Bayesian Simulation-based Inference for Cosmological Initial Conditions

Reconstructing astrophysical and cosmological fields from observations is challenging. It requires accounting for non-linear transformations, mixing of spatial structure, and noise. In contrast, forward simulators that map fields to observations are readily available for many applications. We present a versatile Bayesian field reconstruction algorithm rooted in simulation-based inference and enhanced by autoregressive modeling. The proposed technique is applicable to generic (non-differentiable) forward simulators and allows sampling from the posterior for the underlying field. We show first promising results on a proof-of-concept application: the recovery of cosmological initial conditions from late-time density fields.Comment: Accepted for the NeurIPS 2023 workshop Machine Learning and the Physical Sciences; 5 pages, 1 figur

BAG3 Overexpression and Cytoprotective Autophagy Mediate Apoptosis Resistance in Chemoresistant Breast Cancer Cells

Target-specific treatment modalities are currently not available for triple-negative breast cancer (TNBC), and acquired chemotherapy resistance is a primary obstacle for the treatment of these tumors. Here we employed derivatives of BT-549 and MDA-MB-468 TNBC cell lines that were adapted to grow in the presence of either 5-Fluorouracil, Doxorubicin or Docetaxel in an aim to identify molecular pathways involved in the adaptation to drug-induced cell killing. All six drug-adapted BT-549 and MDA-MB-468 cell lines displayed cross resistance to chemotherapy and decreased apoptosis sensitivity. Expression of the anti-apoptotic co-chaperone BAG3 was notably enhanced in two thirds (4/6) of the six resistant lines simultaneously with higher expression of HSP70 in comparison to parental controls. Doxorubicin-resistant BT-549 (BT-549DOX) and 5-Fluorouracil-resistant MDA-MB-468 (MDA-MB-4685-FU) cells were chosen for further analysis with the autophagy inhibitor Bafilomycin A1 and lentiviral depletion of ATG5, indicating that enhanced cytoprotective autophagy partially contributes to increased drug resistance and cell survival. Stable lentiviral BAG3 depletion was associated with a robust down-regulation of Mcl-1, Bcl-2 and Bcl-xL, restoration of drug-induced apoptosis and reduced cell adhesion in these cells, and these death-sensitizing effects could be mimicked with the BAG3/Hsp70 interaction inhibitor YM-1 and by KRIBB11, a selective transcriptional inhibitor of HSF-1. Furthermore, BAG3 depletion was able to revert the EMT-like transcriptional changes observed in BT-549DOX and MDA-MB-4685-FU cells. In summary, genetic and pharmacological interference with BAG3 is capable to resensitize TNBC cells to treatment, underscoring its relevance for cell death resistance and as a target to overcome therapy resistance of breast cancer

Etude d'une approche de synthèse totale du (-)-FR182877

PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Treatment of congenital thrombocytopenia and decreased collagen reactivity in G6b-B-deficient mice

Mice lacking the immunoreceptor tyrosine-based inhibition motif-containing co-inhibitory receptor G6b-B (Mpig6b, G6b knockout, KO) are born with a complex megakaryocyte (MK) per platelet phenotype, characterized by severe macrothrombocytopenia, expansion of the MK population, and focal myelofibrosis in the bone marrow and spleen. Platelets are almost completely devoid of the glycoprotein VI (GPVI)-FcRγ-chain collagen receptor complex, have reduced collagen integrin α2β1, elevated Syk tyrosine kinase activity, and a subset has increased surface immunoglobulins. A similar phenotype was recently reported in patients with null and loss-of-function mutations in MPIG6B. To better understand the cause and treatment of this pathology, we used pharmacological- and genetic-based approaches to rescue platelet counts and function in G6b KO mice. Intravenous immunoglobulin resulted in a transient partial recovery of platelet counts, whereas immune deficiency did not affect platelet counts or receptor expression in G6b KO mice. Syk loss-of-function (R41A) rescued macrothrombocytopenia, GPVI and α2β1 expression in G6b KO mice, whereas treatment with the Syk kinase inhibitor BI1002494 partially rescued platelet count but had no effect on GPVI and α2β1 expression or bleeding. The Src family kinase inhibitor dasatinib was not beneficial in G6b KO mice. In contrast, treatment with the thrombopoietin mimetic romiplostim rescued thrombocytopenia, GPVI expression, and platelet reactivity to collagen, suggesting that it may be a promising therapeutic option for patients lacking functional G6b-B. Intriguingly, GPVI and α2β1 expression were significantly downregulated in romiplostim-treated wild-type mice, whereas GPVI was upregulated in romiplostim-treated G6b KO mice, suggesting a cell intrinsic feedback mechanism that autoregulates platelet reactivity depending on physiological needs

Treatment of congenital thrombocytopenia and decreased collagen reactivity in G6b-B-deficient mice

Mice lacking the immunoreceptor tyrosine-based inhibition motif-containing co-inhibitory receptor G6b-B (Mpig6b, G6b knockout, KO) are born with a complex megakaryocyte (MK)/platelet phenotype characterized by severe macrothrombocytopenia, expansion of the MK population and focal myelofibrosis in the bone marrow and spleen. Platelets are almost completely devoid of the GPVI-FcRγ-chain collagen receptor complex, have reduced collagen integrin α2β1, elevated Syk tyrosine kinase activity, and a subset have increased surface immunoglobulins. A strikingly similar phenotype was recently reported in patients with null and loss-of-function mutations in MPIG6B. To better understand the cause and treatment of this pathology, we used pharmacological- and genetic-based approaches to rescue platelet counts and function in G6b KO mice. Intravenous-immunoglobulin resulted in a transient partial recovery of platelet counts, whereas immune deficiency had no bearing on platelet count or receptor expression in G6b KO mice. Syk loss-of-function (R41A) rescued macrothrombocytopenia, GPVI and α2β1 expression in G6b KO mice, whereas treatement with the Syk kinase inhibitor BI1002494 partially rescued platelet counts, but had no effect on GPVI and α2β1 expression, or bleeding. Src family kinase inhibitor dasatinib had no benefit in G6b KO mice. In contrast, treatment with the thrombopoietin mimetic romiplostim rescued thrombocytopenia, GPVI expression, and platelet reactivity to collagen, suggesting this may be a promising therapeutic for patients lacking functional G6b-B. Intriguingly, GPVI and α2β1 expression are significantly downregulated in romiplostim-treated wild-type mice, whereas GPVI was upregulated in romiplostim-treated G6b KO mice, suggesting a cell intrinsic feedback mechanism that auto-regulates platelet reactivity, depending physiological needs

Contester au Moyen Âge : de la désobéissance à la révolte

Les sociétés médiévales accordent une grande importance à la culture de l'obéissance, au respect de la tradition et au principe hiérarchique. Mais elles sont aussi régulièrement secouées par toutes sortes de rébellions, de dissidences ou de révoltes, voire par de véritables révolutions. Ces différentes figures de la contestation ont constitué un domaine de recherche majeur dans les années 1960-1970, porté par les vents de l’époque, avant d’être délaissés ou traités de façon plus parcellaire. À l’heure où les nouvelles recherches sur l’hérésie revisitent les rapports entre désobéissance et rébellion, où l’histoire intellectuelle réexamine la destinée de figures contestataires et où les grandes révoltes paysannes, urbaines ou nobiliaires suscitent un net regain d’intérêt, il convenait de rouvrir le dossier, sans nécessairement évoquer l’anniversaire de la Jacquerie paysanne de 1358, ni l’actualité brûlante du mouvement des « gilets jaunes ». C’est ce qu’a entrepris le XLIXe Congrès de la Société des historiens médiévistes de l’Enseignement supérieur public, réuni à Rennes en 2018. Les études rassemblées dans ce volume explorent ainsi tour à tour la manière dont les sociétés latines, byzantines ou musulmanes du Moyen Âge ont dit et défini les contestations, les motifs variés qui animaient dissidents ou révoltés, et les formes que prit la remise en cause de l’ordre établi, avant de s’interroger sur la fin des contestations et leurs effets par-delà leur dénouement souvent tragique et leur mémoire dissonante

Les métaux précieux en Méditerranée médiévale

Cet ouvrage rassemble les actes d’un colloque international tenu à la Maison Méditerranéenne des Sciences de l’Homme d’Aix-en-Provence les 6, 7 et 8 octobre 2016. Organisée par le Laboratoire d’Archéologie Médiévale et Moderne en Méditerranée (CNRS, Aix-Marseille Université) et par le Dipartimento di Scienze Storiche e dei Beni Culturali de l’Université de Sienne, cette rencontre a réuni près de cinquante spécialistes du Moyen Âge – archéologues, historiens, géochimistes – autour des métaux précieux en Méditerranée. Ce livre entend examiner un long processus qui s’étend de l’extraction des minerais jusqu’à la diffusion des métaux, en articulant les techniques aux sociétés et aux pouvoirs. Le panorama des principaux lieux de la production, ici présenté sous forme de synthèses régionales, côtoie des études qui suivent les différentes phases de ce processus, de façon à confronter les sources, les approches et à faciliter les comparaisons. L’enquête se focalise enfin sur les circulations des métaux, en mettant en évidence les problèmes de sources et de méthodes que cela induit, tout en proposant des relectures historiographiques fondées sur les résultats de travaux récents. Pour la première fois, la Méditerranée médiévale fournit le cadre géographique d’une réflexion collective consacrée aux productions et circulations des métaux précieux. Au-delà du simple bilan de connaissances, ce livre entend finalement proposer quelques jalons pour une histoire comparée et connectée : l’approfondissement, puis la confrontation d’enquêtes monographiques et régionales offrent dans cette optique de fécondes perspectives pour les années à venir