bluuebunny/crossref_metadata_2025_split huggingface dataset:
Skin Melanoma Development in ret Transgenic Mice Despite the Depletion of CD25+Foxp3+ Regulatory T Cells in Lymphoid Organs
Authors: Kimpfler Silvia , Sevko Alexandra , Ring Sabine , Falk Christine , Osen Wolfram , Frank Kathrin , Kato Masashi , Mahnke Karsten , Schadendorf Dirk , Umansky Viktor 
Published: October 2009

Abstract
CD4+CD25+Foxp3+ regulatory T cells (Treg) known to mediate self-tolerance were also shown to contribute to tumor progression. In mouse melanoma transplantation models, Treg depletion resulted in the stimulation of antitumor immune responses and tumor eradication. To study Treg in conditions close to the clinical situation, we used a ret transgenic mouse spontaneous melanoma model, which, in contrast to transplantation models, resembles human melanoma regarding clinical development. Significantly higher numbers of Treg were found in skin tumors and metastatic lymph nodes at early stages of melanoma progression compared with more advanced stages accompanied by the elevated CCR4 expression on Treg and higher production of its ligand CCL2 in tumor lesions. Numbers of tumor infiltrating Treg inversely correlated with Treg amounts in the bone marrow, suggesting their possible recruitment to melanoma lesions from this organ. The immunosuppressive function of Treg from transgenic tumor-bearing mice was similar to that from transgenic tumor-free mice or nontransgenic littermates. Although anti-CD25 mAb injections resulted in the efficient Treg depletion from lymphoid organs of transgenic mice, melanoma development was not significantly delayed. Furthermore, the treatment of mice with macroscopical tumors also failed to inhibit tumor progression, which correlated with the inability to deplete intratumoral Treg. We suggest that in the autochthonous melanoma genesis, other immunosuppressive cells could play an important role and replace immunosuppressive, tumor-promoting functions of Treg. Therefore, effective melanoma immunotherapy should include the inhibition of Treg migration into the tumor combined with neutralization of other immunosuppressive cells and factors in the tumor microenvironment.
Regulation of Airway MUC5AC Expression by IL-1β and IL-17A; the NF-κB Paradigm
Authors: Fujisawa Tomoyuki , Velichko Sharlene , Thai Philip , Hung Li-Yin , Huang Fei , Wu Reen 
Published: October 2009

Abstract
Mucin over-production is one of the hallmarks of chronic airway diseases such as chronic obstructive pulmonary disease, asthma, and cystic fibrosis. NF-κB activation in airway epithelial cells has been shown to play a positive inflammatory role in chronic airway diseases; however, the role of NF-κB in mucin gene expression is unresolved. In this study, we have shown that the proinflammatory cytokines, IL-1β and IL-17A, both of which utilize the NF-κB pathway, are potent inducers of mucin (MUC)5AC mRNA and protein synthesis by both well-differentiated primary normal human bronchial epithelial cells and the human bronchial epithelial cell line, HBE1. MUC5AC induction by these cytokines was both time- and dose-dependent and occurred at the level of promoter activation, as measured by a reporter gene assay. These effects were attenuated by the small molecule inhibitor NF-κB inhibitor III, as well as p65 small-interfering RNA, suggesting that the regulation of MUC5AC expression by these cytokines is via an NF-κB-based transcriptional mechanism. Further investigation of the promoter region identified a putative NF-κB binding site at position-3594/-3582 in the promoter of MUC5AC as critical for the regulation of MUC5AC expression by both IL-1β and IL-17A. Chromatin immunoprecipitation analysis confirmed enhanced binding of the NF-κB subunit p50 to this region following cytokine stimulation. We conclude that an NF-κB-based transcriptional mechanism is involved in MUC5AC regulation by IL-1β and IL-17A in the airway epithelium. This is the first demonstration of the participation of NF-κB and its specific binding site in cytokine-mediated airway MUC5AC expression.
Role of Gut Commensal Microflora in the Development of Experimental Autoimmune Encephalomyelitis
Authors: Ochoa-Repáraz Javier , Mielcarz Daniel W. , Ditrio Lauren E. , Burroughs Ashley R. , Foureau David M. , Haque-Begum Sakhina , Kasper Lloyd H. 
Published: October 2009

Abstract
Mucosal tolerance has been considered a potentially important pathway for the treatment of autoimmune disease, including human multiple sclerosis and experimental conditions such as experimental autoimmune encephalomyelitis (EAE). There is limited information on the capacity of commensal gut bacteria to induce and maintain peripheral immune tolerance. Inbred SJL and C57BL/6 mice were treated orally with a broad spectrum of antibiotics to reduce gut microflora. Reduction of gut commensal bacteria impaired the development of EAE. Intraperitoneal antibiotic-treated mice showed no significant decline in the gut microflora and developed EAE similar to untreated mice, suggesting that reduction in disease activity was related to alterations in the gut bacterial population. Protection was associated with a reduction of proinflammatory cytokines and increases in IL-10 and IL-13. Adoptive transfer of low numbers of IL-10-producing CD25+CD4+ T cells (&gt;75% FoxP3+) purified from cervical lymph nodes of commensal bacteria reduced mice and in vivo neutralization of CD25+ cells suggested the role of regulatory T cells maintaining peripheral immune homeostasis. Our data demonstrate that antibiotic modification of gut commensal bacteria can modulate peripheral immune tolerance that can protect against EAE. This approach may offer a new therapeutic paradigm in the treatment of multiple sclerosis and perhaps other autoimmune conditions.
CD69 Gene Is Differentially Regulated in T and B Cells by Evolutionarily Conserved Promoter-Distal Elements
Authors: Vazquez Berta N. , Laguna Teresa , Carabana Juan , Krangel Michael S. , Lauzurica Pilar 
Published: October 2009

Abstract
CD69 is a type II C-type lectin involved in lymphocyte migration and cytokine secretion. CD69 expression represents one of the earliest available indicators of leukocyte activation and its rapid induction occurs through transcriptional activation. In this study we examined the molecular mechanism underlying mouse CD69 gene transcription in vivo in T and B cells. Analysis of the 45-kb region upstream of the CD69 gene revealed evolutionary conservation at the promoter and at four noncoding sequences (CNS) that were called CNS1, CNS2, CNS3, and CNS4. These regions were found to be hypersensitive sites in DNase I digestion experiments, and chromatin immunoprecipitation assays showed specific epigenetic modifications. CNS2 and CNS4 displayed constitutive and inducible enhancer activity in transient transfection assays in T cells. Using a transgenic approach to test CNS function, we found that the CD69 promoter conferred developmentally regulated expression during positive selection of thymocytes but could not support regulated expression in mature lymphocytes. Inclusion of CNS1 and CNS2 caused suppression of CD69 expression, whereas further addition of CNS3 and CNS4 supported developmental-stage and lineage-specific regulation in T cells but not in B cells. We concluded CNS1–4 are important cis-regulatory elements that interact both positively and negatively with the CD69 promoter and that differentially contribute to CD69 expression in T and B cells.
T-Lineage Cells Require the Thymus but Not V(D)J Recombination to Produce IL-17A and Regulate Granulopoiesis In Vivo
Authors: Smith Emily , von Vietinghoff Sibylle , Stark Matthew A. , Zarbock Alexander , Sanders John M. , Duley Amanda , Rivera-Nieves Jesus , Bender Timothy P. , Ley Klaus 
Published: October 2009

Abstract
IL-17A and IL-17F regulate granulopoiesis and are produced by memory T cells. Rag1−/− recombinase-activating gene-deficient mice cannot produce mature T cells but maintain normal neutrophil counts. Athymic nude mice are neutropenic or have near-normal neutrophil counts, depending on the prevailing intestinal flora, and do not produce IL-17A. By contrast, thymi from Rag1−/− mice contain as much IL-17A as those from wild-type (WT) mice. IL-17A-producing cells are found in the double negative DN1 compartment of the Rag1−/− thymus and express intracellular CD3. These cells colonize the spleen and mesenteric lymph node and secrete IL-17A in vitro following stimulation with IL-23 at a level similar to that of WT splenocytes. Adoptively transferred Rag1−/− or WT thymocytes correct neutrophil counts in neutropenic nude mice. We conclude that the development of IL-17A-producing T-lineage cells requires an intact thymic epithelium, but not V(D)J recombination.
Mouse ChemR23 Is Expressed in Dendritic Cell Subsets and Macrophages, and Mediates an Anti-Inflammatory Activity of Chemerin in a Lung Disease Model
Authors: Luangsay Souphalone , Wittamer Valérie , Bondue Benjamin , De Henau Olivier , Rouger Laurie , Brait Maryse , Franssen Jean-Denis , de Nadai Patricia , Huaux François , Parmentier Marc 
Published: October 2009

Abstract
Chemerin is the ligand of the ChemR23 receptor and a chemoattractant factor for human immature dendritic cells (DCs), macrophages, and NK cells. In this study, we characterized the mouse chemerin/ChemR23 system in terms of pharmacology, structure-function, distribution, and in vivo biological properties. Mouse chemerin is synthesized as an inactive precursor (prochemerin) requiring, as in human, the precise processing of its C terminus for generating an agonist of ChemR23. Mouse ChemR23 is highly expressed in immature plasmacytoid DCs and at lower levels in myeloid DCs, macrophages, and NK cells. Mouse prochemerin is expressed in most epithelial cells acting as barriers for pathogens but not in leukocytes. Chemerin promotes calcium mobilization and chemotaxis on DCs and macrophages and these functional responses were abrogated in ChemR23 knockout mice. In a mouse model of acute lung inflammation induced by LPS, chemerin displayed potent anti-inflammatory properties, reducing neutrophil infiltration and inflammatory cytokine release in a ChemR23-dependent manner. ChemR23 knockout mice were unresponsive to chemerin and displayed an increased neutrophil infiltrate following LPS challenge. Altogether, the mouse chemerin/ChemR23 system is structurally and functionally conserved between human and mouse, and mouse can therefore be considered as a good model for studying the anti-inflammatory role of this system in the regulation of immune responses and inflammatory diseases.
c-Myb Is Required for Pro-B Cell Differentiation
Authors: Fahl Shawn P. , Crittenden Rowena B. , Allman David , Bender Timothy P. 
Published: October 2009

Abstract
The c-Myb transcription factor is required for normal adult hematopoiesis. However, the embryonic lethality of Myb-null mutations has been an impediment to identifying roles for c-Myb during lymphocyte development. We have used tissue-specific inactivation of the Myb locus in early progenitor cells to demonstrate that c-Myb is absolutely required for the differentiation of CD19+ B-lineage cells and B cell differentiation is profoundly blocked beyond the pre-pro-B cell stage in Mybf/f Mb1-cre mice. We demonstrate that c-Myb is required for the intrinsic survival of CD19+ pro-B cells as well as the proper expression of the α-chain of the IL-7 receptor (CD127) and Ebf1. However, survival of c-Myb-deficient CD19+ pro-B cells cannot be rescued by transduction with CD127-producing retrovirus, suggesting that c-Myb controls a survival pathway independent of CD127. Furthermore, c-Myb-deficient progenitor cells inefficiently generate CD19+ B-lineage cells during stromal cell culture but this process can be partially rescued with exogenous Ebf1. Thus, c-Myb does not appear to be required for commitment to B cell differentiation but is crucial for B cell differentiation to the CD19+ pro-B cell stage as well as survival of CD19+ pro-B cells. Surprisingly, forced c-Myb expression in lymphoid-primed multipotent progenitors favors differentiation toward the myeloid lineage, suggesting that proper c-Myb expression is crucial for B-lineage development.
Mcl-1-Mediated Impairment of the Intrinsic Apoptosis Pathway in Circulating Neutrophils from Critically Ill Patients Can Be Overcome by Fas Stimulation
Authors: Paunel-Görgülü Adnana , Zörnig Martin , Lögters Tim , Altrichter Jens , Rabenhorst Uta , Cinatl Jindrich , Windolf Joachim , Scholz Martin 
Published: October 2009

Abstract
The systemic inflammatory response syndrome and subsequent organ failure are mainly driven by activated neutrophils with prolonged life span, which is believed to be due to apoptosis resistance. However, detailed underlying mechanisms leading to neutrophil apoptosis resistance are largely unknown, and possible therapeutic options to overcome this resistance do not exist. Here we report that activated neutrophils from severely injured patients exhibit cell death resistance due to impaired activation of the intrinsic apoptosis pathway, as evidenced by limited staurosporine-induced mitochondrial membrane depolarization and decreased caspase-9 activity. Moreover, we found that these neutrophils express high levels of antiapoptotic Mcl-1 and low levels of proapoptotic Bax protein. Mcl-1 up-regulation was dependent on elevated concentrations of GM-CSF in patient serum. Accordingly, increased Mcl-1 protein stability and GM-CSF serum concentrations were shown to correlate with staurosporine-induced apoptosis resistance. However, cross-linking of neutrophil Fas by immobilized agonistic anti-Fas IgM resulted in caspase-dependent mitochondrial membrane depolarization and apoptosis induction. In conclusion, the observed impairment of the intrinsic pathway and the resulting apoptosis resistance may be overcome by immobilized agonistic anti-Fas IgM. Targeting of neutrophil Fas by immobilized agonistic effector molecules may represent a new therapeutic tool to limit neutrophil hyperactivation and its sequelae in patients with severe immune disorders.
Cyclooxygenase-1 Orchestrates Germinal Center Formation and Antibody Class-Switch via Regulation of IL-17
Authors: Blaho Victoria A. , Buczynski Matthew W. , Dennis Edward A. , Brown Charles R. 
Published: October 2009

Abstract
The cyclooxygenase (COX) enzymes are known modulators of innate immune cell function; however, their contributions to adaptive immunity are relatively unknown. We investigated the roles of COX-1 and COX-2 in the humoral immune response to infection with the Lyme disease pathogen Borrelia burgdorferi. We report that in vitro, murine B cells constitutively expressed COX-1 and up-regulated expression of both COX-1 and COX-2 as well as their products PGE2, PGF2α, and thromboxane B2 and their receptors following stimulation with B. burgdorferi or anti-CD40. In vitro inhibition of COX-1 and/or COX-2 in murine B cells resulted in decreased eicosanoid production and altered Ab production. Importantly, infection of mice lacking COX-1, but not COX-2, activity resulted in a defect in Ig class-switching and a lack of Borrelia-specific IgG production. This defect correlated with decreased germinal center formation and IL-6 and IL-17 production, and it could be partially recovered by restoration of IL-6, but fully recovered by IL-17. Furthermore, sera from COX-1 inhibitor-treated mice were dramatically less effective in killing B. burgdorferi, but borreliacidal activity was restored in COX-1 inhibitor-treated mice administered IL-17. We conclude that IL-17 plays a role in Ab production and Ig class-switching in response to infection and that COX-1 is a critical, previously unrecognized regulator of this response.
Thymic Regulation of Autoimmune Disease by Accelerated Differentiation of Foxp3+ Regulatory T Cells through IL-7 Signaling Pathway
Authors: Chen Xi , Fang Lei , Song Shengli , Guo Taylor B. , Liu Ailian , Zhang Jingwu Z. 
Published: October 2009

Abstract
The exact role of adult thymus in autoimmune disease state is poorly understood. We show here that thymus regulated experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, as evidenced by loss of spontaneous recovery in thymectomized EAE mice. There was progressive enrichment for CD4 single-positive Foxp3+ regulatory T cells in thymocytes during the course of EAE and they suppressed the disease when adoptively transferred. Thymus was shown to undergo an active process characterized by accelerated differentiation and proliferation of regulatory T (Treg) cells through a mechanism involving increased expression of IL-7 in stromal cells and dynamic expression of IL-7 receptor in thymic Treg cells. This process preceded EAE recovery and selectively affected Treg over non-Treg cells in the thymus, leading to increased output of thymic Treg cells and self-regulation of EAE. The study reveals a novel role of thymus in self-regulation of autoimmune condition.
Generation of B Cell Memory to the Bacterial Polysaccharide α-1,3 Dextran
Authors: Foote Jeremy B. , Kearney John F. 
Published: October 2009

Abstract
B1b B cells generate a novel form of memory and provide Ab mediated-protection to persisting bacterial pathogens. To understand how B1b B cells establish memory to polysaccharide Ags, we studied an oligoclonal B cell response to α-1,3 dextran (DEX) expressed on Enterobacter cloacae. B cells specific for DEX enrich in the marginal zone (MZ) and B1b B cell populations. After E. cloacae immunization, MZ B cells were responsible for the generation of initial peak DEX-specific Ab titers, whereas, DEX-specific B1b B cells expanded and played an important role in boosted production of DEX-specific Ab titers upon E. cloacae rechallenge. Cell transfer experiments demonstrate that B1b B cells possess the capacity for both robust proliferation and plasma cell differentiation, thus distinguishing themselves from MZ B cells, which uniformly commit to plasma cell differentiation. These results define B1b B cells as the principal reservoir for memory to bacterial-associated polysaccharide Ags.
Algebraic Properties of a Family of Generalized Laguerre Polynomials
Authors: Hajir Farshid 
Published: October 2009

Abstract.We study the algebraic properties of Generalized Laguerre Polynomials for negative integral values of the parameter. For integers r, n ≥ 0, we conjecture that is a ℚ-irreducible polynomial whose Galois group contains the alternating group on n letters. That this is so for r = n was conjectured in the 1950's by Grosswald and proven recently by Filaseta and Trifonov. It follows fromrecent work of Hajir andWong that the conjecture is true when r is large with respect to n ≥ 5. Here we verify it in three situations: (i) when n is large with respect to r, (ii) when r ≤ 8, and (iii) when n ≤ 4. The main tool is the theory of p-adic Newton Polygons.
A Construction of Rigid Analytic Cohomology Classes for Congruence Subgroups of SL3(ℤ)
Authors: Pollack David , Pollack Robert 
Published: October 2009

Abstract.We give a constructive proof, in the special case of GL3, of a theorem of Ash and Stevens which compares overconvergent cohomology to classical cohomology. Namely, we show that every ordinary classical Hecke-eigenclass can be lifted uniquely to a rigid analytic eigenclass. Our basic method builds on the ideas of M. Greenberg; we first form an arbitrary lift of the classical eigenclass to a distribution-valued cochain. Then, by appropriately iterating the Up-operator, we produce a cocycle whose image in cohomology is the desired eigenclass. The constructive nature of this proof makes it possible to perform computer computations to approximate these interesting overconvergent eigenclasses.
Prehomogeneity on Quasi-Split Classical Groups and Poles of Intertwining Operators
Authors: Yu Xiaoxiang 
Published: October 2009

Abstract.Suppose that P = MN is amaximal parabolic subgroup of a quasisplit, connected, reductive classical group G defined over a non-Archimedean field and A is the standard intertwining operator attached to a tempered representation of G induced from M . In this paper we determine all the cases in which Lie(N ) is prehomogeneous under Ad(m) when N is non-abelian, and give necessary and sufficient conditions for A to have a pole at 0.
Regular Homeomorphisms of Finite Order on Countable Spaces
Authors: Zelenyuk Yevhen 
Published: October 2009

Abstract.We present a structure theorem for a broad class of homeomorphisms of finite order on countable zero dimensional spaces. As applications we show the following.(a) Every countable nondiscrete topological group not containing an open Boolean subgroup can be partitioned into infinitely many dense subsets.(b) If G is a countably infinite Abelian group with finitely many elements of order 2 and βG is the Stone–Čech compactification of G as a discrete semigroup, then for every idempotent p ∈ βG\﹛0﹜, the subset ﹛p,−p﹜ ⊂ βG generates algebraically the free product of one-element semigroups ﹛p﹜ and ﹛−p﹜.
Comparison of decoupling methods for analyzing pressure fluctuations in gas‐fluidized beds
Authors: Zhang Yongmin , Bi Hsiaotao T. , Grace John R. , Lu Chunxi 
Published: October 2009

AbstractTwo methods of decoupling pressure fluctuations in fluidized beds by using the incoherent part (IOP) of absolute pressure (AP) and differential pressure (DP) fluctuations are evaluated in this study. Analysis is conducted first to demonstrate their similarities, differences, and drawbacks. Then, amplitudes, power spectral densities, mean frequencies, coherence functions, and filtering indices of the IOP of AP and DP fluctuations are calculated and compared based on experimental data from a two‐dimensional fluidized column of FCC particles. Derived bubble sizes are also compared with the sizes of bubbles viewed in the two‐dimensional bed. The results demonstrate the similarity of these two methods in filtering out global compression wave components from absolute pressure fluctuations, especially those generated from oscillations of fluidized particles and gas flow rate fluctuations. However, both methods are imperfect. Neither can filter out all the compression wave components and retain all the useful bubble‐related wave components. Their amplitudes can be used to characterize global bubble property and quality of gas–solids contacting in bed, but they do not give accurate measurement of bubble sizes. © 2009 American Institute of Chemical Engineers AIChE J, 2010