PPARbeta/delta regulates paneth cell differentiation via controlling the hedgehog signaling pathway.

BACKGROUND & AIMS: All 4 differentiated epithelial cell types found in the intestinal epithelium derive from the intestinal epithelial stem cells present in the crypt unit, in a process whose molecular clues are intensely scrutinized. Peroxisome proliferator-activated receptor beta (PPARbeta) is a nuclear hormone receptor activated by fatty acids and is highly expressed in the digestive tract. However, its function in intestinal epithelium homeostasis is understood poorly. METHODS: To assess the role of PPARbeta in the small intestinal epithelium, we combined various cellular and molecular approaches in wild-type and PPARbeta-mutant mice. RESULTS: We show that the expression of PPARbeta is particularly remarkable at the bottom of the crypt of the small intestine where Paneth cells reside. These cells, which have an important role in the innate immunity, are strikingly affected in PPARbeta-null mice. We then show that Indian hedgehog (Ihh) is a signal sent by mature Paneth cells to their precursors, negatively regulating their differentiation. Importantly, PPARbeta acts on Paneth cell homeostasis by down-regulating the expression of Ihh, an effect that can be mimicked by cyclopamine, a known inhibitor of the hedgehog signaling pathway. CONCLUSIONS: We unraveled the Ihh-dependent regulatory loop that controls mature Paneth cell homeostasis and its modulation by PPARbeta. PPARbeta currently is being assessed as a drug target for metabolic diseases; these results reveal some important clues with respect to the signals controlling epithelial cell fate in the small intestine.

Muerte en Venecia de Thomas Mann o la via plutarquea hacia Eros

En Muerte en Venecia Thomas Mann se refiere explícitamente al Simposio y al Fedro de Platón para explicar la relación entre Gustav von Aschenbach y Tadzio, pero oculta que su novela se inspira también en el Erótico de Plutarco. ¿Por qué? El objetivo de este artículo es justamente revelar las razones de este proceder. En efecto, Plutarco elogia el amor matrimonial en el Erótico y éste no es el camino que sigue Mann, pero, al mismo tiempo, el escritor alemán halla en el diálogo plutarqueo todo lo necesario para construir su historia de amor masculino y decide no prescindir de él.

Accelerated Microstructure Imaging via Convex Optimization (AMICO) from diffusion MRI data.

Microstructure imaging from diffusion magnetic resonance (MR) data represents an invaluable tool to study non-invasively the morphology of tissues and to provide a biological insight into their microstructural organization. In recent years, a variety of biophysical models have been proposed to associate particular patterns observed in the measured signal with specific microstructural properties of the neuronal tissue, such as axon diameter and fiber density. Despite very appealing results showing that the estimated microstructure indices agree very well with histological examinations, existing techniques require computationally very expensive non-linear procedures to fit the models to the data which, in practice, demand the use of powerful computer clusters for large-scale applications. In this work, we present a general framework for Accelerated Microstructure Imaging via Convex Optimization (AMICO) and show how to re-formulate this class of techniques as convenient linear systems which, then, can be efficiently solved using very fast algorithms. We demonstrate this linearization of the fitting problem for two specific models, i.e. ActiveAx and NODDI, providing a very attractive alternative for parameter estimation in those techniques; however, the AMICO framework is general and flexible enough to work also for the wider space of microstructure imaging methods. Results demonstrate that AMICO represents an effective means to accelerate the fit of existing techniques drastically (up to four orders of magnitude faster) while preserving accuracy and precision in the estimated model parameters (correlation above 0.9). We believe that the availability of such ultrafast algorithms will help to accelerate the spread of microstructure imaging to larger cohorts of patients and to study a wider spectrum of neurological disorders.

La mort a Venècia de Thomas Mann o la via plutarquea vers Eros

A Mort a Venècia Thomas Mann es refereix explícitament al Simposi i al Fedre de Plató per explicar la relació entre Gustav von Aschenbach i Tadzio, però amaga que la seva novel·la s'inspira també en l'Eròtic de Plutarc. Per què? L'objectiu d'aquest article és justament revelar les raons d'aquest capteniment. En efecte, Plutarc elogia l'amor matrimonial a l'Eròtic i aquest no és el camí que segueix Mann, però, alhora, l'escriptor alemany troba en el diàleg plutarqueu tot el que necessita per bastir la seva història d'amor masculí i decideix no prescindir-ne.

Billy Budd: de H. Melville a E. M. Forster, o la via Plutarquea vers Plató

L'objectiu d'aquest article és proposar i fonamentar una via plutarquea -no només Les Vides Paral·leles, sinó també L'Eròtic- vers el contingut platònic de Billy Budd de B. Britten amb libretto d'E. M. Fosrter en col·laboració amb Eric Crozier. H. Melville no cita pas Plutarc en la seva novel·la, però l'excel·lent coneixement dels textos de l'escriptor i filòsof grec per part d'E. M. Foster fa que aquesta hipòtesi sigui altament versemblant.

Billy Budd: de H. Melville a E. M. Forster, o la via Plutarquea hacia Platón

El objetivo de este artículo es proponer y fundamentar una vía plutarquea -no sólo Las Vidas Parelelas, sino tambén El Eròtico- al contenido platónico de Billy Budd de B. Britten con libreto de E. M. Foster en colaboración con Eric Crozier. H. Melville no cita a Plutarco en su novela, pero el excelente conocimiento de los textos del escritor y filósofo griego por parte de E. M. Forster hace que esta hipótesis sea altamente verosímil.

Intracellular ubiquitylation of the epithelial Na+ channel controls extracellular proteolytic channel activation via conformational change.

The epithelial Na(+) channel ENaC is a key player in the maintenance of whole body Na(+) balance, and consequently of blood pressure. It is tightly regulated by numerous signaling pathways including ubiquitylation via the ubiquitin-protein ligase Nedd4-2. This mechanism is itself under the control of several kinases, which phosphorylate Nedd4-2, thereby interfering with ENaC/Nedd4-2 interaction, or by Usp2-45, which binds to and deubiquitylates ENaC. Another, different regulatory mechanism concerns the proteolytic activation of ENaC, during which the channel is cleaved on its luminal side by intracellular convertases such as furin, and further activated by extracellular proteases such as CAP-1. This process is regulated as well but the underlying mechanisms are not understood. Previously, evidence was provided that the ubiquitylation status of ENaC may affect the cleavage of the channel. When ubiquitylation of ENaC was reduced, either by co-expressing Usp2-45, or mutating either the ENaC PY-motifs (i.e. the binding sites for Nedd4-2) or intracellular lysines (i.e. ubiquitylation sites), the level of channel cleavage was increased. Here we demonstrate that lysine-mutated ENaC channels are not ubiquitylated at the cell surface, are preferentially cleaved, and Usp2-45 does not affect their cleavage efficiency. We further show by limited proteolysis that the intracellular ubiquitylation status of ENaC affects the extracellular conformation of αENaC, by demonstrating that non-ubiquitylated channels are more efficiently cleaved when treated with extracellularly added trypsin or chymotrypsin. These results present a new paradigm in which an intracellular, post-translational modification (e.g. ubiquitylation) of a transmembrane protein can affect its extracellular conformation.

GW501516-activated PPARβ/δ promotes liver fibrosis via p38-JNK MAPK-induced hepatic stellate cell proliferation.

ABSTRACT: BACKGROUND: After liver injury, the repair process comprises activation and proliferation of hepatic stellate cells (HSCs), which produce extracellular matrix (ECM) proteins. Peroxisome proliferator-activated receptor beta/delta (PPARβ/δ) is highly expressed in these cells, but its function in liver repair remains incompletely understood. This study investigated whether activation of PPARβ/δ with the ligand GW501516 influenced the fibrotic response to injury from chronic carbon tetrachloride (CCl4) treatment in mice. Wild type and PPARβ/δ-null mice were treated with CCl4 alone or CCl4 co-administered with GW501516. To unveil mechanisms underlying the PPARβ/δ-dependent effects, we analyzed the proliferative response of human LX-2 HSCs to GW501516 in the presence or absence of PPARβ/δ. RESULTS: We found that GW501516 treatment enhanced the fibrotic response. Compared to the other experimental groups, CCl4/GW501516-treated wild type mice exhibited increased expression of various profibrotic and pro-inflammatory genes, such as those involved in extracellular matrix deposition and macrophage recruitment. Importantly, compared to healthy liver, hepatic fibrotic tissues from alcoholic patients showed increased expression of several PPAR target genes, including phosphoinositide-dependent kinase-1, transforming growth factor beta-1, and monocyte chemoattractant protein-1. GW501516 stimulated HSC proliferation that caused enhanced fibrotic and inflammatory responses, by increasing the phosphorylation of p38 and c-Jun N-terminal kinases through the phosphoinositide-3 kinase/protein kinase-C alpha/beta mixed lineage kinase-3 pathway. CONCLUSIONS: This study clarified the mechanism underlying GW501516-dependent promotion of hepatic repair by stimulating proliferation of HSCs via the p38 and JNK MAPK pathways.

Estimation of jump-diffusion processes via empirical characteristic functions

Preface The starting point for this work and eventually the subject of the whole thesis was the question: how to estimate parameters of the affine stochastic volatility jump-diffusion models. These models are very important for contingent claim pricing. Their major advantage, availability T of analytical solutions for characteristic functions, made them the models of choice for many theoretical constructions and practical applications. At the same time, estimation of parameters of stochastic volatility jump-diffusion models is not a straightforward task. The problem is coming from the variance process, which is non-observable. There are several estimation methodologies that deal with estimation problems of latent variables. One appeared to be particularly interesting. It proposes the estimator that in contrast to the other methods requires neither discretization nor simulation of the process: the Continuous Empirical Characteristic function estimator (EGF) based on the unconditional characteristic function. However, the procedure was derived only for the stochastic volatility models without jumps. Thus, it has become the subject of my research. This thesis consists of three parts. Each one is written as independent and self contained article. At the same time, questions that are answered by the second and third parts of this Work arise naturally from the issues investigated and results obtained in the first one. The first chapter is the theoretical foundation of the thesis. It proposes an estimation procedure for the stochastic volatility models with jumps both in the asset price and variance processes. The estimation procedure is based on the joint unconditional characteristic function for the stochastic process. The major analytical result of this part as well as of the whole thesis is the closed form expression for the joint unconditional characteristic function for the stochastic volatility jump-diffusion models. The empirical part of the chapter suggests that besides a stochastic volatility, jumps both in the mean and the volatility equation are relevant for modelling returns of the S&P500 index, which has been chosen as a general representative of the stock asset class. Hence, the next question is: what jump process to use to model returns of the S&P500. The decision about the jump process in the framework of the affine jump- diffusion models boils down to defining the intensity of the compound Poisson process, a constant or some function of state variables, and to choosing the distribution of the jump size. While the jump in the variance process is usually assumed to be exponential, there are at least three distributions of the jump size which are currently used for the asset log-prices: normal, exponential and double exponential. The second part of this thesis shows that normal jumps in the asset log-returns should be used if we are to model S&P500 index by a stochastic volatility jump-diffusion model. This is a surprising result. Exponential distribution has fatter tails and for this reason either exponential or double exponential jump size was expected to provide the best it of the stochastic volatility jump-diffusion models to the data. The idea of testing the efficiency of the Continuous ECF estimator on the simulated data has already appeared when the first estimation results of the first chapter were obtained. In the absence of a benchmark or any ground for comparison it is unreasonable to be sure that our parameter estimates and the true parameters of the models coincide. The conclusion of the second chapter provides one more reason to do that kind of test. Thus, the third part of this thesis concentrates on the estimation of parameters of stochastic volatility jump- diffusion models on the basis of the asset price time-series simulated from various "true" parameter sets. The goal is to show that the Continuous ECF estimator based on the joint unconditional characteristic function is capable of finding the true parameters. And, the third chapter proves that our estimator indeed has the ability to do so. Once it is clear that the Continuous ECF estimator based on the unconditional characteristic function is working, the next question does not wait to appear. The question is whether the computation effort can be reduced without affecting the efficiency of the estimator, or whether the efficiency of the estimator can be improved without dramatically increasing the computational burden. The efficiency of the Continuous ECF estimator depends on the number of dimensions of the joint unconditional characteristic function which is used for its construction. Theoretically, the more dimensions there are, the more efficient is the estimation procedure. In practice, however, this relationship is not so straightforward due to the increasing computational difficulties. The second chapter, for example, in addition to the choice of the jump process, discusses the possibility of using the marginal, i.e. one-dimensional, unconditional characteristic function in the estimation instead of the joint, bi-dimensional, unconditional characteristic function. As result, the preference for one or the other depends on the model to be estimated. Thus, the computational effort can be reduced in some cases without affecting the efficiency of the estimator. The improvement of the estimator s efficiency by increasing its dimensionality faces more difficulties. The third chapter of this thesis, in addition to what was discussed above, compares the performance of the estimators with bi- and three-dimensional unconditional characteristic functions on the simulated data. It shows that the theoretical efficiency of the Continuous ECF estimator based on the three-dimensional unconditional characteristic function is not attainable in practice, at least for the moment, due to the limitations on the computer power and optimization toolboxes available to the general public. Thus, the Continuous ECF estimator based on the joint, bi-dimensional, unconditional characteristic function has all the reasons to exist and to be used for the estimation of parameters of the stochastic volatility jump-diffusion models.

In vitro antitumor activity of methotrexate via pH-sensitive chitosan nanoparticles

Nanoparticles with pH-sensitive behavior may enhance the success of chemotherapy in many cancers by efficient intracellular drug delivery. Here, we investigated the effect of a bioactive surfactant with pH-sensitive properties on the antitumor activity and intracellular behavior of methotrexate-loaded chitosan nanoparticles (MTX-CS-NPs). NPs were prepared using a modified ionotropic complexation process, in which was included the surfactant derived from Nα,Nε-dioctanoyl lysine with an inorganic lithium counterion. The pH-sensitive behavior of NPs allowed accelerated release of MTX in an acidic medium, as well as membrane-lytic pH-dependent activity, which facilitated the cytosolic delivery of endocytosed materials. Moreover, our results clearly proved that MTX-CSNPs were more active against the tumor HeLa and MCF-7 cell lines than the free drug. The feasibilty of using NPs to target acidic tumor extracellular pH was also shown, as cytotoxicity against cancer cells was greater in a mildly acidic environment. Finally, the combined physicochemical and pH-sensitive properties of NPs generally allowed the entrapped drug to induce greater cell cycle arrest and apoptotic effects. Therefore, our overall results suggest that pH-sensitive MTX-CS-NPs could be potentially useful as a carrier system for tumor and intracellular drug delivery in cancer therapy.

Characterization of Ornamental Rock Residue and Potassium Liberation Via Organic Acid Application

ABSTRACT Organic acids present in organic matter and, or, exudates by microorganisms and plants can increase the liberation of potassium present in minerals. The objective of this study was to characterize the residue from ornamental rocks and evaluate the release of K from these residues after the application of organic acids. The experiment was conducted under laboratory conditions and followed a 2 × 3 × 5 factorial design with three replicates. The studied factors were: two organic acids (citric acid and malic acid), three ornamental rock residues (R1, R2 and R3) and five organic acid rates (0, 5, 10, 20 and 40 mmol L-1). After agitation, K concentrations were determined in the equilibrium solution. Successive extractions were performed (1, 5, 10, 15, 30 and 60 days after the start of the experiment). The organic acids used (citric and malic) promoted the release of up to 4.86 and 4.34 % of the total K contained in the residue, respectively, reinforcing the role of organic acids in the weathering of minerals and in providing K to the soil. The K quantities were, on average, 6.1 % higher when extracted with citric acid compared to malic acid.

Feasibility Study on Proposed Amtrak service from Chicago, to Iowa City, Iowa via Quad Cities, December 5, 2007

Soon after the Illinois Department of Transportation (“Ill. DOT”) requested Amtrak to conduct a feasibility study on proposed Amtrak service between Chicago and the Illinois Quad Cities, the Iowa Department of Transportation (“Iowa DOT”) asked that the study be extended to Iowa City and later to Des Moines. This report examines the feasibility of extending service to Iowa City. The completed report for the proposed Chicago – Quad Cities’ service was delivered to Ill. DOT in early January 2008. It assumes a stand-alone train operation strictly within the State of Illinois and makes no reference to extending the service into the State of Iowa. Therefore, there is no discussion about potential cost sharing allocations for capital improvements or operating losses between the two states which will become a matter of future negotiations between the two jurisdictions. That being said, this report on extending the service to Iowa City is simply an addendum to the Quad Cities report and covers such topics as additional capital infrastructure improvements that would be required in Iowa, impacts on operating expenses, revised ridership and revenue projections, and the like. With one minor exception, the recommended level of capital improvements within Illinois will still be required if the service to Iowa City is initiated. It is thus important for the readers of this report to refer to the Illinois study for detailed information on that state’s portion of the route alternatives.

Periodic points of holomorphic maps via Lefschetz numbers

In this paper we study the set of periods of holomorphic maps on compact manifolds, using the periodic Lefschetz numbers introduced by Dold and Llibre, which can be computed from the homology class of the map. We show that these numbers contain information about the existence of periodic points of a given period; and, if we assume the map to be transversal, then they give us the exact number of such periodic orbits. We apply this result to the complex projective space of dimension n and to some special type of Hopf surfaces, partially characterizing their set of periods. In the first case we also show that any holomorphic map of CP(n) of degree greater than one has infinitely many distinct periodic orbits, hence generalizing a theorem of Fornaess and Sibony. We then characterize the set of periods of a holomorphic map on the Riemann sphere, hence giving an alternative proof of Baker's theorem.