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991.
Jie Tian Jie Ma Ke Ma Bin Ma Xinyi Tang Samuel Essien Baidoo Jia Tong Jun Yan Liwei Lu Huaxi Xu Shengjun Wang 《PloS one》2012,7(10)
Background
β-Glucans have been shown to function as a potent immunomodulator to stimulate innate and adaptive immune responses, which contributes to their anti-tumor property. However, their mechanisms of action are still elusive. Glucocorticoid-induced TNF receptor ligand (GITRL), a member of the TNF superfamily, binds to its receptor, GITR, on both effector and regulatory T cells, generates a positive co-stimulatory signal implicated in a wide range of T cell functions, which is important for the development of immune responses.Methodology/Principal Findings
In this study, we found that whole β-glucan particles (WGPs) could activate dendritic cells (DCs) via dectin-1 receptor, and increase the expression of GITRL on DCs in vitro and in vivo. Furthermore, we demonstrated that the increased GITRL on DCs could impair the regulartory T cell (Treg)-mediated suppression and enhance effector T cell proliferation in a GITR/GITRL dependent way. In tumor models, DCs with high levels of GITRL were of great potential to prime cytotoxic T lymphocyte (CTL) responses and down-regulate the suppressive activity of Treg cells, thereby leading to the delayed tumor progression.Conclusions/Significance
These findings suggest that particulate β-glucans can be used as an immunomodulator to stimulate potent T cell-mediated adaptive immunity while down-regulate suppressive immune activity via GITR/GITRL interaction, leading to a more efficient defense mechanism against tumor development. 相似文献992.
Excitatory drive enters the cerebellum via mossy fibers, which activate granule cells, and climbing fibers, which activate Purkinje cell dendrites. Until now, the coordinated regulation of these pathways has gone unmonitored in spatially resolved neuronal ensembles, especially in awake animals. We imaged cerebellar activity using functional two-photon microscopy and extracellular recording in awake mice locomoting on an air-cushioned spherical treadmill. We recorded from putative granule cells, molecular layer interneurons, and Purkinje cell dendrites in zone A of lobule IV/V, representing sensation and movement from trunk and limbs. Locomotion was associated with widespread increased activity in granule cells and interneurons, consistent with an increase in mossy fiber drive. At the same time, dendrites of different Purkinje cells showed increased co-activation, reflecting increased synchrony of climbing fiber activity. In resting animals, aversive stimuli triggered increased activity in granule cells and interneurons, as well as increased Purkinje cell co-activation that was strongest for neighboring dendrites and decreased smoothly as a function of mediolateral distance. In contrast with anesthetized recordings, no 1-10 Hz oscillations in climbing fiber activity were evident. Once locomotion began, responses to external stimuli in all three cell types were strongly suppressed. Thus climbing and mossy fiber representations can shift together within a fraction of a second, reflecting in turn either movement-associated activity or external stimuli. 相似文献
993.
994.
Alberto Molano Zhaofeng Huang Melissa G. Marko Angelo Azzi Dayong Wu Elaine Wang Samuel L. Kelly Alfred H. Merrill Jr Stephen C. Bunnell Simin Nikbin Meydani 《PloS one》2012,7(10)
To determine whether changes in sphingolipid composition are associated with age-related immune dysfunction, we analyzed the core sphingolipidome (i.e., all of the metabolites through the first headgroup additions) of young and aged CD4+ T cells. Since sphingolipids influence the biophysical properties of membranes, we evaluated the compositions of immune synapse (IS) and non-IS fractions prepared by magnetic immuno-isolation. Broadly, increased amounts of sphingomyelins, dihydrosphingomyelins and ceramides were found in aged CD4+ T cells. After normalizing for total sphingolipid content, a statistically significant decrease in the molar fraction of glucosylceramides was evident in both the non-IS and IS fractions of aged T cells. This change was balanced by less dramatic increases in the molar fractions of sphingomyelins and dihydrosphingomyelins in aged CD4+ T cells. In vitro, the direct or enzymatic enhancement of ceramide levels decreased CD4+ T cell proliferation without regard for the age of the responding T cells. In contrast, the in vitro inhibition of glucosylceramidase preferentially increased the proliferation of aged CD4+ T cells. These results suggest that reductions in glucosylceramide abundance contribute to age-related impairments in CD4+ T cell function. 相似文献
995.
Use of small interfering RNA (siRNA) is a promising approach for AML treatment as the siRNA molecule can be designed to specifically target proteins that contribute to aberrant cell proliferation in this disease. However, a clinical-relevant means of delivering siRNA molecules must be developed, as the cellular delivery of siRNA is problematic. Here, we report amphiphilic carriers combining a cationic polymer (2 kDa polyethyleneimine, PEI2) with lipophilic moieties to facilitate intracellular delivery of siRNA to AML cell lines. Complete binding of siRNA by the designed carriers was achieved at a polymer:siRNA ratio of ~0.5 and led to siRNA/polymer complexes of ~100 nm size. While the native PEI2 did not display cytotoxicity on AML cell lines THP-1, KG-1 and HL-60, lipid-modification on PEI2 slightly increased the cytotoxicity, which was consistent with increased interaction of polymers with cell membranes. Cellular delivery of siRNA was dependent on the nature of lipid substituent and the extent of lipid substitution, and varied among the three AML cell lines used. Linoleic acid-substituted polymers performed best among the prepared polymers and gave a siRNA delivery equivalent to better performing commercial reagents. Using THP-1 cells and a reporter (GFP) and an endogenous (CXCR4) target, effective silencing of the chosen targets was achieved with 25 to 50 nM of siRNA concentrations, and without adversely affecting subsequent cell growth. We conclude that lipid-substituted PEI2 can serve as an effective delivery of siRNA to leukemic cells and could be employed in molecular therapy of leukemia. 相似文献
996.
Samuel Wintermute Shawn Betts Jennifer L. Ferris Jon M. Fincham John R. Anderson 《PloS one》2012,7(12)
This fMRI study examines how students extend their mathematical competence. Students solved a set of algebra-like problems. These problems included Regular Problems that have a known solution technique and Exception Problems that but did not have a known technique. Two distinct networks of activity were uncovered. There was a Cognitive Network that was mainly active during the solution of problems and showed little difference between Regular Problems and Exception Problems. There was also a Metacognitive Network that was more engaged during a reflection period after the solution and was much more engaged for Exception Problems than Regular Problems. The Cognitive Network overlaps with prefrontal and parietal regions identified in the ACT-R theory of algebra problem solving and regions identified in the triple-code theory as involved in basic mathematical cognition. The Metacognitive Network included angular gyrus, middle temporal gyrus, and anterior prefrontal regions. This network is mainly engaged by the need to modify the solution procedure and not by the difficulty of the problem. Only the Metacognitive Network decreased with practice on the Exception Problems. Activity in the Cognitive Network during the solution of an Exception Problem predicted both success on that problem and future mastery. Activity in the angular gyrus and middle temporal gyrus during feedback on errors predicted future mastery. 相似文献
997.
Development and change in forest communities are strongly influenced by plant-soil interactions. The primary objective of this paper was to identify how forest soil characteristics vary along gradients of forest community composition in aspen-conifer forests to better understand the relationship between forest vegetation characteristics and soil processes. The study was conducted on the Fishlake National Forest, Utah, USA. Soil measurements were collected in adjacent forest stands that were characterized as aspen dominated, mixed, conifer dominated or open meadow, which includes the range of vegetation conditions that exist in seral aspen forests. Soil chemistry, moisture content, respiration, and temperature were measured. There was a consistent trend in which aspen stands demonstrated higher mean soil nutrient concentrations than mixed and conifer dominated stands and meadows. Specifically, total N, NO3 and NH4 were nearly two-fold higher in soil underneath aspen dominated stands. Soil moisture was significantly higher in aspen stands and meadows in early summer but converged to similar levels as those found in mixed and conifer dominated stands in late summer. Soil respiration was significantly higher in aspen stands than conifer stands or meadows throughout the summer. These results suggest that changes in disturbance regimes or climate scenarios that favor conifer expansion or loss of aspen will decrease soil resource availability, which is likely to have important feedbacks on plant community development. 相似文献
998.
Raul Y. Tito Dan Knights Jessica Metcalf Alexandra J. Obregon-Tito Lauren Cleeland Fares Najar Bruce Roe Karl Reinhard Kristin Sobolik Samuel Belknap Morris Foster Paul Spicer Rob Knight Cecil M. Lewis Jr 《PloS one》2012,7(12)
In an effort to better understand the ancestral state of the human distal gut microbiome, we examine feces retrieved from archaeological contexts (coprolites). To accomplish this, we pyrosequenced the 16S rDNA V3 region from duplicate coprolite samples recovered from three archaeological sites, each representing a different depositional environment: Hinds Cave (∼8000 years B.P.) in the southern United States, Caserones (1600 years B.P.) in northern Chile, and Rio Zape in northern Mexico (1400 years B.P.). Clustering algorithms grouped samples from the same site. Phyletic representation was more similar within sites than between them. A Bayesian approach to source-tracking was used to compare the coprolite data to published data from known sources that include, soil, compost, human gut from rural African children, human gut, oral and skin from US cosmopolitan adults and non-human primate gut. The data from the Hinds Cave samples largely represented unknown sources. The Caserones samples, retrieved directly from natural mummies, matched compost in high proportion. A substantial and robust proportion of Rio Zape data was predicted to match the gut microbiome found in traditional rural communities, with more minor matches to other sources. One of the Rio Zape samples had taxonomic representation consistent with a child. To provide an idealized scenario for sample preservation, we also applied source tracking to previously published data for Ötzi the Iceman and a soldier frozen for 93 years on a glacier. Overall these studies reveal that human microbiome data has been preserved in some coprolites, and these preserved human microbiomes match more closely to those from the rural communities than to those from cosmopolitan communities. These results suggest that the modern cosmopolitan lifestyle resulted in a dramatic change to the human gut microbiome. 相似文献
999.
Bruno Mendes Roatt Rodrigo Dian de Oliveira Aguiar-Soares Juliana Vitoriano-Souza Wendel Coura-Vital Samuel Le?ncio Braga Rodrigo Corrêa-Oliveira Olindo Assis Martins-Filho Andréa Teixeira-Carvalho Marta de Lana Nelder Figueiredo Gontijo Marcos José Marques Rodolfo Cordeiro Giunchetti Alexandre Barbosa Reis 《PloS one》2012,7(11)
In the last decade, the search for new vaccines against canine visceral leishmaniasis has intensified. However, the pattern related to immune protection during long periods after experimental infection in vaccine trials is still not fully understood. Herein, we investigated the immunogenicity and parasitological levels after intradermal challenge with Leishmania infantum plus salivary gland extract in dogs immunized with a vaccine composed of L. braziliensis antigens plus saponin as an adjuvant (LBSap vaccine). The LBSap vaccine elicited higher levels of total anti-Leishmania IgG as well as both IgG1 and IgG2. Furthermore, dogs vaccinated had increased levels of lymphocytes, particularly circulating B cells (CD21+) and both CD4+ and CD8+ T lymphocytes. LBSap also elicited an intense in vitro cell proliferation associated with higher levels of CD4+ T lymphocytes specific for vaccine soluble antigen and soluble lysate of L. infantum antigen even 885 days after experimental challenge. Furthermore, LBSap vaccinated dogs presented high IFN-γ and low IL-10 and TGF-β1 expression in spleen with significant reduction of parasite load in this tissue. Overall, our results validate the potential of LBSap vaccine to protect against L. infantum experimental infection and strongly support further evaluation of efficiency of LBSap against CVL in natural infection conditions. 相似文献
1000.
SE Ward HS Kim K Komurov S Mendiratta PL Tsai M Schmolke N Satterly B Manicassamy CV Forst MG Roth A García-Sastre KM Blazewska CE McKenna BM Fontoura MA White 《PloS one》2012,7(8):e39284
Influenza A virus infects 5-20% of the population annually, resulting in ~35,000 deaths and significant morbidity. Current treatments include vaccines and drugs that target viral proteins. However, both of these approaches have limitations, as vaccines require yearly development and the rapid evolution of viral proteins gives rise to drug resistance. In consequence additional intervention strategies, that target host factors required for the viral life cycle, are under investigation. Here we employed arrayed whole-genome siRNA screening strategies to identify cell-autonomous molecular components that are subverted to support H1N1 influenza A virus infection of human bronchial epithelial cells. Integration across relevant public data sets exposed druggable gene products required for epithelial cell infection or required for viral proteins to deflect host cell suicide checkpoint activation. Pharmacological inhibition of representative targets, RGGT and CHEK1, resulted in significant protection against infection of human epithelial cells by the A/WS/33 virus. In addition, chemical inhibition of RGGT partially protected against H5N1 and the 2009 H1N1 pandemic strain. The observations reported here thus contribute to an expanding body of studies directed at decoding vulnerabilities in the command and control networks specified by influenza virulence factors. 相似文献