bluuebunny/crossref_metadata_2025 huggingface dataset:
Macrophage PTEN Regulates Expression and Secretion of Arginase I Modulating Innate and Adaptive Immune Responses
Authors: Sahin Emine , Haubenwallner Stefan , Kuttke Mario , Kollmann Isabella , Halfmann Angela , Dohnal Alexander B. , Chen Li , Cheng Paul , Hoesel Bastian , Einwallner Elisa , Brunner Julia , Kral Julia B. , Schrottmaier Waltraud C. , Thell Kathrin , Saferding Victoria , Blüml Stephan , Schabbauer Gernot
Published: July 2014

The activation of innate immune cells triggers numerous intracellular signaling pathways, which require tight control to mount an adequate immune response. The PI3K signaling pathway is intricately involved in innate immunity, and its activation dampens the expression and release of proinflammatory cytokines in myeloid cells. These signaling processes are strictly regulated by the PI3K antagonist, the lipid phosphatase, PTEN, a known tumor suppressor. Importantly, PTEN is responsible for the elevated production of cytokines such as IL-6 in response to TLR agonists, and deletion of PTEN results in diminished inflammatory responses. However, the mechanisms by which PI3K negatively regulates TLR signaling are only partially resolved. We observed that Arginase I expression and secretion were markedly induced by PTEN deletion, suggesting PTEN−/− macrophages were alternatively activated. This was mediated by increased expression and activation of the transcription factors C/EBPβ and STAT3. Genetic and pharmacologic experimental approaches in vitro, as well as in vivo autoimmunity models, provide convincing evidence that PI3K/PTEN-regulated extracellular Arginase I acts as a paracrine regulator of inflammation and immunity.
IL-2 Induction of Blimp-1 Is a Key In Vivo Signal for CD8+ Short-Lived Effector T Cell Differentiation
Authors: Boulet Salix , Daudelin Jean-François , Labrecque Nathalie
Published: July 2014

During infection or vaccination, only a small proportion of CD8+ T cells differentiate into memory cells. The mechanisms underlying the differentiation of CD8+ T cells into short-lived effector cells (SLECs) or memory precursor effector cells are poorly defined. It was recently shown in infectious models that the transcriptional repressor B lymphocyte–induced maturation protein 1 (Blimp-1) enhances the formation of SLECs. The factors controlling Blimp-1 expression leading to the in vivo formation of SLECs are still not known. However, it has been shown that cytokines such as IL-2 induce Blimp-1 expression in vitro. In this study, we took advantage of the low-inflammation model of dendritic cell immunization to study the role of the IL-2/Blimp-1 axis in SLEC differentiation as well as the importance of Blimp-1 expression in memory precursor effector cells for proper CD8+ memory generation. Our results show that Blimp-1 deficiency affects effector differentiation and function in the absence of inflammation. Unexpectedly, memory generation was not affected in Blimp-1–deficient OT-I cells responding to vaccination. In addition, modulation of the bioavailability of IL-2 by injection either of a blocking Ab or of the cytokine, demonstrates a link between IL-2, Blimp-1 induction, and SLEC formation in wild-type cells. Conversely, injection of IL-2 had less effect on Blimp-1–deficient CD8+ T cells, indicating that the effect of IL-2 on in vivo SLEC differentiation is mediated by Blimp-1. In conclusion, IL-2 induction of Blimp-1 expression is a key regulator of SLEC differentiation in vivo.
NK Cells Are the Crucial Antitumor Mediators When STAT3-Mediated Immunosuppression Is Blocked in Hepatocellular Carcinoma
Authors: Sui Qiangjun , Zhang Jian , Sun Xiaoxia , Zhang Cai , Han Qiuju , Tian Zhigang
Published: July 2014

STAT3 is highly activated in a wide variety of cancers and functions to promote tumor survival. We previously reported that blocking STAT3 activation inhibited human hepatocellular carcinoma (HCC) growth in vitro, but whether this treatment also triggered antitumor immune responses in vivo remained unknown. In this study, we found that blocking the STAT3 pathway in HCC cells dramatically inhibited murine HCC growth in vivo and prolonged survival of tumor-bearing mice. Importantly, the presence of STAT3-blocked HCC augmented NK cell cytotoxicity against HCC and increased expression of molecules associated with NK cell activation and cytotoxicity. In T cell–deficient nude mice, a unique NK cell–mediated antitumor function against STAT3-blocked HCC was suggested. NK cells were shown to be necessary and sufficient in NK or T cell depletion experiments, or by adoptively transferring NK cells. Furthermore, regulatory T cells and immunosuppressive IL-10 and TGF-β cytokines were reduced in mice bearing STAT3-blocked HCC cells, suggesting that these factors may be involved in HCC-induced NK cell suppression. These findings indicate that blocking STAT3 in HCC cells can initiate innate immunity in vivo.
TRIL Is Involved in Cytokine Production in the Brain following Escherichia coli Infection
Authors: Wochal Paulina , Rathinam Vijay A. K. , Dunne Aisling , Carlson Thaddeus , Kuang Wen , Seidl Katherine J. , Hall J. Perry , Lin Lih-Ling , Collins Mary , Schattgen Stefan A. , MacKay Christopher R. , Fagundes Caio T. , Carpenter Susan , Fitzgerald Katherine A. , O’Neill Luke A. J.
Published: July 2014

TLR4 interactor with leucine-rich repeats (TRIL) is a brain-enriched accessory protein that is important in TLR3 and TLR4 signaling. In this study, we generated Tril−/− mice and examined TLR responses in vitro and in vivo. We found a role for TRIL in both TLR4 and TLR3 signaling in mixed glial cells, consistent with the high level of expression of TRIL in these cells. We also found that TRIL is a modulator of the innate immune response to LPS challenge and Escherichia coli infection in vivo. Tril−/− mice produce lower levels of multiple proinflammatory cytokines and chemokines specifically within the brain after E. coli and LPS challenge. Collectively, these data uncover TRIL as a mediator of innate immune responses within the brain, where it enhances neuronal cytokine responses to infection.
Does β-Hexosaminidase Function Only as a Degranulation Indicator in Mast Cells? The Primary Role of β-Hexosaminidase in Mast Cell Granules
Authors: Fukuishi Nobuyuki , Murakami Shinya , Ohno Akane , Yamanaka Naoya , Matsui Nobuaki , Fukutsuji Kenji , Yamada Sakuo , Itoh Kouji , Akagi Masaaki
Published: July 2014

β-Hexosaminidase, which is generally present in the lysosome, is essential for glycoprotein metabolism in the maintenance of cell homeostasis. In mast cells (MCs), large amounts of β-hexosaminidase are present in the granules as opposed to the lysosome, and the biological role of MC β-hexosaminidase has yet to be fully elucidated. Therefore, we investigated the biological role of β-hexosaminidase in MC granules. Bone marrow-derived MCs from C57BL/6 (BL/6-BMMC) or β-hexosaminidase gene–deficient (hexb−/−-BMMC) mice were transplanted into MC-deficient (WBB6F1/J-KitW/KitW-v [W/Wv]) mice to generate MC-reconstituted models. In asthma model experiments, no differences were observed in the symptoms of BL/6, W/Wv, BL/6-BMMC–reconstituted W/Wv, or hexb−/−-BMMC–reconstituted W/Wv mice. In Staphylococcus epidermidis experimental infection model experiments, the severity of symptoms and frequency of death were markedly higher in W/Wv and hexb−/−-BMMC–reconstituted W/Wv mice than in BL/6 and BL/6-BMMC–reconstituted W/Wv mice. The growth of S. epidermidis in an in vitro study was clearly inhibited by addition of BL/6-BMMC lysate, but not by addition of hexb−/−-BMMC lysate. Moreover, suppression of bacterial proliferation was completely recovered when bacteria were incubated with hexb−/−-BMMC lysate plus β-hexosaminidase. Transmission electron microscopy indicated that the cell wall of S. epidermidis was heavily degraded following coincubation of bacteria with BL/6-BMMC lysate, but not following coincubation with hexb−/−-BMMC lysate. These findings strongly suggest that MC granule β-hexosaminidase is crucial for defense against bacterial invasion, but is not involved in the allergic response. Our results also suggest that the bactericidal mechanism of β-hexosaminidase involves degradation of bacterial cell wall peptidoglycan.
Leukocyte β7 Integrin Targeted by Krüppel-like Factors
Authors: Alles Melanie , Turchinovich Gleb , Zhang Pumin , Schuh Wolfgang , Agenès Fabien , Kirberg Jörg
Published: July 2014

Constitutive expression of Krüppel-like factor 3 (KLF3, BKLF) increases marginal zone (MZ) B cell numbers, a phenotype shared with mice lacking KLF2. Ablation of KLF3, known to interact with serum response factor (SRF), or SRF itself, results in fewer MZ B cells. It is unknown how these functional equivalences result. In this study, it is shown that KLF3 acts as transcriptional repressor for the leukocyte-specific integrin β7 (Itgb7, Ly69) by binding to the β7 promoter, as revealed by chromatin immunoprecipitation. KLF2 overexpression antagonizes this repression and also binds the β7 promoter, indicating that these factors may compete for target sequence(s). Whereas β7 is identified as direct KLF target, its repression by KLF3 is not connected to the MZ B cell increase because β7-deficient mice have a normal complement of these and the KLF3-driven increase still occurs when β7 is deleted. Despite this, KLF3 overexpression abolishes lymphocyte homing to Peyer’s patches, much like β7 deficiency does. Furthermore, KLF3 expression alone overcomes the MZ B cell deficiency when SRF is absent. SRF is also dispensable for the KLF3-mediated repression of β7. Thus, despite the shared phenotype of KLF3 and SRF-deficient mice, cooperation of these factors appears neither relevant for the formation of MZ B cells nor for the regulation of β7. Finally, a potent negative regulatory feedback loop limiting KLF3 expression is shown in this study, mediated by KLF3 directly repressing its own gene promoter. In summary, KLFs use regulatory circuits to steer lymphocyte maturation and homing and directly control leukocyte integrin expression.
Differential Role for p120-Catenin in Regulation of TLR4 Signaling in Macrophages
Authors: Yang Zhiyong , Sun Dong , Yan Zhibo , Reynolds Albert B. , Christman John W. , Minshall Richard D. , Malik Asrar B. , Zhang Yang , Hu Guochang
Published: July 2014

Activation of TLR signaling through recognition of pathogen-associated molecular patterns is essential for the innate immune response against bacterial and viral infections. We have shown that p120-catenin (p120) suppresses TLR4-mediated NF-кB signaling in LPS-challenged endothelial cells. In this article, we report that p120 differentially regulates LPS/TLR4 signaling in mouse bone marrow–derived macrophages. We observed that p120 inhibited MyD88-dependent NF-κB activation and release of TNF-α and IL-6, but enhanced TIR domain–containing adapter-inducing IFN-β–dependent IFN regulatory factor 3 activation and release of IFN-β upon LPS exposure. p120 silencing diminished LPS-induced TLR4 internalization, whereas genetic and pharmacological inhibition of RhoA GTPase rescued the decrease in endocytosis of TLR4 and TLR4-MyD88 signaling, and reversed the increase in TLR4–TIR domain–containing adapter-inducing IFN-β signaling induced by p120 depletion. Furthermore, we demonstrated that altered p120 expression in macrophages regulates the inflammatory phenotype of LPS-induced acute lung injury. These results indicate that p120 functions as a differential regulator of TLR4 signaling pathways by facilitating TLR4 endocytic trafficking in macrophages, and support a novel role for p120 in influencing the macrophages in the lung inflammatory response to endotoxin.
IL-33 and Thymic Stromal Lymphopoietin Mediate Immune Pathology in Response to Chronic Airborne Allergen Exposure
Authors: Iijima Koji , Kobayashi Takao , Hara Kenichiro , Kephart Gail M. , Ziegler Steven F. , McKenzie Andrew N. , Kita Hirohito
Published: July 2014

Humans are frequently exposed to various airborne allergens in the atmospheric environment. These allergens may trigger a complex network of immune responses in the airways, resulting in asthma and other chronic airway diseases. In this study, we investigated the immunological mechanisms involved in the pathological changes induced by chronic exposure to multiple airborne allergens. Naive mice were exposed intranasally to a combination of common airborne allergens, including the house dust mite, Alternaria, and Aspergillus, for up to 8 wk. These allergens acted synergistically and induced robust eosinophilic airway inflammation, specific IgE Ab production, type 2 cytokine response, and airway hyperresponsiveness in 4 wk, followed by airway remodeling in 8 wk. Increased lung infiltration of T cells, B cells, and type 2 innate lymphoid cells was observed. CD4+ T cells and type 2 innate lymphoid cells contributed to the sources of IL-5 and IL-13, suggesting involvement of both innate and adaptive immunity in this model. The lung levels of IL-33 increased quickly within several hours after allergen exposure and continued to rise throughout the chronic phase of inflammation. Mice deficient in IL-33R (Il1rl1−/−) and thymic stromal lymphopoietin receptor (Tslpr−/−) showed significant reduction in airway inflammation, IgE Ab levels, and airway hyperresponsiveness. In contrast, mice deficient in IL-25R or IL-1R showed minimal differences as compared with wild-type animals. Thus, chronic exposure to natural airborne allergens triggers a network of innate and adaptive type 2 immune responses and airway pathology, and IL-33 and thymic stromal lymphopoietin most likely play key roles in this process.
Activation of Rheumatoid Factor–Specific B Cells Is Antigen Dependent and Occurs Preferentially Outside of Germinal Centers in the Lupus-Prone NZM2410 Mouse Model
Authors: Sang Allison , Niu Haitao , Cullen Jaime , Choi Seung Chul , Zheng Ying Yi , Wang Haowei , Shlomchik Mark J. , Morel Laurence
Published: July 2014

AM14 rheumatoid factor (RF) B cells in the MRL/lpr mice are activated by dual BCR and TLR7/9 ligation and differentiate into plasmablasts via an extrafollicular (EF) route. It was not known whether this mechanism of activation of RF B cells applied to other lupus-prone mouse models. We investigated the mechanisms by which RF B cells break tolerance in the NZM2410-derived B6.Sle1.Sle2.Sle3 (TC) strain in comparison with C57BL/6 (B6) controls, each expressing the AM14 H chain transgene in the presence or absence of the IgG2aa autoantigen. The TC, but not B6, genetic background promotes the differentiation of RF B cells into Ab-forming cells (AFCs) in the presence of the autoantigen. Activated RF B cells preferentially differentiated into plasmablasts in EF zones. Contrary to the MRL/lpr strain, TC RF B cells were also located within germinal centers, but only the formation of EF foci was positively correlated with the production of RF AFCs. Immunization of young TC.AM14 H chain transgenic mice with IgG2aa anti-chromatin immune complexes (ICs) activated RF B cells in a BCR- and TLR9-dependent manner. However, these IC immunizations did not result in the production of RF AFCs. These results show that RF B cells break tolerance with the same general mechanisms in the TC and the MRL/lpr lupus-prone genetic backgrounds, namely the dual activation of the BCR and TLR9 pathways. There are also distinct differences, such as the presence of RF B cells in GCs and the requirement of chronic IgG2aa anti-chromatin ICs for full differentiation of RF AFCs.
Inhibition of the Classical Pathway of Complement by Meningococcal Capsular Polysaccharides
Authors: Agarwal Sarika , Vasudhev Shreekant , DeOliveira Rosane B. , Ram Sanjay
Published: July 2014

Almost all invasive Neisseria meningitidis isolates express capsular polysaccharide. Ab is required for complement-dependent killing of meningococci. Although alternative pathway evasion has received considerable attention, little is known about classical pathway (CP) inhibition by meningococci, which forms the basis of this study. We engineered capsulated and unencapsulated isogenic mutant strains of groups A, B, C, W, and Y meningococci to express similar amounts of the same factor H–binding protein (fHbp; a key component of group B meningococcal vaccines) molecule. Despite similar anti-fHbp mAb binding, significantly less C4b was deposited on all five encapsulated mutants compared with their unencapsulated counterparts (p < 0.01) when purified C1 and C4 were used to deposit C4b. Reduced C4b deposition was the result of capsule-mediated inhibition of C1q engagement by Ab. C4b deposition correlated linearly with C1q engagement by anti-fHbp. Whereas B, C, W, and Y capsules limited CP-mediated killing by anti-fHbp, the unencapsulated group A mutant paradoxically was more resistant than its encapsulated counterpart. Strains varied considerably in their susceptibility to anti-fHbp and complement despite similar Ab binding, which may have implications for the activity of fHbp-based vaccines. Capsule also limited C4b deposition by anti–porin A mAbs. Capsule expression decreased binding of an anti-lipooligosaccharide IgM mAb (∼1.2- to 2-fold reduction in fluorescence). Akin to observations with IgG, capsule also decreased IgM-mediated C4b deposition when IgM binding to the mutant strain pairs was normalized. In conclusion, we show that capsular polysaccharide, a critical meningococcal virulence factor, inhibits the CP of complement.
γδT Cells Drive Myeloid-Derived Suppressor Cell–Mediated CD8+ T Cell Exhaustion in Hepatitis B Virus–Induced Immunotolerance
Authors: Kong Xiaohui , Sun Rui , Chen Yongyan , Wei Haiming , Tian Zhigang
Published: July 2014

The mechanisms of liver hepatitis B virus (HBV)–induced systemic immune tolerance are still elusive, and the role of γδT cells has not yet been described. We examined the function of γδT cells in HBV-carrier mice––immunocompetent mice with plasmid-mediated persistent HBV expression in the liver. In this study, we found that γδT cell deficiency led to a break in HBV-induced tolerance and subsequent recovery of hepatic HBV-specific CD8+ T cells. Of interest, IL-17−/− mice phenocopied TCRδ−/− mice in terms of losing HBV persistence, and adoptive transfer of γδT cells restored HBV-persistent expression in TCRδ−/− mice. We further observed that hepatic CD11b+Gr1+ myeloid-derived suppressor cells (MDSCs) play a major role in this mechanism, as they were significantly reduced in both HBV-carrier TCRδ−/− and IL-17−/− mice. MDSC numbers also recovered after adoptive transfer of γδT cells, particularly Vγ4+ T cells. Furthermore, anti-Gr1–mediated MDSC depletion in HBV-carrier mice accelerated HBV elimination from the host, whereas MDSCs transferred to γδT cell-deficient mice restored HBV-induced tolerance. Accordingly, inhibition of MDSCs by the arginase-1 inhibitor norNOHA enhanced the number of HBV-specific CD8+ T cells and promoted HBV clearance. We also observed enhanced CD8+ T cell number with a notable decline of MDSCs in TCRδ−/− mice compared with wild-type mice during the recombinant adeno-associated virus/HBV1.3 virus infection. Importantly, HBV-carrier TCRδ−/− mice not only exhibited increased anti-HBV CD8+ T cells but also markedly reduced MDSCs. Overall, the current study reveals that γδT cells play a previously unrecognized regulatory role in liver tolerance by mobilizing MDSC infiltration to the liver, leading to MDSC-mediated CD8+ T cell exhaustion.
Platelet Activation and Apoptosis Modulate Monocyte Inflammatory Responses in Dengue
Authors: Hottz Eugenio D. , Medeiros-de-Moraes Isabel M. , Vieira-de-Abreu Adriana , de Assis Edson F. , Vals-de-Souza Rogério , Castro-Faria-Neto Hugo C. , Weyrich Andrew S. , Zimmerman Guy A. , Bozza Fernando A. , Bozza Patrícia T.
Published: July 2014

Dengue is the most prevalent human arbovirus disease in the world. Dengue infection has a large spectrum of clinical manifestations, from self-limited febrile illness to severe syndromes accompanied by bleeding and shock. Thrombocytopenia and vascular leak with altered cytokine profiles in plasma are features of severe dengue. Although monocytes have been recognized as important sources of cytokines in dengue, the contributions of platelet–monocyte interactions to inflammatory responses in dengue have not been addressed. Patients with dengue were investigated for platelet–monocyte aggregate formation. Platelet-induced cytokine responses by monocytes and underlying mechanisms were also investigated in vitro. We observed increased levels of platelet–monocyte aggregates in blood samples from patients with dengue, especially patients with thrombocytopenia and increased vascular permeability. Moreover, the exposure of monocytes from healthy volunteers to platelets from patients with dengue induced the secretion of the cytokines IL-1β, IL-8, IL-10 and MCP-1, whereas exposure to platelets from healthy volunteers only induced the secretion of MCP-1. In addition to the well-established modulation of monocyte cytokine responses by activated platelets through P-selectin binding, we found that interaction of monocytes with apoptotic platelets mediate IL-10 secretion through phosphatidylserine recognition in platelet–monocyte aggregates. Moreover, IL-10 secretion required platelet–monocyte contact but not phagocytosis. Together, our results demonstrate that activated and apoptotic platelets aggregate with monocytes during dengue infection and signal specific cytokine responses that may contribute to the pathogenesis of dengue.
Marginal Zone B Cells Transport IgG3-Immune Complexes to Splenic Follicles
Authors: Zhang Lu , Ding Zhoujie , Xu Hui , Heyman Birgitta
Published: July 2014

Ag administered together with specific IgG3 induces a higher Ab response than Ag administered alone, an effect requiring the presence of complement receptors 1 and 2 (CR1/2). In this study, we have investigated the fate of Ag, the development of germinal centers (GCs), and the Ab response after i.v. administration of IgG3 anti-trinitrophenyl (TNP) in complex with OVA-TNP. After 2 h, OVA-TNP was detected on marginal zone (MZ) B cells, and a substantial amount of Ag was detected in splenic follicles and colocalized with follicular dendritic cells (FDCs). After 10 d, the percentage of GCs and the IgG responses were markedly higher than in mice immunized with uncomplexed OVA-TNP. The effects of IgG3 were dependent on CR1/2 known to be expressed on B cells and FDCs. Using bone marrow chimeric mice, we demonstrate that an optimal response to IgG3-Ag complexes requires that CR1/2 is expressed on both cell types. These data suggest that CR1/2+ MZ B cells transport IgG3-Ag-C complexes from the MZ to the follicles, where they are captured by FDCs and induce GCs and IgG production. This pathway for initiating the transport of Ags into splenic follicles complements previously known B-cell dependent pathways where Ag is transported by 1) MZ B cells, binding large Ags-IgM-C complexes via CR1/2; 2) recirculating B cells, binding Ag via BCR; or 3) recirculating B cells, binding IgE-Ag complexes via the low-affinity receptor for IgE, CD23.
Antigen-Specific Naive CD8+ T Cells Produce a Single Pulse of IFN-γ In Vivo within Hours of Infection, but without Antiviral Effect
Authors: Hosking Martin P. , Flynn Claudia T. , Whitton J. Lindsay
Published: July 2014

In vitro studies have shown that naive CD8+ T cells are unable to express most of their effector proteins until after at least one round of cell division has taken place. We have reassessed this issue in vivo and find that naive CD8+ T cells mount Ag-specific responses within hours of infection, before proliferation has commenced. Newly activated naive Ag-specific CD8+ T cells produce a rapid pulse of IFN-γ in vivo and begin to accumulate granzyme B and perforin. Later, in vivo cytolytic activity is detectable, coincident with the initiation of cell division. Despite the rapid development of these functional attributes, no antiviral effect was observed early during infection, even when the cells are present in numbers similar to those of virus-specific memory cells. The evolutionary reason for the pulse of IFN-γ synthesis by naive T cells is uncertain, but the lack of antiviral impact suggests that it may be regulatory.
The Ability To Rearrange Dual TCRs Enhances Positive Selection, Leading to Increased Allo- and Autoreactive T Cell Repertoires
Authors: Ni Peggy P. , Solomon Benjamin , Hsieh Chyi-Song , Allen Paul M. , Morris Gerald P.
Published: July 2014

Thymic selection is designed to ensure TCR reactivity to foreign Ags presented by self-MHC while minimizing reactivity to self-Ags. We hypothesized that the repertoire of T cells with unwanted specificities such as alloreactivity or autoreactivity are a consequence of simultaneous rearrangement of both TCRα loci. We hypothesized that this process helps maximize production of thymocytes capable of successfully completing thymic selection, but results in secondary TCRs that escape stringent selection. In T cells expressing two TCRs, one TCR can mediate positive selection and mask secondary TCR from negative selection. Examination of mice heterozygous for TRAC (TCRα+/−), capable of only one functional TCRα rearrangement, demonstrated a defect in generating mature T cells attributable to decreased positive selection. Elimination of secondary TCRs did not broadly alter the peripheral T cell compartment, though deep sequencing of TCRα repertoires of dual TCR T cells and TCRα+/− T cells demonstrated unique TCRs in the presence of secondary rearrangements. The functional impact of secondary TCRs on the naive peripheral repertoire was evidenced by reduced frequencies of T cells responding to autoantigen and alloantigen peptide–MHC tetramers in TCRα+/− mice. T cell populations with secondary TCRs had significantly increased ability to respond to altered peptide ligands related to their allogeneic ligand as compared with TCRα+/− cells, suggesting increased breadth in peptide recognition may be a mechanism for their reactivity. Our results imply that the role of secondary TCRs in forming the T cell repertoire is perhaps more significant than what has been assumed.
Cutting Edge: RIPK1 Kinase Inactive Mice Are Viable and Protected from TNF-Induced Necroptosis In Vivo
Authors: Polykratis Apostolos , Hermance Nicole , Zelic Matija , Roderick Justine , Kim Chun , Van Trieu-My , Lee Thomas H. , Chan Francis K. M. , Pasparakis Manolis , Kelliher Michelle A.
Published: July 2014

The serine/threonine kinase RIPK1 is recruited to TNFR1 to mediate proinflammatory signaling and to regulate TNF-induced cell death. A RIPK1 deficiency results in perinatal lethality, impaired NFκB and MAPK signaling, and sensitivity to TNF-induced apoptosis. Chemical inhibitor and in vitro–reconstitution studies suggested that RIPK1 displays distinct kinase activity–dependent and –independent functions. To determine the contribution of RIPK1 kinase to inflammation in vivo, we generated knock-in mice endogenously expressing catalytically inactive RIPK1 D138N. Unlike Ripk1−/− mice, which die shortly after birth, Ripk1D138N/D138N mice are viable. Cells expressing RIPK1 D138N are resistant to TNF- and polyinosinic-polycytidylic acid–induced necroptosis in vitro, and Ripk1D138N/D138N mice are protected from TNF-induced shock in vivo. Moreover, Ripk1D138N/D138N mice fail to control vaccinia virus replication in vivo. This study provides genetic evidence that the kinase activity of RIPK1 is not required for survival but is essential for TNF-, TRIF-, and viral-initiated necroptosis.
Mammalian Target of Rapamycin Complex 1 Orchestrates Invariant NKT Cell Differentiation and Effector Function
Authors: Zhang Lianjun , Tschumi Benjamin O. , Corgnac Stéphanie , Rüegg Markus A. , Hall Michael N. , Mach Jean-Pierre , Romero Pedro , Donda Alena
Published: July 2014

Invariant NKT (iNKT) cells play critical roles in bridging innate and adaptive immunity. The Raptor containing mTOR complex 1 (mTORC1) has been well documented to control peripheral CD4 or CD8 T cell effector or memory differentiation. However, the role of mTORC1 in iNKT cell development and function remains largely unknown. By using mice with T cell–restricted deletion of Raptor, we show that mTORC1 is selectively required for iNKT but not for conventional T cell development. Indeed, Raptor-deficient iNKT cells are mostly blocked at thymic stage 1–2, resulting in a dramatic decrease of terminal differentiation into stage 3 and severe reduction of peripheral iNKT cells. Moreover, residual iNKT cells in Raptor knockout mice are impaired in their rapid cytokine production upon αGalcer challenge. Bone marrow chimera studies demonstrate that mTORC1 controls iNKT differentiation in a cell-intrinsic manner. Collectively, our data provide the genetic evidence that iNKT cell development and effector functions are under the control of mTORC1 signaling.
Cell Cycle Control and HIV-1 Susceptibility Are Linked by CDK6-Dependent CDK2 Phosphorylation of SAMHD1 in Myeloid and Lymphoid Cells
Authors: Pauls Eduardo , Ruiz Alba , Badia Roger , Permanyer Marc , Gubern Albert , Riveira-Muñoz Eva , Torres-Torronteras Javier , Álvarez Mar , Mothe Beatriz , Brander Christian , Crespo Manel , Menéndez-Arias Luis , Clotet Bonaventura , Keppler Oliver T. , Martí Ramon , Posas Francesc , Ballana Ester , Esté José A.
Published: July 2014

Proliferating cells are preferentially susceptible to infection by retroviruses. Sterile α motif and HD domain–containing protein-1 (SAMHD1) is a recently described deoxynucleotide phosphohydrolase controlling the size of the intracellular deoxynucleotide triphosphate (dNTP) pool, a limiting factor for retroviral reverse transcription in noncycling cells. Proliferating (Ki67+) primary CD4+ T cells or macrophages express a phosphorylated form of SAMHD1 that corresponds with susceptibility to infection in cell culture. We identified cyclin-dependent kinase (CDK) 6 as an upstream regulator of CDK2 controlling SAMHD1 phosphorylation in primary T cells and macrophages susceptible to infection by HIV-1. In turn, CDK2 was strongly linked to cell cycle progression and coordinated SAMHD1 phosphorylation and inactivation. CDK inhibitors specifically blocked HIV-1 infection at the reverse transcription step in a SAMHD1-dependent manner, reducing the intracellular dNTP pool. Our findings identify a direct relationship between control of the cell cycle by CDK6 and SAMHD1 activity, which is important for replication of lentiviruses, as well as other viruses whose replication may be regulated by intracellular dNTP availability.
Structure of the Superantigen Staphylococcal Enterotoxin B in Complex with TCR and Peptide–MHC Demonstrates Absence of TCR–Peptide Contacts
Authors: Rödström Karin E. J. , Elbing Karin , Lindkvist-Petersson Karin
Published: July 2014

Superantigens are immune-stimulatory toxins produced by Staphylococcus aureus, which are able to interact with host immune receptors to induce a massive release of cytokines, causing toxic shock syndrome and possibly death. In this article, we present the x-ray structure of staphylococcal enterotoxin B (SEB) in complex with its receptors, the TCR and MHC class II, forming a ternary complex. The structure, in combination with functional analyses, clearly shows how SEB adopts a wedge-like position when binding to the β-chain of TCR, allowing for an interaction between the α-chain of TCR and MHC. Furthermore, the binding mode also circumvents contact between TCR and the peptide presented by MHC, which enables SEB to initiate a peptide-independent activation of T cells.
Obstructions of Connectivity Two for Embedding Graphs into the Torus
Authors: Mohar Bojan , Škoda Petr
Published: July 2014

The complete set of minimal obstructions for embedding graphs into the torus is still not determined. In this paper, we present all obstructions for the torus of connectivity 2. Furthermore, we describe the building blocks of obstructions of connectivity 2 for any orientable surface.
On the Structure of Cuntz Semigroups in (Possibly) Nonunital C*-algebras
Authors: Peter Tikuisis Aaron , Toms Andrew
Published: July 2014

We examine the ranks of operators in semi-finite C*-algebras as measured by their densely defined lower semicontinuous traces. We first prove that a unital simple C*-algebra whose extreme tracial boundary is nonempty and finite contains positive operators of every possible rank, independent of the property of strict comparison. We then turn to nonunital simple algebras and establish criteria that imply that the Cuntz semigroup is recovered functorially from the Murray–von Neumann semigroup and the space of densely defined lower semicontinuous traces. Finally, we prove that these criteria are satisfied by not-necessarily-unital approximately subhomogeneous algebras of slow dimension growth. Combined with results of the first author, this shows that slow dimension growth coincides with Z-stability for approximately subhomogeneous algebras.
Dihedral Groups of Order 2p of Automorphisms of Compact Riemann Surfaces of Genus p – 1
Authors: Yang Qingjie , Zhong Weiting
Published: July 2014

In this paper we prove that there is only one conjugacy class of dihedral group of order 2p in the 2(p – 1) × 2(p – 1) integral symplectic group that can be realized by an analytic automorphism group of compact connected Riemann surfaces of genus p – 1. A pair of representative generators of the realizable class is also given.
On the distribution of perturbations of propagated Schrödinger eigenfunctions
Authors: Canzani Yaiza , Jakobson Dmitry , Toth John
Published: July 2014

Let

(M,g_0)

be a compact Riemmanian manifold of dimension

n

. Let

P_0 (h) \stackrel{\text{def}}= -h^2\Delta_{g}+V

be the semiclassical Schrödinger operator for

h \in (0,h_0]

, and let

E

be a regular value of its principal symbol. Write

\varphi_h

for an

L^2

-normalized eigenfunction of

P_0(h)

with eigenvalue

E(h) \in [E-o(1),E+ o(1)]

. Consider a smooth family of metric perturbations

g_u

of

g_0

with

u

in the

k

-ball

B^k(\varepsilon) \subset \mathbb R^k

of radius

\varepsilon>0

. For

P_{u}(h) := -h^2 \Delta_{g_u} +V

and small

|t|>0

, we define the propagated perturbed eigenfunctions

\varphi_{h,t}^{(u)}\stackrel{\text{def}}= e^{-\frac{i}{h}t P_u(h) } \varphi_h.

They appear in the mathematical description of the Loschmidt echo effect in physics. Motivated by random wave conjectures in quantum chaos, we study the distribution of the real part of the perturbed eigenfunctions regarded as random variables

\operatorname{Re} (\varphi^{(\cdot)}_{h,t}(x)): B^{k}(\varepsilon) \to \mathbb R, \quad x\in M.

In particular, under an admissibility condition on the metric when

(M,g)

is chaotic, we compute the

h \to 0^+

asymptotics of the variance

\text{Var} [\operatorname{Re}(\varphi^{(\cdot)}_{h,t}(x))]

and show that the odd moments vanish as

h \to 0^+

as long as

x

is not on the generalized caustic set where

V(x)=E

.
Study of the characteristic parameters of the normal voices of Argentinian speakers
Authors: Bonzi Edgardo , Grad Gabriela , Maggi Alicia , Muñoz Marta
Published: July 2014

The voice laboratory permits to study the human voices using a method that is objective and noninvasive. In this work, we have studied the parameters of the human voice such as pitch, formant, jitter, shimmer and harmonic-noise ratio of a group of young people. This statistical information of parameters is obtained from Argentinian speakers.Received: 29 December 2013,  Accepted: 27 May 2014; Reviewed by: J. Brum, Instituto de Física, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay; Edited by: E. Mizraji; DOI: http://dx.doi.org/10.4279/PIP.060002Cite as: E V Bonzi, G B Grad, A M Maggi, M R Muñoz, Papers in Physics 6, 060002 (2014)
Top-down estimates of biomass burning emissions of black carbon in the Western United States
Authors: Mao Y. H. , Li Q. B. , Chen D. , Zhang L. , Hao W.-M. , Liou K.-N.
Published: July 2014

Abstract. We estimate biomass burning and anthropogenic emissions of black carbon (BC) in the western US for May–October 2006 by inverting surface BC concentrations from the Interagency Monitoring of PROtected Visual Environment (IMPROVE) network using a global chemical transport model. We first use active fire counts from the Moderate Resolution Imaging Spectroradiometer (MODIS) to improve the spatiotemporal distributions of the biomass burning BC emissions from the Global Fire Emissions Database (GFEDv2). The adjustment primarily shifts emissions from late to middle and early summer (a 33% decrease in September–October and a 56% increase in June–August) and leads to appreciable increases in modeled surface BC concentrations in early and middle summer, especially at the 1–2 and 2–3 km altitude ranges. We then conduct analytical inversions at both 2° × 2.5° and 0.5° × 0.667° (nested over North America) horizontal resolutions. The a posteriori biomass burning BC emissions for July–September are 31.7 Gg at 2° × 2.5° (an increase by a factor of 4.7) and 19.2 Gg at 0.5° × 0.667° (an increase by a factor of 2.8). The inversion results are rather sensitive to model resolution. The a posteriori biomass burning emissions at the two model resolutions differ by a factor of ~6 in California and the Southwest and by a factor of 2 in the Pacific Northwest. The corresponding a posteriori anthropogenic BC emissions are 9.1 Gg at 2° × 2.5° (a decrease of 48%) and 11.2 Gg at 0.5° × 0.667° (a decrease of 36%). Simulated surface BC concentrations with the a posteriori emissions capture the observed major fire episodes at most sites and the substantial enhancements at the 1–2 and 2–3 km altitude ranges. The a posteriori emissions also lead to large bias reductions (by ~30% on average at both model resolutions) in modeled surface BC concentrations and significantly better agreement with observations (increases in Taylor skill scores of 95% at 2° × 2.5° and 42 % at 0.5° × 0.667°).
Validation of spectral sky radiance derived from all-sky camera images – a case study
Authors: Tohsing K. , Schrempf M. , Riechelmann S. , Seckmeyer G.
Published: July 2014

Abstract. Spectral sky radiance (380–760 nm) is derived from measurements with a hemispherical sky imager (HSI) system. The HSI consists of a commercial compact CCD (charge coupled device) camera equipped with a fish-eye lens and provides hemispherical sky images in three reference bands such as red, green and blue. To obtain the spectral sky radiance from these images, non-linear regression functions for various sky conditions have been derived. The camera-based spectral sky radiance was validated using spectral sky radiance measured with a CCD spectroradiometer. The spectral sky radiance for complete distribution over the hemisphere between both instruments deviates by less than 20% at 500 nm for all sky conditions and for zenith angles less than 80°. The reconstructed spectra of the wavelengths 380–760 nm between both instruments at various directions deviate by less than 20% for all sky conditions.
Validation of GOMOS ozone precision estimates in the stratosphere
Authors: Sofieva V. F. , Tamminen J. , Kyrölä E. , Laeng A. , von Clarmann T. , Dalaudier F. , Hauchecorne A. , Bertaux J.-L. , Barrot G. , Blanot L. , Fussen D. , Vanhellemont F.
Published: July 2014

Abstract. Accurate information about uncertainties is required in nearly all data analyses, e.g., inter-comparisons, data assimilation, combined use. Validation of precision estimates (viz., the random component of estimated uncertainty) is important for remote sensing measurements, which provide the information about atmospheric parameters by solving an inverse problem. For the Global Ozone Monitoring by Occultation of Stars (GOMOS) instrument, this is a real challenge, due to the dependence of the signal-to-noise ratio (and thus precision estimates) on stellar properties, small number of self-collocated measurements, and growing noise as a function of time due to instrument aging. The estimated ozone uncertainties are small in the stratosphere for bright star occultations, which complicates validation of precision values, given the natural ozone variability. In this paper, we discuss different methods for geophysical validation of precision estimates and their applicability to GOMOS data. We propose a simple method for validation of GOMOS precision estimates for ozone in the stratosphere. This method is based on comparisons of differences in sample variance with differences in uncertainty estimates for measurements from different stars selected in a region of small natural variability. For GOMOS, the difference in sample variances for different stars at tangent altitudes 25–45 km is well explained by the difference in squared precisions, if the stars are not dim. Since this is observed for several stars, and since normalized χ2 is close to 1 for these occultations in the stratosphere, we conclude that the GOMOS precision estimates are realistic in occultations of sufficiently bright stars. For dim stars, errors are overestimated due to improper accounting of the dark charge correction uncertainty in the error budget. The proposed method can also be applied to stratospheric ozone data from other instruments, including multi-instrument analyses.
Investigating bias in the application of curve fitting programs to atmospheric time series
Authors: Pickers P. A. , Manning A. C.
Published: July 2014

Abstract. The decomposition of an atmospheric time series into its constituent parts is an essential tool for identifying and isolating variations of interest from a data set, and is widely used to obtain information about sources, sinks and trends in climatically important gases. Such procedures involve fitting appropriate mathematical functions to the data, however, it has been demonstrated that the application of such curve fitting procedures can introduce bias, and thus influence the scientific interpretation of the data sets. We investigate the potential for bias associated with the application of three curve fitting programs, known as HPspline, CCGCRV and STL, using CO2, CH4 and O3 data from three atmospheric monitoring field stations. These three curve fitting programs are widely used within the greenhouse gas measurement community to analyse atmospheric time series, but have not previously been compared extensively. The programs were rigorously tested for their ability to accurately represent the salient features of atmospheric time series, their ability to cope with outliers and gaps in the data, and for sensitivity to the values used for the input parameters needed for each program. We find that the programs can produce significantly different curve fits, and these curve fits can be dependent on the input parameters selected. There are notable differences between the results produced by the three programs for many of the decomposed components of the time series, such as the representation of seasonal cycle characteristics and the long-term growth rate. The programs also vary significantly in their response to gaps and outliers in the time series. Overall, we found that none of the three programs were superior, and that each program had its strengths and weaknesses. Thus, we provide a list of recommendations on the appropriate use of these three curve fitting programs for certain types of data sets, and for certain types of analyses and applications. In addition, we recommend that sensitivity tests are performed in any study using curve fitting programs, to ensure that results are not unduly influenced by the input smoothing parameters chosen. Our findings also have implications for previous studies that have relied on a single curve fitting program to interpret atmospheric time series measurements. This is demonstrated by using two other curve fitting programs to replicate work in Piao et al. (2008) on zero-crossing analyses of atmospheric CO2 seasonal cycles to investigate terrestrial biosphere changes. We highlight the importance of using more than one program, to ensure results are consistent, reproducible, and free from bias.
Political Systems and the Perspective on Nursing Education during the Spanish Transition (from the Franco Regime to Democracy). A Contribution based on Nursing History
Authors: Siles José , Solano-Ruiz María del Carmen , Fernández de Freitas Genival , Oguisso Taka ,   Universidad de Alicante
Published: July 2014

El objetivo del estudio consiste en describir los cambios que afectan a enfermería dentro del sistema educativo durante el proceso previo y posterior al establecimiento de la democracia en España. Se parte de la siguiente hipótesis: las diferencias en la organización social y política influenciaron la evolución de la enfermería española manteniéndola dentro de los esquemas del neopositivismo y los enfoques exclusivamente técnicos hasta la llegada de la democracia. La relación entre los sistemas de organización social y política en España ha determinado la evolución de un perfil específico de enfermería en el sistema educativo. Para comprender la integración de asignaturas como la antropología del los cuidados en los programas educativos de la enfermería española hay que se considerar los factores culturales, interculturales y transculturales que constituyen las claves para el entendimiento de los cambios en la educación enfermera haciendo posible la adopción de una perspectiva holística en los currículos. Hasta la llegada del sistema democrático en 1977, la educación en la Enfermería española fue solamente de naturaleza técnica y los roles de las enfermeras se limitaban al cumplimiento de tareas y procedimientos definidos por el pensamiento burocrático característico del paradigma racional tecnológico. Conclusiones: Durante el largo período predemocrático la enfermería española estuvo bajo la influencia del pensamiento neopositivista y técnico, lo cual se plasmaba en los currículos educativos. La integración en los currículos de materias humanísticas y antropológicas que facilitaban el enfoque holístico se produjo tras la integración de la enfermería en la Universidad en 1977 coincidiendo con los inicios de la democracia en España.
Lifestyle and Body Mass Index of an Adult Population in Southern Tamaulipas, Mexico
Authors: Reséndiz Eunice , Aguilera Paulina , Rocher Martha Elia ,   Universidad Autónoma de Tamaulipas
Published: July 2014

La obesidad es una enfermedad multifactorial que involucra aspectos genéticos y ambientales. Objetivo: valorar la influencia del estilo de vida en el índice de masa corporal de una población de adultos. Método: este estudio descriptivo transversal se deriva del proyecto "Hábitos alimentarios y composición corporal (IMC) de adultos con sobrepeso y obesidad"; cuya fase de recolección se realizó entre enero y julio de 2009; preliminarmente se presentan resultados relativos al estilo de vida. Se aplicó una cédula de datos personales y se realizaron mediciones antropométricas. Para el análisis estadístico se utilizaron medidas de tendencia central y se construyeron modelos de regresión lineal múltiple. Resultados: las mayores proporciones tanto del grupo de hombres como del de mujeres, señalaron no fumar, ni realizar algún deporte o ejercicio. En el caso del consumo de alcohol, la mayor proporción del grupo de hombres dijo consumirlo. Los modelos de regresión mostraron que en el total del grupo, así como en el grupo de mujeres, las variables tabaco y ejercicio influyeron en el IMC de los participantes, ya que tuvieron efecto en el modelo de regresión. Dichas variables se correlacionaron significativa e inversamente con el IMC, lo que particularmente llamó la atención en el caso del tabaco. Discusión: el estudio muestra que el estilo de vida influye de manera importante en el IMC de esta población de adultos.
Estilo de vida, índice de masa corporal, obesidad. (Fuente: DeCs, BIREME)