Suchergebnisse

BACKGROUND: Activated phosphoinositide 3-kinase δ syndrome (APDS) is a recently described combined immunodeficiency resulting from gain-of-function mutations in PIK3CD, the gene encoding the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ). OBJECTIVE: We sought to review the clinical, immunologic, histopathologic, and radiologic features of APDS in a large genetically defined international cohort. METHODS: We applied a clinical questionnaire and performed review of medical notes, radiology, histopathology, and laboratory investigations of 53 patients with APDS. RESULTS: Recurrent sinopulmonary infections (98%) and nonneoplastic lymphoproliferation (75%) were common, often from childhood. Other significant complications included herpesvirus infections (49%), autoinflammatory disease (34%), and lymphoma (13%). Unexpectedly, neurodevelopmental delay occurred in 19% of the cohort, suggesting a role for PI3Kδ in the central nervous system; consistent with this, PI3Kδ is broadly expressed in the developing murine central nervous system. Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60%). Increased IgM levels (78%), IgG deficiency (43%), and CD4 lymphopenia (84%) were significant immunologic features. No immunologic marker reliably predicted clinical severity, which ranged from asymptomatic to death in early childhood. The majority of patients received immunoglobulin replacement and antibiotic prophylaxis, and 5 patients underwent hematopoietic stem cell transplantation. Five patients died from complications of APDS. CONCLUSION: APDS is a combined immunodeficiency with multiple clinical manifestations, many with incomplete penetrance and others with variable expressivity. The severity of complications in some patients supports consideration of hematopoietic stem cell transplantation for severe childhood disease. Clinical trials of selective PI3Kδ inhibitors offer new prospects for APDS treatment. ; T.C. is supported by National Children's Research Centre, Our Lady's Children's Hospital Crumlin, Dublin, Ireland. A.C. has a Wellcome Trust Postdoctoral Training Fellowship for Clinicians (103413/Z/13/Z). K.O. is supported by funding from BBSRC, MRC, Wellcome Trust and GSK. R.D. and D.S.K are funded by National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, Cambridge, UK. C.S. and S.E. are supported by the German Federal Ministry of Education and Research (BMBF 01 EO 0803 grant to the Center of Chronic immunodeficiency and BMBF 01GM1111B grant to the PID-NET initiative). S.N.F is supported in part by the Southampton UK National Institute for Health Research (NIHR) Wellcome Trust Clinical Research Facility and NIHR Respiratory Biomedical Research Unit. M.A.A.I. is funded by NHS Innovation London and King's College Hospital Charitable Trust. A.F., S.L., A.D., F.R-L and S.K. are supported by the European Union's 7th RTD Framework Programme (ERC advanced grant PID-IMMUNE contract 249816) and a government grant managed by the French Agence Nationale de la Recherche as part of the "Investments for the Future" program (ANR-10-IAHU-01). S.L. is supported by the Agence Nationale de la Recherche (ANR) (ANR-14-CE14-0028-01), the Foundation ARC pour la Recherche sur le Cancer (France), the Rare Diseases Foundation (France) and François Aupetit Association (France). S.L. is a senior scientist and S.K is a researcher at the Centre National de la Recherche Scientifique-CNRS (France). A.D. and S.K. are supported by the "Institut National de la Santé et de la Recherche Médicale". S.K. also supported by the Fondation pour la Recherche Médicale (grant number: ING20130526624), la Ligue Contre le Cancer (Comité de Paris) and the Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH). S.O.B is supported by the Higher Education Funding Council for England. B.V. is supported by the UK Biotechnology and Biological Sciences Research Council [BB/I007806/1], Cancer Research UK [C23338/A15965) and the National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre. B.V. is consultant to Karus Therapeutics (Oxford, UK). S.N. is a Wellcome Trust Senior Research Fellow in Basic Biomedical Science (095198/Z/10/Z). S.N. is also supported by the European Research Council Starting grant 260477, the EU FP7 collaborative grant 261441 (PEVNET project) and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, UK. A.M.C. is funded by the Medical Research Council, British Lung Foundation, University of Sheffield and Cambridge NIHR-BRC. Research in A.M.C. laboratory has received non-commercial grant support from GSK, Novartis, and MedImmune. ; This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.jaci.2016.06.021

From humble beginnings over 25 years ago as a lipid kinase activity associated with certain oncoproteins, PI3K (phosphoinositide 3-kinase) has been catapulted to the forefront of drug development in cancer, immunity and thrombosis, with the first clinical trials of PI3K pathway inhibitors now in progress. Here the authors give a brief overview of some key discoveries in the PI3K area and their impact, and include thoughts on the current state of the field, and where it could go from here.

11 pages, 8 figures.-- PMID: 17998387 [PubMed].-- PMCID: PMC2118532.-- Printed version published Nov 26, 2007. ; Supporting information attached: Information on Western blots, Immunoprecipitation assays, the Rac activation assay, the FACS-based conjugate formation assay, the Actin polymerization assay, and Stimulation with antibody-coated beads and immunofluorescence.-- Also available at: http://jem.rupress.org/cgi/content/full/jem.20070366/DC1 ; Class I phosphoinositide 3–kinases (PI3Ks) constitute a family of enzymes that generates 3-phosphorylated polyphosphoinositides at the cell membrane after stimulation of protein tyrosine (Tyr) kinase–associated receptors or G protein–coupled receptors (GPCRs). The class I PI3Ks are divided into two types: class I(A) p85/p110 heterodimers, which are activated by Tyr kinases, and the class I(B) p110γ isoform, which is activated by GPCR. Although the T cell receptor (TCR) is a protein Tyr kinase–associated receptor, p110γ deletion affects TCR-induced T cell stimulation. We examined whether the TCR activates p110γ, as well as the consequences of interfering with p110γ expression or function for T cell activation. We found that after TCR ligation, p110γ interacts with Gα(q/11), lymphocyte-specific Tyr kinase, and ζ-associated protein. TCR stimulation activates p110γ which affects 3-phosphorylated polyphosphoinositide levels at the immunological synapse. We show that TCR-stimulated p110γ controls RAS-related C3 botulinum substrate 1 activity, F-actin polarization, and the interaction between T cells and antigen-presenting cells, illustrating a crucial role for p110γ in TCR-induced T cell activation. ; I. Alcázar holds a predoctoral fellowship from the Association for International Cancer Research, M. Marqués receives a predoctoral fellowship from the Spanish Ministry of Education and Science University Instructor Training Program, and D.F. Barber held a Ramón y Cajal contract from the Spanish Ministry of Education and Science and a Contract-in-Aid from the Fundación Científica de la Asociación Española Contra el Cancer. This work was supported by grants from the European Union (QLRT2001-02171), the Community of Madrid (8.3/0030/2000), the Ramón Areces Foundation (to D.F. Barber and A.C. Carrera), and the Spanish Dirección General de Ciencia y Desarrollo Tecnológico (SAF2004-00815 and SAF2004-05955- C02-01 to D.F. Barber A.C. Carrera, respectively). The Department of Immunology and Oncology was founded and is supported by the Spanish National Research Council (Consejo Superior de Investigaciones Científicas) and by Pfizer. ; Peer reviewed

3'-Phosphoinositide-dependent-Kinase-1(PDK1) is a master regulator whereby its PI3- kinase-dependent dysregulation in human pathologies is well documented. Understanding the direct role for Ptdlns(3,4,5)P-3 and other anionic phospholipids in the regulation of PDK1 conformational dynamics and its downstream activation remains incomplete. Using advanced quantitative-time-resolved imaging (Fluorescence Lifetime Imaging and Fluorescence Correlation Spectroscopy) and molecular modelling, we show an interplay of antagonistic binding effects of Ptdlns(3,4,5)P-3 and other anionic phospholipids, regulating activated PDK1 homodimers. We demonstrate that phosphatidylserine maintains PDK1 in an inactive conformation. The dysregulation of the PI3K pathway affects the spatio-temporal and conformational dynamics of PDK1 and the activation of its downstream substrates. We have established a new anionic-phospholipid-dependent model for PDK1 regulation, depicting the conformational dynamics of multiple homodimer states. We show that the dysregulation of the PI3K pathway perturbs equilibrium between the PDK1 homodimer conformations. Our findings provide a role for the PtdSer binding site and its previously unrewarding role in PDK1 downregulation, suggesting a possible therapeutic strategy where the constitutively active dimer conformer of PDK1 may be rendered inactive by small molecules that drive it to its PtdSer-bound conformer. ; Supported by the Spanish Ministry of Economy grant to B.L. [BFU2015- 65625-P] & Ministerio de Economía y Competitividad in Spain grant to J.R.-I., (MINECO FIS2009-07966); Royal Society grants to J.R.-I. and V.C. (IE120953). Basque Government PhD studentship to G.d.H.; Cancer Research UK Core Funding grants to B.L.; We also acknowledge the support of the Ikerbasque Foundation of Science to BL; Centre National de la Recherche Sciéntifique (CNRS) and Ministere de l'Education Nationale et de l'Enseignement Supérieur et de la Recherche (MENSR) grants to J.D.

Idelalisib (Zydelig™, also known as CAL-101 and GS-1101) was approved in 2014 in the United States and European Union for the treatment of three indolent B-cell neoplasms: relapsed/refractory chronic lymphocytic leukemia (CLL, in combination with rituximab), relapsed follicular lymphoma, and relapsed small lymphocytic lymphoma (as monotherapy). Furthermore, it was approved in the European Union as first-line therapy for poor-prognosis CLL with 17p deletions or TP53 mutations and in patients unsuitable for chemo-immunotherapy. Idelalisib is an orally bioavailable ATP-competitive kinase inhibitor that targets the phosphoinositide 3-kinase p110 isoform δ (PI3Kδ) with high potency and selectivity. PI3Kδ is hyperactivated in B-cell malignancies and plays a pivotal role in the B-cell receptor (BCR) pathway, a key oncogenic driver in B-cell malignancies. The near exclusive expression of the PI3Kδ isoform in hematopoietic cells and the selectivity of idelalisib for the PI3Kδ isoform are essential for its efficacy and tolerability, even in elderly patients unfit for chemotherapy. Idelalisib is the first PI3K inhibitor approved by the regulatory agencies; this approval will change the treatment landscape of indolent B-cell malignancies.

SrFeO3-δ is mixed ionic-electronic conductor with complex magnetic structure which reveals also colossal magnetoresistance effect. This material and its solid solutions are attractive for various spintronic, catalytic and electrochemical applications, including cathodes for solid oxide fuel cells and permeation membranes. Its properties strongly depend on oxygen non-stoichiometry. Ab initio hybrid functional approach was applied here for a study of thermodynamic stability of a series of SrFeO3-δ compositions with several non-stoichiometries δ, ranging from 0 to 0.5 (SrFeO3 - SrFeO2.875 - SrFeO2.75 - SrFeO2.5) as the function of temperature and oxygen pressure. The results obtained by considering Fe as all-electron atom and within the effective core potential technique are compared. Based on our calculations, the phase diagrams were constructed allowing the determination of environmental conditions for the existence of stable phases. It is shown that (within an employed model) only the SrFeO2.5 phase appears to be stable. The stability region for this phase is re-drawn at the contour map of oxygen chemical potential, presented as a function of temperature and oxygen partial pressure. A similar analysis is also performed using experimental Gibbs energies of perovskite formation from the elements. The present modelling strongly suggests a considerable attraction between neutral oxygen vacancies. These vacancies are created during a series of above mentioned SrFeO3-δ mutual transformations accompanied by oxygen release. ; Latvian Council of Science LZP FLPP grant lzp-2018/1-0147; Institute of Solid State Physics, University of Latvia as the Center of Excellence has received funding from the European Union's Horizon 2020 Framework Programme H2020-WIDESPREAD-01-2016-2017-TeamingPhase2 under grant agreement No. 739508, project CAMART²

Trabajo presentado al: "11th European SOFC & SOE Forum" celebrado en Lucerne (Suiza) del 1 al 4 de julio de 2014. ; The performance of YSZ-Ni supported microtubular solid oxide fuel cells (mT-SOFCs) with thin YSZ electrolyte and three different cathodes: La0.8Sr0.2MnO3-δ (LSM), La0.6Sr0.4Co0.2Fe0.8O3-δ (LSCF) and Pr2NiO4+δ (PNO) is compared. The mT-SOFC cells were fabricated using NiO-YSZ support precursors manufactured by Powder Extrusion Moulding (PEM). The YSZ layer was deposited by dip coating. The electrolyte deposition parameters and the sintering parameters were optimized to obtain a dense and thin layer. Three different cathode materials, LSM, LSCF and PNO were then deposited by dip coating. To circumvent reactivity at the sintering temperatures between LSCF and PNO with the YSZ electrolyte, barrier layers were also deposited. Electrochemical characterization under the same fuelling conditions for all the three cells was performed. The results are discussed and compared. As for example, the cell with a LSM-YSZ cathode presented a power density at 0.5V and 850 °C of 0.7 Wcm-2 with an ASR (area specific resistance) at OCV (open circuit voltage) of _0.9 Ωcm2. Similar performance was obtained when using LSCF or PNO cathodes at about 750 ºC, allowing for a significant reduction of the operation temperature of these mT-SOFCs. ; Authors also acknowledge grant MAT2012-30763 financed by the Spanish Government (Ministerio de Ciencia e Innovación) and Feder program of the European Community, for funding the project. ; Peer Reviewed

Kinas økonomi boomer. For at imødekomme den stigende efterspørgsel har Kina etableret en ny og aktiv Mellemøstpolitik, der skal sikre landets næsten umættelige energibehov.

Les fonctions impulsives associées à la fonction de Dirac jouissent de propriétés remarquables dont nous avons fait l'exposé dans des notes antérieures (Bull. de l'Académie, août 1954). Elles se révèlent notamment très utiles dans toutes les questions faisant intervenir des fonctions définies sur un demi-axe des temps, et en particulier, s'appliquent avantageusement à l'étude des signaux des télécommunications qui sont toujours définis pour t > 0.
Dans cette note, nous établissons d'une manière très rapide les relations de Bayard-Bode, liant partie réelle et imaginaire de la fonction de transfert d'un filtre.