bluuebunny/crossref_metadata_2025 huggingface dataset:
On the Date of the Khazars' Conversion to Judaism and the Chronology of the Kings of the Rus Oleg and Igor. A Study of the Anonymous Khazar Letter from the Genizah of Cairo
Authors: Zuckerman Constantin
Published: February 2011

REB 53 1995 France p. 237-270

C. Zuckerman, On the Date of the Khazars' Conversion lo Judaism and the Chronology of the Kings of the Bus Oleg and Igor. — This study dwells on several key issues in the history of the Khazars : the date of their conversion to Judaism — which is set in 861 or very soon afterwards — , the constitutional changes in the Khazar state, its relations with Byzantium and the Rus. An examination of the wars of the early 940s, which involved the Byzantines, the Khazars and the Rus, leads to a new chronology of the reign of the king of Rus Igor, summer 941 -winter 945, instead of the traditional 912- 945. The reign of Igor's predecessor, Oleg (traditional dates 879-912), moves up to little before 911-summer 941 (died in the winter 944/5). The history of the «Rus' of Kiev» is consequently abridged by at least forty years.
Factors Contributing to Formation of Edema in Volume Overloaded Continuous Ambulatory Peritoneal Dialysis Patients
Authors: Tang Wen , Xue Tian , Lu Xin-Hong , Luo Ya-Jun , Wang Tao
Published: February 2011

Background

Volume control is critical for the success of peritoneal dialysis (PD) but dry weight in PD has been difficult to obtain. Edema free is, in general, accepted clinically as a target for volume control in PD patients. However, PD patients can be free of edema despite significant volume overload. The present study investigates the possible factors that influence the formation of pitting edema in volume-overloaded PD patients.

Methods

In this cross-sectional study, patients’ fluid status was evaluated by multifrequency bioelectrical impedance spectroscopy analysis. Values for overhydration were obtained. Patients with overhydration ≥ 2.0 kg were considered volume overloaded and were eligible for inclusion. From 1 March 2009 to 1 December 2009, a total of 96 patients on continuous ambulatory PD were included. Endothelial function was evaluated by flow-mediated dilatation (FMD). Other clinical indicators, such as blood pressure, dialysis adequacy, nutrition status, and biochemical parameters, were recorded. Patients were divided into 2 groups based on edema status: the edema group ( n = 35 volume-overloaded patients with bilateral pitting edema) and the non-edema group ( n = 61 volume-overloaded patients without bilateral pitting edema).

Results

Overhydration in the edema group was significantly higher than in the non-edema group (4.28 ± 1.75 kg vs 3.12 ± 0.81 kg, p < 0.001), whereas both FMD and serum albumin in the edema group were significantly lower than in the non-edema group (6.65% ± 5.2% vs 10.3% ± 5.1%, p = 0.001; 37.6 ± 4.2 g/L vs 39.3 ± 3.5 g/L, p = 0.047, respectively). Edema status (edema = 1, non-edema = 0) was positively correlated with overhydration ( r = 0.341, p < 0.001), gender (male = 1, female = 2: r = 0.184, p = 0.072), and total fluid removal ( r = 0.188, p = 0.074) and negatively correlated with endothelial function, as assessed by FMD ( r = -0.33, p = 0.001), and serum albumin ( r = -0.18, p = 0.055). Logistic regression analysis showed that FMD [odds ratio (OR) 0.90, 95% confidence interval (CI) 0.81 - 0.99; p = 0.036], gender (male = 1, female = 2: OR 4.06, 95% CI 1.23 - 13.35; p = 0.021), overhydration (OR 3.06, 95% CI 1.53 - 6.13; p = 0.002), and serum albumin (OR 0.86, 95% CI 0.75 - 0.99; p = 0.035) were independent factors affecting the edema status of the study population.

Conclusion

Our study showed that endothelial function (assessed by FMD), gender, serum albumin, and over hydration are independent determinants of edema status in PD patients. This may explain why some PD patients can maintain free of edema despite significant volume overload.
Clinical Consequences of Delayed Addition of Adalimumab to Methotrexate Therapy Over 5 Years in Patients with Rheumatoid Arthritis
Authors: KEYSTONE EDWARD C. , KAVANAUGH ARTHUR , WEINBLATT MICHAEL E. , PATRA KAUSHIK , PANGAN AILEEN L.
Published: February 2011

Objective.

This Year 5 analysis of an open-label extension (OLE) study assessed radiographic progression, clinical efficacy, and safety of adalimumab with concomitant methotrexate (MTX) for patients with active rheumatoid arthritis.

Methods.

In a double-blind study (DE019, NCT00195702), inadequate responders to MTX were randomized to MTX plus either adalimumab 40 mg eow, adalimumab 20 mg weekly, or placebo for 52 weeks. Eligible patients entered an ongoing OLE and received adalimumab 40 mg eow plus MTX. Longterm efficacy and safety were evaluated.

Results.

Of 457 patients who had enrolled in the OLE, 304 remained in the study at Year 5, including 112, 107, and 85 from the original adalimumab 40 mg, adalimumab 20 mg, and placebo groups, respectively. Year 5 radiographs demonstrated mean changes in modified total Sharp score for the original adalimumab 40 mg eow and 20 mg weekly groups of 0.8 and 2.6, respectively, versus 3.9 for placebo; 58% from the adalimumab 40 mg eow group had no radiographic progression versus 40% of those who initially received placebo. Of patients who received adalimumab 40 mg eow for 5 years, 26.1% achieved clinical remission (Disease Activity Score 28-joint count < 2.6), had no radio graphic progression (change in modified total Sharp score ≤ 0.5), and had normal function (Health Assessment Questionnaire ≤ 0.5), versus 11.9% of those who initially received placebo. Serious infection rate for 553 patients who received at least one dose of adalimumab was 4.4/100 patient-years.

Conclusion.

A 52-week delay in adding adalimumab to MTX led to worse radiographic, functional, and clinical outcomes at Year 5 for most patients who initially received placebo instead of adalimumab.
Intermodal and inter-genre translation in scientific writing
Authors: Sionis Claude
Published: January 2011

L’article découle de l’observation du travail d’un groupe de scientifiques français confirmés qui participaient à un cours d’anglais pour universitaires orienté vers la rédaction d’articles de recherche. Le scientifique doit être plusieurs personnes simultanément et en alternance: enseignant de son propre domaine, membre contesté et contestataire d’une équipe, vulgarisateur de sa recherche pour des spécialistes d’autres domaines ou même pour ses proches, etc. L’une des observations nombreuses et souvent inattendues de l’étude est le besoin pour ce scientifique de se livrer constamment à une traduction intermodale et intergénérique en fonction des changements de situations, de milieux, de moments de la journée, etc. L’article tente de montrer le fonctionnement de ce processus de traduction pendant le cours d’anglais pour universitaires et de défendre l’idée que ce processus est une composante inhérente et essentielle de l’évolution du savoir conceptuel et de sa représentation.
Quelques approches sociologiques de réseaux sociaux
Authors: Bagla-Gökalp Lusin
Published: January 2011

Le présent article poursuit un double objectif. Il présente les différentes approches sociologiques du concept-image de réseau qui prolifèrent depuis les années soixante-dix, donnant ainsi l’impression d’un domaine émergent. Il souhaite montrer qu’il ne s’agit, cependant, ni d’un phénomène inédit ni d’un nouvel objet d’étude. Après avoir résumé les utilisations précoces de ce concept ainsi que ses différentes sources d’inspiration, l’article présente et commente l’essentiel des approches qui y ont recours en sociologie économique, en sociologie des organisations et en sociologie de l’innovation, à partir de problématiques, de méthodes et d’outils d’analyse différents. Si les réseaux ont toujours existé et si divers corps de littérature en ont rendu compte, pour des raisons expliquées dans l’article, le concept-image de réseau a désormais acquis un nouveau statut qui sert de grille de lecture pour les diverses analyses des rapports sociaux et facilite l’interdisciplinarité.
De la répulsion à la fascination : l’Internet et les représentations des NTIC
Authors: Serfaty Viviane
Published: January 2011

L’Internet suscite des interprétations contradictoires mais il est aussi l’objet d’une immense quantité de discours qui véhiculent un ensemble de représentations sociales. Leur étude permet d’identifier les structures profondes de l’imaginaire qui sous-tend l’Internet. L’utopie et l’anti-utopie sont les deux notions antinomiques au travers desquelles l’Internet est perçu et qui sont à l’origine de véritables conflits d’imaginaires. L’étude des discours sur l’Internet fait également apparaître trois grands paradigmes traversés par l’ambivalence puisqu’ils se rattachent au clivage utopie/anti-utopie. Il s’agit du paradigme culturel et communicationnel, du paradigme de l’anarchie et du paradigme spatio-temporel. L’exploration de l’histoire des idées permet de retrouver les origines de cette ambivalence et d’identifier l’existence de représentations sociales stéréotypées présentes sous des formes quasiment identiques depuis l’invention des premiers outils de communication modernes au XVIIIe siècle. Le sens et la fonction de ces conflits d’imaginaire ainsi que des stéréotypes sont analysés dans leur rapport aux NTIC et singulièrement à l’Internet.
Épistémologie et méthodologie de la recherche dans le secteur LANSAD : qu’apporterait une harmonisation des pratiques ?
Authors: Narcy-Combes Jean-Paul , Narcy-Combes Marie-Françoise
Published: January 2011

Cet article a pour objectif de suggérer des conditions pour que les recherches du secteur aient une plus grande lisibilité tant pour les chercheurs du domaine que pour ceux des autres domaines. Il convient aussi d'accroître notre légitimité scientifique par des pratiques rigoureuses. Une première conséquence est, à la suite d’E. Morin, de réintégrer l'observateur dans son observation et de prendre la mesure des biais que son point de vue et ses options introduisent dans les résultats. Un modèle du cycle de la recherche est présenté ; il prend en compte ce qui précède et une conception « polythéiste » des références aux diverses théories vers lesquelles nous nous tournons. Des implications pratiques sont mises en avant, en particulier en ce qui concerne la rédaction des thèses. Enfin, les relations avec les chercheurs des autres domaines de référence ont été abordées. Il s'agit de trouver la complémentarité des regards et d'éviter toute velléité d'ignorance de leurs critères ou toute tendance à œuvrer dans l'ancillarité.
Teacher talking time: couldn’t there be more?
Authors: Cooke Ray
Published: January 2011

Depuis la fin des années 1970, il est fortement question dans l’enseignement et l’apprentissage des langues vivantes de minimiser le temps de parole de l’enseignant pour optimiser le temps d’apprentissage en groupe. En effet, le temps passé à écouter l’enseignant serait autant de temps perdu pour la communication entre apprenants et pour le travail personnel. Les fondements pédagogiques d’une telle opinion paraissent dorénavant acquis. En revanche, la maturité grandissante de l’anglais de spécialité en France, et de ses praticiens, permettrait d’atténuer cette position. L’auteur plaide donc en faveur d’aspects aussi qualitatifs que quantitatifs de cette problématique. Il émet l’hypothèse qu’il existe déjà un ensemble de conditions apparemment disparates mais complémentaires qui amènerait les praticiens de l’anglais de spécialité en France à se sentir plus à l’aise pour augmenter leurs temps de parole en certaines circonstances.
L’évaluation de la compréhension et la problématique de la restitution
Authors: Isani Shaeda
Published: January 2011

Cet article se donne comme objectif d’explorer le problème de contamination inhérente à l’évaluation des compétences de compréhension de la langue étrangère. Nous examinons les pratiques actuellement en vigueur concernant la restitution active et passive et les différents formats utilisés, leur adéquation par rapport au contexte d’une évaluation des compétences communicatives et les trois critères docimologiques de validité, de fiabilité et de facilité de mise en œuvre.
Human Cord Blood CD4+CD25hi Regulatory T Cells Suppress Prenatally Acquired T Cell Responses toPlasmodium falciparumAntigens
Authors: Mackroth Maria S. , Malhotra Indu , Mungai Peter , Koech Davy , Muchiri Eric , King Christopher L.
Published: January 2011

In malaria endemic regions, a fetus is often exposed in utero to Plasmodium falciparum blood-stage Ags. In some newborns, this can result in the induction of immune suppression. We have previously shown these modulated immune responses to persist postnatally, with a subsequent increase in a child’s susceptibility to infection. To test the hypothesis that this immune suppression is partially mediated by malaria-specific regulatory T cells (Tregs) in utero, cord blood mononuclear cells (CBMC) were obtained from 44 Kenyan newborns of women with and without malaria at delivery. CD4+CD25lo T cells and CD4+CD25hi FOXP3+ cells (Tregs) were enriched from CBMC. Treg frequency and HLA-DR expression on Tregs were significantly greater for Kenyan as compared with North American CBMC (p < 0.01). CBMC/CD4+ T cells cultured with P. falciparum blood-stage Ags induced production of IFN-γ, IL-13, IL-10, and/or IL-5 in 50% of samples. Partial depletion of CD25hi cells augmented the Ag-driven IFN-γ production in 69% of subjects with malaria-specific responses and revealed additional Ag-reactive lymphocytes in previously unresponsive individuals (n = 3). Addition of Tregs to CD4+CD25lo cells suppressed spontaneous and malaria Ag-driven production of IFN-γ in a dose-dependent fashion, until production was completely inhibited in most subjects. In contrast, Tregs only partially suppressed malaria-induced Th2 cytokines. IL-10 or TGF-β did not mediate this suppression. Thus, prenatal exposure to malaria blood-stage Ags induces Tregs that primarily suppress Th1-type recall responses to P. falciparum blood-stage Ags. Persistence of these Tregs postnatally could modify a child’s susceptibility to malaria infection and disease.
Innate Immune Function of the Adherens Junction Protein p120-Catenin in Endothelial Response to Endotoxin
Authors: Wang Yan-lei , Malik Asrar B. , Sun Yu , Hu Sanyuan , Reynolds Albert B. , Minshall Richard D. , Hu Guochang
Published: January 2011

Sepsis-induced acute lung injury is a common clinical disorder in critically ill patients that is associated with high mortality. In this study, we investigated the role of p120-catenin (p120), a constituent of endothelial adherens junctions, in regulating the innate immune function of lungs. In mice in which acute lung injury was induced by i.p. administration of LPS, we observed a rapid decrease in the expression of p120 in lungs. The p120 protein expression was correlated inversely with severity of inflammation. Suppression of p120 expression in lung endothelial cells in mice using small interfering RNA resulted in high sensitivity to endotoxin and greatly increased the mortality compared with controls. Knockdown of p120 also increased the expression of ICAM-1, neutrophil recruitment, production of cytokines TNF-α and IL-6, pulmonary transvascular protein permeability, and lung water content in response to LPS. We demonstrated that endothelial p120 modulates lung innate immune function by interfering with the association of TLR4 with its adaptor MyD88 to block TLR4 signaling and NF-κB activation in endothelial cells. In conclusion, these studies have uncovered a novel innate immune function of endothelial p120 in downregulating the lung inflammatory response to endotoxin through the suppression of TLR4 signaling.
The Critical Role of IL-1 Receptor-Associated Kinase 4-Mediated NF-κB Activation in Modified Low-Density Lipoprotein-Induced Inflammatory Gene Expression and Atherosclerosis
Authors: Kim Tae Whan , Febbraio Maria , Robinet Peggy , DuGar Brandon , Greene Diane , Cerny Anna , Latz Eicke , Gilmour Raymond , Staschke Kirk , Chisolm Guy , Fox Paul L. , DiCorleto Paul E. , Smith Jonathan D. , Li Xiaoxia
Published: January 2011

Exciting discoveries related to IL-1R/TLR signaling in the development of atherosclerosis plaque have triggered intense interest in the molecular mechanisms by which innate immune signaling modulates the onset and development of atherosclerosis. Previous studies have clearly shown the definitive role of proinflammatory cytokine IL-1 in the development of atherosclerosis. Recent studies have provided direct evidence supporting a link between innate immunity and atherogenesis. Although it is still controversial about whether infectious pathogens contribute to cardiovascular diseases, direct genetic evidence indicates the importance of IL-1R/TLR signaling in atherogenesis. In this study, we examined the role of IL-1R–associated kinase 4 (IRAK4) kinase activity in modified low-density lipoprotein (LDL)-mediated signaling using bone marrow-derived macrophage as well as an in vivo model of atherosclerosis. First, we found that the IRAK4 kinase activity was required for modified LDL-induced NF-κB activation and expression of a subset of proinflammatory genes but not for the activation of MAPKs in bone marrow-derived macrophage. IRAK4 kinase-inactive knockin (IRAK4KI) mice were bred onto ApoE−/− mice to generate IRAK4KI/ApoE−/− mice. Importantly, the aortic sinus lesion formation was impaired in IRAK4KI/ApoE−/− mice compared with that in ApoE−/− mice. Furthermore, proinflammatory cytokine production was reduced in the aortic sinus region of IRAK4KI/ApoE−/− mice compared with that in ApoE−/− mice. Taken together, our results indicate that the IRAK4 kinase plays an important role in modified LDL-mediated signaling and the development of atherosclerosis, suggesting that pharmacological inhibition of IRAK4 kinase activity might be a feasible approach in the development of antiatherosclerosis drugs.
Conventional Dendritic Cells Mount a Type I IFN Response againstCandidaspp. Requiring Novel Phagosomal TLR7-Mediated IFN-β Signaling
Authors: Bourgeois Christelle , Majer Olivia , Frohner Ingrid E. , Lesiak-Markowicz Iwona , Hildering Kwang-Soo , Glaser Walter , Stockinger Silvia , Decker Thomas , Akira Shizuo , Müller Mathias , Kuchler Karl
Published: February 2011

Human fungal pathogens such as the dimorphic Candida albicans or the yeast-like Candida glabrata can cause systemic candidiasis of high mortality in immunocompromised individuals. Innate immune cells such as dendritic cells and macrophages establish the first line of defense against microbial pathogens and largely determine the outcome of infections. Among other cytokines, they produce type I IFNs (IFNs-I), which are important modulators of the host immune response. Whereas an IFN-I response is a hallmark immune response to bacteria and viruses, a function in fungal pathogenesis has remained unknown. In this study, we demonstrate a novel mechanism mediating a strong IFN-β response in mouse conventional dendritic cells challenged by Candida spp., subsequently orchestrating IFN-α/β receptor 1-dependent intracellular STAT1 activation and IFN regulatory factor (IRF) 7 expression. Interestingly, the initial IFN-β release bypasses the TLR 4 and TLR2, the TLR adaptor Toll/IL-1R domain-containing adapter-inducing IFN-β and the β-glucan/phagocytic receptors dectin-1 and CD11b. Notably, Candida-induced IFN-β release is strongly impaired by Src and Syk family kinase inhibitors and strictly requires completion of phagocytosis as well as phagosomal maturation. Strikingly, TLR7, MyD88, and IRF1 are essential for IFN-β signaling. Furthermore, in a mouse model of disseminated candidiasis we show that IFN-I signaling promotes persistence of C. glabrata in the host. Our data uncover for the first time a pivotal role for endosomal TLR7 signaling in fungal pathogen recognition and highlight the importance of IFNs-I in modulating the host immune response to C. glabrata.
Cutting Edge: Cyclic Polypeptide and Aminoglycoside Antibiotics Trigger IL-1β Secretion by Activating the NLRP3 Inflammasome
Authors: Allam Ramanjaneyulu , Darisipudi Murthy Narayana , Rupanagudi Khader Valli , Lichtnekert Julia , Tschopp Jurg , Anders Hans-Joachim
Published: January 2011

Clinical use of antibiotics is based on their capacity to inhibit bacterial growth via bacteriostatic or bacteriocidal effects. In this article, we show that the aminoglycoside antibiotic neomycin, the cyclic lipopeptide antibiotic polymyxin B, and the cyclic peptide antibiotics gramicidin and tyrothricin can induce IL-1β secretion in bone marrow dendritic cells and macrophages. LPS priming was required to trigger the transcription and translation of pro–IL-1β but was independent of TNFR or IL-1R signaling. All four antibiotics required the NLRP3 inflammasome, the adaptor ASC, and caspase-1 activation to secrete IL-1β, a process that depended on potassium efflux but was independent of P2X7 receptor. All four antibiotics induced neutrophil influx into the peritoneal cavity of mice, which required NLRP3 only in the case of polymyxin B. Together, certain antibiotics have the potential to directly activate innate immunity of the host.
The Endocannabinoid 2-Arachidonoyl-Glycerol Activates Human Neutrophils: Critical Role of Its Hydrolysis and De Novo Leukotriene B4 Biosynthesis
Authors: Chouinard François , Lefebvre Julie S. , Navarro Pauline , Bouchard Line , Ferland Claudine , Lalancette-Hébert Mélanie , Marsolais David , Laviolette Michel , Flamand Nicolas
Published: January 2011

Although endocannabinoids are important players in nociception and obesity, their roles as immunomodulators remain elusive. The main endocannabinoids described to date, namely 2-arachidonoyl-glycerol (2-AG) and arachidonyl-ethanolamide (AEA), induce an intriguing profile of pro- and anti-inflammatory effects. This could relate to cell-specific cannabinoid receptor expression and/or the action of endocannabinoid-derived metabolites. Importantly, 2-AG and AEA comprise a molecule of arachidonic acid (AA) in their structure and are hydrolyzed rapidly. We postulated the following: 1) the released AA from endocannabinoid hydrolysis would be metabolized into eicosanoids; and 2) these eicosanoids would mediate some of the effects of endocannabinoids. To confirm these hypotheses, experiments were performed in which freshly isolated human neutrophils were treated with endocannabinoids. Unlike AEA, 2-AG stimulated myeloperoxidase release, kinase activation, and calcium mobilization by neutrophils. Although 2-AG did not induce the migration of neutrophils, it induced the release of a migrating activity for neutrophils. 2-AG also rapidly (1 min) induced a robust biosynthesis of leukotrienes, similar to that observed with AA. The effects of 2-AG were not mimicked nor prevented by cannabinoid receptor agonists or antagonists, respectively. Finally, the blockade of either 2-AG hydrolysis, leukotriene (LT) B4 biosynthesis, or LTB4 receptor 1 activation prevented all the effects of 2-AG on neutrophil functions. In conclusion, we demonstrated that 2-AG potently activates human neutrophils. This is the consequence of 2-AG hydrolysis, de novo LTB4 biosynthesis, and an autocrine activation loop involving LTB4 receptor 1.
Chikungunya Virus Envelope-Specific Human Monoclonal Antibodies with Broad Neutralization Potency
Authors: Warter Lucile , Lee Chia Yin , Thiagarajan Rekha , Grandadam Marc , Lebecque Serge , Lin Raymond T. P. , Bertin-Maghit Sebastien , Ng Lisa F. P. , Abastado Jean-Pierre , Desprès Philippe , Wang Cheng-I , Nardin Alessandra
Published: January 2011

Chikungunya virus (CHIKV) is an alphavirus responsible for numerous epidemics in Africa and Asia. Infection by CHIKV is often characterized by long-lasting, incapacitating arthritis, and some fatal cases have been described among elderly and newborns. Currently, there is no available vaccine or specific treatment against CHIKV. Blood B cells from a donor with history of CHIKV infection were activated, immortalized, amplified, and cloned. Two human mAbs against CHIKV, 5F10 and 8B10, were identified, sequenced, and expressed in recombinant form for characterization. In a plaque reduction neutralization test, 5F10 and 8B10 show mean IC50 of 72 and 46 ng/ml, respectively. Moreover, both mAbs lead to a strong decrease in extracellular spreading of infectious viral particles from infected to uninfected cells. Importantly, the mAbs neutralize different CHIKV isolates from Singapore, Africa, and Indonesia, as well as O’nyong-nyong virus, but do not recognize other alphaviruses tested. Both mAbs are specific for the CHIKV envelope: 5F10 binds to the E2 glycoprotein ectodomain and 8B10 to E1 and/or E2. In conclusion, these two unique human mAbs strongly, broadly, and specifically neutralize CHIKV infection in vitro and might become possible therapeutic tools against CHIKV infection, especially in individuals at risk for severe disease. Importantly, these mAbs will also represent precious tools for future studies on host–pathogen interactions and the rational design of vaccines against CHIKV.
Conformational Melding Permits a Conserved Binding Geometry in TCR Recognition of Foreign and Self Molecular Mimics
Authors: Borbulevych Oleg Y. , Piepenbrink Kurt H. , Baker Brian M.
Published: February 2011

Molecular mimicry between foreign and self Ags is a mechanism of TCR cross-reactivity and is thought to contribute to the development of autoimmunity. The αβ TCR A6 recognizes the foreign Ag Tax from the human T cell leukemia virus-1 when presented by the class I MHC HLA-A2. In a possible link with the autoimmune disease human T cell leukemia virus-1–associated myelopathy/tropical spastic paraparesis, A6 also recognizes a self peptide from the neuronal protein HuD in the context of HLA-A2. We found in our study that the complexes of the HuD and Tax epitopes with HLA-A2 are close but imperfect structural mimics and that in contrast with other recent structures of TCRs with self Ags, A6 engages the HuD Ag with the same traditional binding mode used to engage Tax. Although peptide and MHC conformational changes are needed for recognition of HuD but not Tax and the difference of a single hydroxyl triggers an altered TCR loop conformation, TCR affinity toward HuD is still within the range believed to result in negative selection. Probing further, we found that the HuD–HLA-A2 complex is only weakly stable. Overall, these findings help clarify how molecular mimicry can drive self/nonself cross-reactivity and illustrate how low peptide-MHC stability can permit the survival of T cells expressing self-reactive TCRs that nonetheless bind with a traditional binding mode.
CX3CR1+ Lung Mononuclear Phagocytes Spatially Confined to the Interstitium Produce TNF-α and IL-6 and Promote Cigarette Smoke-Induced Emphysema
Authors: Xiong Zeyu , Leme Adriana S. , Ray Prabir , Shapiro Steven D. , Lee Janet S.
Published: January 2011

Increased numbers of macrophages are found in the lungs of smokers and those with chronic obstructive pulmonary disease. Experimental evidence shows the central role of macrophages in elaboration of inflammatory mediators such as TNF-α and the progression toward cigarette smoke-induced emphysema. We investigated the role of CX3CR1 in recruitment of mononuclear phagocytes, inflammatory cytokine responses, and tissue destruction in the lungs after cigarette smoke exposure. Using mice in which egfp is expressed at the locus of the cx3cr1 gene, we show that alveolar macrophages increased transmembrane ligand CX3CL1 expression and soluble CX3CL1 was detectable in the airspaces, but cx3cr1GFP/GFP and cx3cr1GFP/+ mice failed to show recruitment of CX3CR1+ cells into the airspaces with cigarette smoke. In contrast, cigarette smoke increased the accumulation of CX3CR1+CD11b+ mononuclear phagocytes that were spatially confined to the lung interstitium and heterogenous in their expression of CD11c, MHC class II, and autofluorescent property. Although an intact CX3CL1–CX3CR1 pathway amplified the percentage of CX3CR1+CD11b+ mononuclear phagocytes in the lungs, it was not essential for recruitment. Rather, functional CX3CR1 was required for a subset of tissue-bound mononuclear phagocytes to produce TNF-α and IL-6 in response to cigarette smoke, and the absence of functional CX3CR1 protected mice from developing tissue-destructive emphysema. Thus, CX3CR1+ “tissue resident” mononuclear phagocytes initiate an innate immune response to cigarette smoke by producing TNF-α and IL-6 and are capable of promoting emphysema.
Cutting Edge: Tubulin α Functions as an Adaptor in NFAT–Importin β Interaction
Authors: Ishiguro Kazuhiro , Ando Takafumi , Maeda Osamu , Watanabe Osamu , Goto Hidemi
Published: January 2011

Upon T cell stimulation, NFAT is dephosphorylated by calcineurin, leading to nuclear translocation via NFAT–importin β interaction. Whereas the process of NFAT dephosphorylation has been well researched, the molecular mechanism of NFAT–importin β interaction remains unknown. In contrast to NF-κB and STAT, no importin α family members have been reported as adaptor proteins for NFAT. Our study shows that tubulin α, but not tubulin β, binds to the N-terminal region of NFAT containing the regulatory and Rel homology domains. Importin β interacts with the NFAT–tubulin α complex rather than NFAT or tubulin α alone, resulting in cotranslocation of NFAT and tubulin α into the nucleus. Furthermore, the interaction is suppressed by acetate-induced tubulin α acetylation at lysine 40. In conclusion, tubulin α functions as an adaptor in NFAT–importin β interaction, and this function is regulated by acetate-induced acetylation.
Cutting Edge: Persistently Open Chromatin at Effector Gene Loci in Resting Memory CD8+ T Cells Independent of Transcriptional Status
Authors: Zediak Valerie P. , Johnnidis Jonathan B. , Wherry E. John , Berger Shelley L.
Published: January 2011

Memory CD8+ T cells are characterized by more rapid and robust effector function upon infection compared with naive T cells, but factors governing effector gene responsiveness are incompletely understood. We sought to understand transcriptional control of the effector genes IFN-γ (Ifng), granzyme B (Gzmb), and perforin 1 (Prf1) in murine memory CD8+ T cells by characterizing their transcriptional profiles and chromatin states during lymphocytic choriomeningitis virus infection. Each effector gene has a distinct transcriptional profile in resting memory cells and following restimulation. Primary infection leads to reduced nucleosomal density near the transcription start sites and reduced H3K27 methylation throughout the Ifng and Gzmb loci, and these chromatin changes persist in the memory phase. Despite similarities in chromatin at the memory stage, PolII recruitment and continuous transcription occur at the Ifng locus but not the Gzmb locus. We propose that these chromatin changes poise effector genes for rapid upregulation, but are insufficient for PolII recruitment and transcription.
The Disgust Threat Interpretation Bias is Not Moderated by Anxiety & Disgust Sensitivity
Authors: Leathers-Smith Emily , Davey Graham C. L.
Published: January 2011

The present study used the homophone spelling task to investigate whether induced disgust facilitates an interpretational bias. In addition, it considered whether factors related to anxiety and disgust moderate this disgust-generated threat-interpretation bias. Participants were assigned to one of three groups in which they experienced a neutral, anxiety, or disgust mood induction. Participants subsequently completed the homophone spelling task. Results indicated that participants who experienced induced anxiety or disgust interpreted significantly more neutral/threatening homophones in a threatening way, relative to participants who experienced a neutral mood induction. This supports the proposal that experienced disgust generates a threat interpretation bias and implicates disgust as a causal factor involved in anxious psychopathology. Subsequent analyses also indicated that measures of anxiety sensitivity, generalized anxiety, and disgust sensitivity and propensity did not moderate the disgust generated interpretation bias. Suggestions as to why this may have occurred are discussed, along with proposals for future research into the possible role of disgust in anxious psychopathology.
An Experimental Investigation of Factors Involved in Excessive Reassurance Seeking: The Effects of Perceived Threat, Responsibility and Ambiguity on Compulsive Urges and Anxiety
Authors: Parrish Chris L. , Radomsky Adam S.
Published: January 2011

Excessive reassurance seeking is a common problem among individuals diagnosed with Obsessive-Compulsive Disorder (OCD). Given the proposed functional similarities between OCD-related reassurance seeking and compulsive checking (Rachman, 2002), it was hypothesized that some of the factors contributing to the onset and maintenance of episodes of these two behaviours might be shared, whereas other factors (e.g., ambiguity of feedback) may play a unique role in the persistence of reassurance seeking. The current experiment examined how manipulations of threat, responsibility, and ambiguity of feedback impacted upon non-clinical participants' (N = 176) anxiety and compulsive urges (to seek reassurance and to check) in a series of experimental vignettes. Consistent with hypotheses, higher levels of perceived threat, responsibility and ambiguity of feedback were associated with higher anxiety and compulsive urges. Results are discussed in terms of cognitive-behavioural models of, and treatments for OCD.
Substance Use to Regulate Affective Experiences in Posttraumatic Stress Disorder: A Review of Laboratory-Based Studies
Authors: Smith Rose C. , Feldner Matthew T. , Badour Christal L.
Published: January 2011

Posttraumatic stress disorder (PTSD) and elevated levels of substance use (SU) regularly co-occur and are increasingly viewed as functionally related. While PTSD and SU may be comorbid for a variety of reasons, central theoretical work posits that individuals with PTSD use substances to regulate affective experiences. In particular, two theories of psychopathology and SU comorbidity - the Self Medication Hypothesis and the Negative Reinforcement Model - make distinct predictions about the role of SU in regulating affective or emotional experiences. Laboratory methods employed to study PTSD and SU are well suited to test these unique predictions by using in vivo, experimental paradigms. The current review delineates the distinct predications made by these models and reviews the common methods used to study PTSD-SU comorbidity in the laboratory. Studies that have employed these methods are then reviewed and discussed in relation to theoretical predictions. Evidence supports facets of both the Self Medication Hypothesis and the Negative Reinforcement Model, suggesting a complex relation between PTSD and SU, which may be influenced by the particular substance of use, type of affective experience, and related factors such as substance-related withdrawal and risk taking propensity.
Test of the Metacognitive Model of Generalized Anxiety Disorder in Anxiety-Disordered Adolescents
Authors: Ellis Danielle M. , Hudson Jennifer L.
Published: January 2011

The metacognitive model of generalized anxiety disorder (GAD) suggests that positive and negative beliefs about worry contribute to pathological worry. This study explores the relationship between metacognition and worry in youth aged 12–17 years. The sample consisted of 81 anxiety-disordered youth, with 70 mothers included, and 42 non-clinical controls, with 40 mothers included. Metacognitive beliefs were associated with emotional symptoms. Both GAD and non-GAD youth, and anxious and anxious/depressed youth, reported higher metacognitive beliefs compared to non-clinical controls, but there were no differences in metacognition between emotional disorders. There was no significant association between age and metacognition, and there were no gender differences in metacognition. These results provide partial support for using the metacognitive model of GAD to understand worry in young people.
Water content of aged aerosol
Authors: Engelhart G. J. , Hildebrandt L. , Kostenidou E. , Mihalopoulos N. , Donahue N. M. , Pandis S. N.
Published: February 2011

Abstract. The composition and physical properties of aged atmospheric aerosol were characterized at a remote sampling site on the northern coast of Crete, Greece during the Finokalia Aerosol Measurement Experiment in May 2008 (FAME-2008). A reduced Dry-Ambient Aerosol Size Spectrometer (DAASS) was deployed to measure the aerosol water content and volumetric growth factor of fine particulate matter. The particles remained wet even at relative humidity (RH) as low as 20%. The aerosol was acidic during most of the measurement campaign, which likely contributed to the water uptake at low RH. The water content observations were compared to the thermodynamic model E-AIM, neglecting any contribution of the organics to aerosol water content. There was good agreement between the water measurements and the model predictions. Adding the small amount of water associated with the organic aerosol based on monoterpene water absorption did not change the quality of the agreement. These results strongly suggest that the water uptake by aged organic aerosol is relatively small (a few percent of the total water for the conditions during FAME-08) and generally consistent with what has been observed in laboratory experiments. The water concentration measured by a Q-AMS was well correlated with the DAASS measurements and in good agreement with the predicted values for the RH of the Q-AMS inlet. This suggests that, at least for the conditions of the study, the Q-AMS can provide valuable information about the aerosol water concentrations if the sample is not dried.
CO source contribution analysis for California during ARCTAS-CARB
Authors: Pfister G. G. , Avise J. , Wiedinmyer C. , Edwards D. P. , Emmons L. K. , Diskin G. D. , Podolske J. , Wisthaler A.
Published: February 2011

Abstract. Air pollution is of concern in many parts of California and is impacted by both local emissions and also by pollution inflow from the Pacific. In this study, we use the regional chemical transport model WRF-Chem V3.2 to examine the CO budget over California. We include model CO tracers for different emission sources in the model, which allow estimating the relative importance of local sources versus pollution inflow on the distribution of CO at the surface and in the free troposphere. The focus of our study is on the 15 June–15 July 2008 time period, which coincides with the aircraft deployment of the NASA Arctic Research of the Composition of the Troposphere from Aircraft and Satellites (ARCTAS) mission over California. Model simulations are evaluated using these aircraft observations as well as satellite retrievals and surface observations of CO. Evaluation results show that the model overall predicts the observed CO fields well, but points towards an underestimate of CO from the fires in Northern California, which had a strong influence during the study period, and towards a slight overestimate of CO from pollution inflow and local anthropogenic sources. The analysis of the CO budget over California reveals that inflow of CO explains on average 53 ± 21% of surface CO during the study period, compared to 22 ± 18% for local anthropogenic sources and 18 ± 22% for fires. In the free troposphere, the average CO contributions are estimated as 78 ± 16% for CO inflow, 6 ± 4% for CO from local anthropogenic sources and 11 ± 13% for CO from fires.
The influence of iron and light on net community production in the Subantarctic and Polar Frontal Zones
Authors: Cassar N. , DiFiore P. J. , Barnett B. A. , Bender M. L. , Bowie A. R. , Tilbrook B. , Petrou K. , Westwood K. J. , Wright S. W. , Lefevre D.
Published: February 2011

Abstract. The roles of iron and light in controlling biomass and primary productivity are clearly established in the Southern Ocean. However, their influence on net community production (NCP) and carbon export remains to be quantified. To improve our understanding of NCP and carbon export production in the Subantarctic Zone (SAZ) and the northern reaches of the Polar Frontal Zone (PFZ), we conducted continuous onboard determinations of NCP as part of the Sub-Antarctic Sensitivity to Environmental Change (SAZ-Sense) study, which occurred in January–February 2007. Biological O2 supersaturation was derived from measuring O2/Ar ratios by equilibrator inlet mass spectrometry. Based on these continuous measurements, NCP during the austral summer 2007 in the Australian SAZ was approximately 43 mmol O2 m−2 d−1. NCP showed significant spatial variability, with larger values near the Subtropical front, and a general southward decrease. For shallower mixed layers (<50 m), dissolved Fe concentrations and Fe sufficiency, estimated from variable fluorescence, correlated strongly with NCP. The strong correlation between NCP and dissolved Fe may be difficult to interpret because of the correlation of dissolved Fe to MLD and because the concentration of iron may not be a good indicator of its availability. At stations with deeper mixed layers, NCP was consistently low, regardless of iron sufficiency, consistent with light availability also being an important control of NCP. Our new observations provide independent evidence for the critical roles of iron and light in mediating carbon export from the Southern Ocean mixed layer.
Predicting outcomes of lupus nephritis with tubulointerstitial inflammation and scarring
Authors: Hsieh Christine , Chang Anthony , Brandt Daniel , Guttikonda Riteesha , Utset Tammy O. , Clark Marcus R.
Published: January 2011

Objective

In lupus nephritis, glomerular injury correlates poorly with progression to renal failure. While the tubulointerstitium is also commonly involved, the importance of such involvement is not well defined. Therefore, we developed a simple method to assess the prognostic utility of measuring tubulointerstitial inflammation (TI).

Methods

Sixty‐eight systemic lupus erythematosus patients with lupus nephritis were enrolled. Tubulointerstitial lymphocytic infiltrates were quantitated both by anti‐CD45 antibody staining and standard histochemical staining. Followup data were obtained and survival analysis was carried out to determine which histologic features were predictive of subsequent renal failure.

Results

By CD45 staining, TI was a common pathologic finding, with 72% of biopsies having moderate or severe involvement. The extent of TI correlated with serum creatinine, but not with double‐stranded DNA antibodies, serum C3, or glomerular inflammation. TI severity, but not glomerular injury, identified patients at greater risk for renal failure (P = 0.02). A high National Institutes of Health (NIH) chronicity index also identified patients at risk for renal failure. However, when the glomerular and tubulointerstitial subcomponents of the NIH chronicity index were separated in a bivariate model, only tubulointerstitial chronicity provided prognostic information (hazard ratio [HR] 2.2, 95% confidence interval [95% CI] 1.3–3.6; P = 0.002 versus HR 1.0, 95% CI 0.7–1.5; P = 0.97 for glomerular chronicity).

Conclusion

TI identifies lupus nephritis patients at greatest risk for progression to renal failure. The immunologic mechanisms underlying TI may provide novel targets for therapeutic intervention.
Multilayer Systems for Cutting Tools: On the Relationship between Coating Design, Surface Processing, and Residual Stress
Authors: Klaus Manuela , Genzel Christoph
Published: January 2011

Cutting tools made of cemented carbide (WC/Co) are coated by chemical vapor deposition with Al2O3 and TiC1−xNx (x = 0 … 1) or combinations of these materials to improve wear resistance. Due to the high deposition temperature > 800 °C and the differences in the thermal expansion coefficients the as grown coating systems show unfavorable tensile residual stresses. To generate beneficial compressive residual stresses which improve the toughness behavior of the tools, mechanical post‐treatment processing like dry or wet blasting is introduced after coating deposition. By variation of the blasting parameters as well as of the coating design and the structural coating properties, it is possible to tailor the residual stresses with respect to both amount and depth distribution. In the present study we demonstrate by the example of Al2O3/TiCN coating systems on WC cutting inserts that an efficient assessment of this “residual stress engineering” step is possible by employing X‐ray methods which allow for nondestructive, phase selective, and depth resolved materials characterization. In order to be sensitive in different depth zones below the surface, low energy angle‐dispersive diffraction and high energy white beam synchrotron diffraction were applied to analyze the residual stress state within the coatings and in the interfacial substrate region, respectively.
Atomistisches Verständnis der Keimbildung und des Kristallwachstums durch molekulare Simulationen
Authors: Anwar Jamshed , Zahn Dirk
Published: January 2011

Die Modellierung von Keimbildungsprozessen durch molekulare Simulation ermöglicht nicht nur die Berechnung kinetischer und thermodynamischer Eigenschaften, sondern bietet zugleich mechanistische Einblicke auf atomarer Ebene. Die vielfältigen Möglichkeiten, Experimente durch Modellsimulationen zu ergänzen, sind jedoch mit der Überwindung einer Reihe von technischen Schwierigkeiten verbunden. Keimbildungsprozesse sind seltene Ereignisse, die direkten Brute‐Force‐Molekulardynamiksimulationen nur in Ausnahmefällen zugänglich sind. Erst durch Fortschritte bei der Überbrückung von Zeit‐ und Längenskalen konnten kürzlich entwickelte Ansätze auch solche Simulationen ermöglichen, die lange Zeit als undurchführbar galten. Dabei können einerseits generische Modelle zur Erarbeitung eines allgemeinen Verständnisses genutzt werden. Zum anderen sind aber auch detaillierte Einblicke in realitätsnahe Systeme möglich, sofern die Kristallbildungsprozesse in handhabbare Module unterteilt werden. So können die Assoziation einzelner Ionen in der Lösung, die Bildung von geordneten Motiven, Reifungsreaktionen, Keimbildung und postkritisches Wachstum von Nanokristallen auf molekularer Ebene untersucht werden. Durch die Analyse des Wechselspiels mit additiven Molekülen lassen sich zudem Einblicke in funktionalisierte Nanopartikel und Kompositmaterialien gewinnen.
2‐Iodoxybenzoesäure – ein einfaches Oxidationsmittel mit einer Vielfalt an Anwendungsmöglichkeiten
Authors: Duschek Alexander , Kirsch Stefan F.
Published: January 2011

Seit seiner Entdeckung durch Christoph Hartmann und Victor Meyer im Jahr 1893 hat sich 2‐Iodoxybenzoesäure (IBX) zu einem geradezu ubiquitär einsetzbaren Oxidationsmittel entwickelt. Insbesondere in den vergangenen zehn Jahren wurde eine Vielzahl von Anwendungsmöglichkeiten beschrieben, die weit über die einfache Oxidation von Alkoholen hinausgehen. Dieser Aufsatz behandelt das Potenzial von IBX in der Synthese, wobei insbesondere unerwartete Reaktivitäten und moderne Anwendungen im Mittelpunkt der Diskussion stehen.
Uncovering Molecular Processes in Crystal Nucleation and Growth by Using Molecular Simulation
Authors: Anwar Jamshed , Zahn Dirk
Published: January 2011

Exploring nucleation processes by molecular simulation provides a mechanistic understanding at the atomic level and also enables kinetic and thermodynamic quantities to be estimated. However, whilst the potential for modeling crystal nucleation and growth processes is immense, there are specific technical challenges to modeling. In general, rare events, such as nucleation cannot be simulated using a direct “brute force” molecular dynamics approach. The limited time and length scales that are accessible by conventional molecular dynamics simulations have inspired a number of advances to tackle problems that were considered outside the scope of molecular simulation. While general insights and features could be explored from efficient generic models, new methods paved the way to realistic crystal nucleation scenarios. The association of single ions in solvent environments, the mechanisms of motif formation, ripening reactions, and the self‐organization of nanocrystals can now be investigated at the molecular level. The analysis of interactions with growth‐controlling additives gives a new understanding of functionalized nanocrystals and the precipitation of composite materials.