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991.
Anna L. Xavier Jo?o R. L. Menezes Steven A. Goldman Maiken Nedergaard 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2014,369(1654)
Microglia constitute as much as 10–15% of all cells in the mammalian central nervous system (CNS) and are the only glial cells that do not arise from the neuroectoderm. As the principal CNS immune cells, microglial cells represent the first line of defence in response to exogenous threats. Past studies have largely been dedicated to defining the complex immune functions of microglial cells. However, our understanding of the roles of microglia has expanded radically over the past years. It is now clear that microglia are critically involved in shaping neural circuits in both the developing and adult CNS, and in modulating synaptic transmission in the adult brain. Intriguingly, microglial cells appear to use the same sets of tools, including cytokine and chemokine release as well as phagocytosis, whether modulating neural function or mediating the brain''s innate immune responses. This review will discuss recent developments that have broadened our views of neuro-glial signalling to include the contribution of microglial cells. 相似文献
992.
Cristina Velázquez-Marrero Garrett E. Seale Steven N. Treistman Gilles E. Martin 《The Journal of biological chemistry》2014,289(42):29261-29272
Tolerance is a well described component of alcohol abuse and addiction. The large conductance voltage- and Ca2+-gated potassium channel (BK) has been very useful for studying molecular tolerance. The influence of association with the β4 subunit can be observed at the level of individual channels, action potentials in brain slices, and finally, drinking behavior in the mouse. Previously, we showed that 50 mm alcohol increases both α and αβ4 BK channel open probability, but only α BK develops acute tolerance to this effect. Currently, we explore the possibility that the influence of the β4 subunit on tolerance may result from a striking effect of β4 on kinase modulation of the BK channel. We examine the influence of the β4 subunit on PKA, CaMKII, and phosphatase modulation of channel activity, and on molecular tolerance to alcohol. We record from human BK channels heterologously expressed in HEK 293 cells composed of its core subunit, α alone (Insertless), or co-expressed with the β4 BK auxiliary subunit, as well as, acutely dissociated nucleus accumbens neurons using the cell-attached patch clamp configuration. Our results indicate that BK channels are strongly modulated by activation of specific kinases (PKA and CaMKII) and phosphatases. The presence of the β4 subunit greatly influences this modulation, allowing a variety of outcomes for BK channel activity in response to acute alcohol. 相似文献
993.
Zhen-yong Keck Allan G. N. Angus Wenyan Wang Patrick Lau Yong Wang Derek Gatherer Arvind H. Patel Steven K. H. Foung 《PLoS pathogens》2014,10(8)
A challenge for hepatitis C virus (HCV) vaccine development is to define epitopes that are able to elicit protective antibodies against this highly diverse virus. The E2 glycoprotein region located at residues 412–423 is conserved and antibodies to 412–423 have broadly neutralizing activities. However, an adaptive mutation, N417S, is associated with a glycan shift in a variant that cannot be neutralized by a murine but by human monoclonal antibodies (HMAbs) against 412–423. To determine whether HCV escapes from these antibodies, we analyzed variants that emerged when cell culture infectious HCV virions (HCVcc) were passaged under increasing concentrations of a specific HMAb, HC33.1. Multiple nonrandom escape pathways were identified. Two pathways occurred in the context of an N-glycan shift mutation at N417T. At low antibody concentrations, substitutions of two residues outside of the epitope, N434D and K610R, led to variants having improved in vitro viral fitness and reduced sensitivity to HC33.1 binding and neutralization. At moderate concentrations, a S419N mutation occurred within 412–423 in escape variants that have greatly reduced sensitivity to HC33.1 but compromised viral fitness. Importantly, the variants generated from these pathways differed in their stability. N434D and K610R-associated variants were stable and became dominant as the virions were passaged. The S419N mutation reverted back to N419S when immune pressure was reduced by removing HC33.1. At high antibody concentrations, a mutation at L413I was observed in variants that were resistant to HC33.1 neutralization. Collectively, the combination of multiple escape pathways enabled the virus to persist under a wide range of antibody concentrations. Moreover, these findings pose a different challenge to vaccine development beyond the identification of highly conserved epitopes. It will be necessary for a vaccine to induce high potency antibodies that prevent the formation of escape variants, which can co-exist with lower potency or levels of neutralizing activities. 相似文献
994.
Qais Al-Hadid Kevin Roy William Munroe Maria C. Dzialo Guillaume F. Chanfreau Steven G. Clarke 《Molecular and cellular biology》2014,34(15):2903-2916
Histidine protein methylation is an unusual posttranslational modification. In the yeast Saccharomyces cerevisiae, the large ribosomal subunit protein Rpl3p is methylated at histidine 243, a residue that contacts the 25S rRNA near the P site. Rpl3p methylation is dependent upon the presence of Hpm1p, a candidate seven-beta-strand methyltransferase. In this study, we elucidated the biological activities of Hpm1p in vitro and in vivo. Amino acid analyses reveal that Hpm1p is responsible for all of the detectable protein histidine methylation in yeast. The modification is found on a polypeptide corresponding to the size of Rpl3p in ribosomes and in a nucleus-containing organelle fraction but was not detected in proteins of the ribosome-free cytosol fraction. In vitro assays demonstrate that Hpm1p has methyltransferase activity on ribosome-associated but not free Rpl3p, suggesting that its activity depends on interactions with ribosomal components. hpm1 null cells are defective in early rRNA processing, resulting in a deficiency of 60S subunits and translation initiation defects that are exacerbated in minimal medium. Cells lacking Hpm1p are resistant to cycloheximide and verrucarin A and have decreased translational fidelity. We propose that Hpm1p plays a role in the orchestration of the early assembly of the large ribosomal subunit and in faithful protein production. 相似文献
995.
Tang Yunming Cen Liang Chu Bo Li Changchun Xu Min Luo Ying Lu Cheng 《Frontiers of Biology in China》2006,1(3):246-253
Alkaline phosphatase (AKP), from the succus entericus of silkworm, was purified using 10%–50% ammonium sulfate fractions,
ion exchange chromatography of DEAE-Sepharose, and size exclusion chromatography of Sephacryl S-200. The purification fold
was 464 times and specified activity was 3 936 U/mg. Optimum pH value of the phosphatase was 10.5, and was stable between
pH 7.5 and 11. The optimum temperature of the phosphatase was 40°C and it was unstable over 50°C. K
m value of the phosphatase was 1.25 mmol/L. In a given condition, the phosphatase was selectively modified by PCMB, NBS, PMSF,
TNBS, SUAN, DTT, BrAc, and IAc, the results indicate that PMSF, SUA, BrAc, IAc, and TNBS could obviously inhibit the activity
of the phosphatase, and the degree of inhibition depended on the concentration of these reagents. There was little effect
on the activity of phosphatase after treatment by PMSF, DTT, and NBT. We primarily conclude that mercapto and imidazole are
essential for AKP from silkworm. Also, Lys residue and disulfide bands are necessary to protect the catalysis of the AKP.
__________
Translated from Journal of Southwest Normal University (Natural Science), 2005, 30(5): 925–934 [译自: 西南师范大学学报 (自然科学版), 2005, 30(5): 925–934] 相似文献
996.
Cell-derived microparticles participate in intercellular communication similar to the classical messenger systems of small and macro-molecules that bind to specialized membrane receptors. Microparticles have been implicated in the regulation of a variety of complex physiopathologic processes, such as thrombosis, the control of innate and adaptive immunity, and cancer. The neurokinin 1 receptor (NK1R) is a Gq-coupled receptor present on the membrane of a variety of tissues, including neurons in the central and peripheral nervous system, immune cells, endocrine and exocrine glands, and smooth muscle. The endogenous agonist of NK1R is the undecapeptide substance P (SP). We have previously described intracellular signaling mechanisms that regulate NK1R-mediated rapid cell shape changes in HEK293 cells and U373MG cells. In the present study, we show that the activation of NK1R in HEK293 cells, but not in U373MG cells, leads to formation of sheer-stress induced microparticles that stain positive with the membrane-selective fluorescent dye FM 2–10. SP-induced microparticle formation is independent of elevated intracellular calcium concentrations and activation of NK1R present on HEK293-derived microparticles triggers detectable calcium increase in SP-induced microparticles. The ROCK inhibitor Y27632 and the dynamin inhibitor dynasore inhibited membrane blebbing and microparticle formation in HEK293 cells, strongly suggesting that microparticle formation in this cell type is dependent on membrane blebbing. 相似文献
997.
Nikolay O. Bukanov Sarah E. Moreno Thomas A. Natoli Kelly A. Rogers Laurie A. Smith Steven R. Ledbetter Nassima Oumata Hervé Galons Laurent Meijer Oxana Ibraghimov-Beskrovnaya 《Cell cycle (Georgetown, Tex.)》2012,11(21):4040-4046
Autosomal dominant polycystic kidney disease (ADPKD) and other forms of PKD are associated with dysregulated cell cycle and proliferation. Although no effective therapy for the treatment of PKD is currently available, possible mechanism-based approaches are beginning to emerge. A therapeutic intervention targeting aberrant cilia-cell cycle connection using CDK-inhibitor R-roscovitine showed effective arrest of PKD in jck and cpk models that are not orthologous to human ADPKD. To evaluate whether CDK inhibition approach will translate into efficacy in an orthologous model of ADPKD, we tested R-roscovitine and its derivative S-CR8 in a model with a conditionally inactivated Pkd1 gene (Pkd1 cKO). Similar to ADPKD, Pkd1 cKO mice developed renal and hepatic cysts. Treatment of Pkd1 cKO mice with R-roscovitine and its more potent and selective analog S-CR8 significantly reduced renal and hepatic cystogenesis and attenuated kidney function decline. Mechanism of action studies demonstrated effective blockade of cell cycle and proliferation and reduction of apoptosis. Together, these data validate CDK inhibition as a novel and effective approach for the treatment of ADPKD. 相似文献
998.
Genetic variation and population structure in desert bighorn sheep: implications for conservation 总被引:7,自引:0,他引:7
Gustavo A. Gutiérrez-Espeleta Steven T. Kalinowski Walter M. Boyce Philip W. Hedrick 《Conservation Genetics》2000,1(1):3-15
Bighorn sheep populations experienced a drastic reduction in both distribution and abundance until the advent of modern wildlife management, where improving viability of extant populations and translocating animals into historical habitat range have been the most important management policies. The fact that subspecies relationships among bighorn are ambiguous,together with the importance of selecting appropriate source stock and the expense of translocation projects, makes an understanding of subspecies relationships and genetic variation, within and between populations, important for the management and conservation of this species. In this study, genetic variation in 279 bighorn sheep from 13 study sites in Arizona, California, New Mexico and Alberta, Canada were examined by analyzing ten microsatellite loci to determine interpopulation differentiation and relationships between closely related taxa. All populations contained a substantial amount of genetic variation. Genetic differences between populations were large and roughly proportional to geographic distance. The significance of this to desert subspecies relationships and management is discussed. 相似文献
999.
Matthias Oelze Swenja Kr?ller-Sch?n Philipp Welschof Thomas Jansen Michael Hausding Yuliya Mikhed Paul Stamm Michael Mader Elena Zin?ius Saule Agdauletova Anna Gottschlich Sebastian Steven Eberhard Schulz Serge P. Bottari Eric Mayoux Thomas Münzel Andreas Daiber 《PloS one》2014,9(11)
Objective
In diabetes, vascular dysfunction is characterized by impaired endothelial function due to increased oxidative stress. Empagliflozin, as a selective sodium-glucose co-transporter 2 inhibitor (SGLT2i), offers a novel approach for the treatment of type 2 diabetes by enhancing urinary glucose excretion. The aim of the present study was to test whether treatment with empagliflozin improves endothelial dysfunction in type I diabetic rats via reduction of glucotoxicity and associated vascular oxidative stress.Methods
Type I diabetes in Wistar rats was induced by an intravenous injection of streptozotocin (60 mg/kg). One week after injection empagliflozin (10 and 30 mg/kg/d) was administered via drinking water for 7 weeks. Vascular function was assessed by isometric tension recording, oxidative stress parameters by chemiluminescence and fluorescence techniques, protein expression by Western blot, mRNA expression by RT-PCR, and islet function by insulin ELISA in serum and immunohistochemical staining of pancreatic tissue. Advanced glycation end products (AGE) signaling was assessed by dot blot analysis and mRNA expression of the AGE-receptor (RAGE).Results
Treatment with empagliflozin reduced blood glucose levels, normalized endothelial function (aortic rings) and reduced oxidative stress in aortic vessels (dihydroethidium staining) and in blood (phorbol ester/zymosan A-stimulated chemiluminescence) of diabetic rats. Additionally, the pro-inflammatory phenotype and glucotoxicity (AGE/RAGE signaling) in diabetic animals was reversed by SGLT2i therapy.Conclusions
Empagliflozin improves hyperglycemia and prevents the development of endothelial dysfunction, reduces oxidative stress and improves the metabolic situation in type 1 diabetic rats. These preclinical observations illustrate the therapeutic potential of this new class of antidiabetic drugs. 相似文献1000.
Matthew D. Campbell Mark Walker Michael I. Trenell Steven Luzio Gareth Dunseath Daniel Tuner Richard M. Bracken Stephen C. Bain Mark Russell Emma J. Stevenson Daniel J. West 《PloS one》2014,9(5)