213 research outputs found
Supplemental_Material_for_CETSA_aRPPA_by_Herledan_et_al_rev – Supplemental material for Drug Target Engagement Using Coupled Cellular Thermal Shift Assay—Acoustic Reverse-Phase Protein Array
No full textSupplemental material, Supplemental_Material_for_CETSA_aRPPA_by_Herledan_et_al_rev for Drug Target Engagement Using Coupled Cellular Thermal Shift Assay—Acoustic Reverse-Phase Protein Array by Adrien Herledan, Marine Andres, Aurore Lejeune-Dodge, Florence Leroux, Alexandre Biela, Catherine Piveteau, Sandrine Warenghem, Cyril Couturier, Benoit Deprez and Rebecca Deprez-Poulain in SLAS Discovery</p
Aspects of the biological sulphur cycle in limnological ecosystems in the Vestfold Hills, Antarctica
No full textProgress Code: completedStatement: The quality of the scanned pages may vary. An OCR process has been run over the document.This is a scanned copy of the report, 'Aspects of the biological sulphur cycle in limnological ecosystems in the Vestfold Hills, Antarctica' by P.P. Deprez and P.D. Franzmann.<br/><br/>Taken from the document:<br/><br/>This document is a report of the work carried out by two wintering biologists at Davis in 1984. It encompasses work completed between January 1984 and October 30 1984. It is not a publication in the scientific sense. It was written quickly, in the first two weeks of November, 1984 and was not revised. It was edited by Harry Burton in December, 1984.<br/><br/>It includes:<br/><br/>1) Determination of sulphate reduction rates by radiometric methods in the sediments of Burton Lake, Ace Lake, Watts Lake, Shield Lake and Ellis Fjord.<br/>2) Measurement of reduced sulphur compounds in Antarctic Lakes by gas chromatography with dual flame photometric detection.<br/>3) Chemical measurements and parameters of some Antarctic lakes.<br/>4) Collection and preliminary investigation of Antarctic micro-organisms.<br/>5) Other bits
Vertical Integration and Capital Theory: a comment
No full textThe author, in this comment, replies to a criticism made by Johan Deprez in his article “Vertical Integration and the problem of fixed capital” (JPKE, Fall 1990, vol.33,No. 1, pp.47-64). The Author claims that Deprez’ interpretation of the process of vertical integration misplaces both its function and its purpose. Deprez’ asserts that “vertical integration is a method of synchronic logic compatible to the analysis of natural dynamics in a system without structural change... it ultimately fails to capture important diachronic considerations”. The author does not accept the negative propositions nor the implicit assertion that vertical integration is a development of “synchronic thinking”. The process of vertical integration goes beyond both synchronic and diachronic thinking. Vertical integration IS A WAY OF LOOKING AT THE ECONOMIC SYSTEM. It takes each physical quantity in the final demand vector as the point of reference, and collapses all the interrelations that are behind it simply into a physical labor coefficient and a physical unit of productive capacity. It does not impose a restriction on the real world. The model is meant to be an analytical device rather than a description of reality
Ozawa's class for locally compact groups and unique prime factorization of group von Neumann algebras
No full textWe study class for locally compact groups. We characterize locally compact groups in this class as groups having an amenable action on a boundary that is small at infinity, generalizing a theorem of Ozawa. Using this characterization, we provide new examples of groups in class and prove a unique prime factorization theorem for group von Neumann algebras of products of locally compact groups in this class. We also prove that class is a measure equivalence invariant.sponsorship: The author is supported by a PhD fellowship of the Research Foundation Flanders (FWO). Part of this research was performed while the author was visiting the Institute for Pure and Applied Mathematics (IPAM), which is supported by the National Science Foundation. The author would like to thank Arnaud Brothier and Stefaan Vaes for interesting discussions and helpful comments. (Research Foundation Flanders (FWO), National Science Foundation)status: Publishe
Développement et application de méthodes de spectrométrie de masse pour qualifier les modèles et les composés pour la découverte de petites molécules modulatrices de la présentation antigénique
No full textThe challenges of drug discovery can be addressed through a multidisciplinary approach that integrates various scientific disciplines. Analytical chemistry has contributed significantly to advances in research and development of new drugs, with mass spectrometry-based techniques being widely applied in this context. The primary objective of this thesis is to support a drug discovery program targeting the endoplasmic reticulum aminopeptidases, ERAP1 and ERAP2, by developing and applying advanced analytical methods, specifically spectrometry imaging (MSI) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). ERAPs are involved in processing and presenting immunogenic antigens to T cells, and their inhibition is considered an innovative therapeutic strategy for autoimmune and oncological diseases. Three research projects targeted the validation of preclinical models and the characterization of candidate compounds to evaluate their pharmacodynamic (PD) and pharmacokinetic (PK) profiles.In the first project, matrix-assisted laser desorption/ionization (MALDI)-MSI was used to study biochemical changes in a preclinical model of ankylosing spondylitis, the HLA-B27 transgenic rat.Spatially resolved, untargeted metabolomic and lipidomic analyses revealed candidate biomarkers of two deregulated mechanisms linked to gut inflammation, intestinal permeability and immune infiltration. These findings validate the relevance of this model for testing the efficacy of ERAPs inhibitors. In the second project, a quantitative LC-MS/MS method was developed to measure the ERAP1-dependent tumour antigen GSW11, serving as a biomarker of efficacy for an ERAP1 inhibitor, and further validating the compound’s mechanism of action in vitro. Despite method optimization, the endogenous peptide could not be detected, highlighting the technical challenges associated with peptide extraction and analysis from complex biological samples. This led to the identification offactors affecting peptide recovery and detection, offering insights for future method development in peptidomics for pharmacodynamic studies. The third project focused on the biodistribution and metabolism of a candidate ERAP2 inhibitor in vivo. Quantitative MSI was successfully employed to measure the compound's concentration invarious organs, revealing its potential therapeutic applicability. Biotransformation products of the compound were detected and investigated both in vitro and in vivo. These findings pave the way for further characterization of the compound, supporting decision-making processes in future stages of drug development.This research highlights the importance of continuously evaluating preclinical models and compounds to support informed decision-making in drug discovery, ultimately reducing the risk of failures in advanced stages. Future research will focus on integrating these approaches to provide a comprehensive characterization of ERAP inhibitors, combining quantitative tissue analysis with biomarker modulation in preclinical models. The ultimate goal is to identify ERAPs inhibitors with a favourable therapeutic profile for clinical development in autoimmune and oncological indications.Les défis de la découverte de médicaments peuvent être abordés par une approche multidisciplinaire qui intègre diverses disciplines scientifiques. La chimie analytique a contribué de manière significative aux avancées dans la recherche et le développement de nouveaux médicaments, les techniques basées sur la spectrométrie de masse étant largement appliquées dans ce contexte.L'objectif principal de cette thèse est de soutenir un programme de découverte de médicaments ciblant les aminopeptidases du réticulum endoplasmique, ERAP1 et ERAP2, en développant et en appliquant des méthodes analytiques avancées, spécifiquement l'imagerie par spectrométrie (MSI) et la spectrométrie de masse en tandem avec chromatographie liquide (LC-MS/MS). Les ERAPs sont impliquées dans le traitement et la présentation d'antigènes immunogènes aux lymphocytes T, et leur inhibition est considérée comme une stratégie thérapeutique innovante pour les maladies autoimmunes et oncologiques. Trois projets de recherche ont ciblé la validation des modèles précliniques et la caractérisation des composés candidats pour évaluer leurs profils pharmacodynamiques (PD) et pharmacocinétiques (PK). Dans le premier projet, l’imagerie par spectrométrie de masse à désorption-ionisation laser assistée par matrice a été utilisée pour étudier les changements biochimiques dans un modèle préclinique de spondylarthrite ankylosante, le rat transgénique HLA-B27. Des analyses métabolomiques et lipidomiques untargeted résolues spatialement ont révélé des biomarqueurs candidats de deux mécanismes dérégulés liés à l'inflammation intestinale, la perméabilité intestinale et l'infiltration immunitaire. Ces résultats valident la pertinence de ce modèle pour tester l'efficacité des inhibiteurs des ERAP.Dans le deuxième projet, une méthode LC-MS/MS quantitative a été développée pour mesurer l'antigène tumoral dépendant de l'ERAP1, GSW11, servant de biomarqueur d'efficacité pour un inhibiteur de l'ERAP1, et validant davantage le mécanisme d'action du composé in vitro. Malgré l'optimisation de la méthode, le peptide endogène n'a pas pu être détecté, soulignant les défistechniques associés à l'extraction et à l'analyse de peptides à partir d'échantillons biologiques complexes. Cela a conduit à l'identification de facteurs affectant la récupération et la détection des peptides, offrant des perspectives pour le développement futur de méthodes en peptidomique pour des études pharmacodynamiques.Le troisième projet a porté sur la biodistribution et le métabolisme d'un inhibiteur candidat del'ERAP2 in vivo. La MSI quantitative a été employée avec succès pour mesurer la concentration du composé dans divers organes, révélant son applicabilité thérapeutique potentielle. Des produits de biotransformation du composé ont été détectés et étudiés à la fois in vitro et in vivo. Ces résultats ouvrent la voie à une caractérisation plus approfondie du composé, soutenant les processus de prise de décision dans les étapes futures du développement de médicaments.Cette recherche souligne l'importance d'évaluer en permanence les modèles précliniques et les composés pour soutenir une prise de décision éclairée dans la découverte de médicaments, réduisant ainsi le risque d'échecs dans les phases avancées. Les recherches futures se concentreront sur l'intégration de ces approches pour fournir une caractérisation complète des inhibiteurs de l'ERAPs,en combinant l'analyse tissulaire quantitative avec la modulation des biomarqueurs dans des modèles précliniques. L'objectif ultime est d'identifier des inhibiteurs des ERAP ayant un profil thérapeutique favorable pour le développement clinique dans les indications auto-immunes et oncologiques
ERAP Inhibitors in Autoimmunity and Immuno-Oncology: Medicinal Chemistry Insights
No full textInternational audienceEndoplasmic reticulum aminopeptidases ERAP1 and 2 are intracellular aminopeptidases, that trim antigenic precursors and generate antigens presented by Major Histocompatibility Complex Class I (MHC-I) molecules. They thus modulate the antigenic repertoire and drive the adaptive immune response. ERAPs are considered as emerging targets for precision immune-oncology or for the treatment of autoimmune diseases, in particular MHC-I-opathies. This perspective covers the structural and biological characterization of ERAP, their relevance to these diseases and the ongoing research on small-molecule inhibitors. We describe the chemical and pharmacological space explored by medicinal chemists to exploit the potential of these targets given their localisation, biological functions and family depth. Specific emphasis is put on binding mode, potency, selectivity and physchem properties of inhibitors featuring diverse scaffolds. The discussion provides valuable insights for the future development of ERAP inhibitors and analysis of persisting challenges for the translation for clinical applications
ChemInform Abstract: Friedlaender Synthesis of Polysubstituted Quinolines and Naphthyridines Promoted by Propylphosphonic Anhydride (T3P®) under Mild Conditions.
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Kinetic target-guided synthesis in drug discovery and chemical biology: a comprehensive facts and figures survey
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