David et Salomon, rois d'Israël : d'après le texte de la Sainte-Écriture, la tradition et les commentateurs israélites les plus accrédités

par Gédéon Netter

MUTATIONS IN STAT3 ASSOCIATED WITH HUMAN HYPER IgE SYNDROME ENHANCE NFκB AND MAPK-MEDIATED GENE EXPRESSION

Hyper IgE syndrome (HIES) is a multisystem disorder resulting in bone and immune system abnormalities. It is associated with mutations in STAT3, which disrupt protein domains responsible for transcriptional function. Patients with HIES display osteoporosis and enhanced inflammatory cytokine production similar to hematopoietic Stat3-deficient mice. Since osteoclast and inflammatory cytokine genes are NFκB targets, these observations indicate a possible deregulation of NFκB signaling in both mice and humans with STAT3-deficiency. Here, we sought to examine the role of STAT3 in the regulation of NFκB-mediated gene expression through analysis of three HIES STAT3 point mutations in both hematopoietic and non- hematopoietic cells. We found that IL-6-induced tyrosine phosphorylation of STAT3 was partially or completely abrogated by HIES mutations in the transactivation domain (V713L) or SH2 domain (V637M), respectively, in both hematopoietic and non- hematopoietic cells. By contrast, IL-6-induced tyrosine phosphorylation of an HIES mutant in the STAT3 DNA-binding domain (R382W) was intact. The R382W and V713L mutants significantly reduced IL-6-dependent STAT3 transcriptional activity in reporter gene assays. Moreover, the R382W and V637M mutants significantly diminished IL-6-responsive expression of the endogenous STAT3 target gene, Socs3, as assessed by quantitative real-time PCR (qPCR) in the RAW macrophage cell line. These observations indicate the HIES mutants dominantly suppress the transcriptional activity of wild type STAT3, albeit to varying degrees. All three HIES mutants enhanced LPS-induced expression of the NFκB target genes IL6 (IL-6), Cxcl10 (IP- 10), and Tnf (TNFα) in RAW cells, as indicated by qPCR. Furthermore, overexpression of wild type STAT3 in Stat3-deficient murine embryonic fibroblasts significantlyreduced LPS-stimulated expression of IL6, Cxcl10, and IL12p35. In addition, in aprimary murine osteoclast differentiation assay, a STAT3-specific SH2 domain inhibitor led to significantly increased levels of osteoclast-specific gene expression. These results suggest that STAT3 serves as a negative regulator of NFκB-mediated gene expression, and furthermore imply that STAT3 mutations associated with HIES contribute to the osteopenia and inflammation observed in HIES patients.

Family Strengths: A Long Tradition

Alvin Sallee, Angelo Giardino, and Robert Sanborn discuss the latest issue of Journal of Family Strengths, celebrating the centennial of the Children's Bureau.

Physics potential of a long-baseline neutrino oscillation experiment using a J-PARC neutrino beam and Hyper-Kamiokande

Hyper-Kamiokande will be a next generation underground water Cherenkov detector with a total (fiducial) mass of 0.99 (0.56) million metric tons, approximately 20 (25) times larger than that of Super-Kamiokande. One of the main goals of HyperKamiokande is the study of CP asymmetry in the lepton sector using accelerator neutrino and anti-neutrino beams. In this paper, the physics potential of a long baseline neutrino experiment using the Hyper-Kamiokande detector and a neutrino beam from the J-PARC proton synchrotron is presented. The analysis uses the framework and systematic uncertainties derived from the ongoing T2K experiment. With a total exposure of 7.5 MW × 10⁷ s integrated proton beam power (corresponding to 1.56 × 10²² protons on target with a 30 GeV proton beam) to a 2.5-degree off-axis neutrino beam, it is expected that the leptonic CP phase δCP can be determined to better than 19 degrees for all possible values of δCP , and CP violation can be established with a statistical significance of more than 3 σ (5 σ) for 76% (58%) of the δCP parameter space. Using both νe appearance and νµ disappearance data, the expected 1σ uncertainty of sin²θ₂₃ is 0.015(0.006) for sin²θ₂₃ = 0.5(0.45).

Portuguese Vaulting System at the Dawn and Early Modern Period. Between tradition and Innovation

Portuguese Vaulting System at the Dawn and Early Modern Period. Between tradition and Innovation. III International Congress on Construction History . Brandenburg university of technology Cottbus, Germany. Colab: Soraya Genin, Krista de Jonge.

Eosinophil recruitment into the respiratory epithelium following antigenic challenge in hyper-IgE mice is accompanied by interleukin 5-dependent bronchial hyperresponsiveness.

A murine model for antigen-induced bronchial hyperreactivity (BHR) and airway eosinophilia, two hallmarks of asthma, was developed using ovalbumin-immunized mice, which produce large amounts of IgE (named BP2, "Bons Producteurs 2," for High Line of Selection 2). A single intranasal ovalbumin challenge failed to modify the bronchial responses, despite the intense eosinophil recruitment into the bronchoalveolar lavage fluid and airways. When mice were challenged twice a day for 2 days or once a day for 10 days, BHR in response to i.v. 5-hydroxytryptamine or to inhaled methacholine was induced in BP2 mice but not in BALB/c mice. Histological examination showed that eosinophils reached the respiratory epithelium after multiple ovalbumin challenges in BP2 mice but remained in the bronchial submucosa in BALB/c mice. Total IgE titers in serum were augmented significantly with immunization in both strains, but much more so in BP2 mice. Interleukin 5 (IL-5) titers in serum and bronchoalveolar lavage fluid of BP2 mice were augmented by the antigenic provocation, and a specific anti-IL5 neutralizing antibody suppressed altogether airway eosinophilia and BHR, indicating a participation of IL-5 in its development. Our results indicate that the recruitment of eosinophils to the airways alone does not induce BHR in mice and that the selective effect on BP2 mice is related to their increased IgE titers associated with antigen-driven eosinophil migration to the epithelium, following formation and secretion of IL-5.

Islamic Political Thought: Reviving a Rationalist Tradition

This work develops the foundations of an Islamic argument for secular, liberal democracy from within the Islamic discursive tradition. First, it challenges the presentation of contemporary Islamic political thought as a unified, continuous development of the classical canon by showing the influence of the now marginalized medieval rationalists in the development of Islamic political thought. The classical rationalist concern with divine justice forced the founders of Sunni orthodoxy to state their epistemologies and their positions on ethical ontology. The orthodox positions, and their related methods of legal-juristic reasoning, are shown to be incapable of accommodating the modern Islamic positions on political representation, slavery, and just war. This leads to the second argument of the work, that the modern Islamic discourse is better understood as a reflection of the central concern with justice and its rationalist epistemology and ethical ontology we find in the writings of classical rationalists. This argument is made by examining the works of three classical rationalists, a theologian, a philosopher, and a historian. Their political positions, shaped by their rationalism and concern with justice, challenged their orthodox contemporaries, and provide substantive critiques of the classical political accommodations, methods of politico-legal reasoning, and hence, of modern Islamist political projects. The final chapter reveals how far the mainstream of Islamic political thought has deviated from the classical discourses, since the 19th century, by adopting the language and ideals of the European Enlightenment. This shift is presented as a triumph of classical rationalism over literalism, whose epistemological foundations and ontological implications have yet to be acknowledged and appreciated.

The Caustic Pen Is Mightiest: A Tradition of Female Satire in the Novels of Jane Austen, Ivy Compton-Burnett, and Muriel Spark

Female satirists have long been treated by critics as anomalies within an androcentric genre because of the reticence to acknowledge women's right to express aggression through their writing. In Pride and Prejudice (1813), A House and Its Head (1935), and The Girls of Slender Means (1963), Jane Austen (1775-1817), Ivy Compton-Burnett (1884-1969), and Muriel Spark (1918-2006) all combine elements of realism and satire within the vehicle of the domestic novel to target institutions of their patriarchal societies, including marriage and family dynamics, as well as the evolving conceptions of domesticity and femininity, with a subtle feminism. These female satirists illuminate the problems they have with society more through presentation than judgment in their satire, which places them on the fringes of a society they wish to educate, distinguishing their satire from that written by male satirists who are judging from a privileged height above the society they are attempting to correct. All three women create heroines and secondary female characters who find ways to survive, and occasionally thrive, within the confines of a polite society that has a streak of savagery running just beneath its polished surface.

Convention, Tradition, and the New Wave : Assessing Clinician Identity within Behavior Therapy

In the first wave, behaviorists questioned the conventional wisdom that inner experience was relevant to understanding human behavior. In the 1970s, cognitive-behavioral theories emphasized the importance of the cognitive element, not just the environment, in explaining and modifying behavior. The third wave is drawn from advances in basic and applied behavior analysis of language, Eastern mystical traditions, and less empirically oriented therapeutic approaches. Examples include Acceptance and Commitment Therapy (ACT), Dialectical Behavior Therapy (DBT), Functional Analytic Psychotherapy (FAP), and Mindfulness Based Cognitive Therapy (IBCT). This study reports a survey of clinicians and non-clinicians who self-identify with second or third wave approaches, and a group of undergraduate psychology students intended to represent a layperson or folk psychological approach. Their preferences, in the context of 10 clinical vignettes, among 5 different therapeutic responses or interventions that included "ACT-like," "cognitive," and commonsense or "neutral" options were measured. Third wave-oriented respondents exhibited more consistency than others in their preference for interventions that match their self-identified theoretical orientation, however the author suggests that construction of the vignettes may have influenced this result.

Wrestling With Tradition: Japanese Activities at Amache, a World War II Incarceration Facility

I employ archaeological analyses, archival research, and oral histories to investigate traditional Japanese practices that were performed at Amache, a World War II Japanese American incarceration facility. I argue that these inter-generational practices helped to bridge a cultural gap that existed between several generations of Japanese Americans. For many incarcerated Japanese Americans, their first exposure to many traditional activities occurred during incarceration. The resulting social environment incorporated aspects of Japanese, Japanese American, and mainstream American influences, all of which were adapted to conditions during incarceration. Similarly, archaeological analyses allow for the investigation of traditional practice features. These provide evidence regarding the significance of the adapted landscape at Amache. Evidence of these practices suggests Amache internees had both a strong desire to maintain and celebrate these aspects of their Japanese heritage but they also incorporated non-traditional elements that reflected the unique living conditions during incarceration. Incarceration, I argue, created an environment in which a unique internee consciousness was formed in which the use of traditional practices was a focal point. The physical remains of traditional practices allow archaeologists to determine aspects of this newly formed consciousness that are not readily apparent in historical documentation.