bluuebunny/crossref_metadata_2025_split huggingface dataset:
Topical Application of Soluble CD83 Induces IDO-Mediated Immune Modulation, Increases Foxp3+ T Cells, and Prolongs Allogeneic Corneal Graft Survival
Authors: Bock Felix , Rössner Susanne , Onderka Jasmine , Lechmann Matthias , Pallotta Maria Teresa , Fallarino Francesca , Boon Louis , Nicolette Charles , DeBenedette Mark A. , Tcherepanova Irina Y. , Grohmann Ursula , Steinkasserer Alexander , Cursiefen Claus , Zinser Elisabeth 
Published: July 2013

Abstract
Modulation of immune responses is one of the main research aims in transplant immunology. In this study, we investigate the local immunomodulatory properties of soluble CD83 (sCD83) at the graft-host interface using the high-risk corneal transplantation model. In this model, which mimics the inflammatory status and the preexisting vascularization of high-risk patients undergoing corneal transplantation, allogeneic donor corneas are transplanted onto sCD83-treated recipient animals. This model allows the direct and precise application of the immune modulator at the transplantation side. Interestingly, sCD83 was able to prolong graft survival after systemic application as well as after topical application, which is therapeutically more relevant. The therapeutic effect was accompanied by an increase in the frequency of regulatory T cells and was mediated by the immune-regulatory enzyme IDO and TGF-β. In vitro, sCD83 induced long-term IDO expression in both conventional and plasmacytoid dendritic cells via autocrine or paracrine production of TGF-β, a cytokine previously shown to be an essential mediator of IDO-dependent, long-term tolerance. These findings open new treatment avenues for local immune modulation after organ and tissue transplantation.
Anti–Dengue Virus Nonstructural Protein 1 Antibodies Cause NO-Mediated Endothelial Cell Apoptosis via Ceramide-Regulated Glycogen Synthase Kinase-3β and NF-κB Activation
Authors: Chen Chia-Ling , Lin Chiou-Feng , Wan Shu-Wen , Wei Li-Shiung , Chen Mei-Chun , Yeh Trai-Ming , Liu Hsiao-Sheng , Anderson Robert , Lin Yee-Shin 
Published: July 2013

Abstract
Immunopathogenetic mechanisms of dengue virus (DENV) infection are involved in hemorrhagic syndrome resulting from thrombocytopenia, coagulopathy, and vasculopathy. We have proposed a mechanism of molecular mimicry in which Abs against DENV nonstructural protein 1 (NS1) cross-react with human endothelial cells and cause NF-κB–regulated immune activation and NO-mediated apoptosis. However, the signaling pathway leading to NF-κB activation after the binding of anti-DENV NS1 Abs to endothelial cells is unresolved. In this study, we found that anti-DENV NS1 Abs caused the formation of lipid raftlike structures, and that disrupting lipid raft formation by methyl-β-cyclodextrin decreased NO production and apoptosis. Treatment with anti-DENV NS1 Abs elevated ceramide generation in lipid rafts. Pharmacological inhibition of acid sphingomyelinase (aSMase) decreased anti-DENV NS1 Ab-mediated ceramide and NO production, as well as apoptosis. Exogenous ceramide treatment induced biogenesis of inducible NO synthase (iNOS)/NO and apoptosis through an NF-κB–regulated manner. Furthermore, activation of glycogen synthase kinase-3β (GSK-3β) was required for ceramide-induced NF-κB activation and iNOS expression. Notably, anti-DENV NS1 Abs caused GSK-3β–mediated NF-κB activation and iNOS expression, which were regulated by aSMase. Moreover, pharmacological inhibition of GSK-3β reduced hepatic endothelial cell apoptosis in mice passively administered anti-DENV NS1 Abs. These results suggest that anti-DENV NS1 Abs bind to the endothelial cell membrane and cause NO production and apoptosis via a mechanism involving the aSMase/ceramide/GSK-3β/NF-κB/iNOS/NO signaling pathway.
Critical Role of TCR Specificity in the Development of Vγ1Vδ6.3+ Innate NKTγδ Cells
Authors: Pereira Pablo , Berthault Claire , Burlen-Defranoux Odile , Boucontet Laurent 
Published: July 2013

Abstract
A large fraction of innate NKTγδ T cells uses TCRs composed of a semi-invariant Vδ6.3/6.4-Dδ2-Jδ1 chain together with more diverse Vγ1-Jγ4 chains. To address the role of γδTCR specificity in their generation, we analyzed their development in mice transgenic (Tg) for a Vγ1-Jγ4 chain frequently expressed by NKTγδ cells (Tg-γ) and in mice Tg for the same Vγ1-Jγ4 chain together with a Vδ6BDδ2Jδ1 chain not usually found among NKTγδ cells (Tg-γδ). Surprisingly, both promyelocytic leukemia zinc finger (PLZF)+ and NK1.1+ NKTγδ cells were found in the thymus of Tg-γδ albeit at lower numbers than in Tg-γ mice, and virtually all of them expressed the Tg TCR. However, the PLZF+ subset, but not the NK1.1+ subset, also expressed an endogenous Vδ6.3/6.4 chain, and its size was severely reduced in TCRδ−/− Tg-γδ mice. These results could suggest that the PLZF+ and the NK1.1+ subsets are developmentally unrelated. However, PLZF+ and NK1.1+ NKTγδ cells express identical Vδ6.3/6.4 chains, and NK1.1+ cells can be obtained upon intrathymic injection of sorted PLZF+ cells, thus indicating their developmental relationship. In fact, the NK1.1+ γδ thymocytes present in Tg-γδ mice correspond to a small subset of NK1.1+ γδ thymocytes in wild-type animals, which express a more diverse repertoire of TCRs and can be recognized by the expression of the CD62L Ag. Collectively, our data demonstrated that TCR specificity is essential for the development of most NKTγδ T cells and revealed a developmental heterogeneity in γδ T cells expressing the NK1.1 marker.
Cholinergic Receptors Modulate Immune Complex–Induced Inflammation In Vitro and In Vivo
Authors: Vukelic Milena , Qing Xiaoping , Redecha Patricia , Koo Gloria , Salmon Jane E. 
Published: July 2013

Abstract
Cholinergic neural output has been shown to modulate innate immune responses to infection, injury and ischemia through stimulation of α7 nicotinic acetylcholine receptors (α7nAChR) on mononuclear phagocytes. We tested the hypothesis that cholinergic neurotransmitters, similar to those released through activation of a neural reflex, regulate responses to products of the adaptive immune system, specifically immune complex (IC)–mediated activation of effector cells. In this study, we show that stimulation of α7nAChR on human polymorphonuclear neutrophils (PMNs) and blood mononuclear phagocytes in vitro attenuates C5aR- and FcγR-triggered generation of reactive oxygen species, expression of leukocyte markers involved in cell recruitment and adhesion, and release of TNF-α and other proinflammatory cytokines. We show that this pathway is operative in vivo. Ligation of cholinergic receptors blunts IC-triggered responses in the reverse peritoneal Arthus reaction in mice. The selective 7nAChR agonist GTS21 decreased PMN accumulation and release of cytokines and chemokines at sites of IC deposition. In addition, mice lacking α7nAChR had exaggerated responses to reverse peritoneal Arthus reaction characterized by increased infiltration of PMNs and elevated of levels of TNF-α and CXCL1 in peritoneal fluid compared with wild-type mice. Taken together, these findings suggest that cholinergic output has the potential to exert tonic inhibitory activity that dampens responses to ICs and C5a and thus may be a target to minimize tissue damage in autoimmune diseases.
Ndfip1 Enforces a Requirement for CD28 Costimulation by Limiting IL-2 Production
Authors: Ramos-Hernández Natalia , Ramon Hilda E. , Beal Allison M. , Laroche Ami , Dekleva Erin A. , Oliver Paula M. 
Published: July 2013

Abstract
Although the pathways that permit IL-2 production and the full activation of T cells upon Ag encounter are fairly well defined, the negative regulatory circuits that limit these pathways are poorly understood. In this study, we show that the E3 ubiquitin ligase adaptor Ndfip1 directs one such negative regulatory circuit. T cells lacking Ndfip1 produce IL-2, upregulate IL-2Rα, and proliferate, in the absence of CD28 costimulation. Furthermore, T cells in mice lacking both Ndfip1 and CD28 become activated, produce IL-4, and drive inflammation at barrier surfaces. Ndfip1 constrains T cell activation by limiting the duration of IL-2 mRNA expression after TCR stimulation. Ndfip1 and IL-2 have a similar expression pattern, and, following TCR stimulation, expression of both Ndfip1 and IL-2 requires the activity of NFAT and Erk. Taken together, these data support a negative regulatory circuit in which factors that induce IL-2 expression downstream of TCR engagement also induce the expression of Ndfip1 to limit the extent of IL-2 production and, thus, dampen T cell activation.
Impaired Function of CTLA-4 in the Lungs of Patients with Chronic Beryllium Disease Contributes to Persistent Inflammation
Authors: Chain Jennifer L. , Martin Allison K. , Mack Douglas G. , Maier Lisa A. , Palmer Brent E. , Fontenot Andrew P. 
Published: July 2013

Abstract
Chronic beryllium disease (CBD) is an occupational lung disorder characterized by granulomatous inflammation and the accumulation of beryllium-responsive CD4+ T cells in the lung. These differentiated effector memory T cells secrete IL-2, IFN-γ, and TNF-α upon in vitro activation. Beryllium-responsive CD4+ T cells in the lung are CD28 independent and have increased expression of the coinhibitory receptor, programmed death 1, resulting in Ag-specific T cells that proliferate poorly yet retain the ability to express Th1-type cytokines. To further investigate the role of coinhibitory receptors in the beryllium-induced immune response, we examined the expression of CTLA-4 in blood and bronchoalveolar lavage cells from subjects with CBD. CTLA-4 expression was elevated on CD4+ T cells from the lungs of study subjects compared with blood. Furthermore, CTLA-4 expression was greatest in the beryllium-responsive subset of CD4+ T cells that retained the ability to proliferate and express IL-2. Functional assays show that the induction of CTLA-4 signaling in blood cells inhibited beryllium-induced T cell proliferation while having no effect on the proliferative capacity of beryllium-responsive CD4+ T cells in the lung. Collectively, our findings suggest a dysfunctional CTLA-4 pathway in the lung and its potential contribution to the persistent inflammatory response that characterizes CBD.
Critical Role of p38 and GATA3 in Natural Helper Cell Function
Authors: Furusawa Jun-ichi , Moro Kazuyo , Motomura Yasutaka , Okamoto Kazuo , Zhu Jinfang , Takayanagi Hiroshi , Kubo Masato , Koyasu Shigeo 
Published: July 2013

Abstract
Natural helper (NH) cells, a member of Lin−IL-2R+IL-7R+IL-25R+IL-33R+GATA3+ group 2 innate lymphoid cell subset, are characterized by the expression of transcription factors GATA3 and RORα and production of large amounts of Th2 cytokines such as IL-5, IL-6, and IL-13 upon IL-33 stimulation or a combination of IL-2 and IL-25. We have studied the signal transduction pathways critical for the cytokine expression and development of NH cell. Either stimulation with IL-33 or a combination of IL-2 and IL-25 induced p38 activation and phosphorylation of GATA3 in NH cells, and the phosphorylated form of GATA3 bound to the IL-5 and IL-13 promoters. All these events were blocked by SB203580, a p38 inhibitor. Inhibition of p38 also blocked IL-6 production. The mature NH cells lacking Gata3 were impaired in the proliferation and production of IL-5 and IL-13, but not IL-6, indicating that both p38 and GATA3 are critical for the proliferation and production of IL-5 and IL-13 and that the mechanisms downstream of p38 differ between IL-6 and IL-5/IL-13. In contrast, the NH cells lacking RORα showed no impairment in the proliferation and cytokine production, indicating that GATA3 but not RORα plays a pivotal role in the effector functions of mature NH cell. However, deletion of either GATA3 or RORα in hematopoietic stem cells severely blocked the development into NH cells. Our results demonstrate the important roles of p38 and GATA3 in NH cell functions.
IL-17RA Is Essential for Optimal Localization of Follicular Th Cells in the Germinal Center Light Zone To Promote Autoantibody-Producing B Cells
Authors: Ding Yanna , Li Jun , Wu Qi , Yang Pingar , Luo Bao , Xie Shutao , Druey Kirk M. , Zajac Allan J. , Hsu Hui-Chen , Mountz John D. 
Published: July 2013

Abstract
Germinal centers (GCs) provide a microenvironment that promotes and regulates the interactions of B cells with follicular Th (TFH) cells. In this study, we show that there are significantly higher frequencies of CXCR5+ICOS+ TFH cells in autoimmune BXD2 mice, and these cells express both IL-21R and IL-17RA. Although IL-17 and IL-21 are both important for the formation of spontaneous GCs and development of pathogenic autoantibodies, IL-21, but not IL-17, is required for the proper development of TFH cells in BXD2 mice. The total numbers of TFH cells and their ability to induce B cell responses in vitro were not affected by a deficiency of IL-17RA in BXD2-Il17ra−/− mice, the majority of CXCR5+ TFH cells from BXD2-Il17ra−/− mice were, however, not localized in the GC light zone (LZ). Interruption of IL-17 signaling, either acutely by AdIL-17R:Fc or chronically by Il17ra−/−, disrupted TFH–B interactions and abrogated the generation of autoantibody-forming B cells in BXD2 mice. IL-17 upregulated the expression of regulator of G-protein signaling 16 (RGS16) to promote the ability of TFH to form conjugates with B cells, which was abolished in TFH cells from BXD2-Rgs16−/− mice. The results suggests that IL-17 is an extrinsic stop signal that it acts on postdifferentiated IL-17RA+ TFH to enable its interaction with responder B cells in the LZ niche. These data suggest a novel concept that TFH differentiation and its stabilization in the LZ are two separate checkpoints and that IL-21 and IL-17 act at each checkpoint to enable pathogenic GC development.
Study of the amount of Human Resources Architecture Archetype application at University of Isfahan
Authors: Boroujerdi Raziyeh Yosof , Siadat Seyed Ali , Hoveida Reza 
Published: July 2013

Each organization needs specific Human capital which have high unique and strategic value creation .Hence, human resources management of organizations must comply itself with these key people. So, it is clear that organizations in order to gain competitive advantage, must focus on this most important factor, human resources.Which has a strategic role in Excellence of organizations.This research is focused on human resources architecture.Therefore,the purpose of this article was to study the amount of application of the Human Resources Architecture Archetype dimensions, Human Resources practices at University of Isfahan Research method was Descriptive and statistical, population includes all faculty members at University of Isfahan (561 people) in academic year 2011-2012.Sample size using stratified random sampling proportionate to volume was estimated at 231 people. Data collection tool was a researcher made questionnaire designed ​​based on the five-point Likert scale.Its reliability coefficient using Cronbach’s alpha was calculated 0/80.And data analysis was performed by using SPSS statistical software. Findings of human resources architecture archetype at the University of Isfahan is less than average.
Democratization in India and Pakistan (1999-2012)
Authors: Musarrat Prof. Dr. Razia , Ibrahim Muhammad 
Published: July 2013

The democratic system is accepted and favored system in the contemporary world. It has the ability to consolidate the needs of the people’s participation and reasoning in the legislative process. Effects to implement democracy in states are known as democratization. India and Pakistan adopted the democratic system. Pakistan has undergone a progression of nation-building and struggle for development of institutions for stable democracy. Indian and Pakistani politicians as well as public have important role democratization. Free and fair elections are prerequisite for democratization. The state must rehearse the norm of equivalent citizenship irrespective of religion, caste, ethnicity and regional background. Many states of civilized world are unable to fulfill commitment merely rhetorical. Democratic mechanism is used to control over power of state organ to contraption non democratic agenda. The leaders are so fascinated in their power game that they are not agitated about the inquisitiveness and prosperity of the common people. Such a perception of low political effectiveness is replicated in the lessening voting proportion in the general elections.
A Possible New Class of Prehistoric Musical Instruments from New England: Portable Cylindrical Lithophones
Authors: Caldwell Duncan 
Published: July 2013

AbstractWith one exception, which has been described as a suspended “kiva bell,” long stone rods have been interpreted throughout the archaeological literature of North America as whetstones or pestles. Two particularly long rods in a collection of prehistoric artifacts from New England raise questions as to the real use of some of these objects. The prevailing interpretations of the two artifacts may be incorrect, or at least incomplete, because the rods lack the kinds of wear that are found on most whetstones or pestles. They also have different acoustical properties from true pestles, which are usually shorter, and are identical in materials, acoustics, and form to probable prehistoric lithophones from the Old World, which can be played on the lap. The identification of the pair of rods as good candidates for being the first known cylindrical, two-toned prehistoric lithophones from New England introduces a new avenue for the study of fossil sounds and rituals in both the region and continent because it is likely that similar artifacts will be examined for characteristic wear, tested acoustically, and recognized as the objects of prestige and ceremony that they may have been in their role as un-suspended musical instruments.
Screening of different species of Phoma for the synthesis of silver nanoparticles
Authors: Gade Aniket , Gaikwad Swapnil , Duran Nelson , Rai Mahendra 
Published: July 2013

AbstractWe have screened 18 Phoma spp. for the mycosynthesis of silver nanoparticles (AgNPs). Out of 18, 17 Phoma spp. demonstrated mycosynthesis of AgNPs, which were characterized by UV–vis spectrophotometry, Fourier transform infrared, X‐ray diffraction, transmission electron microscopy (TEM), scanning electron microscopy (SEM), nanoparticle tracking and analysis system, and zeta potential measurement. SEM and TEM analysis showed the mycosynthesis of polydispersed spherical AgNPs, with the exception by P. sorghina (MTCC‐2096), which revealed the fabrication of silver nanorods. The effect of pH, temperature, silver nitrate, fungal filtrate, and light intensity was studied to understand the mechanism of mycosynthesis of AgNPs by P. sorghina. The involvement of protein was found during the mycosynthesis but the process failed to follow the Michaelis–Menton kinetics of the enzyme‐catalyzed reaction. A three‐step hypothetical mechanism, that is, activation, nucleation, and reduction, for the mycosynthesis of silver nanorods is proposed. The present study will be useful for the stable and rapid mycosynthesis of AgNPs. The extracellular process involved in synthesis of AgNPs was found to be rapid, simple, easy, and ecofriendly.
Effects of cytochrome P450 inhibitors and inducers on the metabolism and pharmacokinetics of ospemifene
Authors: Lehtinen Terhi , Tolonen Ari , Turpeinen Miia , Uusitalo Jouko , Vuorinen Jouni , Lammintausta Risto , Pelkonen Olavi , Scheinin Mika 
Published: July 2013

ABSTRACTPurpose: The objectives were to determine the cytochrome P450 (CYP) enzymes involved in the metabolism of ospemifene and its main hydroxylated metabolites and to examine the effects of CYP inhibitors and inducers on ospemifene pharmacokinetics. Methods: In vitro metabolism studies were conducted using human liver microsomes; CYP‐selective inhibitors and CYP‐specific substrates were used to determine the roles of nine CYP isoforms in ospemifene metabolism. Two Phase 1 clinical trials were conducted in healthy postmenopausal women; crossover designs examined the effects of pretreatment with the CYP modulators rifampicin, ketoconazole, fluconazole and omeprazole on ospemifene pharmacokinetics. Results: Although several CYP inhibitors decreased the in vitro formation of ospemifene metabolites, none of them completely blocked metabolism. Roles for CYP3A4, CYP2C9, CYP2C19 and CYP2B6 in the metabolism of ospemifene and its two main metabolites, 4‐­hydroxyospemifene and 4′‐hydroxyospemifene, were confirmed. The in vivo experiments demonstrated that ospemifene serum concentrations were decreased by rifampicin pretreatment, increased by ketoconazole or fluconazole pretreatment, and minimally affected by omeprazole pretreatment. Conclusions: The clinical pharmacokinetic findings and in vitro data suggest that CYP3A4 is important for ospemifene metabolism, but other CYP isoforms and metabolic pathways also contribute. Strong CYP3A or CYP2C9 inducers (e.g. rifampicin) would be expected to decrease the exposure to ospemifene. Ospemifene should be used with caution when coadministered with the modest CYP3A inhibitor ketoconazole and should not be coadministered with the potent CYP3A/CYP2C9/CYP2C19 inhibitor fluconazole. The potent CYP2C19 inhibitor omeprazole is unlikely to cause clinically significant changes in ospemifene pharmacokinetics. Copyright © 2013 John Wiley & Sons, Ltd.
Size and CT density of iodine‐containing ethosomal vesicles obtained by membrane extrusion: Potential for use as CT contrast agents
Authors: Na Bomin , Choi Byoung Wook , Kim Bumsang 
Published: July 2013

AbstractComputed tomography (CT) is the primary non‐invasive imaging technique used for most patients with suspected liver disease. In order to improve liver‐specific imaging properties and prevent toxic effects in patients with compromised renal function, we investigated the encapsulation of iodine within ethosomal vesicles. As a first step in the development of novel contrast agents using ethosomes for CT imaging applications, iodine was entrapped within ethosomes and iodine‐containing ethosomes of the desired size were obtained by extrusion using a polycarbonate membrane with a defined pore size. Ethosomes containing iodine showed a relatively high CT density, which decreased when they were extruded, due to the rupture and re‐formation of the lipid bilayer of the ethosome. However, when a solution with a high iodine concentration was used as a dispersion media during the extrusion process, the decrease in CT density could be prevented. In addition, ethosomes containing iodine were taken up efficiently by macrophages, which are abundant in the liver, and these ethosomes exhibited no cellular toxicity. These results demonstrate that iodine could be entrapped within ethosomal vesicles, giving the ethosomes a relatively high CT density, and that the extrusion technique used in this study could conveniently and reproducibly produce ethosomal vesicles with a desired size. Therefore, ethosomes containing iodine, as prepared in this study, have potential as contrast agents with applications in CT imaging.