TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are age-related neurodegenerative disorders with shared genetic etiologies and overlapping clinical and pathological features. Here we studied a novel ALS/FTD family and identified the P362L mutation in the low-complexity domain (LCD) of T cell-restricted intracellular antigen-1 (TIA1). Subsequent genetic association analyses showed an increased burden of TIA1 LCD mutations in ALS patients compared to controls (p = 8.7 × 1

Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1,131 unrelated Caucasian patients, we estimated that C9orf72 repeat expansions and GRN loss-of-function mutations account for 25.5% and 13.9% of FTLD-TDP patients, respectively. Mutations in TBK1 (1.5%) and other known FTLD genes (1.4%) were rare, and the disease in 57.7% of FTLD-TDP patients was unexplained by the known FTLD genes. To unravel the contribution of common genetic factors to the FTLD-TDP etiology in these patients, we conducted a two-stage association study comprising the analysis of whole-genome sequencing data from 517 FTLD-TDP patients and 838 controls, followed by targeted genotyping of the most associated genomic loci in 119 additional FTLD-TDP patients and 1653 controls. We identified three genome-wide significant FTLD-TDP risk loci: one new locus at chromosome 7q36 within the DPP6 gene led by rs118113626 (pvalue=4.82e-08, OR=2.12), and two known loci: UNC13A, led by rs1297319 (pvalue=1.27e-08, OR=1.50) and HLA-DQA2 led by rs17219281 (pvalue=3.22e-08, OR=1.98). While HLA represents a locus previously implicated in clinical FTLD and related neurodegenerative disorders, the association signal in our study is independent from previously reported associations. Through inspection of our whole genome sequence data for genes with an excess of rare loss-of-function variants in FTLD-TDP patients (n≥3) as compared to controls (n=0), we further discovered a possible role for genes functioning within the TBK1-related immune pathway (e.g. DHX58, TRIM21, IRF7) in the genetic etiology of FTLD-TDP. Together, our study based on the largest cohort of unrelated FTLD-TDP patients assembled to date provides a comprehensive view of the genetic landscape of FTLD-TDP, nominates novel FTLD-TDP risk loci, and strongly implicates the immune pathway in FTLD-TDP pathogenesis

Contribution à l'analyse de la réponse polarimétrique d'un couvert forestier

Un des buts de la télédétection est de faire des mesures non intrusives d'environnements naturels. Dans le cadre d'une application à la végétation, l'objectif est de retrouver les paramètres biophysiques d'une forêt à partir des mesures. Pour cela il est possible d'utiliser des modèles électromagnétiques pour simuler les paramètres polarimétriques mesurés. Cette étude détaille donc la constitution d'un modèle polarimétrique incohérent de végétation et son utilisation couplée à celle d'un modèle cohérent. Ces modèles s'appuient sur des mesures in-situ de la forêt fournies par l'INRA. Les résultats des simulations sont comparés à des mesures faites en chambre anéchoïque et à des images du capteur SAR polarimétrique RAMSES de l'ONERA acquises en bande P durant la campagne PYLA-2001. Cela pose les jalons de l'étude des relations directes entre les paramètres polarimétriques et les paramètres biophysiques, relations qui doivent ensuite être inversées.RENNES1-BU Sciences Philo (352382102) / SudocSudocFranceF

Caractérisation polarimétrique de la végétation par modélisation

National audienc

Full Polarimetric and Multi-Frequency Vegetation Model for a Better Understanding of Polarimetric Properties

International audienc

MRI contrast variation of thermosensitive magnetoliposomes triggered by focused ultrasound: a tool for image-guided local drug delivery

Improved drug delivery control during chemotherapy is a major concern to increase their therapeutic index. Drug accumulation in solid tumor can be visualized using MRI contrast agent such as iron oxide nanoparticles encapsulated in liposomes. Once accumulated in tumor, the combination of a thermosensitive composition with an external source of activation allows local release of drug. MRI guided-High intensity focused ultrasound (HIFU) represents a non invasive technique to generate local hyperthermia for drug release of thermosensitive magnetoliposomes (TSM). In this study we performed encapsulation of ultrasmall superparamagnetic iron oxide nanoparticles (USPIO) in thermosensitive liposomes to obtain TSM. Magnetic behavior of this MRI contrast agent was observed during TSM membrane permeabilization. For this, measurement of transverse and longitudinal relaxivities on MRI, and real time experiments were performed on TSM samples loaded with USPIO during heating using a water bath or HIFU. Results showed significant differences for MRI signal enhancement and relaxivities ratios before and after heating, which were absent for non-thermosensitive liposomes and free nanoparticles used as controls. Thus, incorporation of USPIO as MRI-contrast agents into thermosensitive liposomes should, besides TSM tumor accumulation, allows the visualization of TSM membrane permeabilization upon temperature elevation. In conclusion, HIFU under MR image guidance in combination with USPIO loaded thermosensitive liposomes as drug delivery system has the potential for a better control of drug delivery and to increase the therapeutic index of chemotherapy

Overall mutational spectrum of SLC20A2, PDGFB and PDGFRB in idiopathic basal ganglia calcification

International audienc