Microscopic Model of Charge Carrier Transfer in Complex Media

We present a microscopic model of a charge carrier transfer under an action of a constant electric field in a complex medium. Generalizing previous theoretical approaches, we model the dynamical environment hindering the carrier motion by dynamic percolation, i.e., as a medium comprising particles which move randomly on a simple cubic lattice, constrained by hard-core exclusion, and may spontaneously annihilate and re-appear at some prescribed rates. We determine analytically the density profiles of the "environment" particles, as seen from the stationary moving charge carrier, and calculate its terminal velocity as the function of the applied field and other system parameters. We realize that for sufficiently small external fields the force exerted on the carrier by the "environment" particles shows a viscous-like behavior and define an analog of the Stokes formula for such dynamic percolative environments. The corresponding friction coefficient is also derived.Comment: appearing in Chem. Phys. Special Issue on Molecular Charge Transfer in Condensed Media - from Physics and Chemistry to Biology and Nano-Engineering, edited by A.Kornyshev (Imperial College London), M.Newton (Brookhaven Natl Lab) and J.Ulstrup (Technical University of Denmark

Spatially-resolved 3ω thermal flow sensing for microfluidics and biology

This paper reports an alternating current (AC) thermal flow sensor, based on the 3ω method, capable of measuring fluid flow in stacked microfluidic channels and through separating membranes. The measurement concept is tested in a triple-layer polydimethylsiloxane (PDMS) device containing two parallel channels separated by a membrane. A 3ω element integrated into the bottom channel was used to determine the flow direction and magnitude in both channels. Our results show that the phase of the temperature wave is linked not only to fluid velocity, but the physical dimensions of the channel, thus providing a novel non-contact tool to probe fluid flows

The travel demands of an elite rugby sevens team: Effects on objective and subjective sleep parameters

Purpose: To explore the effects of travel related to international rugby sevens competition on sleep patterns. Methods: Seventeen international male rugby sevens players participated in this study. Sleep assessments were performed daily during two separate Sevens World Series competition legs (Oceania and America). The duration of each competition leg was subdivided into key periods (pre-tour, pre-competition, tournament 1 and 2, relocation and post-tour) lasting 2 to 7 nights. Linear mixed models in combination with magnitude-based decision were used to assess 1) the difference between pre-season and key periods and 2) the effect of travel direction (eastward or westward). Results: Shorter total sleep time (hh:mm) was observed during tournament 2 (mean ± SD, 06:16 ± 01:08), relocation (06:09 ± 01:09) and pre-tour week (06:34 ± 01:24) compared with pre-season (06:52 ± 01:00). Worse sleep quality (AU) was observed during tournament 1 (6.1 ± 65 2.0) and 2 (5.7 ± 1.2) as well as during the relocation week (6.3 ± 1.5) than during pre-season (6.5 ± 1.8). When traveling eastward compared with westward, earlier fall asleep time was observed during tournament 1 (ES -0.57, 90%CI [-1.12 to -0.01]), relocation week (-0.70 [-1.11 to -0.28]), and post-tour (-0.57 [-0.95 to -0.18]). However, possibly trivial and unclear differences were observed during pre-competition week (0.15 [-0.15 to 0.45]) and tournament 2 (0.81 [-0.29 to 1.91]). Conclusion: Sleep patterns of elite rugby sevens players are robust to the effects of long-haul travel and jet lag. However, staff should consider promoting sleep during the tournament and 73 relocation week

Generalized model for dynamic percolation

We study the dynamics of a carrier, which performs a biased motion under the influence of an external field E, in an environment which is modeled by dynamic percolation and created by hard-core particles. The particles move randomly on a simple cubic lattice, constrained by hard-core exclusion, and they spontaneously annihilate and re-appear at some prescribed rates. Using decoupling of the third-order correlation functions into the product of the pairwise carrier-particle correlations we determine the density profiles of the "environment" particles, as seen from the stationary moving carrier, and calculate its terminal velocity, V_c, as the function of the applied field and other system parameters. We find that for sufficiently small driving forces the force exerted on the carrier by the "environment" particles shows a viscous-like behavior. An analog Stokes formula for such dynamic percolative environments and the corresponding friction coefficient are derived. We show that the density profile of the environment particles is strongly inhomogeneous: In front of the stationary moving carrier the density is higher than the average density, $\rho_s$, and approaches the average value as an exponential function of the distance from the carrier. Past the carrier the local density is lower than $\rho_s$ and the relaxation towards $\rho_s$ may proceed differently depending on whether the particles number is or is not explicitly conserved.Comment: Latex, 32 pages, 4 ps-figures, submitted to PR

Nuclear delivery of NFκB-assisted DNA/polymer complexes: plasmid DNA quantitation by confocal laser scanning microscopy and evidence of nuclear polyplexes by FRET imaging

Quantification of a plasmid DNA (pDNA) and investigation of its polymer-associated state in the nucleus are crucial to evaluate the effectiveness of a gene-delivery system. This study was conducted with p3NF-luc-3NF, a pDNA-bearing optimized κB motif to favour NFκB-driven nuclear import. Here, a quantification of pDNA copies in the nucleus was performed by real-time confocal laser scanning microscopy in HeLa and C2C12 cells transfected with linear polyethylenimine or histidylated polylysine. Förster Resonance Energy Transfer (FRET) from the fluorescein-p3NF-luc-3NF donor to the co-localized rhodamine-polymer acceptor was carried out to investigate whether the pDNA was still condensed with the polymer in the nucleus. Upon 5 h of transfection, the nuclear amount of p3NF-luc3NF was ∼1500 copies in both cell lines whereas that of pTAL-luc, a 3NF-free counterpart pDNA, was less than 250. This quantity of p3NF-luc-3NF dropped dramatically to that of pTAL-luc in the presence of the BAY 11-7085, an inhibitor of NFκB activation. These data strongly support a nuclear import of p3NF-luc3NF mediated by NFκB. Moreover, FRET experiments clearly revealed that most of nuclear pDNA were still condensed with the polymer raising the question of their passage through the nuclear pore complex and their impact on the gene-expression efficiency

La conservazione preventiva del patrimonio librario come possibile alternativa al restauro tradizionale

The present paper focuses on the close relation between library collections and their preservation environment, aiming, in particular, at highlighting the importance of promoting and sustaining the monitoring. The paper proposes some simple and ready-to-use technologies – smart monitoring – to prevent future damages

Rôle de la protéine STING dans la résistance du cancer du sein à la chimiothérapie

Breast cancer is a major public health issue that kills more than 600 000 women per year worldwide. Most patients initially respond to treatment, but in many cases, cancer cells develop resistance mechanisms that lead to tumor recurrence and ultimately patient death. To identify mechanisms of breast cancer resistance to chemotherapy, our industrial partner (Xentech) has developed a large panel of Patient-Derived Xenografts (PDXs). These preclinical models consist in implanting fragments of patient tumor into immunodeficient mice. Using these models, Xentech discovered that residual cells, which resist the treatment and cause the recurrence, specifically overexpress a set of interferon (IFN)-stimulated genes referred to as the 'IFN/STAT1 signature'. The aim of my PhD project was i) to elucidate the molecular mechanisms of induction of this signature and ii) to determine its impact on mammary tumor progression. First, we identified breast cancer cell lines that express in vitro the IFN/STAT1 signature in response to genotoxic stress (chemotherapy). We showed that this signature was induced by IFNs that activate the canonical JAK/STAT signaling in an autocrine/paracrine manner. Then, we showed that the expression of IFNs was induced by the STING/TBK1/IRF3 signaling pathway. STING, for Stimulator of Interferon Genes, is a well-known DNA sensor that activates immune responses following viral and bacterial infection. We propose that, in cancer cells, STING is activated by damaged genomic DNA that accumulates within the cytoplasm following genotoxic stress. During this work, we uncovered an unexpected subcellular localization of STING. Indeed, while this protein is usually described as an endoplasmic reticulum resident protein, we detected it at the inner nuclear membrane of cancer cells. This observation led us to discover that STING stimulates DNA repair by interacting with, and promoting the assembly of, the DNA repair complex DNA-PK. Genetic inhibition of STING increased DNA damage, reduced cancer cell survival and sensitized them to genotoxic stress. This work unveils the first function of STING that is independent of the induction of pro-inflammatory genes. Based on the rational that STING stimulates anti-tumor immunity (immunosurveillance), STING agonists are currently being tested in clinical trials for different cancer types. Against the current dogma, our work demonstrates a cell-autonomous pro-tumoral role of STING that involves two distinct molecular mechanisms: the induction of survival genes and DNA repair. Our work unveils a new paradigm for STING involvement and therapeutic targeting in cancer. While the clinic is currently inclined towards STING activation, its inhibition could be in some cases beneficial.Le cancer du sein est un problème de santé publique majeur qui tue plus de 600 000 femmes par an dans le monde. La majorité des patientes répondent bien au traitement initial, mais dans de nombreux cas, les cellules cancéreuses développent des mécanismes de résistance au traitement, ce qui conduit à une récidive tumorale fatale pour la patiente. Pour tenter d'élucider les mécanismes de résistance du cancer du sein à la chimiothérapie, le partenaire industriel de cette thèse CIFRE (Xentech) a développé un large panel de PDX (pour Patient Derived Xenograft). Ce modèle expérimental préclinique consiste à implanter, sur des souris immunodéficientes, des fragments de tumeurs directement prélevées chez les patientes. L'analyse de ces PDXs après traitement des souris par chimiothérapie a permis de mettre en évidence la surexpression d'une signature de gènes cibles des interférons (IFN), dénommée signature IFN/STAT1, par les cellules cancéreuses résiduelles, c'est-à-dire les cellules qui ont résisté à la chimiothérapie et qui sont responsables de la récidive tumorale. Le but de ce travail de thèse était i) d'élucider les mécanismes d'induction de cette signature et ii) d'évaluer son impact sur la progression tumorale mammaire. Nous avons d'abord identifié des modèles cellulaires de cancer du sein qui reproduisent in vitro l'induction de cette signature suite à un stress génotoxique (chimiothérapie). Nous avons démontré que cette signature était induite par l'expression d'IFNs qui, par un mécanisme autocrine/paracrine, activent la voie de signalisation canonique JAK/STAT. Nous avons ensuite démontré que cette production d'IFN était induite par la voie STING/TBK1/IRF3. STING (Stimulator of Interferon Genes) est un senseur de l'ADN cytosolique, bien connu pour être activé dans les cellules immunitaires suite à une infection par un pathogène à ADN (virus, bactéries). Nous avons proposé que, dans les cellules cancéreuses, STING est activé par l'ADN génomique endommagé qui s'accumule dans le cytoplasme suite au traitement génotoxique. C'est la première fois que l'activation de la voie STING/TBK1/IRF3 est mise en évidence dans le contexte tumoral humain. Au plan fonctionnel, nous avons démontré que l'expression de la grande majorité des gènes de la signature IFN/STAT1 conférait une résistance au traitement génotoxique. Au cours de ces travaux, nous avons découvert une localisation subcellulaire inattendue de STING. Alors que cette protéine est habituellement décrite comme résidente du réticulum endoplasmique, nous avons détecté sa présence à la membrane interne du noyau des cellules cancéreuses. Cette observation nous a conduit à découvrir que STING stimulait la réparation de l'ADN des cellules cancéreuses, en interagissant avec le complexe nucléaire de réparation DNA-PK, et en stimulant son assemblage aux sites de cassures de l'ADN. Ainsi, l'inhibition génétique de STING augmente la quantité d'ADN endommagé, diminue la viabilité des cellules cancéreuses, et les rend plus sensibles à un traitement génotoxique. Ces travaux révèlent la première fonction de STING indépendante de l'induction de gènes pro-inflammatoires. Au vu de la capacité de STING à stimuler l'immunité anti-tumorale (immunosurveillance), des agonistes de STING sont actuellement testés en essais cliniques dans différents cancers. Allant à l'encontre du dogme actuel, notre travail démontre un rôle pro-tumoral de STING intrinsèque aux cellules cancéreuses, impliquant deux mécanismes : l'expression de gènes de survie et la réparation de l'ADN. Cette découverte dévoile un nouveau paradigme quant à l'implication de STING dans le cancer et pose la question de son ciblage thérapeutique. Alors que la tendance actuelle est à la stimulation, son inhibition pourrait dans certains cas être bénéfique