Efficacy of the Janus kinase 1/2 inhibitor ruxolitinib in the treatment of vasculopathy associated with TMEM173-activating mutations in 3 children

International audienc

Negotiating the modern cross-class ‘model home’:domestic experiences in Basil Spence’s Claremont Court

This article investigates the spatial articulation of architecture and home through the exploration of current domestic experiences in Basil Spence’s Claremont Court housing scheme (1959-1962), Edinburgh. How architecture and home are both idealized and lived is the backdrop for a discussion that draws on the concept of “model home,” or physical representation of a domestic ideal. The article reads Claremont Court as an architectural prototype of the modern domestic ideal, before exploring its reception by five of its households through the use of visual methods and semistructured interviews. Receiving the model home involves negotiating between ideal and lived homes. Building on this idea, the article contributes with a focus on the spatiality of such reception, showing how it is modulated according to the architectural affordances that the “model home” represents. The article expands on scholarship on architecture and home with empirical evidence that argues the reciprocal spatiality of home

The First Data Release of the Sloan Digital Sky Survey

The Sloan Digital Sky Survey has validated and made publicly available its First Data Release. This consists of 2099 square degrees of five-band (u, g, r, i, z) imaging data, 186,240 spectra of galaxies, quasars, stars and calibrating blank sky patches selected over 1360 square degrees of this area, and tables of measured parameters from these data. The imaging data go to a depth of r ~ 22.6 and are photometrically and astrometrically calibrated to 2% rms and 100 milli-arcsec rms per coordinate, respectively. The spectra cover the range 3800--9200 A, with a resolution of 1800--2100. Further characteristics of the data are described, as are the data products themselves.Comment: Submitted to The Astronomical Journal. 16 pages. For associated documentation, see http://www.sdss.org/dr

A community effort in SARS-CoV-2 drug discovery.

peer reviewedThe COVID-19 pandemic continues to pose a substantial threat to human lives and is likely to do so for years to come. Despite the availability of vaccines, searching for efficient small-molecule drugs that are widely available, including in low- and middle-income countries, is an ongoing challenge. In this work, we report the results of an open science community effort, the "Billion molecules against Covid-19 challenge", to identify small-molecule inhibitors against SARS-CoV-2 or relevant human receptors. Participating teams used a wide variety of computational methods to screen a minimum of 1 billion virtual molecules against 6 protein targets. Overall, 31 teams participated, and they suggested a total of 639,024 molecules, which were subsequently ranked to find 'consensus compounds'. The organizing team coordinated with various contract research organizations (CROs) and collaborating institutions to synthesize and test 878 compounds for biological activity against proteases (Nsp5, Nsp3, TMPRSS2), nucleocapsid N, RdRP (only the Nsp12 domain), and (alpha) spike protein S. Overall, 27 compounds with weak inhibition/binding were experimentally identified by binding-, cleavage-, and/or viral suppression assays and are presented here. Open science approaches such as the one presented here contribute to the knowledge base of future drug discovery efforts in finding better SARS-CoV-2 treatments.R-AGR-3826 - COVID19-14715687-CovScreen (01/06/2020 - 31/01/2021) - GLAAB Enric

Ten golden rules for optimal antibiotic use in hospital settings: the WARNING call to action

Antibiotics are recognized widely for their benefits when used appropriately. However, they are often used inappropriately despite the importance of responsible use within good clinical practice. Effective antibiotic treatment is an essential component of universal healthcare, and it is a global responsibility to ensure appropriate use. Currently, pharmaceutical companies have little incentive to develop new antibiotics due to scientific, regulatory, and financial barriers, further emphasizing the importance of appropriate antibiotic use. To address this issue, the Global Alliance for Infections in Surgery established an international multidisciplinary task force of 295 experts from 115 countries with different backgrounds. The task force developed a position statement called WARNING (Worldwide Antimicrobial Resistance National/International Network Group) aimed at raising awareness of antimicrobial resistance and improving antibiotic prescribing practices worldwide. The statement outlined is 10 axioms, or “golden rules,” for the appropriate use of antibiotics that all healthcare workers should consistently adhere in clinical practice

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Recherche de gènes monogéniques à l'origine du Lupus : description d'un nouveau gène responsable d'un syndrome auto-immune inflammatoire

Le Lupus est une maladie systémique auto-immune complexe, caractérisée notamment par la perte de tolérance vis-à-vis d’antigènes nucléaires, qui affecte majoritairement les femmes à l’âge adulte. Cette maladie est hétérogène tant du point de vue clinique que génétique, ce qui a considérablement limité les progrès dans la compréhension de sa pathogénèse. Dans ce projet, nous avons mis à profit la technologie de séquençage de nouvelle génération de type « Whole Exome Sequencing (WES)» pour explorer la génétique du Lupus à l’échelle de familles individuelles. De plus, nous avons centré notre étude sur des formes à début pédiatrique qui sont cliniquement plus sévères que les formes adultes. Nous avons fait l’hypothèse que ce sous-groupe de patients devrait être enrichi en formes monogéniques. Nous avons ainsi inclus dans cette étude des cas familiaux de lupus ou des familles dans lesquelles il existait un patient lupique et des apparentés atteints de pathologies auto-immunes. Un séquençage WES a été réalisé dans ces familles et la validation des gènes identifiés par cette stratégie a fait l’objet de ce travail. Nous avons découvert une mutation hétérozygote gain de fonction du gène TMEM173 qui code STING, un adaptateur clé dans la signalisation de la détection des ADNs cytosoliques et la production d’interféron de type-I (IFN-I). Quatre membres de cette famille porteurs de la mutation présentent une pathologie auto-inflammatoire et auto-immune, dont un cas de Lupus, avec une expression clinique hautement variable. Une modélisation structurale in silico de la forme mutée prédisait initialement une stabilisation de la forme dimérique de STING avec pour conséquence possible une activation constitutive. En accord avec ces données, nous avons montré, en absence du ligand naturel, une activité constitutive de la forme mutée de STING exprimée dans une lignée cellulaire, ainsi qu’une localisation spontanée dans l’appareil de Golgi des fibroblastes de patients indiquant un état activé. Corrélativement, nous avons observé une concentration sérique élevée d’IFNa chez les patients ainsi qu’une signature transcriptionnelle fortement augmentée d’un panel de gènes induits par les IFN-I. A la suite de cette découverte, nous avons identifié de nouvelles mutations activatrices de STING chez des patients atteints de pathologies vasculaires et de fibroses pulmonaires sévères en relation avec un syndrome inflammatoire, et deux patients ont pu recevoir un traitement ciblant l’inhibition de la voie des IFN-I. Ce travail a permis de mettre en lumière le rôle clé de STING dans l’homéostasie du système immunitaire chez l’homme et de mieux comprendre la physiopathologie de maladies inflammatoires et auto-immunes, motivant la mise en place d’un traitement spécifique chez les patients. Au-delà de cette découverte importante pour ces malades, ce travail suggère que des variants rares et délétères permettent de décrire les causes génétiques de maladies auto-immunes dites complexes.Lupus is a complex systemic autoimmune disease characterized by a loss of tolerance to nuclear antigens predominantly afflicting women of childbearing age. The disease is both clinically and genetically heterogeneous and this has greatly limited progress in understanding disease pathogenesis. In this project, we utilize next generation sequencing technology such as “Whole Exome Sequencing (WES)” to explore the genetics of lupus at the level of individual families. Furthermore, we focused on a rare subgroup of lupus patients, which develop the disease in childhood and usually present with a more severe clinical phenotype compared to the adult-onset form. We hypothesized that this subgroup would be enriched for monogenic forms of the disease. Thus, we recruited several families with early-onset in the proband and at least one other familial member presenting with lupus or associated autoimmune disease. WES was performed and the validation of the gene identified by this strategy is described. We identified a familial gain of function dominant mutation in TMEM173, encoding STING, a key adaptor molecule in the cytosolic DNA sensing pathway and Type-I interferon (IFN-I) production. The four affected family members demonstrate a systemic inflammatory and autoimmune condition, including lupus, with variable clinical expression. Structural modeling initially predicted a stabilized dimerization of the mutant STING and thereby a constitutive activation. In agreement with this, we found that the STING mutant spontaneously localizes in the Golgi of patient fibroblasts, and is constitutively active in the absence of its ligand in vitro. Accordingly, we observed elevated serum interferon activity and a IFN-I signature in peripheral blood. We have also identified several other patients with activating STING mutations presenting with vascular inflammation and or pulmonary fibrosis, and two patients received a treatment targeting the IFN-I signaling pathway. This discovery highlights the key role of STING in human immune homeostasis and its implication in severe inflammatory and autoimmune diseases, leading to new and more specific therapeutical approaches. Beyond these important findings with regards to patients, this work suggests that rare deleterious variants can describe the genetic cause of autoimmune pathologies previously defined as complex diseases

PReS-FINAL-2353: Are rasopathies new monogenic predisposing conditions to the development of systemic lupus erythematosus?

International audienc

Is introducing rapid culture into the diagnostic algorithm of smear-negative tuberculosis cost-effective?

S E T T I N G : In 2007, the World Health Organization recommended introducing rapid Mycobacterium tuberculosis culture into the diagnostic algorithm of smearnegative pulmonary tuberculosis (TB). O B J E C T IVE : To assess the cost-effectiveness of introducing a rapid non-commercial culture method (thinlayer agar), together with L¨ owenstein-Jensen culture to diagnose smear-negative TB at a district hospital in Kenya. D E S I G N : Outcomes (number of true TB cases treated) were obtained from a prospective study evaluating the effectiveness of a clinical and radiological algorithm (conventional) against the alternative algorithm (conventional plus M. tuberculosis culture) in 380 smearnegative TB suspects. The costs of implementing each algorithm were calculated using a 'micro-costing' or 'ingredient-based' method. We then compared the cost and effectiveness of conventional vs. culture-based algorithms and estimated the incremental cost-effectiveness ratio. RESULT S : The costs of conventional and culture-based algorithms per smear-negative TB suspect were respectively E39.5 and E144. The costs per confirmed and treated TB case were respectively E452 and E913. The culture-based algorithm led to diagnosis and treatment of 27 more cases for an additional cost of E1477 per case. CONCLUSION: Despite the increase in patients started on treatment thanks to culture, the relatively high cost of a culture-based algorithm will make it difficult for resource-limited countries to afford