bluuebunny/crossref_metadata_2025_split huggingface dataset:
Runx1/Cbfβ2 Complexes Are Required for Lymphoid Tissue Inducer Cell Differentiation at Two Developmental Stages
Authors: Tachibana Masashi , Tenno Mari , Tezuka Chieko , Sugiyama Machiko , Yoshida Hisahiro , Taniuchi Ichiro 
Published: December 2010

Abstract
Hematopoietic lymphoid tissue inducer (LTi) cells are essential for the development of secondary lymphoid tissues including lymph nodes and Peyer’s patches. Two transcription factors, the helix-loop-helix inhibitor Id2 and the retinoic acid-related orphan receptor γt (Rorγt), have been shown to be crucial for LTi cell development. However, it remains unclear how the specification of multipotent hematopoietic progenitor cells toward the LTi lineage is programmed. In this study, we report impaired lymphoid tissue organogenesis in mice in which the function of Runx1/Cbfβ transcription factor complexes was attenuated by the loss of either the distal promoter-derived Runx1 or Cbfβ2 variant protein. We found that LTi progenitors in fetal liver, defined previously as a lineage marker-negative α4β7 integrin (α4β7)+ IL-7R α-chain (IL-7Rα)+ population, can be subdivided into Rorγt-expressing IL-7Rαhigh cells and nonexpressing IL-7Rαmid cells. Whereas Id2 and Rorγt are required to direct α4β7+IL-7Rαmid cells to become α4β7+IL-7Rαhigh cells, Runx1/Cbfβ2 complexes are necessary for the emergence of α4β7+IL-7Rαmid cells. In addition, the loss of Cbfβ2, but not P1-Runx1, resulted in an inefficient upregulation of Rorγt in residual α4β7+IL-7Rα+ LTi cells at anlagen. Our results thus revealed that Runx1/Cbfβ2 complexes regulate the differentiation of LTi cells at two stages: an early specification of hematopoietic progenitors toward the LTi lineage and a subsequent activation of Rorγt expression at anlagen.
CCL20 and β-Defensin-2 Induce Arrest of Human Th17 Cells on Inflamed Endothelium In Vitro under Flow Conditions
Authors: Ghannam Soufiane , Dejou Cécile , Pedretti Nathalie , Giot Jean-Philipe , Dorgham Karim , Boukhaddaoui Hassan , Deleuze Virginie , Bernard François-Xavier , Jorgensen Christian , Yssel Hans , Pène Jérôme 
Published: December 2010

AbstractCCR6 is a chemokine receptor that is expressed at the cell surface of Th17 cells, an IL-17– and IL-22–secreting population of CD4+ T cells with antipathogenic, as well as inflammatory, properties. In the current study, we have determined the involvement of CCR6 in human Th17 lymphocyte migration toward inflamed tissue by analyzing the capacity of its ligands to induce arrest of these cells onto inflamed endothelium in vitro under flow conditions. We show that polarized, in situ-differentiated, skin-derived Th17 clones activated via the TCR–CD3 complex produce CCL20 in addition to IL-17 and IL-22. The latter cytokines induce, in a synergic fashion, the production of human β-defensin (hBD)-2, but neither hBD-1 nor hBD-3, by epidermal keratinocytes. Both CCL20 and hBD-2 are capable of inducing the arrest of Th17 cells, but not Th1 or Th2 cells, on HUVEC in an CD54-dependent manner that is CCR6 specific and independent from the expression of CXCR4, reported to be an alternative receptor for hBD-2. In addition, Ag-specific activation induces a transient loss of CCR6 expression, both at the transcriptional and protein level, which occurs with slow kinetics and is not due to endogenous CCL20-mediated internalization of CCR6. Together, these results indicate that Ag-specific activation will initially contribute to CCR6-mediated Th17 cell trafficking toward and sequestration in inflamed tissue, but that it eventually results in a transitory state of nonresponsiveness to further stimulation of these cells with CCR6 ligands, thus permitting their subsequent migration out of the inflamed site.
A Novel Role for IFN-Stimulated Gene Factor 3II in IFN-γ Signaling and Induction of Antiviral Activity in Human Cells
Authors: Morrow Angel N. , Schmeisser Hana , Tsuno Takaya , Zoon Kathryn C. 
Published: December 2010

Abstract
Type I (e.g., IFN-α, IFN-β) and type II IFNs (IFN-γ) have antiviral, antiproliferative, and immunomodulatory properties. Both types of IFN signal through the Jak/STAT pathway to elicit antiviral activity, yet IFN-γ is thought to do so only through STAT1 homodimers, whereas type I IFNs activate both STAT1- and STAT2-containing complexes such as IFN-stimulated gene factor 3. In this study, we show that IFN-stimulated gene factor 3 containing unphosphorylated STAT2 (ISGF3II) also plays a role in IFN-γ–mediated antiviral activity in humans. Using phosphorylated STAT1 as a marker for IFN signaling, Western blot analysis of IFN-α2a–treated human A549 cells revealed that phospho-STAT1 (Y701) levels peaked at 1 h, decreased by 6 h, and remained at low levels for up to 48 h. Cells treated with IFN-γ showed a biphasic phospho-STAT1 response with an early peak at 1–2 h and a second peak at 15–24 h. Gene expression microarray following IFN-γ treatment for 24 h indicated an induction of antiviral genes that are induced by IFN-stimulated gene factor 3 and associated with a type I IFN response. Induction of these genes by autocrine type I and type III IFN signaling was ruled out using neutralizing Abs to these IFNs in biological assays and by quantitative RT-PCR. Despite the absence of autocrine IFNs, IFN-γ treatment induced formation of ISGF3II. This novel transcription factor complex binds to IFN-stimulated response element promoter sequences, as shown by chromatin immunoprecipitation analysis of the protein kinase R promoter. STAT2 and IFN regulatory factor 9 knockdown in A549 cells reversed IFN-γ–mediated IFN-stimulated response element induction and antiviral activity, implicating ISGF3II formation as a significant component of the cellular response and biological activity of IFN-γ.
TLR 2 and CD14 Mediate Innate Immunity and Lung Inflammation to Staphylococcal Panton–Valentine Leukocidin In Vivo
Authors: Zivkovic Ana , Sharif Omar , Stich Karin , Doninger Bianca , Biaggio Mario , Colinge Jacques , Bilban Martin , Mesteri Ildiko , Hazemi Parastoo , Lemmens-Gruber Rosa , Knapp Sylvia 
Published: December 2010

Abstract
The pore-forming toxin Panton–Valentine leukocidin (PVL) is carried by community-acquired methicillin-resistant Staphylococcus aureus and associated with necrotizing pneumonia together with poor prognosis of infected patients. Although the cell-death–inducing properties of PVL have previously been examined, the pulmonary immune response to PVL is largely unknown. Using an unbiased transcriptional profiling approach, we show that PVL induces only 29 genes in mouse alveolar macrophages, which are associated with TLR signaling. Further studies indicate that PVL directly binds to TLR2 and induces immune responses via NF-κB in a TLR2, CD14, MyD88, IL-1R–associated kinase 1, and TNFR-associated factor 6-dependent manner. PVL-mediated inflammation is independent of pore formation but strongly depends on the LukS subunit and is suppressed in CD14/TLR2−/− cells. In vivo PVL or LukS induced a robust inflammatory response in lungs, which was diminished in CD14/TLR2−/− mice. These results highlight the proinflammatory properties of PVL and identify CD14/TLR2 as an essential receptor complex for PVL-induced lung inflammation.
Persistence of Gut Mucosal Innate Immune Defenses by Enteric α-Defensin Expression in the Simian Immunodeficiency Virus Model of AIDS
Authors: Zaragoza Melinda M. , Sankaran-Walters Sumathi , Canfield Don R. , Hung Jason K. S. , Martinez Enrique , Ouellette André J. , Dandekar Satya 
Published: December 2010

Abstract
Gastrointestinal mucosa is an early target of HIV and a site of viral replication and severe CD4+ T cell depletion. However, effects of HIV infection on gut mucosal innate immune defense have not been fully investigated. Intestinal Paneth cell-derived α-defensins constitute an integral part of the gut mucosal innate defense against microbial pathogens. Using the SIV-infected rhesus macaque model of AIDS, we examined the level of expression of rhesus enteric α-defensins (REDs) in the jejunal mucosa of rhesus macaques during all stages of SIV infection using real-time PCR, in situ hybridization, and immunohistochemistry. An increased expression of RED mRNAs was found in PC at the base of the crypts in jejunum at all stages of SIV infection as compared with uninfected controls. This increase correlated with active viral replication in gut-associated lymphoid tissue. Loss of RED protein accumulation in PC was seen in animals with simian AIDS. This was associated with the loss of secretory granules in PC, suggesting an increase in degranulation during advanced SIV disease. The α-defensin–mediated innate mucosal immunity was maintained in PC throughout the course of SIV infection despite the mucosal CD4+ T cell depletion. The loss of RED protein accumulation and secretion was associated with an increased incidence of opportunistic enteric infections and disease progression. Our findings suggest that local innate immune defense exerted by PC-derived defensins contributes to the protection of gut mucosa from opportunistic infections during the course of SIV infection.
Influenza A Inhibits Th17-Mediated Host Defense against Bacterial Pneumonia in Mice
Authors: Kudva Anupa , Scheller Erich V. , Robinson Keven M. , Crowe Chris R. , Choi Sun Mi , Slight Samantha R. , Khader Shabaana A. , Dubin Patricia J. , Enelow Richard I. , Kolls Jay K. , Alcorn John F. 
Published: December 2010

Abstract
Staphylococcus aureus is a significant cause of hospital and community acquired pneumonia and causes secondary infection after influenza A. Recently, patients with hyper-IgE syndrome, who often present with S. aureus infections of the lung and skin, were found to have mutations in STAT3, required for Th17 immunity, suggesting a potential critical role for Th17 cells in S. aureus pneumonia. Indeed, IL-17R−/− and IL-22−/− mice displayed impaired bacterial clearance of S. aureus compared with that of wild-type mice. Mice challenged with influenza A PR/8/34 H1N1 and subsequently with S. aureus had increased inflammation and decreased clearance of both virus and bacteria. Coinfection resulted in greater type I and II IFN production in the lung compared with that with virus infection alone. Importantly, influenza A coinfection resulted in substantially decreased IL-17, IL-22, and IL-23 production after S. aureus infection. The decrease in S. aureus-induced IL-17, IL-22, and IL-23 was independent of type II IFN but required type I IFN production in influenza A-infected mice. Furthermore, overexpression of IL-23 in influenza A, S. aureus-coinfected mice rescued the induction of IL-17 and IL-22 and markedly improved bacterial clearance. These data indicate a novel mechanism by which influenza A-induced type I IFNs inhibit Th17 immunity and increase susceptibility to secondary bacterial pneumonia.
Mechanistic Role of MicroRNA-146a in Endotoxin-Induced Differential Cross-Regulation of TLR Signaling
Authors: Nahid Md A. , Satoh Minoru , Chan Edward K. L. 
Published: December 2010

Abstract
Human TLRs are critical sensors for microbial components leading to the production of proinflammatory cytokines that are controlled by various mechanisms. Monocytes pretreated with LPS exhibit a state of hyporesponsiveness, referred to as cross-tolerance, to both homologous and heterologous ligands, which play a broader role in innate immunity. To date, LPS-induced cross-tolerance has not been examined regarding microRNA expression kinetics. In this study, THP-1 monocytes treated with various inflammatory ligands showed a continuous amplification of microRNA (miR)-146a over 24 h that is inversely correlated to TNF-α production. In contrast, inhibition of miR-146a showed a reciprocal effect. Thus, the characteristic upregulation of miR-146a in LPS-exposed THP-1 monocytes was studied for cross-tolerance. Strikingly, in LPS-tolerized THP-1 monocytes, only miR-146a showed a continuous overexpression, suggesting its crucial role in cross-tolerance. Similarly, peptidoglycan-primed THP-1 cells showed homologous tolerance associated with miR-146a upregulation. Subsequently, interchangeable differential cross-regulation was observed among non-LPS ligands. TLR2 and TLR5 ligands showed both homologous and heterologous tolerance correlated to miR-146a overexpression. More importantly, inflammatory responses to TLR4, TLR2, and TLR5 ligands were reduced due to knockdown of miR-146a targets IL-1R-associated kinase 1 or TNFR-associated factor 6, suggesting the regulatory effect of miR-146a on these TLRs signaling. Transfection of miR-146a into THP-1 cells caused reduction of TNF-α production, mimicking LPS-induced cross-tolerance. Aside from individual ligands, a whole bacterial challenge in LPS-primed THP-1 monocytes was accompanied by less TNF-α production, which is conversely correlated to miR-146a expression. Our studies have thus demonstrated that miR-146a plays a crucial role for in vitro monocytic cell-based endotoxin-induced cross-tolerance.
Functional Redundancy between Thymic CD8α+ and Sirpα+ Conventional Dendritic Cells in Presentation of Blood-Derived Lysozyme by MHC Class II Proteins
Authors: Atibalentja Danielle F. , Murphy Kenneth M. , Unanue Emil R. 
Published: December 2010

Abstract
We evaluated the presentation of blood-derived protein Ags by APCs in the thymus. Two conventional dendritic cells (cDCs), the CD8α+Sirpα−CD11chi (CD8α+ cDC) and the CD8α−Sirpα+CD11chi (Sirpα+ cDC), were previously identified as presenting MHC class II bound peptides from hen egg white lysozyme (HEL) injected intravenously. All thymic APCs acquired the injected HEL, with the plasmacytoid dendritic cell being the best, followed by the Sirpα+ cDC and the CD8α+ cDC. Both cDCs induced to similar extent negative selection and regulatory T cells in HEL TCR transgenic mice, indicating a redundant role of the two cDC subsets in the presentation of blood-borne HEL. Immature dendritic cells or plasmacytoid dendritic cells were considerably less efficient. Batf3−/− mice, with significantly reduced numbers of CD8α+ cDCs, were not impaired in HEL presentation by I-Ak molecules of thymic APCs. Lastly, clodronate liposome treatment of TCR transgenic mice depleted blood APCs including Sirpα+ cDCs without affecting the number of thymic APCs. In such treated mice, there was no effect on negative selection or regulatory T cells in mice when administering HEL, indicating that the T cell responses were mediated primarily by the cDCs localized in the thymus.
Mycobacterium tuberculosisDirects Immunofocusing of CD8+ T Cell Responses Despite Vaccination
Authors: Woodworth Joshua S. , Shin Daniel , Volman Mattijs , Nunes-Alves Cláudio , Fortune Sarah M. , Behar Samuel M. 
Published: December 2010

AbstractVaccines that elicit T cell responses try to mimic protective memory T cell immunity after infection by increasing the frequency of Ag-specific T cells in the immune repertoire. However, the factors that determine immunodominance during infection and after vaccination and the relation between immunodominance and protection are incompletely understood. We previously identified TB10.4(20–28) as an immunodominant epitope recognized by H2-Kd–restricted CD8+ T cells after M. tuberculosis infection. Here we report a second epitope, EspA(150–158), that is recognized by a substantial number of pulmonary CD8+ T cells. The relative abundance of these T cells in the naive repertoire only partially predicts their relative frequency after M. tuberculosis infection. Furthermore, although vaccination with recombinant vaccinia virus expressing these epitopes changes their relative immunodominance in the preinfection T cell repertoire, this change is transient after challenge with M. tuberculosis. We speculate that factors intrinsic to the chronic nature of M. tuberculosis infection establishes the hierarchy of immunodominance and may explain the failure of some vaccines to provide protection.
Tumor-Associated a2 Vacuolar ATPase Acts As a Key Mediator of Cancer-Related Inflammation by Inducing Pro-Tumorigenic Properties in Monocytes
Authors: Kwong Christina , Gilman-Sachs Alice , Beaman Kenneth 
Published: December 2010

Abstract
Cancer-related inflammation profoundly affects tumor progression. Tumor-associated macrophages (TAMs) are known regulators of that inflammation, but the factors that initiate cancer-related inflammation are poorly understood. Tumor invasiveness and poor clinical outcome are linked to increased expression of cell surface-associated vacuolar adenosine triphosphatases. The a2 isoform vacuolar adenosine triphosphatase is found on the surface on many solid tumors, and we have identified a peptide cleaved from a2 isoform vacuolar adenosine triphosphatase called a2NTD. a2NTD has properties necessary to induce monocytes into a pro-oncogenic TAM phenotype. The peptide upregulated both pro- and anti-inflammatory mediators. These included IL-1β and IL-10, which are important in promoting inflammation and immune escape by tumor cells. The secretion of inflammatory cytokine IL-1β was dependent on ATP, K+ efflux, and reactive oxygen species, all mediators that activate the inflammasome. These findings describe a mechanism by which tumor cells affect the maturation of TAMs via a nontraditional cytokine-like signal, the a2NTD peptide.
Transplantation Tolerance to a Single Noninherited MHC Class I Maternal Alloantigen Studied in a TCR-Transgenic Mouse Model
Authors: Akiyama Yoshinobu , Caucheteux Stéphane M. , Vernochet Cécile , Iwamoto Yoshiko , Tanaka Katsunori , Kanellopoulos-Langevin Colette , Benichou Gilles 
Published: December 2010

Abstract
The mechanisms underlying tolerance to noninherited maternal Ags (NIMA) are not fully understood. In this study, we designed a double-transgenic model in which all the offspring’s CD8+ T cells corresponded to a single clone recognizing the Kb MHC class I protein. In contrast, the mother and the father of the offspring differed by the expression of a single Ag, Kb, that served as NIMA. We investigated the influence of NIMA exposure on the offspring thymic T cell selection during ontogeny and on its peripheral T cell response during adulthood. We observed that anti-Kb thymocytes were exposed to NIMA and became activated during fetal life but were not deleted. Strikingly, adult mice exposed to NIMA accepted permanently Kb+ heart allografts despite the presence of normal levels of anti-Kb TCR transgenic T cells. Transplant tolerance was associated with a lack of a proinflammatory alloreactive T cell response and an activation/expansion of T cells producing IL-4 and IL-10. In addition, we observed that tolerance to NIMA Kb was abrogated via depletion of CD4+ but not CD8+ T cells and could be transferred to naive nonexposed mice via adoptive transfer of CD4+CD25high T cell expressing Foxp3 isolated from NIMA mice.
C*-algebras associated with integral domains and crossed products by actions on adele spaces
Authors: Cuntz Joachim , Li Xin 
Published: December 2010

We compute the K-theory for C*-algebras naturally associated with rings of integers in number fields.
The main ingredient is a duality theorem for arbitrary global fields. It allows us to identify the crossed product arising from affine transformations on the finite adeles with the analogous crossed product algebra over the infinite adele space.
Roughness Effects on Continuous and Discrete Flows in Superhydrophobic Microchannels
Authors: Zhang Junfeng , Kwok Daniel Y. 
Published: December 2010

AbstractThe dynamic behaviors of continuous and discrete flows in superhydrophobic microchannels are investigated with a lattice Boltzmann model. Typical characters of the superhydrophobic phenomenon are well observed from our simulations, including air trapped in the surface microstructures, high contact angles, low contact angle hysteresis, and reduced friction to fluid motions. Increasing the roughness of a hydrophobic surface can produce a large flow rate through the channel due to the trapped air, implying less friction or large apparent slip. The apparent slip length appears to be independent to the channel width and could be considered as a surface property. For a moving droplet, its behavior is affected by the surface roughness from two aspects: the contact angle difference between its two ends and the surface-liquid interfacial friction. As a consequence, the resulting droplet velocity changes with the surface roughness as firstly decreasing and then increasing. Simulation results are also compared with experimental observations and better agreement has been obtained than that from other numerical method. The information from this study could be valuable for microfluidic systems.
To debrief or not to debrief our heroes: that is the question
Authors: Hawker Debbie M. , Durkin John , Hawker David S. J. 
Published: December 2010

AbstractPsychological debriefing was developed in the 1980s as an approach for use with people whose work exposes them to stressful incidents. It aims to help them to process the thoughts and emotions arising from their work. Subsequently, several randomized controlled trials tested truncated forms of debriefing in a different population: primary victims of unexpected trauma. These trials, and particularly two in which debriefing appeared to be harmful, led two major reviews to warn practitioners not to offer debriefing. Consequently, many organizations have stopped providing debriefing to employees who face trauma in their routine work. This paper argues that there are at least three reasons for the apparent failure of ‘debriefing’ in the two studies that reported adverse effects. First, the ‘debriefing’ did not follow protocol in terms of timing, length, and training and independence of the debriefer. Second, the patients who were ‘debriefed’ reported more severe initial symptoms than those who were not. Third, ‘debriefing’ was used with individuals for whom it was not originally intended. Psychological debriefing is intended to be used with groups of people who have been briefed together before going on to work together in stressful situations. Such groups have reported that they find psychological debriefing helpful, and research is emerging indicating that appropriate debriefing may indeed benefit these groups. We call for reviewers to recognize the limitations of debriefing research and not to overgeneralize their conclusions. Copyright © 2010 John Wiley & Sons, Ltd.Key Practitioner Message:• Warnings about the dangers of psychological debriefing are based on studies using an intervention that is very different from that used for disaster workers and military personnel.• Evidence relating to primary victims of trauma has been overgeneralized to secondary victims.• Psychological debriefing may harm if it is too short, too probing, conducted too soon or delivered by debriefers with insufficient training or experience.• Research is urgently needed on appropriate debriefing for occupational groups briefed to work in stressful situations.