bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integration of Distinct Intracellular Signaling Pathways at Distal Regulatory Elements Directs T-bet Expression in Human CD4+ T Cells
Authors: Placek Katarzyna , Gasparian Sona , Coffre Maryaline , Maiella Sylvie , Sechet Emmanuel , Bianchi Elisabetta , Rogge Lars 
Published: November 2009

Abstract
T-bet is a key regulator controlling Th1 cell development. This factor is not expressed in naive CD4+ T cells, and the mechanisms controlling expression of T-bet are incompletely understood. In this study, we defined regulatory elements at the human T-bet locus and determined how signals originating at the TCR and at cytokine receptors are integrated to induce chromatin modifications and expression of this gene during human Th1 cell differentiation. We found that T cell activation induced two strong DNase I-hypersensitive sites (HS) and rapid histone acetylation at these elements in CD4+ T cells. Histone acetylation and T-bet expression were strongly inhibited by cyclosporine A, and we detected binding of NF-AT to a HS in vivo. IL-12 and IFN-γ signaling alone were not sufficient to induce T-bet expression in naive CD4+ T cells, but enhanced T-bet expression in TCR/CD28-stimulated cells. We detected a third HS 12 kb upstream of the mRNA start site only in developing Th1 cells, which was bound by IL-12-induced STAT4. Our data suggest that T-bet locus remodeling and gene expression are initiated by TCR-induced NF-AT recruitment and amplified by IL-12-mediated STAT4 binding to distinct distal regulatory elements during human Th1 cell differentiation.
Autoimmune Regulator Deficiency Results in Decreased Expression of CCR4 and CCR7 Ligands and in Delayed Migration of CD4+ Thymocytes
Authors: Laan Martti , Kisand Kai , Kont Vivian , Möll Kaidi , Tserel Liina , Scott Hamish S. , Peterson Pärt 
Published: November 2009

AbstractAutoimmune regulator (Aire) has been viewed as a central player in the induction of tolerance. This study examines whether Aire can modulate the production of the thymic chemokines involved in corticomedullary migration and thus play a role in intrathymic thymocyte migration and maturation. Aire deficiency resulted in reduced gene expression and protein levels of the CCR4 and CCR7 ligands in whole thymi of mice, as determined by quantitative PCR analysis and ELISA. The expression of the CCR4 ligands coincided with Aire expression in the CD80high medullary thymic epithelial cells, whereas the expression of the CCR7 ligands was detected in other cell populations. Also, the expression pattern of the CCR4 and CCR7 ligands follows that of Aire during postnatal but not during embryonic development. In vitro, overexpression of Aire resulted in an up-regulation of selected CCR4 and CCR7 ligands, which induced selective migration of double-positive and single-positive CD4+ cells. In vivo, Aire deficiency resulted in a diminished emigration of mature CD4+ T cells from the thymi of 5-day-old mice. In conclusion, Aire regulates the production of CCR4 and CCR7 ligands in medullary thymic epithelial cells and alters the coordinated maturation and migration of thymocytes. These results suggest a novel mechanism behind the Aire-dependent induction of central tolerance.
Cutting Edge: Depletion of Foxp3+ Cells Leads to Induction of Autoimmunity by Specific Ablation of Regulatory T Cells in Genetically Targeted Mice
Authors: Kim Jeong , Lahl Katharina , Hori Shohei , Loddenkemper Christoph , Chaudhry Ashutosh , deRoos Paul , Rudensky Alexander , Sparwasser Tim 
Published: November 2009

AbstractWe have recently described two independent mouse models in which the administration of diphtheria toxin (DT) leads to specific depletion of regulatory T cells (Tregs) due to expression of DT receptor-enhanced GFP under the control of the Foxp3 promoter. Both mouse models develop severe autoimmune disorders when Foxp3+ Tregs are depleted. Those findings were challenged in a recent study published in this journal suggesting the expression of Foxp3 in epithelial cells as the cause for disease development. By using genetic, cellular, and immunohistochemical approaches, we do not find evidence for Foxp3-expression in nonhematopoietic cells. DT injection does not lead to a loss of epithelial integrity in our Foxp3-DTR models. Instead, Foxp3 expression is Treg-specific and ablation of Foxp3+ Tregs leads to the induction of fatal autoimmune disorders. Autoimmunity can be reversed by the adoptive transfer of Tregs into depleted hosts, and the transfer of Foxp3-deficient bone marrow into T cell-deficient irradiated recipients leads to full-blown disease development.
Soluble B and T Lymphocyte Attenuator Possesses Antitumor Effects and Facilitates Heat Shock Protein 70 Vaccine-Triggered Antitumor Immunity against a Murine TC-1 Cervical Cancer Model In Vivo
Authors: Han Lingfei , Wang Wei , Fang Yong , Feng Zuohua , Liao Shujie , Li Wei , Li Yan , Li Chunxiao , Maitituoheti Mayinuer , Dong Hong , Lai Zhiwen , Gao Qinglei , Xi Ling , Wu Mingfu , Wang Daowen , Zhou Jianfeng , Meng Li , Wang Shixuan , Ma Ding 
Published: November 2009

Abstract
B and T lymphocyte attenuator (BTLA)-herpesvirus entry mediator (HVEM) signaling coinhibitory pathway is believed to impair antitumor immune competences. An intriguing unresolved question is whether blockade of BTLA-HVEM guides an effective therapeutic tool against established tumors. To address this issue, we constructed a eukaryotic expression plasmid (psBTLA) that expressed the extracellular domain of murine BTLA (soluble form of BTLA), which could bind HVEM, the ligand of BTLA, and block BTLA-HVEM interactions. The data in this study showed that treatment by injection of psBTLA resulted in down-regulation of IL-10 and TGF-β and promotion of dendritic cell function by increasing the expression of B7-1 and IL-12, but the adaptive antitumor immune responses achieved by psBTLA administration alone were limited and could not eradicate the tumor effectively. Next, we evaluated the immunotherapeutic efficacy and mechanism of combination therapy of heat shock protein 70 (HSP70) vaccine/psBTLA by using murine TC-1 cervical cancer mice as an ectopic tumor model. Our in vivo studies revealed that treatment with HSP70 vaccine alone did not lead to satisfactory tumor growth inhibition, whereas cotreatment with psBTLA significantly improved antitumor immunity and compensated the deficiency of HSP70 vaccine by increasing the expression of Th1 cytokines, IL-2, and IFN-γ and decreasing transcription levels of IL-10, TGF-β, and Foxp3 in the tumor microenvironment. Taken together, our findings indicate that blocking the BTLA-HVEM interaction with sBTLA enhances antitumor efficacy and results in a significant synergistic effect against existent tumor cells in vivo when combined with the HSP70 vaccine.
CD69 Controls the Pathogenesis of Allergic Airway Inflammation
Authors: Miki-Hosokawa Takako , Hasegawa Akihiro , Iwamura Chiaki , Shinoda Kenta , Tofukuji Soichi , Watanabe Yukiko , Hosokawa Hiroyuki , Motohashi Shinichiro , Hashimoto Kahoko , Shirai Mutsunori , Yamashita Masakatsu , Nakayama Toshinori 
Published: November 2009

AbstractAirway inflammation and airway hyperresponsiveness are central issues in the pathogenesis of asthma. CD69 is a membrane molecule transiently expressed on activated lymphocytes, and its selective expression in inflammatory infiltrates suggests that it plays a role in the pathogenesis of inflammatory diseases. In CD69-deficient mice, OVA-induced eosinophilic airway inflammation, mucus hyperproduction, and airway hyperresponsiveness were attenuated. Cell transfer of Ag-primed wild-type but not CD69-deficient CD4 T cells restored the induction of allergic inflammation in CD69-deficient mice, indicating a critical role of CD69 expressed on CD4 T cells. Th2 responses induced by CD69-deficient CD4 T cells in the lung were attenuated, and the migration of CD4 T cells into the asthmatic lung was severely compromised. The expression of VCAM-1 was also substantially altered, suggesting the involvement of VCAM-1 in the CD69-dependent migration of Th2 cells into the asthmatic lung. Interestingly, the administration of anti-CD69 Ab inhibited the induction of the OVA-induced airway inflammation and hyperresponsiveness. This inhibitory effect induced by the CD69 mAb was observed even after the airway challenge with OVA. These results indicate that CD69 plays a crucial role in the pathogenesis of allergen-induced eosinophilic airway inflammation and hyperresponsiveness and that CD69 could be a possible therapeutic target for asthmatic patients.
IL-7 Enhances Thymic Human T Cell Development in “Human Immune System” Rag2−/−IL-2Rγc−/− Mice without Affecting Peripheral T Cell Homeostasis
Authors: van Lent Anja U. , Dontje Wendy , Nagasawa Maho , Siamari Rachida , Bakker Arjen Q. , Pouw Stephan M. , Maijoor Kelly A. , Weijer Kees , Cornelissen Jan J. , Blom Bianca , Di Santo James P. , Spits Hergen , Legrand Nicolas 
Published: November 2009

AbstractIL-7 is a central cytokine in the development of hematopoietic cells, although interspecies discrepancies have been reported. By coculturing human postnatal thymus hematopoietic progenitors and OP9-huDL1 stromal cells, we found that murine IL-7 is ∼100-fold less potent than human IL-7 for supporting human T cell development in vitro. We investigated the role of human IL-7 in newborn BALB/c Rag2−/−γc−/− mice transplanted with human hematopoietic stem cells (HSC) as an in vivo model of human hematopoiesis using three approaches to improve IL-7 signaling: administration of human IL-7, ectopic expression of human IL-7 by the transplanted human HSC, or enforced expression of a murine/human chimeric IL-7 receptor binding murine IL-7. We show that premature IL-7 signaling at the HSC stage, before entrance in the thymus, impeded T cell development, whereas increased intrathymic IL-7 signaling significantly enhanced the maintenance of immature thymocytes. Increased thymopoiesis was also observed when we transplanted BCL-2- or BCL-xL-transduced human HSC. Homeostasis of peripheral mature T cells in this humanized mouse model was not improved by any of these strategies. Overall, our results provide evidence for an important role of IL-7 in human T cell development in vivo and highlight the notion that IL-7 availability is but one of many signals that condition peripheral T cell homeostasis.
An Innate Response to Allogeneic Nonself Mediated by Monocytes
Authors: Zecher Daniel , van Rooijen Nico , Rothstein David M. , Shlomchik Warren D. , Lakkis Fadi G. 
Published: November 2009

AbstractThe mammalian innate immune system has evolved diverse strategies to distinguish self from microbial nonself. How the innate immune system distinguishes self-tissues from those of other members of the same species (allogeneic nonself) is less clear. To address this question, we studied the cutaneous hypersensitivity response of lymphocyte-deficient RAG−/− mice to spleen cells transplanted from either allogeneic or syngeneic RAG−/− donors. We found that RAG−/− mice mount a specific response to allogeneic cells characterized by swelling and infiltration of the skin with host monocytes/macrophages and neutrophils. The response required prior priming with allogeneic splenocytes or skin grafts and exhibited features of memory as it could be elicited at least 4 wk after immunization. Neither depletion of host NK cells nor rechallenging immunized mice with F1 hybrid splenocytes inhibited the response, indicating that the response is not mediated by NK cells. Depletion of host monocytes/macrophages or neutrophils at the time of rechallenge significantly diminished the response and, importantly, the adoptive transfer of monocytes from alloimmunized RAG−/− mice conferred alloimmunity to naive RAG−/− hosts. Unlike NK- and T cell-dependent alloresponses, monocyte-mediated alloimmunity could be elicited only when donor and responder mice differed at non-MHC loci. These observations indicate that monocytes mount a response to allogeneic nonself, a function not previously attributed to them, and suggest the existence of mammalian innate allorecognition strategies distinct from detection of missing self-MHC molecules by NK cells.
Mesenchymal Stem Cells Derived from Human Gingiva Are Capable of Immunomodulatory Functions and Ameliorate Inflammation-Related Tissue Destruction in Experimental Colitis
Authors: Zhang Qunzhou , Shi Shihong , Liu Yi , Uyanne Jettie , Shi Yufang , Shi Songtao , Le Anh D. 
Published: November 2009

Abstract
Aside from the well-established self-renewal and multipotent differentiation properties, mesenchymal stem cells exhibit both immunomodulatory and anti-inflammatory roles in several experimental autoimmune and inflammatory diseases. In this study, we isolated a new population of stem cells from human gingiva, a tissue source easily accessible from the oral cavity, namely, gingiva-derived mesenchymal stem cells (GMSCs), which exhibited clonogenicity, self-renewal, and multipotent differentiation capacities. Most importantly, GMSCs were capable of immunomodulatory functions, specifically suppressed peripheral blood lymphocyte proliferation, induced expression of a wide panel of immunosuppressive factors including IL-10, IDO, inducible NO synthase (iNOS), and cyclooxygenase 2 (COX-2) in response to the inflammatory cytokine, IFN-γ. Cell-based therapy using systemic infusion of GMSCs in experimental colitis significantly ameliorated both clinical and histopathological severity of the colonic inflammation, restored the injured gastrointestinal mucosal tissues, reversed diarrhea and weight loss, and suppressed the overall disease activity in mice. The therapeutic effect of GMSCs was mediated, in part, by the suppression of inflammatory infiltrates and inflammatory cytokines/mediators and the increased infiltration of regulatory T cells and the expression of anti-inflammatory cytokine IL-10 at the colonic sites. Taken together, GMSCs can function as an immunomodulatory and anti-inflammatory component of the immune system in vivo and is a promising cell source for cell-based treatment in experimental inflammatory diseases.
New Design of MHC Class II Tetramers to Accommodate Fundamental Principles of Antigen Presentation
Authors: Landais Elise , Romagnoli Pablo A. , Corper Adam L. , Shires John , Altman John D. , Wilson Ian A. , Garcia K. Christopher , Teyton Luc 
Published: November 2009

AbstractDirect identification and isolation of Ag-specific T cells became possible with the development of MHC tetramers, based on fluorescent avidins displaying biotinylated peptide-MHC complexes. This approach, extensively used for MHC class I-restricted T cells, has met very limited success with class II peptide-MHC complex tetramers (pMHCT-2) for the detection of CD4+-specific T cells. In addition, a very large number of these reagents, although capable of specifically activating T cells after being coated on solid support, is still unable to stain. To try to understand this puzzle and design usable tetramers, we examined each parameter critical for the production of pMHCT-2 using the I-Ad-OVA system as a model. Through this process, the geometry of peptide-MHC display by avidin tetramers was examined, as well as the stability of rMHC molecules. However, we discovered that the most important factor limiting the reactivity of pMHCT-2 was the display of peptides. Indeed, long peptides, as presented by MHC class II molecules, can be bound to I-A/HLA-DQ molecules in more than one register, as suggested by structural studies. This mode of anchorless peptide binding allows the selection of a broader repertoire on single peptides and should favor anti-infectious immune responses. Thus, beyond the technical improvements that we propose, the redesign of pMHCT-2 will give us the tools to evaluate the real size of the CD4 T cell repertoire and help us in the production and testing of new vaccines.
Monoidal Functors, Acyclic Models and Chain Operads
Authors: Guillén Santos F. , Navarro V. , Pascual P. , Roig Agustí 
Published: November 2009

AbstractWe prove that for a topological operad P the operad of oriented cubical singular chains, , and the operad of simplicial singular chains, S*(P), are weakly equivalent. As a consequence, is formal if and only if is formal, thus linking together some formality results which are spread out in the literature. The proof is based on an acyclic models theorem for monoidal functors. We give different variants of the acyclic models theorem and apply the contravariant case to study the cohomology theories for simplicial sets defined by R-simplicial differential graded algebras.
Quelques calculs de traces compactes et leurs transformées de Satake
Authors: Nguyen-Chu G.-V. 
Published: November 2009

RésuméOn calcule les restrictions à l’algèbre de Hecke sphérique des traces tordues compactes d’un ensemble de représentations explicitement construites du groupe GL(N, F), où F est un corps p-adique. Ces calculs résolve en particulier une question posée dans un article précédent du mˆeme auteur.
Local Bounds for Torsion Points on Abelian Varieties
Authors: Clark Pete L. , Xarles Xavier 
Published: November 2009

AbstractWe say that an abelian variety over ap-adic fieldKhas anisotropic reduction (AR) if the special fiber of its Néronminimal model does not contain a nontrivial split torus. This includes all abelian varieties with potentially good reduction and, in particular, those with complex or quaternionic multiplication. We give a bound for the size of theK-rational torsion subgroup of ag-dimensional AR variety depending only ongand the numerical invariants ofK(the absolute ramification index and the cardinality of the residue field). Applying these bounds to abelian varieties over a number field with everywhere locally anisotropic reduction, we get bounds which, as a function ofg, are close to optimal. In particular, we determine the possible cardinalities of the torsion subgroup of an AR abelian surface over the rational numbers, up to a set of 11 values which are not known to occur. The largest such value is 72.
Endomorphisms of Kronecker Modules Regulated by Quadratic Algebra Extensions of a Function Field
Authors: Okoh F. , Zorzitto F. 
Published: November 2009

AbstractThe Kronecker modules , where m is a positive integer, h is a height function, and α is a K-linear functional on the space K(X) of rational functions in one variable X over an algebraically closed field K, aremodels for the family of all torsion-free rank-2 modules that are extensions of finite-dimensional rank-1 modules. Every such module comes with a regulating polynomial f in K(X)[Y]. When the endomorphism algebra of is commutative and non-trivial, the regulator f must be quadratic in Y. If f has one repeated root in K(X), the endomorphismalgebra is the trivial extension for some vector space S. If f has distinct roots in K(X), then the endomorphisms forma structure that we call a bridge. These include the coordinate rings of some curves. Regardless of the number of roots in the regulator, those End that are domains have zero radical. In addition, each semi-local End must be either a trivial extension or the product K × K.
Isometric Group Actions on Hilbert Spaces: Structure of Orbits
Authors: de Cornulier Yves , Tessera Romain , Valette Alain 
Published: November 2009

AbstractOur main result is that a finitely generated nilpotent group has no isometric action on an infinite-dimensional Hilbert space with dense orbits. In contrast, we construct such an action with a finitely generated metabelian group.
Adjacency Preserving Maps on Hermitian Matrices
Authors: Huang Wen-ling , Šemrl Peter 
Published: November 2009

AbstractHua’s fundamental theorem of the geometry of hermitian matrices characterizes bijective maps on the space of all n×n hermitianmatrices preserving adjacency in both directions. The problem of possible improvements has been open for a while. There are three natural problems here. Do we need the bijectivity assumption? Can we replace the assumption of preserving adjacency in both directions by the weaker assumption of preserving adjacency in one direction only? Can we obtain such a characterization formaps acting between the spaces of hermitian matrices of different sizes? We answer all three questions for the complex hermitian matrices, thus obtaining the optimal structural result for adjacency preserving maps on hermitian matrices over the complex field.
Hölder Compactification for Some Manifolds with Pinched Negative Curvature Near Infinity
Authors: Bahuaud Eric , Marsh Tracey 
Published: November 2009

AbstractWe consider a complete noncompact Riemannian manifold M and give conditions on a compact submanifold K ⊂ M so that the outward normal exponential map off the boundary of K is a diffeomorphism onto M\K. We use this to compactify M and show that pinched negative sectional curvature outside K implies M has a compactification with a well-defined Hölder structure independent of K. The Hölder constant depends on the ratio of the curvature pinching. This extends and generalizes a 1985 result of Anderson and Schoen.
CR Extension from Manifolds of Higher Type
Authors: Baracco Luca , Zampieri Giuseppe 
Published: November 2009

AbstractThis paper deals with the extension of CR functions fromamanifold M ⊂ ℂn into directions produced by higher order commutators of holomorphic and antiholomorphic vector fields. It uses the theory of complex “sectors” attached to real submanifolds introduced in recent joint work of the authors with D. Zaitsev. In addition, it develops a new technique of approximation of sectors by smooth discs.
Theta Lifts of Tempered Representations for Dual Pairs (Sp2n,O(V))
Authors: Muić Goran 
Published: November 2009

AbstractThis paper is the continuation of our previous work on the explicit determination of the structure of theta lifts for dual pairs (Sp2n,O(V)) over a non-archimedean field F of characteristic different than 2, where n is the split rank of Sp2n and the dimension of the space V (over F) is even. We determine the structure of theta lifts of tempered representations in terms of theta lifts of representations in discrete series.
High throughput synthesis and screening of new protein resistant surfaces for membrane filtration
Authors: Zhou Mingyan , Liu Hongwei , Kilduff James E. , Langer Robert , Anderson Daniel G. , Belfort Georges 
Published: November 2009

AbstractA novel high throughput method for synthesis and screening of customized protein‐resistant surfaces was developed. This method is an inexpensive, fast, reproducible and scalable approach to synthesize and screen protein‐resistance surfaces appropriate for a specific feed. The method is illustrated here by combining a high throughput platform (HTP) approach together with our patented photo‐induced graft polymerization (PGP) method developed for facile modification of commercial poly(aryl sulfone) membranes. This new HTP‐PGP method was validated by comparison with our previous published results obtained using a bench‐scale filtration assay of six well‐studied monomers. Optimally‐performing surfaces for resisting a model protein, bovine serum albumin (BSA), were identified from a library of 66 monomers. Surfaces were prepared via graft polymerization onto poly(ether sulfone) (PES) membranes and were evaluated using a protein adsorption assay followed by pressure‐driven filtration. Bench‐scale verification was conducted for selected monomers using HTP‐PGP method; a good correlation with HTP‐PGP results was found. © 2009 American Institute of Chemical Engineers AIChE J, 2010