Concentrative nucleoside transporter 1 (hCNT1) promotes phenotypic changes relevant to tumor biology in a translocation independent manner

Nucleoside transporters (NTs) mediate the uptake of nucleosides and nucleobases across the plasma membrane, mostly for salvage purposes. The canonical NTs belong to two gene families, SLC29 and SLC28. The former encode equilibrative nucleoside transporter proteins (ENTs), which mediate the facilitative diffusion of natural nucleosides with broad selectivity, whereas the latter encode concentrative nucleoside transporters (CNTs), which are sodium-coupled and show high affinity for substrates with variable selectivity. These proteins are expressed in most cell types, exhibiting apparent functional redundancy. This might indicate that CNTs play specific roles in the physiology of the cell beyond nucleoside salvage. Here, we addressed this possibility using adenoviral vectors to restore tumor cell expression of hCNT1 or a polymorphic variant (hCNT1S546P) lacking nucleoside translocation ability. We found that hCNT1 restoration in pancreatic cancer cells significantly altered cell-cycle progression and phosphorylation status of key signal-transducing kinases, promoted poly-(ADP ribose) polymerase hyperactivation and cell death, and reduced tumor growth and cell migration. Importantly, the translocation-defective transporter triggered these same effects on cell physiology. These data predict a novel and totally unexpected biological role for the nucleoside transporter protein hCNT1 that appears to be independent of its role as mediator of nucleoside uptake by cells, thereby suggesting a transceptor function. Cell Death & Disease Anastasis Stephanou Receiving Editor Cell Death & Disease 19th Apr 2013 Dr Perez-Torras Av/ Diagonal 643. Edif. Prevosti, Pl -1 Barcelona 08028 Spain RE: Manuscript CDDIS-13-0136R, 'CDDIS-13-0136R' Dear Dr Perez-Torras, It is a pleasure to inform you that your manuscript has been evaluated at the editorial level and has now been officially accepted for publication in Cell Death & Disease, pending you meet the following editorial requirements: 1) the list of the abbreviations is missing please include Could you send us the revised text as word file via e-mail and we will proceed and transfer the paper onto our typesetters. Please download, print, sign, and return the Licence to Publish Form using the link below. This must be returned via FAX to ++ 39 06 7259 6977 before your manuscript can be published:

GSK3 is involved in the relief of mitochondria pausing in a tau-dependent manner.

Mitochondrial trafficking deficits have been implicated in the pathogenesis of several neurological diseases, including Alzheimer's disease (AD). The Ser/Thre kinase GSK3β is believed to play a fundamental role in AD pathogenesis. Given that GSK3β substrates include Tau protein, here we studied the impact of GSK3β on mitochondrial trafficking and its dependence on Tau protein. Overexpression of GSK3β in neurons resulted in an increase in motile mitochondria, whereas a decrease in the activity of this kinase produced an increase in mitochondria pausing. These effects were dependent on Tau proteins, as Tau (−/−) neurons did not respond to distinct GSK3β levels. Furthermore, differences in GSK3β expression did not affect other parameters like mitochondria velocity or mitochondria run length. We conclude that GSK3B activity regulates mitochondrial axonal trafficking largely in a Tau-dependent manner.

RECASTING THE ELLIOTT CONJECTURE

Let A be a simple, unital, finite, and exact C*-algebra which absorbs the Jiang-Su algebra Z tensorially. We prove that the Cuntz semigroup of A admits a complete order embedding into an ordered semigroup which is obtained from the Elliott invariant in a functorial manner. We conjecture that this embedding is an isomor phism, and prove the conjecture in several cases. In these same cases - Z-stable algebras all - we prove that the Elliott conjecture in its strongest form is equivalent to a conjecture which appears much weaker. Outside the class of Z-stable C*-algebras, this weaker conjecture has no known counterexamples, and it is plausible that none exist. Thus, we reconcile the still intact principle of Elliott's classification conjecture -that K-theoretic invariants will classify separable and nuclear C*-algebras- with the recent appearance of counterexamples to its strongest concrete form.

An ordinal shapley value for economic environments

We propose a new solution concept to address the problem of sharing a surplus among the agents generating it. The sharing problem is formulated in the preferences-endowments space. The solution is defined in a recursive manner incorporating notions of consistency and fairness and relying on properties satisfied by the Shapley value for Transferable Utility (TU) games. We show a solution exists, and refer to it as an Ordinal Shapley value (OSV). The OSV associates with each problem an allocation as well as a matrix of concessions ``measuring'' the gains each agent foregoes in favor of the other agents. We analyze the structure of the concessions, and show they are unique and symmetric. Next we characterize the OSV using the notion of coalitional dividends, and furthermore show it is monotone in an agent's initial endowments and satisfies anonymity. Finally, similarly to the weighted Shapley value for TU games, we construct a weighted OSV as well.

On the regional impact of public capital formation in Spain

The objective of this paper is to investigate, in a methodologically consistent manner, the regional effects of public capital formation and the possible existence of regional spillover effects in Spain. The empirical results are based on VAR estimates at both the aggregate and regional levels using output, employment, and private capital, as well as different measures of public capital. Empirical results suggest that public capital affects output positively at the aggregate level as well as in all but one region. For most regions, the effects of public capital installed in the region itself are important but the spillover effects induced from public capital installed elsewhere are also very important. In fact, the spillover effects account for over half of the total effects of public capital formation in Spain. Furthermore, these spillover effects have a clear geographical pattern in that they tend to be more important in the peripheral regions of the country. We also find that relative to their share of the Spanish output, the biggest beneficiaries of public capital formation are the largest regions in the country. This suggests that public capital formation has contributed to concentration of output in these regions. Finally, in terms of the effects of public capital formation on the private inputs we find that both private capital and employment are affected positively at the aggregate level as well as for most of the regions. Nevertheless, the effects on private capital seem to be larger. Also, the spillover effects are very important for private capital but not for employment. This reflects a great degree of dynamism and mobility in the capital markets as opposed to the labor markets.

Reduction, Linearization and stability of relative equilibria for mechanical systems on riemannian manifolds

Consider a Riemannian manifold equipped with an infinitesimal isometry. For this setup, a unified treatment is provided, solely in the language of Riemannian geometry, of techniques in reduction, linearization, and stability of relative equilibria. In particular, for mechanical control systems, an explicit characterization is given for the manner in which reduction by an infinitesimal isometry, and linearization along a controlled trajectory "commute." As part of the development, relationships are derived between the Jacobi equation of geodesic variation and concepts from reduction theory, such as the curvature of the mechanical connection and the effective potential. As an application of our techniques, fiber and base stability of relative equilibria are studied. The paper also serves as a tutorial of Riemannian geometric methods applicable in the intersection of mechanics and control theory.

Catalan Policies and Experiences on Cooperative Repositories

The Centre de Supercomputació de Catalunya (CESCA) together with the Consorci de Biblioteques Universitàries de Catalunya (CBUC) started in 1999 a cooperative repository, named TDR, to file in digital format the full-text of the read thesis at the universities of our country to spread them worldwide in open access preserving the intellectual copyright of the authors. This became operational in 2001 and today it is a service fully consolidated not only among the Catalan universities, but also used by other Spanish universities. Since then, there are four additional cooperative repositories which have been created: RECERCAT, for research papers; RACO, for scientific, cultural and erudite Catalan magazines; PADICAT, for archiving Catalan web sites; and MDC, for Catalan digital collections of pictures, maps, posters, old magazines... These five repositories have some common characteristics: they are open access, that is, they are accessible on the internet for free; they mostly comply with the Open Archive Initiative interoperability protocol for facilitating the efficient dissemination of content; and they have been built in a cooperative manner so that it is easy to adopt common procedures and to share the repository developing and managing costs, it permits more visibility of the indexed documents throughout the search engines, and a better provision for long-term preservation can be made. In this paper we present the common policy established for the Catalan cooperative repositories, we describe the five of them briefly, and we comment on the results obtained of our 6-year experience since the first one became operational.

Frames and games

Decision-makers are sometimes influenced by the way in which choice situations are presented to them or "framed" This can be seen as an important challenge to the social sciences, since strong and pervasive framing effects would make it difficult to study human behavior in a synthetic or theoretic manner. We present results from experiments with dilemma games designed to shed light on the effects of several frame variations. We study, among others, the particular public bad frame used by Andreoni (1995) and two more naturalistic frames involving stories. Our results show that none of the frame manipulations have a significant effect on average behavior, but we do find some effects on extreme behavior. We also find that incentives do matter where frames do not matter.

Occurrence and bioaccumulation study of PCDD and PCDF from mineral feed additives

Occurrence of polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) was evaluated in sepiolite as a widely employed binder and anti-caking agent for animal feed. Also, naturally contaminated kaolinitic clay was used for comparative purposes. Since sepiolite shows remarkable adsorption properties, particular interest was paid to the extraction steps as they become critical for the final determination of these pollutants in such matrixes. Furthermore, classical Soxhlet extraction using different extracting strategies as well as acid treatment were carried out with simultaneous liquid-liquid extraction. Results obtained depended on the extraction procedure applied. Acid treatment or Soxhlet extraction using a mixture of toluene:ethanol as solvent allowed to reach the minimum requirements of recovery rates. However, Soxhlet extraction using a mixture cyclohexane:toluene as extracting solvent did not allow to comply with minimum specifications for recovery. Significant differences were obtained in TEQ units when acid treatment was applied in comparison to Soxhlet extraction. This fact can be explained because the use of drastic acid conditions allows removing strongly adsorbed analytes which can be uniquely extracted after a total destruction of the crystalline structure of sepiolite. On the contrary, Soxhlet extraction was not able to destroy the structure of sepiolite and as a consequence the PCDDs/Fs were strongly adsorbed in the internal structure of the mineral. From biological point of view the availability of these toxicants constitutes a critical aspect playing an important role in the final decision choosing particular analytical procedures. Then, acid conditions in the digestive tract should be taken into account. In this scenario, a bioaccumulation study was conducted to evaluate the transference of PCDDs/PCDFs from the sepiolite into the animal tissues when fed with feed containing sepiolite. To this end, chickens were used as a model to examine the bioavailability of PCDDs/PCDFs. Four groups of chickens were exposed through their diet to a control feed, feed with 3% w/w sepiolite as additive, feed contaminated with PCDDs/PCDFs at concentration around 2.8 pg WHO-TEQ/g and feed with 2% of a contaminated kaolinitic clay (460 pg TEQ/g mineral). Livers of the four studied groups were analyzed throughout the exposure period. Results of this trial showed that the performance of broilers was not affected by the presence of dioxins at levels tested, and chickens did not show any abnormal behaviour. Dioxins intentionally added to the diet were absorbed and accumulated in the liver in a significant manner, whereas the PCDDs/Fs from sepiolite were not available for chickens since livers from broilers fed 3% sepiolite presented similar WHO-TEQ values than those from broilers fed control diet.

Addressing the net balances problem as a prerequisite for EU budget reform: a proposal

Conflict among member states regarding the distribution of net financial burdens has been allowed to contaminate the entire design of the EU budget with very negative consequences in terms of equity, efficiency and transparency. To get around this problem and pave the way for a substantive budget reform, we propose to decouple distributional negotiations from the rest of the budget process by linking member state net balances in a rigid manner to relative prosperity. This would be achieved through the introduction of a system of compensating horizontal transfers that would take to its logical conclusion the Commission's proposal for a generalized compensation mechanism. We discuss the impact of the proposed scheme on member states? incentives and illustrate its financial implications using revenue and expenditure projections for 2013 that are based on the current Financial Perspectives and Own Resources Decision.

Aplicaciones Single Program Multiple Data (SPMD) en ambientes distribuidos

Un reto al ejecutar las aplicaciones en un cluster es lograr mejorar las prestaciones utilizando los recursos de manera eficiente, y este reto es mayor al utilizar un ambiente distribuido. Teniendo en cuenta este reto, se proponen un conjunto de reglas para realizar el cómputo en cada uno de los nodos, basado en el análisis de cómputo y comunicaciones de las aplicaciones, se analiza un esquema de mapping de celdas y un método para planificar el orden de ejecución, tomando en consideración la ejecución por prioridad, donde las celdas de fronteras tienen una mayor prioridad con respecto a las celdas internas. En la experimentación se muestra el solapamiento del computo interno con las comunicaciones de las celdas fronteras, obteniendo resultados donde el Speedup aumenta y los niveles de eficiencia se mantienen por encima de un 85%, finalmente se obtiene ganancias de los tiempos de ejecución, concluyendo que si se puede diseñar un esquemas de solapamiento que permita que la ejecución de las aplicaciones SPMD en un cluster se hagan de forma eficiente.

La biblioteca està morta, llarga vida a la biblioteca! La pràctica de la biblioteconomia acadèmica i la revolució digital

Com a conseqüència directa de la revolució digital, les biblioteques acadèmiques d'avui dia s'enfronten a la competència com a proveïdors d'informació. Utilitzant les corbes S de tecnologia de Richard N. Foster com a model analític, aquest article mostra que les biblioteques acadèmiques estan enmig d'un canvi discontinu perquè qüestionen un seguit d'assumpcions que recolzen l'actual pràctica de la biblioteconomia acadèmica. Els autors desafien aquestes assumpcions i analitzen la manera en que les comunicacions digitals afecten les biblioteques acadèmiques.

Political alliances and organisational change in political parties: a framework for analysis

This article sets out a theoretical framework for the study of organisational change within political alliances. To achieve this objective it uses as a starting point a series of premises, the most notable of which include the definition of organisational change as a discrete, complex and focussed phenomenon of changes in power within the party. In accordance with these premises, it analyses the synthetic model of organisational change proposed by Panebianco (1988). After examining its limitations, a number of amendments are proposed to adapt it to the way political alliances operate. The above has resulted in the design of four new models. In order to test its validity and explanatory power in a preliminary manner, the second part looks at the organisational change of the UDC within the CiU alliance between 1978 and 2001. The discussion and conclusions reached demonstrate the problems of determinism of the Panebianco model and suggest, tentatively, the importance of the power balance within the alliance as a key factor.

A Data mining approach to indirect inference

Consider a model with parameter phi, and an auxiliary model with parameter theta. Let phi be a randomly sampled from a given density over the known parameter space. Monte Carlo methods can be used to draw simulated data and compute the corresponding estimate of theta, say theta_tilde. A large set of tuples (phi, theta_tilde) can be generated in this manner. Nonparametric methods may be use to fit the function E(phi|theta_tilde=a), using these tuples. It is proposed to estimate phi using the fitted E(phi|theta_tilde=theta_hat), where theta_hat is the auxiliary estimate, using the real sample data. This is a consistent and asymptotically normally distributed estimator, under certain assumptions. Monte Carlo results for dynamic panel data and vector autoregressions show that this estimator can have very attractive small sample properties. Confidence intervals can be constructed using the quantiles of the phi for which theta_tilde is close to theta_hat. Such confidence intervals are found to have very accurate coverage.

Desenvolupament de vacunes peptídiques y dendrímers basats en polietilenglicol per al tractament del càncer

El principal problema de les teràpies actuals contra el càncer es la baixa especificitat envers les cèl•lules tumorals, cosa que comporta gran quantitat d’efectes secundaris. Per això es important el desenvolupament de nous tipus de teràpies i sistemes d’alliberament efectius per als fàrmacs ja existents al mercat. En la immunoteràpia contra el càncer es pretén estimular el sistema immunològic per a eliminar les cèl•lules canceroses de manera selectiva. En aquest projecte s’han sintetitzat derivats de l’antigen peptídic de melanoma NY-ESO1 i s’ha estudiat la seva capacitat per a estimular el sistema immunològic com a vacunes contra el càncer. També s’han encapsulat el antígens peptídics en liposomes com a adjuvants i sistemes d’alliberament. De totes les variants peptídiques la que resultà més immunogènica fou la que contenia el grup palmitoil i el fragment toxoide tetànic en la seva estructura. La utilització de liposomes com a sistema adjuvant sembla una estratègia interessant per al disseny de vacunes contra el càncer donat que l’encapsulació del pèptid en liposomes va augmentar notablement la resposta immunològica de l’antigen. Per altra banda, s’han desenvolupat dendrímers basats en polietilenglicol com a sistemes alliberadors de fàrmacs per al tractament de tumors. El polietilenglicol és àmpliament utilitzat com a sistema d’alliberament de fàrmacs degut a les seves interessants propietats, augment de la solubilitat i dels temps de residència en plasma, entre d’altres. La metodologia química descrita permet la diferenciació controlada de varies posicions en la superfície del dendrímer a més del creixement del dendrímer fins a una segona generació. S’ha sintetitzat la primera generació del dendrímer contenint el fàrmac antitumoral 5-fluorouracil i s’han realitzat estudis de citotoxicitat comprovant que l’activitat del nanoconjugat és del mateix ordre de magnitud que el 5-fluorouracil sense conjugar.