Chromosomal instability and cytoskeletal defects in oral cancer cells

Oral squamous cell carcinomas are characterized by complex, often near-triploid karyotypes with structural and numerical variations superimposed on the initial clonal chromosomal alterations. We used immunohistochemistry combined with classical cytogenetic analysis and spectral karyotyping to investigate the chromosomal segregation defects in cultured oral squamous cell carcinoma cells. During division, these cells frequently exhibit lagging chromosomes at both metaphase and anaphase, suggesting defects in the mitotic apparatus or kinetochore. Dicentric anaphase chromatin bridges and structurally altered chromosomes with consistent long arms and variable short arms, as well as the presence of gene amplification, suggested the occurrence of breakage–fusion–bridge cycles. Some anaphase bridges were observed to persist into telophase, resulting in chromosomal exclusion from the reforming nucleus and micronucleus formation. Multipolar spindles were found to various degrees in the oral squamous cell carcinoma lines. In the multipolar spindles, the poles demonstrated different levels of chromosomal capture and alignment, indicating functional differences between the poles. Some spindle poles showed premature splitting of centrosomal material, a precursor to full separation of the microtubule organizing centers. These results indicate that some of the chromosomal instability observed within these cancer cells might be the result of cytoskeletal defects and breakage–fusion–bridge cycles.

Selective neuronal toxicity of cocaine in embryonic mouse brain cocultures.

Cocaine exposure in utero causes severe alterations in the development of the central nervous system. To study the basis of these teratogenic effects in vitro, we have used cocultures of neurons and glial cells from mouse embryonic brain. Cocaine selectively affected embryonic neuronal cells, causing first a dramatic reduction of both number and length of neurites and then extensive neuronal death. Scanning electron microscopy demonstrated a shift from a multipolar neuronal pattern towards bi- and unipolarity prior to the rounding up and eventual disappearance of the neurons. Selective toxicity of cocaine on neurons was paralleled by a concomitant decrease of the culture content in microtubule-associated protein 2 (MAP2), a neuronal marker measured by solid-phase immunoassay. These effects on neurons were reversible when cocaine was removed from the culture medium. In contrast, cocaine did not affect astroglial cells and their glial fibrillary acidic protein (GFAP) content. Thus, in embryonic neuronal-glial cell cocultures, cocaine induces major neurite perturbations followed by neuronal death without affecting the survival of glial cells. Provided similar neuronal alterations are produced in the developing human brain, they could account for the qualitative or quantitative defects in neuronal pathways that cause a major handicap in brain function following in utero exposure to cocaine.

La convergencia tecnológica audiovisual y la divulgación científica

Afirmar que el desarrollo de la ciencia y sus aplicaciones es uno de los ejes económicos de la sociedad, se puede hacer perfectamente sin necesidad de realizar análisis o aplicar metodologías de estudios especiales. Es evidente que la economía de los países está directamente relacionada con el nivel de desarrollo científico tecnológico de cada uno de ellos y se les atribuye el papel de economías emergentes a aquellos que comienzan a incorporar de manera eficiente el desarrollo científico técnico a su modelo de organización social y de producción. El desarrollo de la ciencia y la tecnología que durante siglos estuvo centrado en Europa Occidental, se ha ido extendiendo a otras áreas y continentes, dando lugar a una nueva situación de desarrollo extenso y multipolar, que tiene como consecuencia una aceleración permanente del desarrollo científico, tecnológico y económico global en paralelo. Se consolida en la sociedad la percepción de ser receptora de las consecuencias positivas y negativas de la ciencia y la tecnología y que esto sucede sin disponer de información suficiente y adecuada para entenderlo o para poder tomar parte de alguna forma en las decisiones que lo pueden condicionar (al menos en la parte que se financia con fondos públicos)...

Pulsar timing irregularities and the imprint of magnetic field evolution

Context. The rotational evolution of isolated neutron stars is dominated by the magnetic field anchored to the solid crust of the star. Assuming that the core field evolves on much longer timescales, the crustal field evolves mainly though Ohmic dissipation and the Hall drift, and it may be subject to relatively rapid changes with remarkable effects on the observed timing properties. Aims. We investigate whether changes of the magnetic field structure and strength during the star evolution may have observable consequences in the braking index n. This is the most sensitive quantity to reflect small variations of the timing properties that are caused by magnetic field rearrangements. Methods. We performed axisymmetric, long-term simulations of the magneto-thermal evolution of neutron stars with state-of-the-art microphysical inputs to calculate the evolution of the braking index. Relatively rapid magnetic field modifications can be expected only in the crust of neutron stars, where we focus our study. Results. We find that the effect of the magnetic field evolution on the braking index can be divided into three qualitatively different stages depending on the age and the internal temperature: a first stage that may be different for standard pulsars (with n ~ 3) or low field neutron stars that accreted fallback matter during the supernova explosion (systematically n < 3); in a second stage, the evolution is governed by almost pure Ohmic field decay, and a braking index n > 3 is expected; in the third stage, at late times, when the interior temperature has dropped to very low values, Hall oscillatory modes in the neutron star crust result in braking indices of a high absolute value and both positive and negative signs. Conclusions. Current magneto-thermal evolution models predict a large contribution to the timing noise and, in particular, to the braking index, from temporal variations of the magnetic field. Models with strong (≳ 1014 G) multipolar or toroidal components, even with a weak (~1012 G) dipolar field are consistent with the observed trend of the timing properties.

Brazilian perspectives on the changing global order and security challenges. CEPS Working Document No. 376, February 2013

This study analyses the current picture and prospects for EU–Brazil relations in the political and security arenas. As actors experiencing relevant changes, albeit in different directions in their respective international status quo, the EU and Brazil have found some common ground for convergence at the macro level on some structural issues, such as the normative framework of a changing global order, the striving for a multipolar world and the relevance and desirability of multilateralism. At the same time, it is argued that they differ significantly as to the strategies pursued in the attainment of those shared interests, resulting in competing, or eventually divergent, policy preferences when addressing specific issues and developments at the international level, limiting the prospects for a deep mutual commitment and engagement in political and security dynamics at the global level.

More Union in European Defence. CEPS Task Force Report, 26 February 2015

Years of uncoordinated cuts in defence spending have eroded the EU’s role as a security actor in what is now a multipolar world. This CEPS Task Force report aims to provide member states and the EU institutions with the narrative to strengthen defence cooperation in the EU, in the face of numerous emergencies in the EU’s strategic neighbourhood and ever-present security threats. The report is a record of the deliberations over several months between high-level experts in the field of European security and defence, who conclude that the Treaty of Lisbon demands and permits a great deal more in terms of our common security and defence activities. And that member states could achieve much more value for money than the €190 billion that they spend to keep up 28 national armies, comprising roughly 1.5 million service personnel. This report suggests policy actions to further the EU’s strategic, institutional, capabilities, and resources cooperation in the field of defence. Ultimately, in the view of the Task Force experts, further integration should amount to a European Defence Union.

The Central European Predicament. Jean Monnet/Robert Schuman Paper Series Vol. 14 No. 9, May 2014

From Introduction. Central and Eastern Europe (CEE) has experienced a very deep economic and political transformation since the beginning of the nineties. The early years of transition were characterized by big hopes for a quick and successful development. The international community, including the EU and the USA showed interest in the transformation of the region for a number of reasons. From a geopolitical perspective, the transformation was of tremendous importance as it confirmed the end of the cold war and the bipolar global system was replaced first by a unipolar superpower system and later gave way to a multipolar or a new bipolar system. This also signaled the weakness of the Soviet Union (and later Russia), as it was not able to prevent this transformation and was soon mired in a serious and long lasting economic and political crisis that undermined its international position. After the dissolution of the Soviet Union during the nineties Russia remained very weak, both economically and politically. The power vacuum and the transformation in Central Europe made the establishment of a new international economic and security structure possible. The new economic and political pattern that started to develop within the region was based on the liberal market economy model, with the objective of opening up markets and integrating the region into the world economy and the North Atlantic security structure.

The Limited Influence of the European Union in Armenia and Azerbaijan: A Domestic Explanation. EU Diplomacy Paper 9/2015

This paper seeks to explain why the European Union (EU) has had limited influence in Armenia and Azerbaijan in the framework of the European Neighbourhood Policy (ENP). Combining approaches from external governance, norm diffusion and structural foreign policy, it offers an explanation based on domestic factors in the two countries: the political regime, state capacity, political structures, domestic incentives and the perceived legitimacy of EU rules. Although willingness to reform appears to exist in Armenia, such willingness remains constrained by the country’s vulnerable geopolitical location and high dependence on Russia. By contrast, none of the domestic preconditions for EU influence identified by the analytical framework were found in Azerbaijan. The author argues that the Eastern Partnership has not properly addressed the extent to which the clan structures feed into informal political practices and enforce the sustainability of an existing regime in both countries, and that, in addition, the EU has underestimated the multipolar environment which the two countries have to operate in, making it unlikely that the current policy can reach its objectives in Armenia and Azerbaijan.

Distinct mechanisms eliminate mother and daughter centrioles in meiosis of starfish oocytes

Centriole elimination is an essential process that occurs in female meiosis of metazoa to reset centriole number in the zygote at fertilization. How centrioles are eliminated remains poorly understood. Here we visualize the entire elimination process live in starfish oocytes. Using specific fluorescent markers, we demonstrate that the two older, mother centrioles are selectively removed from the oocyte by extrusion into polar bodies. We show that this requires specific positioning of the second meiotic spindle, achieved by dynein-driven transport, and anchorage of the mother centriole to the plasma membrane via mother-specific appendages. In contrast, the single daughter centriole remaining in the egg is eliminated before the first embryonic cleavage. We demonstrate that these distinct elimination mechanisms are necessary because if mother centrioles are artificially retained, they cannot be inactivated, resulting in multipolar zygotic spindles. Thus, our findings reveal a dual mechanism to eliminate centrioles: mothers are physically removed, whereas daughters are eliminated in the cytoplasm, preparing the egg for fertilization.

The scaffold protein KSR1, a novel therapeutic target for the treatment of Merlin-deficient tumors

Merlin has broad tumor-suppressor functions as its mutations have been identified in multiple benign tumors and malignant cancers. In all schwannomas, the majority of meningiomas and 1/3 of ependymomas Merlin loss is causative. In neurofibromatosis type 2, a dominantly inherited tumor disease because of the loss of Merlin, patients suffer from multiple nervous system tumors and die on average around age 40. Chemotherapy is not effective and tumor localization and multiplicity make surgery and radiosurgery challenging and morbidity is often considerable. Thus, a new therapeutic approach is needed for these tumors. Using a primary human in vitro model for Merlin-deficient tumors, we report that the Ras/Raf/mitogen-activated protein, extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) scaffold, kinase suppressor of Ras 1 (KSR1), has a vital role in promoting schwannomas development. We show that KSR1 overexpression is involved in many pathological phenotypes caused by Merlin loss, namely multipolar morphology, enhanced cell-matrix adhesion, focal adhesion and, most importantly, increased proliferation and survival. Our data demonstrate that KSR1 has a wider role than MEK1/2 in the development of schwannomas because adhesion is more dependent on KSR1 than MEK1/2. Immunoprecipitation analysis reveals that KSR1 is a novel binding partner of Merlin, which suppresses KSR1's function by inhibiting the binding between KSR1 and c-Raf. Our proteomic analysis also demonstrates that KSR1 interacts with several Merlin downstream effectors, including E3 ubiquitin ligase CRL4DCAF1. Further functional studies suggests that KSR1 and DCAF1 may co-operate to regulate schwannomas formation. Taken together, these findings suggest that KSR1 serves as a potential therapeutic target for Merlin-deficient tumors.

Aneuploidy Tolerance in a Polyploid Organ

Endopolyploid cells (hereafter - polyploid cells), which contain whole genome duplications in an otherwise diploid organism, play vital roles in development and physiology of diverse organs such as our heart and liver. Polyploidy is also observed with high frequency in many tumors, and division of such cells frequently creates aneuploidy (chromosomal imbalances), a hallmark of cancer. Despite its frequent occurrence and association with aneuploidy, little is known about the specific role that polyploidy plays in diverse contexts. Using a new model tissue, the Drosophila rectal papilla, we sought to uncover connections between polyploidy and aneuploidy during organ development. Our lab previously discovered that the papillar cells of the Drosophila hindgut undergo developmentally programmed polyploid cell divisions, and that these polyploid cell divisions are highly error-prone. Time-lapse studies of polyploid mitosis revealed that the papillar cells undergo a high percentage of tripolar anaphase, which causes extreme aneuploidy. Despite this massive chromosome imbalance, we found the tripolar daughter cells are viable and support normal organ development and function, suggesting acquiring extra genome sets enables a cell to tolerate the genomic alterations incurred by aneuploidy. We further extended these findings by seeking mechanisms by which the papillar cells tolerated this resultant aneuploidy.

Para una crítica de la educación democrática

El propósito central de este trabajo consiste en hacer un análisis crítico de la idea de educación democrática. Como hilo conductor se discute la tesis desarrollada por Amy Gutmann, según la cual, la educación democrática tiene como fin garantizar la reproducción consciente de la sociedad. En este contexto, la tesis que se defiende afirma que la educación democrática exige, además de los principios de no represión y la no discriminación desarrollados por Gutmann, un principio de reconocimiento, que articule la orientación de las acciones educativas a fuentes de normatividad asociadas con una interpretación intersubjetivista de la autonomía, de manera que se puedan generar más elementos de juicio, sobre todo, aquellos incorporados en las dimensiones moral, ética, política, legal y social de la persona, al momento de proponer prácticas educativas encaminadas a la formación de una ciudadanía participativa y crítica. Para esto se propone una interpretación que integra las perspectivas deliberativa y agonal de la democracia, se defiende que la expresión clave del ejercicio de la ciudadanía democrática es la participación, que el ejercicio de la participación tiene por condición la realización de la autonomía personal, por lo cual, en la parte final se elabora una lectura intersubjetivista de la autonomía, a partir de los trabajos de Axel Honneth y Rainer Forst.

Relaciones con Medio Oriente: ¿nuevo eje estratégico de la política internacional latinoamericana?

Este artículo analiza las dimensiones económicas, políticas y diplomáticas de las relaciones entre América Latina y Medio Oriente. A pesar del nexo creado a través de las migraciones, las relaciones entre ambas regiones eran hasta hace pocos años débiles y poco significativas. Sin embargo, el desarrollo de las comunicaciones y la voluntad común de diversificar las relaciones internacionales han favorecido una intensificación cuantitativa y cualitativa de los vínculos. Flujos de comercio e inversión crecientes, e intercambios diplomáticos bilaterales y multilaterales cada vez más intensos, configuran una relación inédita entre ambas regiones del mundo. Esta relación favorece el encuentro de economías complementarias, pero también las coincidencias geopolíticas entre países que apelan a construir un orden internacional multipolar.Palabras claves: América Latina, Medio Oriente, diplomacia, comercio, geopolítica, relaciones hemisféricas.