A Novel Indole-3-propanamide Exerts Its Immunosuppressive Activity by Inhibiting JAK3 in T Cells

ABSTRACT We previously identified an indole-3-propanamide derivative, 3-[1-(4-chlorobenzyl)indol-3-yl]-N-(pyridin-4-yl)propanamide (AD412), as a potential immunosuppressive agent. Here, we document that AD412 inhibited the proliferative response of CD3/CD28-stimulated human T cells without inhibiting their interleukin 2 (IL-2) production and also inhibited the proliferation of CTL-L2 cells in response to IL-2. These results prompted us to analyze the effect of our compound on the three main signaling pathways coupled to the IL-2 receptor. We provide evidence that AD412 inhibited the JAK1/3-dependent phosphorylations of Akt, STAT5a/b, and ERK1/2 in IL-2-stimulated CTL-L2 cells. In contrast, AD412 had little effect on the JAK1/2-dependent INF-␥-induced phosphorylation of STAT1 in U266 cells. This suggested a preferential inhibition of JAK3 over JAK1 or JAK 2 activities by AD412 that was confirmed by in vitro kinase assays with purified JAK2 and JAK3 kinases. In addition, we provide evidence that the inhibition of IL-2 response by AD412 was not due to inhibition of IL-2R␣ up-regulation because neither AD412 nor JAK3 inhibitors described previously [4-[(3-bromo-4-hydroxyphenyl)amino]-6,7-dimethoxyquinazoline (WHI-P154) and ␣-cyano-(3,4-dihydroxy)-N-benzylcinnamid (AG-490)] significantly inhibited IL-2-induced IL-2R␣ overexpression. Finally, we further document the immunosuppressive activity of AD412 in vivo by showing that its administration per os significantly prolonged heart allograft graft survival. This molecule may thus represent an interesting lead compound to develop new immunosuppressive agents in the field of transplantation and autoimmune diseases

Pompéi. Villa de Diomède

Dans la continuité du programme initié en 2013, l’objectif de la deuxième campagne menée sur la Villa de Diomède était de mettre en évidence la chronologie du bâtiment et son rapport aux espaces environnants. Pour ce faire, l’étude archéologique a été centrée sur les façades est et sud de la villa, afin d’éclaircir le rapport à la rue (via delle Tombe) et aux tombes adjacentes. Il convenait d’explorer davantage l’évolution de la villa en fonction des rapports de propriété et d’occupation de l..

Novel Insights into the Bovine Polled Phenotype and Horn Ontogenesis in Bovidae

Despite massive research efforts, the molecular etiology of bovine polledness and the developmental pathways involved in horn ontogenesis are still poorly understood. In a recent article, we provided evidence for the existence of at least two different alleles at the Polled locus and identified candidate mutations for each of them. None of these mutations was located in known coding or regulatory regions, thus adding to the complexity of understanding the molecular basis of polledness. We confirm previous results here and exhaustively identify the causative mutation for the Celtic allele (PC) and four candidate mutations for the Friesian allele (PF). We describe a previously unreported eyelash-and-eyelid phenotype associated with regular polledness, and present unique histological and gene expression data on bovine horn bud differentiation in fetuses affected by three different horn defect syndromes, as well as in wild-type controls. We propose the ectopic expression of a lincRNA in PC/p horn buds as a probable cause of horn bud agenesis. In addition, we provide evidence for an involvement of OLIG2, FOXL2 and RXFP2 in horn bud differentiation, and draw a first link between bovine, ovine and caprine Polled loci. Our results represent a first and important step in understanding the genetic pathways and key process involved in horn bud differentiation in Bovidae

Philadelphia (2022)

Données scientifiques produites :https://www.ifao.egnet.net/recherche/archeologie/philadelphie/ The joint French-Austrian Mission of the IFAO, the UMR 7044 Archimède – University of Strasbourg and the Department of Classical Studies of the Austrian Archaeological Institute (ÖAI) worked at Kūm al-Ḫarāba al-Kabīr Ğirza, in the ruins of ancient Philadelphia, from 10 January to 7 February 2022. The Mission team was directed by Ruey-Lin Chang (papyrologist) and included Simone Nannucci (archa..

Antilymphocyte globulin for matched sibling donor transplantation in patients with myelofibrosis

The use of antihuman T-lymphocyte immunoglobulin in the setting of transplantation from an HLA-matched related donor is still much debated. Acute and chronic graft-versus-host disease are the main causes of morbidity and mortality after allogeneic hematopoietic stem cell transplantation in patients with myelofibrosis. The aim of this study was to evaluate the effect of antihuman T-lymphocyte immunoglobulin in a large cohort of patients with myelofibrosis (n= 287). The cumulative incidences of grade II-IV acute graft-versus-host disease among patients who were or were not given antihuman T-lymphocyte immunoglobulin were 26% and 41%, respectively. The corresponding incidences of chronic graft-versus-host disease were 52% and 55%, respectively. Non-adjusted overall survival, disease-free survival and non-relapse mortality rates were 55% versus 53%, 49% versus 45%, and 32% versus 31%, respectively, among the patients who were or were not given antihuman T-lymphocyte immunoglobulin. An adjusted model confirmed that the risk of acute graft-versus-host disease was lower following antihuman T-lymphocyte immunoglobulin (hazard ratio, 0.54; P= 0.010) while it did not decrease the risk of chronic graft-versus-host disease. The hazard ratios for overall survival and non-relapse mortality were 0.66 and 0.64, with P-values of 0.05 and 0.09, respectively. Antihuman T-lymphocyte immunoglobulin did not influence disease-free survival, graft-versus-host disease, relapse-free survival or relapse risk. In conclusion, in the setting of matched related transplantation in myelofibrosis patients, this study demonstrates that antihuman T-lymphocyte immunoglobulin decreases the risk of acute graft-versushost disease without increasing the risk of relapse.Peer reviewe

A future for Hashima: pornography, representation and time

This article sets out to investigate the relationship between ruins, futurity, and ‘ruin porn’ - a visual mode of representation that all too often seeks to fix post-industrial ruins as mere aesthetic objects, devoid of history and/or temporality. It does so by focusing on performance, which, in this context, is understood as a processual mode of art-making that provides spectators with an experience of time. In this expanded definition of performance, as one may perhaps expect, the performativity of the object is not limited to the theatrical event alone; rather, it now inheres in sometimes uncanny durational aspects of both still and moving images. The essay proceeds in three stages. Part one provides a historical and theoretical overview of the type of performance inherent in ‘ruin porn’; part two critiques two images from Yves Marchand's and Romain Meffre's Gunkanjima (2013), a photo album that attempted to document the ruins of Hashima, an island situated 15 kilometres from Nagasaki City in the East China Sea; and part three investigates the very different aesthetic at work in Lee Hassall's film Return to Battleship Island (2013) which was made in response to AHRC- funded project, ‘The Future of Ruins: Reclaiming Abandonment and Toxicity on Hashima Island’ (2013). In this reading of Return to Battleship Island , the onus is on showing how Hassall's film, in its representation of Hashima's crumbling apartment blocks and industrial buildings, intentionally sought to contest the atemporal logic of ‘ruin porn’ by attempting to endow the viewing experience with a sense of futurity. Crucially, this does not mean that film represented the future as an object, but, on the contrary, tried to make it palpable, as something one undergoes physically in the very act of reception

Special Care and School Difficulties in 8-Year-Old Very Preterm Children: The Epipage Cohort Study

OBJECTIVES: To investigate school difficulties, special care and behavioral problems in 8 year-old very preterm (VPT) children. PATIENT AND METHODS: Longitudinal population-based cohort in nine regions of France of VPT children and a reference group born at 39-40 weeks of gestation (WG). The main outcome measures were information about school, special care and behavioral problems using Strengths and Difficulties Questionnaire from a questionnaire to parents. RESULTS: Among the 1439 VPT children, 5% (75/1439) were in a specialised school or class, 18% (259/1439) had repeated a grade in a mainstream class and 77% (1105/1439) were in the appropriate grade-level in mainstream class; these figures were 1% (3/327) , 5% (16/327) and 94% (308/327) , respectively, for the reference group. Also, 15% (221/1435) of VPT children in a mainstream class received support at school versus 5% (16/326) of reference group. More VPT children between the ages of five and eight years received special care (55% (794/1436)) than children born at term (38% (124/325)); more VPT children (21% (292/1387)) had behavioral difficulties than the reference group (11% (35/319)). School difficulties, support at school, special care and behavioral difficulties in VPT children without neuromotor or sensory deficits varied with gestational age, socioeconomic status, and cognitive score at the age of five. CONCLUSIONS: Most 8-year-old VPT children are in mainstream schools. However, they have a high risk of difficulty in school, with more than half requiring additional support at school and/or special care. Referral to special services has increased between the ages of 5 and 8 years, but remained insufficient for those with borderline cognitive scores