bacteriology》1999,181(15):4592-4597
A cell envelope-associated proteinase gene (prtH) was identified in Lactobacillus helveticus CNRZ32. The prtH gene encodes a protein of 1,849 amino acids and with a predicted molecular mass of 204 kDa. The deduced amino acid sequence of the prtH product has significant identity (45%) to that of the lactococcal PrtP proteinases. Southern blot analysis indicates that prtH is not broadly distributed within L. helveticus. A prtH deletion mutant of CNRZ32 was constructed to evaluate the physiological role of PrtH. PrtH is not required for rapid growth or fast acid production in milk by CNRZ32. Cell surface proteinase activity and specificity were determined by hydrolysis of alpha(s1)-casein fragment 1-23 by whole cells. A comparison of CNRZ32 and its prtH deletion mutant indicates that CNRZ32 has at least two cell surface proteinases that differ in substrate specificity. 相似文献
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Brian S. Majors Michael J. Betenbaugh Nels E. Pederson Gisela G. Chiang 《Biotechnology progress》2009,25(4):1161-1168
Bioreactor stresses, including nutrient deprivation, shear stress, and byproduct accumulation can cause apoptosis, leading to lower recombinant protein yields and increased costs in downstream processing. Although cell engineering strategies utilizing the overexpression of antiapoptotic Bcl‐2 family proteins such as Bcl‐2 and Bcl‐xL potently inhibit apoptosis, no studies have examined the use of the Bcl‐2 family protein, Mcl‐1, in commercial mammalian cell culture processes. Here, we overexpress both the wild type Mcl‐1 protein and a Mcl‐1 mutant protein that is not degraded by the proteasome in a serum‐free Chinese hamster ovary (CHO) cell line producing a therapeutic antibody. The expression of Mcl‐1 led to increased viabilities in fed‐batch culture, with cell lines expressing the Mcl‐1 mutant maintaining ~90% viability after 14 days when compared with 65% for control cells. In addition to enhanced culture viability, Mcl‐1‐expressing cell lines were isolated that consistently showed increases in antibody production of 20–35% when compared with control cultures. The quality of the antibody product was not affected in the Mcl‐1‐expressing cell lines, and Mcl‐1‐expressing cells exhibited 3‐fold lower caspase‐3 activation when compared with the control cell lines. Altogether, the expression of Mcl‐1 represents a promising alternative cell engineering strategy to delay apoptosis and increase recombinant protein production in CHO cells. © 2009 American Institute of Chemical Engineers Biotechnol. Prog., 2009 相似文献
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Multiple interacting ecosystem drivers: toward an encompassing hypothesis of oak forest dynamics across eastern North America 总被引:2,自引:0,他引:2
Many forests of eastern North American are undergoing a species composition shift in which maples (Acer spp.) are increasingly important while oak (Quercus spp.) regeneration and recruitment has become increasingly scarce. This dynamic in species composition occurs across a large and geographically complex region. The elimination of fire has been postulated as the driver of this dynamic; however, some assumptions underlying this postulate have not been completely examined, and alternative hypotheses remain underexplored. Through literature review, and a series of new analyses, we examined underlying assumptions of the “oak and fire” hypothesis and explored a series of alternative hypotheses based on well‐known ecosystem drivers: climate change, land‐use change, the loss of foundation and keystone species, and dynamics in herbivore populations. We found that the oak–maple dynamic began during a shift in climate regime‐from a time of frequent, severe, multi‐year droughts to a period of increased moisture availability. Anthropogenic disturbance on the landscape changed markedly during this same time, from an era of Native American utilization, to a time characterized by low population densities, to Euro‐American settlement and subsequent land transmogrification. During the initiation of the oak‐maple dynamic, a foundation species, the American chestnut, was lost as a canopy tree across a broad range. Several important browsers and acorn predators had substantial population dynamics during this period, e.g. white‐tailed deer populations grew substantially concurrent with increasing oak recruitment failure. In conclusion, our analyses suggest that oak forests are reacting to marked changes in a suite of interlocking factors. We propose a “multiple interacting ecosystem drivers hypothesis”, which provides a more encompassing framework for understanding oak forest dynamics. 相似文献
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Vaccination against persistent viral infection exacerbates CD4+ T-cell-mediated immunopathological disease. 总被引:1,自引:0,他引:1
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Lymphocytic choriomeningitis virus (LCMV) infection of normal mice results in a fatal immunopathologic meningitis mediated by CD8+ cytotoxic T lymphocytes (CTL). We have previously shown that female beta2-microglobulin-deficient (beta2m-/-) mice, which are also deficient in CD8+ T cells, are susceptible to LCMV-induced immune-mediated meningitis, characterized by significant weight loss and mortality. This LCMV disease in beta2m-/- mice is mediated by CD4+ T lymphocytes. Our previous studies have also demonstrated that male beta2m-/- mice are less susceptible than female beta2m-/- mice to LCMV-induced, immune-mediated mortality and weight loss. In this report, we show that vaccination of male beta2m-/- mice enhances immunopathology following intracranial infection with LCMV. We observed increased production of gamma interferon (IFN-gamma), an increase in CD4+ CTL precursor frequency, and an increased frequency of IFN-gamma-producing cells from spleen cells of vaccinated male beta2m-/- mice. Vaccinated male beta2m-/- mice also had significantly increased inflammation in the cerebrospinal fluid (CSF), characterized by a large CD4+ T-cell infiltrate. CSF cells from vaccinated mice showed increased production of IFN-gamma on day 7 postchallenge. Neither vaccinated nor control beta2m-/- mice were able to clear virus, and the two groups had similarly high levels of virus early after infection. These results suggest that the magnitude of the early immune response is more important than the level of virus in the brain in determining the outcome of immunopathology in beta2m-/- mice. We show here that vaccination can increase CD4+ T-cell-dependent immunopathology to a persistent viral infection. 相似文献