Slow Dynamics of Ising Models with Energy Barriers

Using Monte Carlo simulations we study the dynamics of three-dimensional Ising models with nearest-, next-nearest-, and four-spin (plaquette) interactions. During coarsening, such models develop growing energy barriers, which leads to very slow dynamics at low temperature. As already reported, the model with only the plaquette interaction exhibits some of the features characteristic of ordinary glasses: strong metastability of the supercooled liquid, a weak increase of the characteristic length under cooling, stretched-exponential relaxation, and aging. The addition of two-spin interactions, in general, destroys such behavior: the liquid phase loses metastability and the slow-dynamics regime terminates well below the melting transition, which is presumably related with a certain corner-rounding transition. However, for a particular choice of interaction constants, when the ground state is strongly degenerate, our simulations suggest that the slow-dynamics regime extends up to the melting transition. The analysis of these models leads us to the conjecture that in the four-spin Ising model domain walls lose their tension at the glassy transition and that they are basically tensionless in the glassy phase.

Slow dynamis in the 3D gonihedric model

We provide analytical evidence of stochastic resonance in polarization switching vertical-cavity surface-emitting lasers (VCSELs). We describe the VCSEL by a two-mode stochastic rate equation model and apply a multiple time-scale analysis. We were able to reduce the dynamical description to a single stochastic differential equation, which is the starting point of the analytical study of stochastic resonance. We confront our results with numerical simulations on the original rate equations, validating the use of a multiple time-scale analysis on stochastic equations as an analytical tool.

Extended treatment of treatment-naive patients with chronic hepatitis c virus (HCV) genotype 1-infection and slow response to pegylated interferon-alfa and ribavirin: a meta-analysis

Aims: Recently, several clinical trials analyzed if extended duration of treatment with pegylated interferon-alfa and ribavirin over 48 weeks can improve sustained virologic response (SVR) rates in HCV genotype 1-infected patients with slow virologic response. Because results of these clinical trials are conflicting, we performed a metaanalysis to determine the overall impact of extended treatment compared to standard treatment on virologic response rates in treatment-naive HCV genotype 1 slow responders. Methods: Literature search was performed independently by two observers using Pub Med, EMBASE, CENTRAL and abstracts presented in English at international liver and gastroenterology meetings. Randomized controlled clinical trials (RCTs; but studies that re-analyzed data retrospectively RCTs were also allowed) were considered if they included monoinfected treatment-naive HCV genotype 1 patients and compared treatment with pegIFN-alfa 2a or 2b in combination with ribavirin for 48 weeks versus extended treatment (up to 72 weeks) in slow responders. Primary and secondary end points were SVR rates and end-of-treatment (EOT) and relapse rates, respectively. In the present meta-analysis, study endpoints were summarized with a DerSimonian-Laird estimate for binary outcome basing on a random effects model. Results: Literature search yielded seven RTCs addressing the benefit of extended treatment with pegylated interferon-alfa and ribavirin in treatment-naive HCV genotype 1 slow responders. In total, 1330 slow responders were included in our meta-analysis. We show that extended treatment duration compared to the standard of care significantly improves SVR rates in HCV genotype 1 slow responders (12.4% improvement of overall SVR rate, 95% CI 0.055- 0.193, P = 0.0005). In addition, we show that rates of viral relapse were significantly reduced by extended treatment (24.1% reduction of relapse, 95% CI −0.3332 to −0.1487, P < 0.0001), whereas no significant impact of extended treatment on EOT response rates was found. Though extended treatment was burdened with an enhanced rate of premature treatment discontinuation due to interferonalfa- and ribavirin-related side effects, the frequency of serious adverse events was not increased. Conclusions: Treatment extension in HCV genotype 1 slow responders can improve SVR rates in difficult to treat patients and should be considered in patients who need to be treated before specific antivirals will be approved.

Western Sand Darter Ammocrypta clara, 2011

Data sheet produced by the Iowa Department of Natural Resources is about different times of animals, insects, snakes, birds, fish, butterflies, etc. that can be found in Iowa.

Development of LRFD Procedures for Bridge Pile Foundations in Iowa: Volume II: Field Testing of Steel Piles in Clay, Sand, and Mixed Soils and Data Analysis, September 2011

In response to the mandate on Load and Resistance Factor Design (LRFD) implementations by the Federal Highway Administration (FHWA) on all new bridge projects initiated after October 1, 2007, the Iowa Highway Research Board (IHRB) sponsored these research projects to develop regional LRFD recommendations. The LRFD development was performed using the Iowa Department of Transportation (DOT) Pile Load Test database (PILOT). To increase the data points for LRFD development, develop LRFD recommendations for dynamic methods, and validate the results ofLRFD calibration, 10 full-scale field tests on the most commonly used steel H-piles (e.g., HP 10 x 42) were conducted throughout Iowa. Detailed in situ soil investigations were carried out, push-in pressure cells were installed, and laboratory soil tests were performed. Pile responses during driving, at the end of driving (EOD), and at re-strikes were monitored using the Pile Driving Analyzer (PDA), following with the CAse Pile Wave Analysis Program (CAPWAP) analysis. The hammer blow counts were recorded for Wave Equation Analysis Program (WEAP) and dynamic formulas. Static load tests (SLTs) were performed and the pile capacities were determined based on the Davisson’s criteria. The extensive experimental research studies generated important data for analytical and computational investigations. The SLT measured loaddisplacements were compared with the simulated results obtained using a model of the TZPILE program and using the modified borehole shear test method. Two analytical pile setup quantification methods, in terms of soil properties, were developed and validated. A new calibration procedure was developed to incorporate pile setup into LRFD.

Resting-State Functional Connectivity Emerges from Structurally and Dynamically Shaped Slow Linear Fluctuations.

Brain fluctuations at rest are not random but are structured in spatial patterns of correlated activity across different brain areas. The question of how resting-state functional connectivity (FC) emerges from the brain's anatomical connections has motivated several experimental and computational studies to understand structure-function relationships. However, the mechanistic origin of resting state is obscured by large-scale models' complexity, and a close structure-function relation is still an open problem. Thus, a realistic but simple enough description of relevant brain dynamics is needed. Here, we derived a dynamic mean field model that consistently summarizes the realistic dynamics of a detailed spiking and conductance-based synaptic large-scale network, in which connectivity is constrained by diffusion imaging data from human subjects. The dynamic mean field approximates the ensemble dynamics, whose temporal evolution is dominated by the longest time scale of the system. With this reduction, we demonstrated that FC emerges as structured linear fluctuations around a stable low firing activity state close to destabilization. Moreover, the model can be further and crucially simplified into a set of motion equations for statistical moments, providing a direct analytical link between anatomical structure, neural network dynamics, and FC. Our study suggests that FC arises from noise propagation and dynamical slowing down of fluctuations in an anatomically constrained dynamical system. Altogether, the reduction from spiking models to statistical moments presented here provides a new framework to explicitly understand the building up of FC through neuronal dynamics underpinned by anatomical connections and to drive hypotheses in task-evoked studies and for clinical applications.

Régulation du canal à sodium épithélial par le sodim extracellulaire et développement d'un microsystème intégré pour l'étude électrophysiologique sur ovocytes de "Xenopus laevis"

Résumé : La première partie de ce travail de thèse est consacrée au canal à sodium épithélial (ENaC), l'élément clé du transport transépithélial de Na+ dans le néphron distal, le colon et les voies aériennes. Ce canal est impliqué dans certaines formes génétiques d'hypo- et d'hypertension (PHA I, syndrome de Liddle), mais aussi, indirectement, dans la mucoviscidose. La réabsorption transépithéliale de Na+ est principalement régulée par des hormones (aldostérone, vasopressine), mais aussi directement par le Na+, via deux phénomènes distincts, la « feedback inhibition » et la « self-inhibition » (SI). Ce second phénomène est dépendant de la concentration de Na+ extracellulaire, et montre une cinétique rapide (constante de temps d'environ 3 s). Son rôle physiologique serait d'assurer l'homogénéité de la réabsorption de Na+ et d'empêcher que celle-ci soit excessive lorsque les concentrations de Na+ sont élevées. Différents éléments appuient l'hypothèse de la présence d'un site de détection de la concentration du Na+ extracellulaire sur ENaC, gouvernant la SI. L'objectif de ce premier projet est de démontrer l'existence du site de détection impliqué dans la SI et de déterminer ses propriétés physiologiques et sa localisation. Nous avons montré que les caractéristiques de la SI (en termes de sélectivité et affinité ionique) sont différentes des propriétés de conduction du canal. Ainsi, nos résultats confirment l'hypothèse de l'existence d'un site de détection du Na+ (responsable de la transmission de l'information au mécanisme de contrôle de l'ouverture du canal), différent du site de conduction. Par ailleurs, ce site présente une affinité basse et indépendante du voltage pour le Na+ et le Li+ extracellulaires. Le site semble donc être localisé dans le domaine extracellulaire, plutôt que transmembranaire, de la protéine. L'étape suivante consiste alors à localiser précisément le site sur le canal. Des études précédentes, ainsi que des résultats préliminaires récemment obtenus, mettent en avant le rôle dans la self-inhibition du premiers tiers des boucles extracellulaires des sous-unités α et γ du canal. Le second projet tire son origine des limitations de la méthode classique pour l'étude des canaux ioniques, après expression dans les ovocytes de Xenopus laevis, par la méthode du voltage-clamp à deux électrodes, en particulier les limitations dues à la lenteur des échanges de solutions. En outre, cette méthode souffre de nombreux désavantages (manipulations délicates et peu rapides, grands volumes de solution requis). Plusieurs systèmes améliorés ont été élaborés, mais aucun ne corrige tous les désavantages de la méthode classique Ainsi, l'objectif ici est le développement d'un système, pour l'étude électrophysiologique sur ovocytes, présentant les caractéristiques suivantes : manipulation des cellules facilitée et réduite, volumes de solution de perfusion faibles et vitesse rapide d'échange de la perfusion. Un microsystème intégré sur une puce a été élaboré. Ces capacités de mesure ont été testées en utilisant des ovocytes exprimant ENaC. Des résultats similaires (courbes IV, courbes dose-réponse au benzamil) à ceux obtenus avec le système traditionnel ont été enregistrés avec le microsystème. Le temps d'échange de solution a été estimé à ~20 ms et des temps effectifs de changement ont été déterminés comme étant 8 fois plus court avec le nouveau système comparé au classique. Finalement, la SI a été étudiée et il apparaît que sa cinétique est 3 fois plus rapide que ce qui a été estimé précédemment avec le système traditionnel et son amplitude de 10 à 20 % plus importante. Le nouveau microsystème intégré apparaît donc comme adapté à la mesure électrophysiologique sur ovocytes de Xenopus, et possèdent des caractéristiques appropriées à l'étude de phénomènes à cinétique rapide, mais aussi à des applications de type « high throughput screening ». Summary : The first part of the thesis is related to the Epithelial Sodium Channel (ENaC), which is a key component of the transepithelial Na+ transport in the distal nephron, colon and airways. This channel is involved in hypo- and hypertensive syndrome (PHA I, Liddle syndrome), but also indirectly in cystic fibrosis. The transepithelial reabsorption of Na+ is mainly regulated by hormones (aldosterone, vasopressin), but also directly by Na+ itself, via two distinct phenomena, feedback inhibition and self-inhibition. This latter phenomenon is dependant on the extracellular Na+ concentration and has rapid kinetics (time constant of about 3 s). Its physiological role would be to prevent excessive Na+ reabsorption and ensure this reabsorption is homogenous. Several pieces of evidence enable to propose the hypothesis of an extracellular Na+ sensing site on ENaC, governing self-inhibition. The aim of this first project is to demonstrate the existence of the sensing site involved in self-inhibition and to determine its physiological properties and localization. We show self-inhibition characteristics (ionic selectivity and affinity) are different from the conducting properties of the channel. Our results support thus the hypothesis that the Na+ sensing site (responsible of the transmission of the information about the extracellular Na+ concentration to the channel gating mechanism), is different from the channel conduction site. Furthermore, the site has a low and voltage-insensitive affinity for extracellular Na+ or Li+. This site appears to be located in the extracellular domain rather than in the transmembrane part of the channel protein. The next step is then to precisely localize the site on the channel. Some previous studies and preliminary results we recently obtained highlight the role of the first third of the extracellular loop of the α and γ subunits of the channel in self-inhibition. The second project originates in the limitation of the classical two-electrode voltageclamp system classically used to study ion channels expressed in Xenopus /aevis oocytes, in particular limitations related to the slow solution exchange time. In addition, this technique undergoes several drawbacks (delicate manipulations, time consumption volumes). Several improved systems have been built up, but none corrected all these detriments. The aim of this second study is thus to develop a system for electrophysiological study on oocytes featuring an easy and reduced cell handling, small necessary perfusion volumes and fast fluidic exchange. This last feature establishes the link with the first project, as it should enable to improve the kinetics analysis of self-inhibition. A PDMS chip-based microsystem has been elaborated. Its electrophysiological measurement abilities have been tested using oocytes expressing ENaC. Similar measurements (IV curves of benzamil-sensitive currents, benzamil dose-response curves) have been obtained with this system, compared to the traditional one. The solution exchange time has been estimated at N20 ms and effective exchange times (on inward currents) have been determined as 8 times faster with the novel system compared to the classical one. Finally, self-inhibition has been studied and it appears its kinetics is 3 times faster and its amplitude 10 to 20 % higher than what has been previously estimated with the traditional system. The novel integrated microsystem appears therefore to be convenient for electrophysiological measurement on Xenopus oocytes, and displays features suitable for the study of fast kinetics phenomenon, but also high throughput screening applications. Résumé destiné large public : Le corps humain est composé d'organes, eux-mêmes constitués d'un très grand nombre de cellules. Chaque cellule possède une paroi appelée membrane cellulaire qui sépare l'intérieur de cette cellule (milieu intracellulaire) du liquide (milieu extracellulaire) dans lequel elle baigne. Le maintien de la composition stable de ce milieu extracellulaire est essentiel pour la survie des cellules et donc de l'organisme. Le sodium est un des composants majeurs du milieu extracellulaire, sa quantité dans celui-ci doit être particulièrement contrôlée. Le sodium joue en effet un rôle important : il conditionne le volume de ce liquide extracellulaire, donc, par la même, du sang. Ainsi, une grande quantité de sodium présente dans ce milieu va de paire avec une augmentation du volume sanguin, ce qui conduit l'organisme à souffrir d'hypertension. On se rend donc compte qu'il est très important de contrôler la quantité de sodium présente dans les différents liquides de l'organisme. Les apports de sodium dans l'organisme se font par l'alimentation, mais la quantité de sodium présente dans le liquide extracellulaire est contrôlée de manière très précise par le rein. Au niveau de cet organe, on appelle urine primaire le liquide résultant de la filtration du sang. Elle contient de nombreuses substances, des petites molécules, dont l'organisme a besoin (sodium, glucose...), qui sont ensuite récupérées dans l'organe. A la sortie du rein, l'urine finale ne contient plus que l'excédent de ces substances, ainsi que des déchets à éliminer. La récupération du sodium est plus ou moins importante, en fonction des ajustements à apporter à la quantité présente dans le liquide extracellulaire. Elle a lieu grâce à la présence de protéines, dans les membranes des cellules du rein, capables de le transporter et de le faire transiter de l'urine primaire vers le liquide extracellulaire, qui assurera ensuite sa distribution dans l'ensemble de l'organisme. Parmi ces protéines « transporteurs de sodium », nous nous intéressons à une protéine en particulier, appelée ENaC. Il a été montré qu'elle jouait un rôle important dans cette récupération de sodium, elle est en effet impliquée dans des maladies génétiques conduisant à l'hypo- ou à l'hypertension. De précédents travaux ont montré que lorsque le sodium est présent en faible quantité dans l'urine primaire, cette protéine permet d'en récupérer une très grande partie. A l'inverse, lorsque cette quantité de sodium dans l'urine primaire est importante, sa récupération par le biais d'ENaC est réduite. On parle alors d'autorégulation : la protéine elle-même est capable d'adapter son activité de transport en fonction des conditions. Ce phénomène d'autorégulation constitue a priori un mécanisme préventif visant à éviter une trop grande récupération de sodium, limitant ainsi les risques d'hypertension. La première partie de ce travail de thèse a ainsi consisté à clarifier le mécanisme d'autorégulation de la protéine ENaC. Ce phénomène se caractérise en particulier par sa grande vitesse, ce qui le rend difficile à étudier par les méthodes traditionnelles. Nous avons donc, dans une deuxième partie, développé un nouveau système permettant de mieux décrire et analyser cette « autorégulation » d'ENaC. Ce second projet a été mené en collaboration avec l'équipe de Martin Gijs de l'EPFL.

Single-step extraction of fluconazole from plasma by ultra-filtration for the measurement of its free concentration by high performance liquid chromatography.

High performance liquid chromatography (HPLC) is the reference method for measuring concentrations of antimicrobials in blood. This technique requires careful sample preparation. Protocols using organic solvents and/or solid extraction phases are time consuming and entail several manipulations, which can lead to partial loss of the determined compound and increased analytical variability. Moreover, to obtain sufficient material for analysis, at least 1 ml of plasma is required. This constraint makes it difficult to determine drug levels when blood sample volumes are limited. However, drugs with low plasma-protein binding can be reliably extracted from plasma by ultra-filtration with a minimal loss due to the protein-bound fraction. This study validated a single-step ultra-filtration method for extracting fluconazole (FLC), a first-line antifungal agent with a weak plasma-protein binding, from plasma to determine its concentration by HPLC. Spiked FLC standards and unknowns were prepared in human and rat plasma. Samples (240 microl) were transferred into disposable microtube filtration units containing cellulose or polysulfone filters with a 5 kDa cut-off. After centrifugation for 60 min at 15000g, FLC concentrations were measured by direct injection of the filtrate into the HPLC. Using cellulose filters, low molecular weight proteins were eluted early in the chromatogram and well separated from FLC that eluted at 8.40 min as a sharp single peak. In contrast, with polysulfone filters several additional peaks interfering with the FLC peak were observed. Moreover, the FLC recovery using cellulose filters compared to polysulfone filters was higher and had a better reproducibility. Cellulose filters were therefore used for the subsequent validation procedure. The quantification limit was 0.195 mgl(-1). Standard curves with a quadratic regression coefficient &gt; or = 0.9999 were obtained in the concentration range of 0.195-100 mgl(-1). The inter and intra-run accuracies and precisions over the clinically relevant concentration range, 1.875-60 mgl(-1), fell well within the +/-15% variation recommended by the current guidelines for the validation of analytical methods. Furthermore, no analytical interference was observed with commonly used antibiotics, antifungals, antivirals and immunosuppressive agents. Ultra-filtration of plasma with cellulose filters permits the extraction of FLC from small volumes (240 microl). The determination of FLC concentrations by HPLC after this single-step procedure is selective, precise and accurate.

Evaluation of the Chemical Durability of Iowa Fly Ash Concretes, HR-327, 1993

The major objective of this research project was to investigate how Iowa fly ashes influenced the chemical durability of portland cement based materials. Chemical durability has become an area of uncertainty because of the winter application of deicer salts (rock salts) that contain a significant amount of sulfate impurities. The sulfate durability testing program consisted of monitoring portland cement-fly ash paste, mortar and concrete test specimens that had been subjected to aqueous solutions containing various concentrations of salts (both sulfate and chloride). The paste and mortar specimens were monitored for length as a function of time. The concrete test specimens were monitored for length, relative dynamic modulus and mass as a function of time. The alkali-aggregate reactivity testing program consisted of monitoring the expansion of ASTM C311 mortar bar specimens that contained three different aggregates (Pyrex glass, Oreapolis and standard Ottawa sand). The results of the sulfate durability study indicated that the paste and concrete test specimens tended to exhibit surface spalling but only very slow expansive tendencies. This suggested that the permeability of the test specimens was controlling the rate of deterioration. Concrete specimens are still being monitored because the majority of the test specimens have expanded less than 0.05%; hence, this makes it difficult to estimate the service life of the concrete test specimens or to quantify the performance of the different fly ashes that were used in the study. The results of the mortar bar studies indicated that the chemical composition of the various fly ashes did have an influence on their sulfate resistance. Typically, Clinton and Louisa fly ashes performed the best, followed by the Ottumwa, Neal 4 and then Council Bluffs fly ashes. Council Bluffs fly ash was the only fly ash that consistently reduced the sulfate resistance of the many different mortar specimens that were investigated during this study. None of the trends that were observed in the mortar bar studies have yet become evident in the concrete phase of this project. The results of the alkali-aggregate study indicated that the Oreapolis aggregate is not very sensitive to alkali attack. Two of the fly ashes, Council Bluffs and Ottumwa, tended to increase the expansion of mortar bar specimens that contained the Oreapolis aggregate. However, it was not clear if the additional expansion was due to the alkali content of the fly ash, the periclase content of the fly ash or the cristobalite content of the fly ash, since all three of these factors have been found to influence the test results.

Modelling hydrodynamics in the Rio Parana, Argentina : an evaluation and inter-comparison of reduced-complexity and physics based models applied to a large sand-bed river

Depth-averaged velocities and unit discharges within a 30 km reach of one of the world's largest rivers, the Rio Parana, Argentina, were simulated using three hydrodynamic models with different process representations: a reduced complexity (RC) model that neglects most of the physics governing fluid flow, a two-dimensional model based on the shallow water equations, and a three-dimensional model based on the Reynolds-averaged Navier-Stokes equations. Row characteristics simulated using all three models were compared with data obtained by acoustic Doppler current profiler surveys at four cross sections within the study reach. This analysis demonstrates that, surprisingly, the performance of the RC model is generally equal to, and in some instances better than, that of the physics based models in terms of the statistical agreement between simulated and measured flow properties. In addition, in contrast to previous applications of RC models, the present study demonstrates that the RC model can successfully predict measured flow velocities. The strong performance of the RC model reflects, in part, the simplicity of the depth-averaged mean flow patterns within the study reach and the dominant role of channel-scale topographic features in controlling the flow dynamics. Moreover, the very low water surface slopes that typify large sand-bed rivers enable flow depths to be estimated reliably in the RC model using a simple fixed-lid planar water surface approximation. This approach overcomes a major problem encountered in the application of RC models in environments characterised by shallow flows and steep bed gradients. The RC model is four orders of magnitude faster than the physics based models when performing steady-state hydrodynamic calculations. However, the iterative nature of the RC model calculations implies a reduction in computational efficiency relative to some other RC models. A further implication of this is that, if used to simulate channel morphodynamics, the present RC model may offer only a marginal advantage in terms of computational efficiency over approaches based on the shallow water equations. These observations illustrate the trade off between model realism and efficiency that is a key consideration in RC modelling. Moreover, this outcome highlights a need to rethink the use of RC morphodynamic models in fluvial geomorphology and to move away from existing grid-based approaches, such as the popular cellular automata (CA) models, that remain essentially reductionist in nature. In the case of the world's largest sand-bed rivers, this might be achieved by implementing the RC model outlined here as one element within a hierarchical modelling framework that would enable computationally efficient simulation of the morphodynamics of large rivers over millennial time scales. (C) 2012 Elsevier B.V. All rights reserved.