Post-translational modifications of voltage-gated sodium channels in chronic pain syndromes.

In the peripheral sensory nervous system the neuronal expression of voltage-gated sodium channels (Navs) is very important for the transmission of nociceptive information since they give rise to the upstroke of the action potential (AP). Navs are composed of nine different isoforms with distinct biophysical properties. Studying the mutations associated with the increase or absence of pain sensitivity in humans, as well as other expression studies, have highlighted Nav1.7, Nav1.8, and Nav1.9 as being the most important contributors to the control of nociceptive neuronal electrogenesis. Modulating their expression and/or function can impact the shape of the AP and consequently modify nociceptive transmission, a process that is observed in persistent pain conditions. Post-translational modification (PTM) of Navs is a well-known process that modifies their expression and function. In chronic pain syndromes, the release of inflammatory molecules into the direct environment of dorsal root ganglia (DRG) sensory neurons leads to an abnormal activation of enzymes that induce Navs PTM. The addition of small molecules, i.e., peptides, phosphoryl groups, ubiquitin moieties and/or carbohydrates, can modify the function of Navs in two different ways: via direct physical interference with Nav gating, or via the control of Nav trafficking. Both mechanisms have a profound impact on neuronal excitability. In this review we will discuss the role of Protein Kinase A, B, and C, Mitogen Activated Protein Kinases and Ca++/Calmodulin-dependent Kinase II in peripheral chronic pain syndromes. We will also discuss more recent findings that the ubiquitination of Nav1.7 by Nedd4-2 and the effect of methylglyoxal on Nav1.8 are also implicated in the development of experimental neuropathic pain. We will address the potential roles of other PTMs in chronic pain and highlight the need for further investigation of PTMs of Navs in order to develop new pharmacological tools to alleviate pain.

Regulation of the cardiac Na+ channel NaV1.5 by post-translational modifications.

The cardiac voltage-gated Na(+) channel, Na(V)1.5, is responsible for the upstroke of the action potential in cardiomyocytes and for efficient propagation of the electrical impulse in the myocardium. Even subtle alterations of Na(V)1.5 function, as caused by mutations in its gene SCN5A, may lead to many different arrhythmic phenotypes in carrier patients. In addition, acquired malfunctions of Na(V)1.5 that are secondary to cardiac disorders such as heart failure and cardiomyopathies, may also play significant roles in arrhythmogenesis. While it is clear that the regulation of Na(V)1.5 protein expression and function tightly depends on genetic mechanisms, recent studies have demonstrated that Na(V)1.5 is the target of various post-translational modifications that are pivotal not only in physiological conditions, but also in disease. In this review, we examine the recent literature demonstrating glycosylation, phosphorylation by Protein Kinases A and C, Ca(2+)/Calmodulin-dependent protein Kinase II, Phosphatidylinositol 3-Kinase, Serum- and Glucocorticoid-inducible Kinases, Fyn and Adenosine Monophosphate-activated Protein Kinase, methylation, acetylation, redox modifications, and ubiquitylation of Na(V)1.5. Modern and sensitive mass spectrometry approaches, applied directly to channel proteins that were purified from native cardiac tissues, have enabled the determination of the precise location of post-translational modification sites, thus providing essential information for understanding the mechanistic details of these regulations. The current challenge is first, to understand the roles of these modifications on the expression and the function of Na(V)1.5, and second, to further identify other chemical modifications. It is postulated that the diversity of phenotypes observed with Na(V)1.5-dependent disorders may partially arise from the complex post-translational modifications of channel protein components.

Theoretical models of planetary system formation II. Post-formation evolution

Aims. We extend the results of planetary formation synthesis by computing the long-term evolution of synthetic systems from the clearing of the gas disk into the dynamical evolution phase. Methods. We use the symplectic integrator SyMBA to numerically integrate the orbits of planets for 100 Myr, using populations from previous studies as initial conditions. Results. We show that within the populations studied, mass and semimajor axis distributions experience only minor changes from post-formation evolution. We also show that, depending upon their initial distribution, planetary eccentricities can statistically increase or decrease as a result of gravitational interactions. We find that planetary masses and orbital spacings provided by planet formation models do not result in eccentricity distributions comparable to observed exoplanet eccentricities, requiring other phenomena, such as stellar fly-bys, to account for observed eccentricities.

Technical Efficiency in Public and Private Sectors in India: Evidence from the Post-Reform Years

While India's state-owned enterprises are widely believed to be inefficient, there is a dearth of studies that document such inefficiency on any rigorous basis. Yet, since improvement in firm efficiency is one of the basic objectives of privatization, it is important to assess whether efficiency is indeed lower in the public sector than in the private sector. This paper compares the performance of state-owned enterprises with those of private sector firms in respect of technical efficiency. The comparison is made in eight different sectors over the period 1991-92 to 1998-99. We measure technical efficiency using the method of Data Envelopment Analysis. Judging by the average levels of technical efficiency, no conclusive evidence of superior performance on the part of the private sector is found.

Emerging Identities in Colonial Tunisia: "Alliancist" and Zionist Representations in Tunis prior to World War I

By 1900 the Jewish community of Tunisia witnessed the emergence of new competing identities: “assimilationist” of the Alliance Israelite Universelle, termed “Alliancist,” and Zionist. Strikingly, two members of the same family in Tunis, Raymond Valensi, President of the AIU Regional Committee, and Alfred Valensi, President of the Zionist Federation, led the struggle for their separate causes. In his discussion of identity in the modern world, Homi Bhabha asks, "How do strategies of representation or empowerment come to be formulated in the competing claims of communities…where, despite shared histories of …discrimination, the exchange of values, meanings and priorities…may be profoundly antagonistic…?" It is in this context that the claims of the Alliance and Zionism will be examined prior to World War I, based on the Archives of the AIU and on such secondary sources as the indispensable work of Paul Sebag. The tensions between the Alliancists and Zionists continued until the outbreak of World War II, as the French-speaking Jews of Tunisia sought to define their individual and collective identities.

Non-Parametric Tests of Real Exchange rates in the Post-Bretton Woods Era

This paper examines the mean-reverting property of real exchange rates. Earlier studies have generally not been able to reject the null hypothesis of a unit-root in real exchange rates, especially for the post-Bretton Woods floating period. The results imply that long-run purchasing power parity does not hold. More recent studies, especially those using panel unit-root tests, have found more favorable results, however. But, Karlsson and Löthgren (2000) and others have recently pointed out several potential pitfalls of panel unit-root tests. Thus, the panel unit-root test results are suggestive, but they are far from conclusive. Moreover, consistent individual country time series evidence that supports long-run purchasing power parity continues to be scarce. In this paper, we test for long memory using Lo's (1991) modified rescaled range test, and the rescaled variance test of Giraitis, Kokoszka, Leipus, and Teyssière (2003). Our testing procedure provides a non-parametric alternative to the parametric tests commonly used in this literature. Our data set consists of monthly observations from April 1973 to April 2001 of the G-7 countries in the OECD. Our two tests find conflicting results when we use U.S. dollar real exchange rates. However, when non-U.S. dollar real exchange rates are used, we find only two cases out of fifteen where the null hypothesis of an unit-root with short-term dependence can be rejected in favor of the alternative hypothesis of long-term dependence using the modified rescaled range test, and only one case when using the rescaled variance test. Our results therefore provide a contrast to the recent favorable panel unit-root test results.

Goals, plans, and behavior changes: A relevant part of the post-treatment cancer experience

Background. Colorectal cancer (CRC) survivors have to manage treatment side effects, psychosocial issues, and co-morbidities, as well as modify their lifestyles to decrease risk of recurrence and prolong life. Identifying survivors’ goals and key factors that influence their goals will highlight the issues cancer survivors face post-treatment and the resources needed to help them engage in health-promoting behaviors.^ Objectives and methods. This dissertation examines the health-related goals of post-treatment CRC survivors using two studies: (1) a qualitative study to identify and describe the health goals of CRC survivors during the transition from active treatment to post-treatment survivorship and follow-up care; and (2) a cross-sectional survey to identify CRC survivors’ goals, and key factors that influence their goals.^ Results. (1) The 41 qualitative interviews indicated participants’ health-related goals were to be healthy, get back to normal, and not have a cancer recurrence. Most of the CRC survivors reported they maintained healthy behaviors, made healthy behavior changes, or had goals to change their behavior. Respondents were empowered to improve their health by maintaining follow-up care and regular health screenings, and many were managing treatment side effects in an effort to improve functional abilities. (2) The cross-sectional study found that CRC survivors’ most prevalent goals were related to healthy behaviors (i.e., eat a healthy diet and engage in physical activity), and cancer care or disease management (i.e., keep up with health screenings and monitor symptoms). Goals that survivors identified as important were similar to goals they perceived were important to their providers (i.e., goals related to cancer care, disease management). Certain goals were statistically associated with age, barriers to achieving goals, social support and health-related quality of life.^ Conclusions. CRC survivors have health-promoting goals post-treatment and are interested in making health behavior changes. Goals ranged from cancer care/surveillance and disease management to healthy lifestyle modifications. Patients may need help resolving or managing treatment side effects or co-morbidities prior to implementing health promoting behaviors. Healthcare providers’ recommendations may be a powerful resource to encourage survivors to engage in health-promoting behaviors. Self-management and goal setting support could be an appropriate strategy to assist patients with achieving their post-treatment health goals.^

NOVEL PHANTOMS AND POST-PROCESSING FOR DIFFUSION SPECTRUM IMAGING

High Angular Resolution Diffusion Imaging (HARDI) techniques, including Diffusion Spectrum Imaging (DSI), have been proposed to resolve crossing and other complex fiber architecture in the human brain white matter. In these methods, directional information of diffusion is inferred from the peaks in the orientation distribution function (ODF). Extensive studies using histology on macaque brain, cat cerebellum, rat hippocampus and optic tracts, and bovine tongue are qualitatively in agreement with the DSI-derived ODFs and tractography. However, there are only two studies in the literature which validated the DSI results using physical phantoms and both these studies were not performed on a clinical MRI scanner. Also, the limited studies which optimized DSI in a clinical setting, did not involve a comparison against physical phantoms. Finally, there is lack of consensus on the necessary pre- and post-processing steps in DSI; and ground truth diffusion fiber phantoms are not yet standardized. Therefore, the aims of this dissertation were to design and construct novel diffusion phantoms, employ post-processing techniques in order to systematically validate and optimize (DSI)-derived fiber ODFs in the crossing regions on a clinical 3T MR scanner, and develop user-friendly software for DSI data reconstruction and analysis. Phantoms with a fixed crossing fiber configuration of two crossing fibers at 90° and 45° respectively along with a phantom with three crossing fibers at 60°, using novel hollow plastic capillaries and novel placeholders, were constructed. T2-weighted MRI results on these phantoms demonstrated high SNR, homogeneous signal, and absence of air bubbles. Also, a technique to deconvolve the response function of an individual peak from the overall ODF was implemented, in addition to other DSI post-processing steps. This technique greatly improved the angular resolution of the otherwise unresolvable peaks in a crossing fiber ODF. The effects of DSI acquisition parameters and SNR on the resultant angular accuracy of DSI on the clinical scanner were studied and quantified using the developed phantoms. With a high angular direction sampling and reasonable levels of SNR, quantification of a crossing region in the 90°, 45° and 60° phantoms resulted in a successful detection of angular information with mean ± SD of 86.93°±2.65°, 44.61°±1.6° and 60.03°±2.21° respectively, while simultaneously enhancing the ODFs in regions containing single fibers. For the applicability of these validated methodologies in DSI, improvement in ODFs and fiber tracking from known crossing fiber regions in normal human subjects were demonstrated; and an in-house software package in MATLAB which streamlines the data reconstruction and post-processing for DSI, with easy to use graphical user interface was developed. In conclusion, the phantoms developed in this dissertation offer a means of providing ground truth for validation of reconstruction and tractography algorithms of various diffusion models (including DSI). Also, the deconvolution methodology (when applied as an additional DSI post-processing step) significantly improved the angular accuracy of the ODFs obtained from DSI, and should be applicable to ODFs obtained from the other high angular resolution diffusion imaging techniques.

TRANSCRIPTIONAL AND POST-TRANSLATIONAL MECHANISMS CONTRIBUTE TO MAINTENANCE OF REST IN NEURAL TUMORS

The RE-1 silencing transcription factor (REST) is an important regulator of normal nervous system development. It negatively regulates neuronal lineage specification in neural progenitors by binding to its consensus RE-1 element(s) located in the regulatory region of its target neuronal differentiation genes. The developmentally coordinated down-regulation of REST mRNA and protein in neural progenitors triggers terminal neurogenesis. REST is overexpressed in pediatric neural tumors such as medulloblastoma and neuroblastoma and is associated with poor neuronal differentiation. High REST protein correlate with poor prognosis for patients with medulloblastoma, however similar studies have not been done with neuroblastoma patients. Mechanism(s) underlying elevated REST levels medulloblastoma and neuroblastoma are unclear, and is the focus of this thesis project. We discovered that transcriptional and post-translational mechanisms govern REST mis-regulation in medulloblastoma and neuroblastoma. In medulloblastoma, REST transcript is aberrantly elevated in a subset of patient samples. Using loss of function and gain of function experiments, we provide evidence that the Hairy Enhancer of Split (HES1) protein represses REST transcription in medulloblastoma cell lines, modulates the expression of neuronal differentiation genes, and alters the survival potential of these cells in vitro. We also show that REST directly represses its own expression in an auto-regulatory feedback loop. Interestingly, our studies identified a novel interaction between REST and HES1. We also observed their co-occupancy at the RE-1 sites, thereby suggesting potential for co-regulation of REST expression. Our pharmacological studies in neuroblastoma using retinoic acid revealed that REST levels are controlled by transcriptional and post-transcriptional mechanisms. Post-transcriptional mechanisms are mediated by modulation of E3 ligase or REST, SCFβ-TRCP, and contribute to resistance of some cells to retinoic acid treatment.

Los grandes grupos económicos : Ganadores y perdedores en la post-convertibilidad : Un estudio basado en la trayectoria del sector servicios y en el nuevo rol del Estado [2002-2010]

A lo largo de la post-convertibilidad el esquema de los ganadores y perdedores entre los grandes grupos económicos 'pertenecientes al sector servicios, financiero, agro-industrial, industrial, petrolero-minero' se fue redefiniendo. Este trabajo de cuenta de tales cambios a partir de considerar los estudios sociales más importantes sobre el tema, que incluyen tanto el problema de la crisis de la convertibilidad como la nueva situación de los grandes grupos económicos y el Estado durante la post-convertibilidad. De esta manera es de suponer como necesario comenzar con una conceptualización de la crisis de la convertibilidad y sus consecuencias, para entender la situación y los problemas que debieron solucionar los grandes grupos económicos y el Estado a comienzos de la post-convertibilidad para impulsar un proceso de crecimiento económico sostenido. Así las dicotomías presentes entre los trabajos que priorizan, por un lado, la lucha entre fracciones, y, por otro, el peso de la crisis, nos servirá para dicho fin. En segundo lugar se analizaran los diferentes trabajos que explican, de diversas maneras, la nueva situación en que se encontraron -y se encuentran- las fracciones de la burguesía, y su relación con las funciones del Estado a lo largo de la post-convertibilidad. De aquí saldrán los principales insumos para pensar el rol del Estado -bajo un nuevo tipo de arbitraje- y las acciones de los grandes grupos económicos, ambos condicionados por la crisis de la convertibilidad y el mercado mundial. Con las conceptualizaciones aceptadas, se analizará la acción de los grandes grupos económicos y las funciones del Estado para un caso específico: los grandes grupos económicos de las empresas privatizadas y su relación con el nuevo tipo de arbitraje estatal en la post-convertibilidad, según dos periodos diferentes. Y, se redefinirá el esquema de ganadores y perdedores para tal caso, teniendo como elemento distintivo la relación de las empresas privatizadas y los subsidios

Los migrantes del noroeste hispánico en el Buenos Aires tardo colonial : La construcción de un tejido relacional luego del traslado ultramarino

A fines del siglo XVIII las migraciones de gallegos y asturianos a la ciudad de Buenos Aires se incrementaron. Estos desplazamientos estuvieron condicionados por diferentes factores, que operaron de ambos lados del Atlántico: la instauración de una línea regular de transporte oficial entre La Coruña y Montevideo (los Correos Marítimos); la larga tradición marítima y migratoria de las zonas costeras de Galicia y Asturias; o el desarrollo económico de la capital virreinal, con sus oportunidades de movilidad social ascendente, entre otros. Dentro de Buenos Aires, los oriundos del noroeste hispánico generaron un tejido de relaciones sociales, que incluyó vínculos con paisanos y con el componente nativo de la sociedad de recepción. A lo largo de este trabajo analizaremos esta ambigua dirección de los lazos sociales postmigratorios, a partir del examen de algunas fuentes primarias básicas, tales como las actas matrimoniales, los testamentos o los padrones de habitantes.

Tributo en la Argentina post-dictadura : Los "muertos por la subversión"

El artículo analiza el lugar de Tributo, órgano de FAMUS (Familiares y Amigos de Muertos por la Subversión), en los años '80, en la reivindicación de la actuación militar en la última dictadura y de la represión en general antes de 1976. El argumento central es que la búsqueda de legitimidad en el espacio público se estructura a partir de formas particulares de matar y morir que permiten, a su vez, establecer una oposición radical entre los muertos propios y los del campo opuesto. Se muestra también la adecuación plástica de Tributo a la cambiante coyuntura de los años de la transición democrática y se rescatan las formas en que se iban construyendo las estrategias de los defensores de la represión, sus intentos en un momento dado de postergar para el futuro la justicia que en el presente no reciben y, vistos desde hoy, las líneas de continuidad con formas actuales de reivindicación, que ya en las páginas de Tributo aparecen claramente esbozadas

Población y ocupación del espacio en la frontera del salado. Chascomús, Ranchos y Monte entre 1815 y 1838

Los numerosos estudios sobre la sociedad rural rioplatense en el período colonial y pos independiente van mostrando, poco a poco, las características de la población, la composición familiar y la disponibilidad de mano de obra, tanto en las áreas de viejo asentamiento como en las más dinámicas de la frontera interior, de manera que puede continuarse la tarea con nuevas aproximaciones, comparando los resultados con los ya obtenidos. Esta será la perspectiva del presente trabajo, en el que se describirá la estructura poblacional de Chascomús entre 1815 y 1838, aunque sumando una relación que se aprecia ausente en los trabajos sobre el tema, como es la ocupación y acceso a la propiedad legal de la tierra. Debido a las características de las fuentes los partidos de Ranchos y Monte se incluirán parcialmente en el análisis

Los grandes grupos económicos : Ganadores y perdedores en la post-convertibilidad : Un estudio basado en la trayectoria del sector servicios y en el nuevo rol del Estado [2002-2010]

A lo largo de la post-convertibilidad el esquema de los ganadores y perdedores entre los grandes grupos económicos 'pertenecientes al sector servicios, financiero, agro-industrial, industrial, petrolero-minero' se fue redefiniendo. Este trabajo de cuenta de tales cambios a partir de considerar los estudios sociales más importantes sobre el tema, que incluyen tanto el problema de la crisis de la convertibilidad como la nueva situación de los grandes grupos económicos y el Estado durante la post-convertibilidad. De esta manera es de suponer como necesario comenzar con una conceptualización de la crisis de la convertibilidad y sus consecuencias, para entender la situación y los problemas que debieron solucionar los grandes grupos económicos y el Estado a comienzos de la post-convertibilidad para impulsar un proceso de crecimiento económico sostenido. Así las dicotomías presentes entre los trabajos que priorizan, por un lado, la lucha entre fracciones, y, por otro, el peso de la crisis, nos servirá para dicho fin. En segundo lugar se analizaran los diferentes trabajos que explican, de diversas maneras, la nueva situación en que se encontraron -y se encuentran- las fracciones de la burguesía, y su relación con las funciones del Estado a lo largo de la post-convertibilidad. De aquí saldrán los principales insumos para pensar el rol del Estado -bajo un nuevo tipo de arbitraje- y las acciones de los grandes grupos económicos, ambos condicionados por la crisis de la convertibilidad y el mercado mundial. Con las conceptualizaciones aceptadas, se analizará la acción de los grandes grupos económicos y las funciones del Estado para un caso específico: los grandes grupos económicos de las empresas privatizadas y su relación con el nuevo tipo de arbitraje estatal en la post-convertibilidad, según dos periodos diferentes. Y, se redefinirá el esquema de ganadores y perdedores para tal caso, teniendo como elemento distintivo la relación de las empresas privatizadas y los subsidios

Los migrantes del noroeste hispánico en el Buenos Aires tardo colonial : La construcción de un tejido relacional luego del traslado ultramarino

A fines del siglo XVIII las migraciones de gallegos y asturianos a la ciudad de Buenos Aires se incrementaron. Estos desplazamientos estuvieron condicionados por diferentes factores, que operaron de ambos lados del Atlántico: la instauración de una línea regular de transporte oficial entre La Coruña y Montevideo (los Correos Marítimos); la larga tradición marítima y migratoria de las zonas costeras de Galicia y Asturias; o el desarrollo económico de la capital virreinal, con sus oportunidades de movilidad social ascendente, entre otros. Dentro de Buenos Aires, los oriundos del noroeste hispánico generaron un tejido de relaciones sociales, que incluyó vínculos con paisanos y con el componente nativo de la sociedad de recepción. A lo largo de este trabajo analizaremos esta ambigua dirección de los lazos sociales postmigratorios, a partir del examen de algunas fuentes primarias básicas, tales como las actas matrimoniales, los testamentos o los padrones de habitantes.