Genetic partitioning of interleukin-6 signalling in mice dissociates Stat3 from Smad3-mediated lung fibrosis

Idiopathic pulmonary fibrosis (IPF) is a fatal disease that is unresponsive to current therapies and characterized by excessive collagen deposition and subsequent fibrosis. While inflammatory cytokines, including interleukin (IL)-6, are elevated in IPF, the molecular mechanisms that underlie this disease are incompletely understood, although the development of fibrosis is believed to depend on canonical transforming growth factor (TGF)-beta signalling. We examined bleomycin-induced inflammation and fibrosis in mice carrying a mutation in the shared IL-6 family receptor gp130. Using genetic complementation, we directly correlate the extent of IL-6-mediated, excessive Stat3 activity with inflammatory infiltrates in the lung and the severity of fibrosis in corresponding gp130757F mice. The extent of fibrosis was attenuated in B lymphocyte-deficient gp130757F;mu MT-/- compound mutant mice, but fibrosis still occurred in their Smad3-/- counterparts consistent with the capacity of excessive Stat3 activity to induce collagen 1a1 gene transcription independently of canonical TGF-beta/Smad3 signalling. These findings are of therapeutic relevance, since we confirmed abundant STAT3 activation in fibrotic lungs from IPF patients and showed that genetic reduction of Stat3 protected mice from bleomycin-induced lung fibrosis

IL-6-Mediated Activation of Stat3α Prevents Trauma/Hemorrhagic Shock-Induced Liver Inflammation

Trauma complicated by hemorrhagic shock (T/HS) is the leading cause of morbidity and mortality in the United States for individuals under the age of 44 years. Initial survivors are susceptible to developing multiple organ failure (MOF), which is thought to be caused, at least in part, by excessive or maladaptive activation of inflammatory pathways. We previously demonstrated in rodents that T/HS results in liver injury that can be prevented by IL-6 administration at the start of resuscitation; however, the contribution of the severity of HS to the extent of liver injury, whether or not resuscitation is required, and the mechanism(s) for the IL-6 protective effect have not been reported. In the experiments described here, we demonstrated that the extent of liver inflammation induced by T/HS depends on the duration of hypotension and requires resuscitation. We established that IL-6 administration at the start of resuscitation is capable of completely reversing liver inflammation and is associated with increased Stat3 activation. Global assessment of the livers showed that the main effect of IL-6 was to normalize the T/HS-induced inflammation transcriptome. Pharmacological inhibition of Stat3 activity within the liver blocked the ability of IL-6 to prevent liver inflammation and to normalize the T/HS-induced liver inflammation transcriptome. Genetic deletion of a Stat3β, a naturally occurring, dominant-negative isoform of the Stat3, attenuated T/HS-induced liver inflammation, confirming a role for Stat3, especially Stat3α, in preventing T/HS-mediated liver inflammation. Thus, T/HS-induced liver inflammation depends on the duration of hypotension and requires resuscitation; IL-6 administration at the start of resuscitation reverses T/HS-induced liver inflammation, through activation of Stat3α, which normalized the T/HS-induced liver inflammation transcriptome

Mapping Philanthropic Foundations’ Characteristics: towards an international integrative framework of foundation types

As philanthropic foundations take on increasingly prominent sociopolitical roles, the need for stronger conceptualizations of foundations as an organizational form is articulated widely across academic, policy, and practice contexts. Building on institutional research’s tradition of categorizing, classifying and typologizing organizational forms, our article critically explores the different ways in which foundations have been cast and differentiated in international academic and practice literatures. Examining and integrating these, we propose an integrative framework of foundation types. Incorporating 13 categories—three contextual, five organizational, and five strategic ones—the framework allows for clarifying distinctions and identifying commonalities between different foundation forms, offering a basis for developing more reflective and differentiated research and practice knowledge

Harnessing the potential of lung stem cells for regenerative medicine

In response to recurrent exposure to environmental insults such as allergens, pollution, irritants, smoke and viral/bacterial infection, the epithelium of the lung is continually damaged. Homeostasis of the lung requires a balance between immune regulation and promotion of tissue regeneration, which requires the co-ordinated proliferation and differentiation of stem and progenitor cells. In this review we reflect on the current understanding of lung epithelial stem and progenitor cells and advocate a model hierarchy in which self-renewing multipotent lung epithelial stem cells give rise to lineage restricted progenitor cells that repopulate airway and alveolar epithelial cell lineages during homeostasis and repair. We also discuss the role of mesenchymal progenitor cells in maintaining the structural integrity of the lung and propose a model in which mesenchymal cells act as the quintessential architects of lung regeneration by providing molecular signals, such as FGF-10, to regulate the fate and specificity of epithelial stem and progenitor cells. Moreover, we discuss the current status and future prospects for translating lung stem cell therapies to the clinic to replace, repair, or regenerate diseased lung tissue. This article is part of a directed issue entitled: Regenerative Medicine: the challenge of translation

Élaboration, frittage et caractérisation d'oxydes mixtes Th1−x_{1-x}Yx_xO2−x/2_{2-x/2} pour la réalisation de sondes électrochimiques pour l'oxygène

National audienc

A 256-TES Array for the Detection of CMB B-Mode Polarisation

International audienceAs part of the Q&U Bolometric Interferometer for Cosmology instrument targeting the cosmic microwave background primordial B-modes, two kilo-pixel focal planes have been designed for a NEP of W adapted for ground-based observations. Those pixels are transition edge sensors (TESs) made of voltage-biased NbSi thin films with a critical temperature 400 mK and TiV absorbing grids. The TESs are coupled to a time-domain multiplexed electronics based on superconducting quantum interference devices and an additional SiGe cryogenic integrated circuit which provides a second multiplexing stage. In this paper, we briefly discuss the instrumental context of a quarter of focal plane (a 256-TES sub-array). Then, we present its typical manufacturing process and first test results at cryogenic temperature

Complementary Measurement of Thermal Architecture of NbSi TES with Alpha Particle and Complex Impedance

As shown by the Planck mission (Planck Collaboration. Astronomy and astrophysics. arXiv1303.5071P, 2013), background limited bolometers in a space environment are very sensitive to high energy particles. In order to not degrade their sensitivity, it is necessary to reduce this unwanted signal. To achieve this goal, a good understanding of the detector's thermal architecture is mandatory. To investigate this question, we used an particle source in front of our niobium silicon (NbSi) alloy Transition edge sensors (TES). The number of time constants required to fit the data and the way these time constants behave as we change the bias power gave us a good insight on the TES thermal architecture. Indeed we expect a decrease of the detector time constant due to the electro-thermal feedback properties. We will first present some standard characterizations of NbSi TES using a simple thermal model and how they indicate the presence of multiple thermal decouplings. Then we will show the results of the particles measurements and how we used them to build our thermal model for Complex Impedance fitting. All this work has been done for the QUBIC experiment, a B-modes instrument