Variance-based reliability sensitivity with dependent inputs using failure samples

Reliability sensitivity analysis is concerned with measuring the influence of a system's uncertain input parameters on its probability of failure. Statistically dependent inputs present a challenge in both computing and interpreting these sensitivity indices; such dependencies require discerning between variable interactions produced by the probabilistic model describing the system inputs and the computational model describing the system itself. To accomplish such a separation of effects in the context of reliability sensitivity analysis we extend on an idea originally proposed by Mara and Tarantola (2012) for model outputs unrelated to rare events. We compute the independent (influence via computational model) and full (influence via both computational and probabilistic model) contributions of all inputs to the variance of the indicator function of the rare event. We compute this full set of variance-based sensitivity indices of the rare event indicator using a single set of failure samples. This is possible by considering $d$ different hierarchically structured isoprobabilistic transformations of this set of failure samples from the original $d$-dimensional space of dependent inputs to standard-normal space. The approach facilitates computing the full set of variance-based reliability sensitivity indices with a single set of failure samples obtained as the byproduct of a single run of a sample-based rare event estimation method. That is, no additional evaluations of the computational model are required. We demonstrate the approach on a test function and two engineering problems

SARS-CoV-2 Infection of Airway Cells

In a laboratory setting, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was inoculated into human bronchial epithelial cells

Mucus clearance in the respiratory tract: A new concept? [Un nouveau concept de mécanisme de clairance respiratoire ?]

Dans toutes les muqueuses, respiratoire, gastro-intestinale ou encore celle des voies génitales, la présence d’un film viscoélastique de mucus est nécessaire pour protéger l’organisme contre l’invasion d’agents pathogènes, qu’il s’agisse de virus, bactéries ou autres polluants. Ce mucus est constitué principalement de larges glycoprotéines, appelées mucines, qui doivent être parfaitement hydratées pour maintenir les propriétés viscoélastiques du mucus. Dans les voies respiratoires, la couche de mucus séquestre les agents inhalés et progresse, grâce aux battements ciliaires des cellules sous-jacentes, vers la glotte. Le mucus est continuellement avalé ou expectoré, ce qui définit le mécanisme de clairance pulmonaire. Depuis des décennies, le dogme veut que les cellules ciliées battent librement dans un milieu aqueux et propulsent le mucus qui flotte sur l’épithélium respiratoire, mais nous avons récemment réfuté ce concept dans une étude publiée dans Science [1]. En effet, l’ancienne notion ne permet pas d’expliquer l’incidence des plaques de mucus observées dans les maladies caractérisées par l’obstruction pulmonaire (par exemple : bronchite chronique, mucoviscidose ou asthme). Notre étude montre que l’espace périciliaire est en fait occupé par de larges glycoprotéines organisées de manière spécifique en un réseau ayant une densité supérieure à celle de la couche mobile de mucus sus-jacente. Ce réseau dense de macromolécules est attaché aux cellules ciliées et possède les mêmes propriétés qu’un gel

Mucin Agarose Gel Electrophoresis: Western Blotting for High-molecular-weight Glycoproteins

Mucins, the heavily-glycosylated proteins lining mucosal surfaces, have evolved as a key component of innate defense by protecting the epithelium against invading pathogens. The main role of these macromolecules is to facilitate particle trapping and clearance while promoting lubrication of the mucosa. During protein synthesis, mucins undergo intense O-glycosylation and multimerization, which dramatically increase the mass and size of these molecules. These post-translational modifications are critical for the viscoelastic properties of mucus. As a result of the complex biochemical and biophysical nature of these molecules, working with mucins provides many challenges that cannot be overcome by conventional protein analysis methods. For instance, their high-molecular-weight prevents electrophoretic migration via regular polyacrylamide gels and their sticky nature causes adhesion to experimental tubing. However, investigating the role of mucins in health (e.g., maintaining mucosal integrity) and disease (e.g., hyperconcentration, mucostasis, cancer) has recently gained interest and mucins are being investigated as a therapeutic target. A better understanding of the production and function of mucin macromolecules may lead to novel pharmaceutical approaches, e.g., inhibitors of mucin granule exocytosis and/or mucolytic agents. Therefore, consistent and reliable protocols to investigate mucin biology are critical for scientific advancement. Here, we describe conventional methods to separate mucin macromolecules by electrophoresis using an agarose gel, transfer protein into nitrocellulose membrane, and detect signal with mucin-specific antibodies as well as infrared fluorescent gel reader. These techniques are widely applicable to determine mucin quantitation, multimerization and to test the effects of pharmacological compounds on mucins

Accumulation de mucus - Le point de départ de la pathogenèse pulmonaire chez les patients atteints de mucoviscidose

La mucoviscidose (en anglais, cystic fibrosis ou CF) est une maladie génétique grave affectant principalement la population caucasienne dans une proportion d’une naissance sur 4 000. Des mutations du gène codant la protéine CFTR (cystic fibrosis transmembrane conductance regulator) entraînent des changements de flux ioniques à travers la membrane plasmique de cellules épithéliales, qui altèrent le réseau de mucines dans plusieurs organes comme les poumons et l’intestin [1-3]. Les mucines polymériques sont de grandes glycoprotéines qui organisent la couche de mucus et assurent la lubrification et la protection des muqueuses contre l’invasion d’agents infectieux. Chez les patients atteints de mucoviscidose, le dysfonctionnement du canal ionique CFTR modifie le mucus, qui devient visqueux et adhère aux parois des bronches et du tube digestif. Dans les poumons, l’obstruction des voies aériennes est propice aux infections bactériennes [4]. De plus, les propriétés antibactériennes de la couche de mucus sont diminuées chez des animaux modèles développant certains symptômes de la maladie [5]. Une infection précède généralement le développement d’une inflammation, il est tentant de penser qu’une infection précoce puisse déclencher la pathogénèse pulmonaire et provoquer une réaction inflammatoire chronique chez les patients atteints de mucoviscidose. A l’appui de cette hypothèse, des lésions pulmonaires causées par l’inflammation peuvent être détectées très tôt par imagerie médicale fondée sur la tomodensitométrie (en anglais, computed tomography ou CT). En effet, 22 % des patients atteints de mucoviscidose présentent des lésions dès l’âge de 1 an [6]. Les descriptions de la progression de la maladie font donc souvent référence au cercle vicieux « obstruction-infection-inflammation » (dans cet ordre), car l’inflammation est fréquemment associée à la présence de microorganismes pathogènes. Cependant, notre étude récemment publiée dans le journal Science Translational Medicine démontre que l’inflammation précède l’infection bactérienne et que le mucus pourrait être à l’origine de cette réponse inflammatoire [7]. L’accumulation de mucus est, de plus, détectée avant les premiers signes de lésions pulmonaires, suggérant, là encore, que les propriétés anormales du mucus chez ces patients déclenchent une réponse immunitaire et constituent ainsi le point de départ de la maladie de la mucoviscidose

Mucins and CFTR: Their Close Relationship

Mucociliary clearance is a critical defense mechanism for the lungs governed by regionally coordinated epithelial cellular activities, including mucin secretion, cilia beating, and transepithelial ion transport. Cystic fibrosis (CF), an autosomal genetic disorder caused by the dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) channel, is characterized by failed mucociliary clearance due to abnormal mucus biophysical properties. In recent years, with the development of highly effective modulator therapies, the quality of life of a significant number of people living with CF has greatly improved; however, further understanding the cellular biology relevant to CFTR and airway mucus biochemical interactions are necessary to develop novel therapies aimed at restoring CFTR gene expression in the lungs. In this article, we discuss recent advances of transcriptome analysis at single-cell levels that revealed a heretofore unanticipated close relationship between secretory MUC5AC and MUC5B mucins and CFTR in the lungs. In addition, we review recent findings on airway mucus biochemical and biophysical properties, focusing on how mucin secretion and CFTR-mediated ion transport are integrated to maintain airway mucus homeostasis in health and how CFTR dysfunction and restoration of function affect mucus properties

Global sensitivity analysis in high dimensions with partial least squares-driven PCEs

We develop an efficient method for the computation of variance-based sensitivity indices using a recently introduced latent-variable-based polynomial chaos expansion, which is particularly suitable for high dimensional problems. By back-transforming the surrogate from its latent variable space-basis to the original input variable space-basis, we derive analytical expressions for these sensitivities that only depend on the model coefficients. Thus, once the surrogate model is built, the variance-based sensitivities can be computed at negligible computational cost as no additional sampling is required. The accuracy of the method is demonstrated with a numerical experiment of an elastic truss.This project was supported by the German Research Foundation (DFG) through Grant STR 1140/6-1 under SPP 1886

Mucus, mucins, and cystic fibrosis

Cystic fibrosis (CF) is both the most common and most lethal genetic disease in the Caucasian population. CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and is characterized by the accumulation of thick, adherent mucus plaques in multiple organs, of which the lungs, gastrointestinal tract and pancreatic ducts are the most commonly affected. A similar pathogenesis cascade is observed in all of these organs: loss of CFTR function leads to altered ion transport, consisting of decreased chloride and bicarbonate secretion via the CFTR channel and increased sodium absorption via epithelial sodium channel upregulation. Mucosa exposed to changes in ionic concentrations sustain severe pathophysiological consequences. Altered mucus biophysical properties and weakened innate defense mechanisms ensue, furthering the progression of the disease. Mucins, the high-molecular-weight glycoproteins responsible for the viscoelastic properties of the mucus, play a key role in the disease but the actual mechanism of mucus accumulation is still undetermined. Multiple hypotheses regarding the impact of CFTR malfunction on mucus have been proposed and are reviewed here. (a) Dehydration increases mucin monomer entanglement, (b) defective Ca2+ chelation compromises mucin expansion, (c) ionic changes alter mucin interactions, and (d) reactive oxygen species increase mucin crosslinking. Although one biochemical change may dominate, it is likely that all of these mechanisms play some role in the progression of CF disease. This article discusses recent findings on the initial cause(s) of aberrant mucus properties in CF and examines therapeutic approaches aimed at correcting mucus properties