Synaptic Plasticity at Intrathalamic Connections via CaV3.3 T-type Ca2+ Channels and GluN2B-Containing NMDA Receptors.

The T-type Ca(2+) channels encoded by the Ca(V)3 genes are well established electrogenic drivers for burst discharge. Here, using Ca(V)3.3(-/-) mice we found that Ca(V)3.3 channels trigger synaptic plasticity in reticular thalamic neurons. Burst discharge via Ca(V)3.3 channels induced long-term potentiation at thalamoreticular inputs when coactivated with GluN2B-containing NMDA receptors, which are the dominant subtype at these synapses. Notably, oscillatory burst discharge of reticular neurons is typical for sleep-related rhythms, suggesting that sleep contributes to strengthening intrathalamic circuits.

Mobilidade de íons em solo sob sistema de semeadura direta submetido às adubações mineral e orgânica¹

A retenção, no perfil do solo, de elementos minerais aplicados em sua superfície é fundamental para manter a qualidade da água e diminuir prejuízos econômicos e ambientais. Este trabalho avaliou a mobilidade do K, Ca, Mg, teores de Al e matéria orgânica, as alterações de pH, em Latossolo Vermelho eutroférrico cultivado sob sistema de semeadura direta, bem como a demanda química de oxigênio (DQO) da água de percolação. A mobilidade foi medida em colunas de solo com estrutura preservada e submetidas a adubação mineral (100 kg ha-1) ou orgânica (150 m³ ha-1). Com uso de adubo mineral houve maior lixiviação de K, Ca e Mg, mesmo com maior quantidade de K aplicado via adubo orgânico do que via adubo mineral. A DQO da água percolada no sistema com adubação orgânica foi menor do que com adubação mineral. Os teores de Ca2+ e de Mg2+ foram maiores na camada de 0 a 2,5 cm, principalmente para a adubação orgânica. O adubo orgânico não aumentou o teor de matéria orgânica no solo, porém, na camada de 0 a 2,5 cm, elevou o pH do solo em uma unidade e neutralizou o Al3+. Os resultados deste trabalho mostram o efeito depurador do solo sobre águas contaminadas, evidenciando os benefícios econômicos e ambientais que poderão advir com a infiltração no solo da água de enxurrada que venha a se formar em lavouras.

Oxygen tension controls the expression of the monocarboxylate transporter MCT4 in cultured mouse cortical astrocytes via a hypoxia-inducible factor-1α-mediated transcriptional regulation.

The monocarboxylate transporter MCT4 is a high capacity carrier important for lactate release from highly glycolytic cells. In the central nervous system, MCT4 is predominantly expressed by astrocytes. Surprisingly, MCT4 expression in cultured astrocytes is low, suggesting that a physiological characteristic, not met in culture conditions, is necessary. Here we demonstrate that reducing oxygen concentration from 21% to either 1 or 0% restored in a concentration-dependent manner the expression of MCT4 at the mRNA and protein levels in cultured astrocytes. This effect was specific for MCT4 since the expression of MCT1, the other astrocytic monocarboxylate transporter present in vitro, was not altered in such conditions. MCT4 expression was shown to be controlled by the transcription factor hypoxia-inducible factor-1α (HIF-1α) since under low oxygen levels, transfecting astrocyte cultures with a siRNA targeting HIF-1α largely prevented MCT4 induction. Moreover, the prolyl hydroxylase inhibitor dimethyloxalylglycine (DMOG) induced MCT4 expression in astrocytes cultured in presence of 21% oxygen. In parallel, glycolytic activity was enhanced by exposure to 1% oxygen as demonstrated by the increased lactate release, an effect dependent on MCT4 expression. Finally, MCT4 expression was found to be necessary for astrocyte survival when exposed for a prolonged period to 1% oxygen. These data suggest that a major determinant of astrocyte MCT4 expression in vivo is likely the oxygen tension. This could be relevant in areas of high neuronal activity and oxygen consumption, favouring astrocytic lactate supply to neurons. Moreover, it could also play an important role for neuronal recovery after an ischemic episode.

Produtividade e qualidade dos grãos de feijão em função da aplicação de nitrogênio em cobertura e via foliar

A adequada disponibilidade de N durante do ciclo do feijoeiro é fundamental para garantir elevada produtividade e qualidade dos grãos produzidos. Esse nutriente pode ser absorvido pelas raízes e folhas da planta. Contudo, ainda existem dúvidas sobre a eficiência da aplicação via foliar de N no feijoeiro e sobre a influência dessa prática na qualidade dos grãos. Objetivou-se neste trabalho avaliar o efeito da adubação nitrogenada em cobertura e via foliar sobre a produtividade e qualidade dos grãos da cultura do feijão. O experimento foi conduzido durante a safra "da seca", em um Latossolo Vermelho distroférrico, no município de Botucatu-SP. O delineamento experimental utilizado foi o de blocos ao acaso com quatro repetições, num esquema fatorial 3 x 4, constituído por três doses de N (0, 45 e 90 kg ha-1) em cobertura e quatro épocas de aplicação de N via foliar (1 - sem aplicação de N via foliar, 2 - pulverização estádio R5 (pré-floração), 3 - pulverização no estádio R7 (início da formação das vagens) e 4 - pulverizações nos estádios R5 e R7). Em cada aplicação de N via foliar foram utilizados 200 L ha-1 de uma solução com 10 % de ureia. Quando foi realizada a adubação nitrogenada de cobertura, a aplicação de N via foliar, independentemente da época, não alterou os componentes da produção, a produtividade e a qualidade dos grãos do feijoeiro. Na ausência da adubação nitrogenada de cobertura, a aplicação de N via foliar na fase reprodutiva aumentou a massa e o tamanho dos grãos, a produtividade de grãos e o teor de proteínas nos grãos do feijoeiro. A aplicação de N via foliar no estádio R5 foi mais eficiente em aumentar a produtividade de grãos do feijoeiro que a aplicação em R7.

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.