196 research outputs found
Caractérisation de la présence d'anticorps anti-mitochondriaux associés au lupus érythémateux disséminé
Les mitochondries sont des organelles intracellulaires impliquĂ©es dans de nombreuses voies biologiques. Suite Ă la mort ou lâactivation de certains types cellulaires, elles peuvent ĂȘtre relarguĂ©es dans le milieu extracellulaire oĂč, elles sont reconnues comme des signaux de danger (DAMPS), gĂ©nĂ©rant une rĂ©ponse pro-inflammatoire par le systĂšme immunitaire innĂ©. Les interactions entre les mitochondries et lâimmunitĂ© adaptative sont encore mĂ©connues. Neuf classes dâanticorps anti mitochondriaux (AMA M1 Ă M9) ont Ă©tĂ© dĂ©crits diffĂ©rentes pathologies telles que la syphilis, la cirrhose biliaire primitive (CBP), le lupus Ă©rythĂ©mateux dissĂ©minĂ© (LED) ou le syndrome des anti phospholipides (APS), sans que leur association avec lâexpression clinique de ces maladies nâait jamais Ă©tĂ© Ă©tudiĂ©e. Dans la prĂ©sente Ă©tude, nous avons dĂ©veloppĂ© des mĂ©thodes de dĂ©tection des AMA et anti-ADN mitochondrial (AMtDNA) puis Ă©tudiĂ© des corrĂ©lations entre la prĂ©sence de ces anticorps et les caractĂ©ristiques de la maladie exprimĂ©es par des patients lupiques. Nous avons mis en Ă©vidence une association protectrice des AMA envers les Ă©vĂšnements thrombotiques ainsi quâune corrĂ©lation entre les niveaux dâAMtDNA et une Ă©lĂ©vation de lâindex dâactivitĂ© de la maladie (SLEDAI) en lien avec un accroissement des anticorps ciblant lâADN double-brins (DsDNA).Mitochondria are intracellular organelles that are involved in a vast number of biological pathways. They may be released in the extracellular milieu upon cell death or the activation of several types of cells where they will be recognized as danger signals (DAMPs), eliciting a pro-inflammatory response by the innate immune system. To this day, interplays between mitochondria and the adaptive branch of the immunity are poorly defined. Nine classes of anti mitochondrial antibodies (AMA M1 to M9) were reported in diseases such as syphilis, primary biliary cirrhosis (PBS), systemic lupus erythematosus (SLE) or the anti-phospholipid syndrome (APS) but their association to the clinical manifestations of these diseases have never been studied. In the present study, we developed methods for the detection of AMA and anti-mitochondrial DNA antibodies (AMtDNA) then studied correlations between the presence of these antibodies and clinical features expressed by lupus patients. We found a protective association of AMA towards thrombotic events and that AMtDNA levels correlates with an increase of the SLE disease activity index (SLEDAI) linked to an increase of the antibodies targeting double-stranded DNA (DsDNA)
Identification des cibles antigéniques d'origine mitochondriale, reconnues par les autoanticorps dans le lupus érythémateux disséminé
Mitochondria are intracellular organelles in control of numerous biological functions (e.g.,from energy supply to steroidogenesis and programmed cell death by apoptosis). Evolutively, mitochondria are considered as derived from the endosymbiosis between an α-proteobacterium and a primitive eukaryotic cell. Due to its origin, the organelle displays prokaryotic motifs such as a circular double-stranded hypomethylated DNA (i.e., mtDNA) and N-formylated peptides. Intact or damaged mitochondria, as well as mitochondrial components may be extruded in the extracellular space upon cell activation or death. These features, as well as several biomolecules localized within the mitochondrion (e.g.,ATP, cytochrome C) are able to be recognized by the innate immune system as mitochondrial damage-associated molecular patterns, thus eliciting a proinflammatory response. A humoral immune response comprising anti-mitochondrial antibodies (AMA) is also described in various autoimmune conditions, such as AMA-M2 in primary biliary cirrhosis (i.e., PBC). Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the alternance of flares and phases of remission, due to the deposition of antibody-antigen scaffolds (i.e., immune complexes) within tissues, leading to various clinical manifestations (e.g., neuropsychiatric, hematological or dermatological disorders). The antiphospholipid syndrome (i.e., APS) is an autoimmune disease, with thromboembolic and/or obstetrical manifestations, that can either be found alone or along with SLE. While the immunogenicity of cardiolipin (i.e., a phospholipid uniquely synthetized by mitochondria In humans) is well described in SLE and APS (i.e., anticardiolipins), mitochondrial proteins targeted by autoantibodies are still poorly known. The present doctoral thesis follows my masters' project during which I developed ELISAs allowing for the detection of AMA targeting intact mitochondria (i.e., AwMA) or mtDNA (i.e., AmtDNA)Âč. The present project aims aims to characterize the mitochondrial immunogenicity in SLE and APS. The University of Toronto Lupus Clinic cohort comprise sera from patients with SLE or APS (n=175 and n=12 respectively). AwMA and AmtDNA levels were assessed in these samples, as well as in sera from healthy volunteers (n=43) or patients with PBC (n=12). I observed that all patients had increased AwMA, compared to healthy individuals. AmtDNA were only increased in SLE patients and were associated with increased past reports of lupus nephritis (p=0.01). These results were published in March 2019 in Scientific ReportsÂČ. During the acquisition of these data, I observed that patients' sera also presented immunoreactivity against mitochondrial RNA (i.e., mtRNA). I thus adapted my assays to detect autoantibodies against mtRNA (i.e., AmtRNA), and assessed their levels in sera from patients includes in the systemic autoimmune rheumatic disease biobank and data repository (i.e., SARD-BDB. Healthy:n=30, SLE:n=87). AmtRNA were significantly elevated in SLE (IgG: p<0.0001, IgM:p=0.0493). Surprisingly, AmtRNA-IgG were associated with decreased reports of past lupus nephritis (p=0.03) and carotid plaque (p=0.04). This study was published in Frontiers in Immunology in May 2019Âł. As each AMA assessed displayed biostatistical associations with antiphospholipids, I replicated these protocols, using sera from patients with APS, included in the SARD-BDB (n=27). AmtRNA (IgG:p=0.0005, IgM:p=0.01) and AmtDNA-IgM were increased in APS (p=0.009). However, only AmtDNA-IgM were associated with reports of arterial thromboses (p=0.047). This pilot study was published in Lupus in August 2020âŽ. In a a recent study, accepted in Arthritis & Rheumatology in January 2022â”, we identified by mass spectrometry 1345 proteins associated with AwMA, 431 of with were assigned to the mitochondrial proteome. These results allowed to identify two candidates: C1qBP and Mfn-1. IgGs to C1qBP were increased in (p=0.0167) and associated with positivity to the lupus anticoagulant (p=0.049) in SLE. IgGs against Mfn-1 are interesting candidates for the prediction of the disease (p=0.0052) and are associated with positivity to antiphospholipids (p=0.011) and antibodies against double-stranded DNA (p = 0.0005). These results highlight the immunogenicity of the organelle in SLE and APS. Mitochondrial antigens are interesting candidates for the development of novel clinical assays allowing improved prognosis, diagnosis, or disease stratification, ultimately contributing to the improvement of medical care for people with autoimmune conditions.Les mitochondries sont des organelles intracellulaires considĂ©rĂ©es comme issues de l'endosymbiose entre une α-protĂ©obactĂ©rie et une cellule eucaryote primitive. L'organelle exprime ainsi des motifs molĂ©culaires en lien avec son origine procaryote tels qu'un ADN hypomĂ©thylĂ©s (i.e., mtDNA) ou des peptides N-formylĂ©s. Des mitochondries ou bien des composantes mitochondriales pourront ĂȘtre libĂ©rĂ©es dans le milieu extracellulaire lors de diffĂ©rents Ă©vĂšnements d'activation ou de mort cellulaire. Ces caractĂ©ristiques ainsi que certaines biomolĂ©cules, spĂ©cifiquement localisĂ©es dans la mitochondrie (e.g.,ATP, cytochrome C) auront la capacitĂ© d'ĂȘtre reconnues comme des motifs de dangers et de stimuler une rĂ©ponse proinflammatoire de la part des cellules du systĂšme immunitaire innĂ©. Une rĂ©ponse humorale constituĂ©e d'anticorps anti-mitochondriaux (AMA) est connue dans diffĂ©rents troubles auto-immuns tels que les AMA-M2 dans la cirrhose biliaire primitive (PBC). Le lupus Ă©rythĂ©mateux dissĂ©minĂ© (SLE) est une maladie auto-immune caractĂ©risĂ©e par une succession de phases d'exacerbation et de rĂ©mission dues au dĂ©pĂŽt d'enchevĂȘtrements d'autoanticorps et de leurs antigĂšnes dans les tissus, aboutissant Ă une grande variĂ©tĂ© de manifestations cliniques (e.g.,manifestations neuropsychiatriques, hĂ©matologiques, dermatologiques). Le syndrome des antiphospholipides (APS) est une maladie qui peut ĂȘtre distincte ou associĂ©e au SLE et prĂ©sente des manifestations thromboemboliques et/ou obstĂ©triques. Bien que l'immunogĂ©nicitĂ© de la cardiolipine (i.e., phospholipide uniquement synthĂ©tisĂ©e dans la mitochondrie chez l'humain) soit connue dans le cadre du SLE et de l'APS (i.e., anticardiolipines), l'antigĂ©nicitĂ© des protĂ©ines mitochondriales reste encore mĂ©connue. Cette thĂšse de doctorat fait suite Ă mes travaux de maĂźtrise au cours desquels, j'ai dĂ©veloppĂ© des ELISAs permettant de mesurer des niveaux des IgGs dirigĂ©s contre les mitochondries intactes (i.e., AwMA) et le mtDNA (i.e., AmtDNA)Âč. Mon projet de thĂšse vise Ă caractĂ©riser l'immunogĂ©nicitĂ© mitochondriale dans l'auto-immunitĂ©. La cohorte de la University of Toronto Lupus Clinic regroupe des Ă©chantillons d'Ă©chantillons de sĂ©ra de patients souffrant de SLE ou d'APS (n=175 et n=12, respectivement). Les AwMA, et AmtDNA ont Ă©tĂ© mesurĂ©s au sein de ces Ă©chantillons ainsi que d'Ă©chantillons de volontaires sains (n=43) et de donneurs souffrant de PBC (n=12). Les patients souffrant des trois conditions prĂ©sentaient une augmentation significative des AwMA par rapport aux contrĂŽles sains. Les AmtDNA, uniquement augmentĂ©s chez les patients SLE (p=0.0004) ont Ă©tĂ© associĂ©s Ă des antĂ©cĂ©dents accrus de nĂ©phrite lupique (p=0.01). Ces rĂ©sultats ont Ă©tĂ© publiĂ©s en mars 2019 dans le journal Scientific ReportsÂČ . Durant ces mesures, j'ai observĂ© que les sĂ©ra de patients prĂ©sentaient aussi une immunorĂ©activitĂ© dirigĂ©e contre l'ARN mitochondrial (mtRNA). J'ai, par la suite, adaptĂ© mes tests pour dĂ©tecter les AMA dirigĂ©s contre le mtRNA (i.e., AmtRNA) et les ai mesurĂ©s Ă l'aide de sĂ©ra inclus dans la cohorte des maladies rhumatismales auto-immunes systĂ©miques (MRAS. Sains:n=30, SLE:n=87). Les d'AmtRNA sont significativement Ă©levĂ©s dans le SLE (IgG:p<0.0001 , IgM:p=0.0493). De façon surprenante, les AmtRNA-IgG sont associĂ©s avec des historiques rĂ©duits de nĂ©phrite lupique (p=0.03) et de plaque carotidienne (p=0.04). Ces travaux ont Ă©tĂ© publiĂ©s dans le journal Frontiers in Immunology en mai 2019Âł. L'ensemble des AMA mesurĂ©s prĂ©sentant des associations biostatistiques avec diffĂ©rents anticorps antiphospholipides. J'ai rĂ©pliquĂ© mon protocole sur des Ă©chantillons de patients souffrant d'APS, inclus dans la cohorte MRAS (n=27). Les AmtRNA (IgG:p=0.0005, IgM:p=0.01) et les AmtDNA-IgM sont augmentĂ©s dans l'APS (p=0.009). Seuls les AmtRNA-IgM sont associĂ©es avec une diminution des antĂ©cĂ©dents de thromboses artĂ©rielles (p=0.047). Ce projet a fait l'objet d'un article, publiĂ© dans Lupus en aout 2020âŽ. Dans une autre Ă©tude, acceptĂ©e dans le journal Arthritis & Rheumatology en janvier 2022â”, nous avons identifiĂ©, par spectromĂ©trie de masse, 1345 protĂ©ines associĂ©es aux AwMA dont 431 sont associĂ©es avec le protĂ©ome mitochondrial. Ces rĂ©sultats m'ont permis d'identifier deux candidats d'intĂ©rĂȘts : C1qBP et Mfn-1. Les anti-C1qBP sont significativement augmentĂ©s chez les patients lupiques (p=0.0167) et sont associĂ©s avec la positivitĂ© pour l'anticoagulant lupique (p=0.049). Les anti-Mfn1 constituent de potentiels candidats pour prĂ©dire la maladie (p=0.0052). Ils sont, par ailleurs, associĂ©s avec la positivitĂ© aux antiphospholipides (p=0.011) et aux anti-ADN double brins (p=0.0005). Ces rĂ©sultats soulignent l'immunogĂ©nicitĂ© de la mitochondrie dans le SLE et l'APS. Les AMA et leurs cibles constituent de nouvelles avenues d'intĂ©rĂȘt dans la mise au point de nouveaux tests cliniques permettant le diagnostic, le pronostic ou la classification de la maladie afin d'amĂ©liorer la prise en charge des patients lupiques
Reliability of mantle tomography models assessed by spectral element simulation
Global tomographic models collected in the Seismic wave Propagation and Imaging in Complex (SPICE media: a European network) model library (http://www.spicertn.org/research/planetaryscale/tomography/) share a similar pattern of long, spatial wavelength heterogeneity, but are not consistent at shorter spatial wavelengths. Here, we assess the performance of global tomographic models by comparing how well they fit seismic waveform observations, in particular Love and Rayleigh wave overtones and fundamental modes. We first used the coupled spectral element method (CSEM) to calculate long-period (>100 s) synthetic seismograms for different global tomography models. The CSEM can incorporate the effect of three-dimensional (3-D) variations in velocity, anisotropy, density and attenuation with very little numerical dispersion. We then compared quantitatively synthetic seismograms and real data. To restrict ourselves to high-quality overtone data, and to minimize the effects of the finite extent of seismic sources and of crustal heterogeneity, we favour deep (>500 km) earthquakes of intermediate magnitude (Mw ⌠7). Our comparisons reveal that: (1) The 3-D global tomographic models explain the data much better than the one-dimensional (1-D) anisotropic Preliminary Reference Earth Model (PREM). The current 3-D tomographic models have captured the large-scale features of upper-mantle heterogeneities, but there is still some room for the improvement of large-scale features of global tomographic models. (2) The average correlation coefficients for deep events are higher than those for shallow events, because crustal structure is too complex to be completely incorporated into CSEM simulations. (3) The average correlation coefficient (or the time lag) for the major-arc wave trains is lower (or higher) than that for the minor-arc wave trains. Therefore, the current tomographic models could be much improved by including the major-arc wave trains in the inversion. (4) The shallow-layer crustal correction has more effects on the fundamental surface waves than on the overtone
The CoLiS Platform for the Analysis of Maintainer Scripts in Debian Software Packages
International audienceThe software packages of the Debian distribution include more than twenty-seven thousand maintainer scripts in total, almost all of them being written in the Posix shell language. These scripts are executed with root privileges at installation, update, and removal of a package, which makes them critical for system maintenance. While the Debian policy provides guidance for package maintainers producing the scripts, only few tools exist to check the compliance of a script to that policy. We present CoLiS, a software platform for discovering violations of non-trivial properties required by the Debian policy in maintainer scripts. We describe our methodology which is based on symbolic execution and feature tree constraints, and we give an overview of the toolchain. We obtain promising results: our toolchain is effective in analysing a large set of Debian maintainer scripts, and it has already detected over 150 policy violations that have lead to bug reports, more than two-third of them now being fixed
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l(1)-regularized maximum likelihood estimation with focused-spot illumination quadruples the diffraction-limited resolution in fluorescence microscopy
Super-resolution fluorescence microscopy has proven to be a useful tool in biological studies. To achieve more than two-fold resolution improvement over the diffraction limit, existing methods require exploitation of the physical properties of the fluorophores. Recently, it has been demonstrated that achieving more than two-fold resolution improvement without such exploitation is possible using only a focused illumination spot and numerical post-processing. However, how the achievable resolution is affected by the processing step has not been thoroughly investigated. In this paper, we focus on the processing aspect of this emerging super-resolution microscopy technique. Based on a careful examination of the dominant noise source and the available prior information in the image, we find that if a processing scheme is appropriate for the dominant noise model in the image and can utilize the prior information in the form of sparsity, improved accuracy can be expected. Based on simulation results, we identify an improved processing scheme and apply it in a real-world experiment to super-resolve a known calibration sample. We show an improved super-resolution of 60nm, approximately four times beyond the conventional diffraction-limited resolution.</p
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Achieving superresolution with illumination-enhanced sparsity.
Recent advances in superresolution fluorescence microscopy have been limited by a belief that surpassing two-fold resolution enhancement of the Rayleigh resolution limit requires stimulated emission or the fluorophore to undergo state transitions. Here we demonstrate a new superresolution method that requires only image acquisitions with a focused illumination spot and computational post-processing. The proposed method utilizes the focused illumination spot to effectively reduce the object size and enhance the object sparsity and consequently increases the resolution and accuracy through nonlinear image post-processing. This method clearly resolves 70nm resolution test objects emitting ~530nm light with a 1.4 numerical aperture (NA) objective, and, when imaging through a 0.5NA objective, exhibits high spatial frequencies comparable to a 1.4NA widefield image, both demonstrating a resolution enhancement above two-fold of the Rayleigh resolution limit. More importantly, we examine how the resolution increases with photon numbers, and show that the more-than-two-fold enhancement is achievable with realistic photon budgets
Interactive Parallelization of Embedded Real-Time Applications Starting from Open-Source Scilab & Xcos
International audienceIn this paper, we introduce the workflow of interactive parallelization for optimizing embedded real-time applications for multicore architectures. In our approach, the real-time applications are written in the Scilab high-level mathematical & scientific programming language or with a Scilab Xcos block-diagram ap-proach. By using code generation and code parallelization technol-ogy combined with an interactive GUI, the end user can map appli-cations to the multicore processor iteratively. The approach is eval-uated on two use cases: (1) an image processing application written in Scilab and (2) an avionic system modeled in Xcos. Using the workflow, an end-to-end model-based approach targeting multicore processors is enabled resulting in a significant reduction in devel-opment effort and high application speedup. The workflow de-scribed in this paper is developed and tested within the EU-funded ARGO project focused on WCET-Aware Parallelization of Model-Based Applications for Heterogeneous Parallel Systems
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