N,N,N-Trimethyl chitosan as a permeation enhancer for inhalation drug delivery: interaction with a model pulmonary surfactant

N,N,N-Trimethyl chitosan (TMC), a biocompatible and biodegradable derivative of chitosan, is currently used as a permeation enhancer to increase the translocation of drugs to the bloodstream in the lungs. This article discusses the effect of TMC on a mimetic pulmonary surfactant, Curosurf, a low-viscosity lipid formulation administered to preterm infants with acute respiratory distress syndrome. Curosurf exhibits a strong interaction with TMC, resulting in the formation of aggregates at electrostatic charge stoichiometry. At nanoscale, Curosurf undergoes a profound reorganization of its lipid vesicles in terms of size and lamellarity. The initial micron-sized vesicles (average size 4.8 microns) give way to a froth-like network of unilamellar vesicles about 300 nm in size. Under such conditions, neutralization of the cationic charges by pulmonary surfactant may inhibit TMC permeation enhancer capacity, especially as electrostatic charge complexation is found at low TMC content. The permeation properties of pulmonary surfactant-neutralized TMC should then be evaluated for its applicability as a permeation enhancer for inhalation in the alveolar region.Comment: 20 pages, 7 figure

IRIM at TRECVID 2013: Semantic Indexing and Instance Search

International audienceThe IRIM group is a consortium of French teams working on Multimedia Indexing and Retrieval. This paper describes its participation to the TRECVID 2013 semantic indexing and instance search tasks. For the semantic indexing task, our approach uses a six-stages processing pipelines for computing scores for the likelihood of a video shot to contain a target concept. These scores are then used for producing a ranked list of images or shots that are the most likely to contain the target concept. The pipeline is composed of the following steps: descriptor extraction, descriptor optimization, classiffication, fusion of descriptor variants, higher-level fusion, and re-ranking. We evaluated a number of different descriptors and tried different fusion strategies. The best IRIM run has a Mean Inferred Average Precision of 0.2796, which ranked us 4th out of 26 participants

IRIM at TRECVID 2012: Semantic Indexing and Instance Search

International audienceThe IRIM group is a consortium of French teams work- ing on Multimedia Indexing and Retrieval. This paper describes its participation to the TRECVID 2012 se- mantic indexing and instance search tasks. For the semantic indexing task, our approach uses a six-stages processing pipelines for computing scores for the likeli- hood of a video shot to contain a target concept. These scores are then used for producing a ranked list of im- ages or shots that are the most likely to contain the tar- get concept. The pipeline is composed of the following steps: descriptor extraction, descriptor optimization, classi cation, fusion of descriptor variants, higher-level fusion, and re-ranking. We evaluated a number of dif- ferent descriptors and tried di erent fusion strategies. The best IRIM run has a Mean Inferred Average Pre- cision of 0.2378, which ranked us 4th out of 16 partici- pants. For the instance search task, our approach uses two steps. First individual methods of participants are used to compute similrity between an example image of in- stance and keyframes of a video clip. Then a two-step fusion method is used to combine these individual re- sults and obtain a score for the likelihood of an instance to appear in a video clip. These scores are used to ob- tain a ranked list of clips the most likely to contain the queried instance. The best IRIM run has a MAP of 0.1192, which ranked us 29th on 79 fully automatic runs

Sol-gel transition induced by alumina nanoparticles in a model pulmonary surfactant

International audienceInhaled airborne particles smaller than 100 nm entering the airways have been shown to deposit in significant amount in the alveolar region of the lungs. The interior of the alveoli is covered with a ~ 1 µm thick lining fluid, called pulmonary surfactant. Inhaled nanoparticles are susceptible to interact with the lung fluid and modify pulmonary functions. Here we evaluate the structural and rheological properties of the pulmonary surfactant substitute Curosurf® which is administered to premature babies for the treatment of respiratory distress syndrome. Curosurf® is considered a reliable model of endogenous pulmonary surfactant in terms of composition, structure and function. Using active microrheology based on magnetically actuated wires, we find that Curosurf® dispersions exhibit a Newtonian behavior at lipid concentration from 0 to 80 g L−1, and that the viscosity follows the Krieger-Dougherty law observed for a wide variety of colloids. Upon addition of 40 nm alumina nanoplatelets, a significant change of the Curosurf® rheology is noticed. The dispersions then enter a soft solid phase characterized by an infinite viscosity and a non-zero equilibrium elastic modulus. The sol-gel transition induced by the nanoparticles is interpreted as the result of the alumina/vesicle interaction, which are illustrated by transmission electron microscopy. It also suggests a potential toxicity associated with the modification of the lung fluid structural and dynamical properties

G-computation and machine learning for estimating the causal effects of binary exposure statuses on binary outcomes

International audienceAbstract In clinical research, there is a growing interest in the use of propensity score-based methods to estimate causal effects. G-computation is an alternative because of its high statistical power. Machine learning is also increasingly used because of its possible robustness to model misspecification. In this paper, we aimed to propose an approach that combines machine learning and G-computation when both the outcome and the exposure status are binary and is able to deal with small samples. We evaluated the performances of several methods, including penalized logistic regressions, a neural network, a support vector machine, boosted classification and regression trees, and a super learner through simulations. We proposed six different scenarios characterised by various sample sizes, numbers of covariates and relationships between covariates, exposure statuses, and outcomes. We have also illustrated the application of these methods, in which they were used to estimate the efficacy of barbiturates prescribed during the first 24 h of an episode of intracranial hypertension. In the context of GC, for estimating the individual outcome probabilities in two counterfactual worlds, we reported that the super learner tended to outperform the other approaches in terms of both bias and variance, especially for small sample sizes. The support vector machine performed well, but its mean bias was slightly higher than that of the super learner. In the investigated scenarios, G-computation associated with the super learner was a performant method for drawing causal inferences, even from small sample sizes

Synthesis and structure–activity relationships of 2-phenyl-1-[(pyridinyl- and piperidinylmethyl)amino]-3-(1H-1,2,4-triazol-1-yl)propan-2-ols as antifungal agents

International audienc

Design of new antifungal agents: synthesis and evaluation of 1-[(1H-indol-5-ylmethyl)amino]-2-phenyl-3-(1H-1,2,4-triazol-1-yl)propan-2-ols

International audienc

Trans-cellular tunnels induced by the fungal pathogen Candida albicans facilitate invasion through successive epithelial cells without host damage

International audienceThe opportunistic fungal pathogen Candida albicans is normally commensal, residing in the mucosa of most healthy individuals. In susceptible hosts, its filamentous hyphal form can invade epithelial layers leading to superficial or severe systemic infection. Although invasion is mainly intracellular, it causes no apparent damage to host cells at early stages of infection. Here, we investigate C. albicans invasion in vitro using live-cell imaging and the damage-sensitive reporter galectin-3. Quantitative single cell analysis shows that invasion can result in host membrane breaching at different stages and host cell death, or in traversal of host cells without membrane breaching. Membrane labelling and three-dimensional ‘volume’ electron microscopy reveal that hyphae can traverse several host cells within trans-cellular tunnels that are progressively remodelled and may undergo ‘inflations’ linked to host glycogen stores. Thus, C. albicans early invasion of epithelial tissues can lead to either host membrane breaching or trans-cellular tunnelling

Cell wall dynamics stabilize tip growth in a filamentous fungus.

Hyphal tip growth allows filamentous fungi to colonize space, reproduce, or infect. It features remarkable morphogenetic plasticity including unusually fast elongation rates, tip turning, branching, or bulging. These shape changes are all driven from the expansion of a protective cell wall (CW) secreted from apical pools of exocytic vesicles. How CW secretion, remodeling, and deformation are modulated in concert to support rapid tip growth and morphogenesis while ensuring surface integrity remains poorly understood. We implemented subresolution imaging to map the dynamics of CW thickness and secretory vesicles in Aspergillus nidulans. We found that tip growth is associated with balanced rates of CW secretion and expansion, which limit temporal fluctuations in CW thickness, elongation speed, and vesicle amount, to less than 10% to 20%. Affecting this balance through modulations of growth or trafficking yield to near-immediate changes in CW thickness, mechanics, and shape. We developed a model with mechanical feedback that accounts for steady states of hyphal growth as well as rapid adaptation of CW mechanics and vesicle recruitment to different perturbations. These data provide unprecedented details on how CW dynamics emerges from material secretion and expansion, to stabilize fungal tip growth as well as promote its morphogenetic plasticity

Design, Synthesis, and in vitro Antifungal Activity of 1-[(4-Substituted-benzyl)methylamino]-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ols

International audienc