The communicative dimension in the translation of the David Lodge's Nice work

Eguíluz, Federico; Merino, Raquel; Olsen, Vickie; Pajares, Eterio; Santamaría, José Miguel (eds.)

Intracellular Ca2+ release through ryanodine receptors contributes to AMPA receptor-mediated mitochondrial dysfunction and ER stress in oligodendrocytes

Overactivation of ionotropic glutamate receptors in oligodendrocytes induces cytosolic Ca2+ overload and excitotoxic death, a process that contributes to demyelination and multiple sclerosis. Excitotoxic insults cause well-characterized mitochondrial alterations and endoplasmic reticulum (ER) dysfunction, which is not fully understood. In this study, we analyzed the contribution of ER-Ca2+ release through ryanodine receptors (RyRs) and inositol triphosphate receptors (IP(3)Rs) to excitotoxicity in oligodendrocytes in vitro. First, we observed that oligodendrocytes express all previously characterized RyRs and IP(3)Rs. Blockade of Ca2+-induced Ca2+ release by TMB-8 following alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor-mediated insults attenuated both oligodendrocyte death and cytosolic Ca2+ overload. In turn, RyR inhibition by ryanodine reduced as well the Ca2+ overload whereas IP3R inhibition was ineffective. Furthermore, AMPA-triggered mitochondrial membrane depolarization, oxidative stress and activation of caspase-3, which in all instances was diminished by RyR inhibition. In addition, we observed that AMPA induced an ER stress response as revealed by alpha subunit of the eukaryotic initiation factor 2 alpha phosphorylation, overexpression of GRP chaperones and RyR-dependent cleavage of caspase-12. Finally, attenuating ER stress with salubrinal protected oligodendrocytes from AMPA excitotoxicity. Together, these results show that Ca2+ release through RyRs contributes to cytosolic Ca2+ overload, mitochondrial dysfunction, ER stress and cell death following AMPA receptor-mediated excitotoxicity in oligodendrocytes. Cell Death and Disease (2010) 1, e54; doi:10.1038/cddis.2010.31; published online 15 July 2010

Metaphysics in the Work of Charles Darwin

It is not hard to see how two visions of nature are intertwined in Darwin’s Journal of Researches: one vision, the province of romantic authors depicting the sentiments awakened by certain landscapes, the other, the domain of natural scientists describing the world without reference to the aesthetic qualities of the scenery. Nevertheless, analyses of this double perspective in Darwin’s work are relatively rare. Most scholars focus on Darwin, the scientist, and more or less ignore the aesthetic aspects of his work. Perceiving the gradual transformation of Darwin’s world view, however, depends on analyzing the two different modes in which Darwin approached and perceived the world. While one can, on occasion, find commentaries on the beauty of the natural world in Darwin’s early work, the passage of time produces a modification in the naturalist’s manner of perceiving nature. This does not, however, mean that Darwin ceases to find beauty in nature; on the contrary, the disenchantment, in Max Weber’s words, that Darwin’s theory produces should not be understood in a pejorative, but rather in a literal sense. The theory of evolution, in effect, divests nature of its magical character and begins to explain it in terms of natural selection, according it, in the process a new and more intense attraction. In the present work, the metaphysical implications of this new vision of the world are analyzed through the eyes of its discoverer.

We can work it out: an enactive look at cooperation

The past years have seen an increasing debate on cooperation and its unique human character. Philosophers and psychologists have proposed that cooperative activities are characterized by shared goals to which participants are committed through the ability to understand each other’s intentions. Despite its popularity, some serious issues arise with this approach to cooperation. First, one may challenge the assumption that high-level mental processes are necessary for engaging in acting cooperatively. If they are, then how do agents that do not possess such ability (preverbal children, or children with autism who are often claimed to be mind-blind) engage in cooperative exchanges, as the evidence suggests? Secondly, to define cooperation as the result of two de-contextualized minds reading each other’s intentions may fail to fully acknowledge the complexity of situated, interactional dynamics and the interplay of variables such as the participants’ relational and personal history and experience. In this paper we challenge such accounts of cooperation, calling for an embodied approach that sees cooperation not only as an individual attitude toward the other, but also as a property of interaction processes. Taking an enactive perspective, we argue that cooperation is an intrinsic part of any interaction, and that there can be cooperative interaction before complex communicative abilities are achieved. The issue then is not whether one is able or not to read the other’s intentions, but what it takes to participate in joint action. From this basic account, it should be possible to build up more complex forms of cooperation as needed. Addressing the study of cooperation in these terms may enhance our understanding of human social development, and foster our knowledge of different ways of engaging with others, as in the case of autism.

CGP37157, an inhibitor of the mitochondrial Na+/Ca2+ exchanger, protects neurons from excitotoxicity by blocking voltage-gated Ca2+ channels

Inhibition of the mitochondrial Na+/Ca2+ exchanger (NCLX) by CGP37157 is protective in models of neuronal injury that involve disruption of intracellular Ca2+ homeostasis. However, the Ca2+ signaling pathways and stores underlying neuroprotection by that inhibitor are not well defined. In the present study, we analyzed how intracellular Ca2+ levels are modulated by CGP37157 (10 mu M) during NMDA insults in primary cultures of rat cortical neurons. We initially assessed the presence of NCLX in mitochondria of cultured neurons by immunolabeling, and subsequently, we analyzed the effects of CGP37157 on neuronal Ca2+ homeostasis using cameleon-based mitochondrial Ca2+ and cytosolic Ca2+ ([Ca2+](i)) live imaging. We observed that NCLX-driven mitochondrial Ca2+ exchange occurs in cortical neurons under basal conditions as CGP37157 induced a decrease in [Ca-2](i) concomitant with a Ca2+ accumulation inside the mitochondria. In turn, CGP37157 also inhibited mitochondrial Ca2+ efflux after the stimulation of acetylcholine receptors. In contrast, CGP37157 strongly prevented depolarization-induced [Ca2+](i) increase by blocking voltage-gated Ca2+ channels (VGCCs), whereas it did not induce depletion of ER Ca2+ stores. Moreover, mitochondrial Ca2+ overload was reduced as a consequence of diminished Ca2+ entry through VGCCs. The decrease in cytosolic and mitochondrial Ca2+ overload by CGP37157 resulted in a reduction of excitotoxic mitochondrial damage, characterized here by a reduction in mitochondrial membrane depolarization, oxidative stress and calpain activation. In summary, our results provide evidence that during excitotoxicity CGP37157 modulates cytosolic and mitochondrial Ca2+ dynamics that leads to attenuation of NMDA-induced mitochondrial dysfunction and neuronal cell death by blocking VGCCs.