Patrones de variación y cambio en la sintaxis del Siglo de Oro: un estudio variacionista de dos perífrasis modales en textos de inmediatez comunicativa

Using the hermeneutic tools of variationism in a corpus of a million and a half words, taken from texts approaching the pole of ‘language immediacy’ (private letters, diaries, etc.), this article analyzes the evolution of constraint factor conditioning the variability between deber & deber de + infi nitive periphrasis in the XVI and XVII centuries. The empirical research shows that deber has a prominent role in Golden Age Spanish, as well as in other moments in its history. However, unlike what has been observed in other periods, deber de has an important vitality in this period, with uses increasing signifi cantly from the second half of the sixteenth century onwards. This vitality is further strengthened in some linguistic contexts, either in isolation (epistemic contexts, modalized utterances –especially, emphasized ones–, negative sentences) or in interaction among them. Furthermore, the fact that these linguistic contexts are much more occasional in discourse than their opposing ones (deontic contexts, non modalized utterances, affi rmative sentences), could explain the secular disadvantage of this periphrasis versus its rival variant. Mediante las herramientas del variacionismo  lingüístico, y a partir de un corpus de un  millón y medio de palabras integrado por textos  cercanos al polo de la inmediatez comunicativa  (cartas privadas, diarios, etc.), en este artículo se  analiza la evolución de los factores que condicionan  la alternancia entre las perífrasis modales deber  y deber de + infinitivo durante el periodo del español  clásico. De la investigación empírica se desprende  que la variante no prepositiva ocupa una posición  predominante en el Siglo de Oro, al igual que en  otros momentos de la historia del español. Ahora  bien, a diferencia de lo que se ha observado en otras  épocas, deber de posee una aceptable vitalidad en  el periodo clásico, con usos que se incrementan significativamente a partir de la segunda mitad del  siglo XVI. Esta vitalidad se ve reforzada además en  algunos contextos lingüísticos, bien aisladamente  (contextos epistémicos, enunciados modalizados  –especialmente, enfáticos–, oraciones negativas),  bien en interacción entre sí. De paso, el hecho de  que estos entornos sean minoritarios en el discurso  con respecto a otros alternativos (contextos  deónticos, enunciados no modalizados, oraciones  afi rmativas) podría explicar la desventaja secular de  esta perífrasis frente a su competidora

Treatment with a serotonin 5-HT4-receptor agonist ameliorates cognitive deficits and amyloid pathology in the 3xTg-AD model of Alzheimer's disease

Trabajo presentado al I Congrés Internacional de Biologia de Catalunya: Global questions on advanced biology, celebrado en Barcelona del 9 al 12 de julio de 2012.Alzheimer's disease (AD) is a neurodegenerative disorder characterized by extracellular neuritic plaques of amyloid-beta peptide (Aβ), non-fibrilar intraneuronal soluble forms of Aβ and intracellular neurofibrillary tangles of hyperphosphorylated tau protein. Aβ is generated from its precursor protein APP after cleavage by β- and γ-secretases. In contrast, cleavage of APP by α-secretase releases the soluble, non-amyloidogenic peptide sAPPα. Activation of serotonin 5-HT4 receptors enhances APP processing by α-secretase, thus increasing sAPPα levels in vitro and in vivo. The triple transgenic mouse model of AD (3xTg-AD), harboring the APPSwe, PS1M146V and tauP301L mutant genes, mimics critical aspects of AD neuropathology including learning and memory deficits. We have studied in this model the effect of chronic stimulation of 5-HT4 receptors on APP processing, Aβ pathology, cognitive deficits and other behavioral symptoms. Six month-old male and 12 month-old female 3xTg-AD mice and age-matched wild-type (wt) animals were given the 5-HT4 partial agonist RS67333 or its vehicle using osmotic minipumps. Spatial learning and memory in the Morris Water Maze (MWM) were unaltered in 6 months-old 3xTg-AD males but severely impaired in 12 month-old 3xTg-AD females compared with age- and sex-matched wt controls. These deficits were rescued by agonist administration: agonist-treated 3xTg-AD mice performed as well as vehicle-treated wt controls. The anxious profile of 3xTg-AD mice in the Open Field and Dark/Light Box tests at both ages, showed a tendency to recovery after treatment with RS67333. Immunohistochemical analysis revealed marked decreases of extracellular amyloid plaques in the subiculum of 12 month-old agonist-treated 3xTg-AD animals compared with vehicle-treated 3xTg-AD animals. These results suggest that sustained activation of 5-HT4 receptors may be beneficial to counteract the cognitive deficits and to ammeliorate Aβ pathology in this model of AD.Grant PS09/00468 (Instituto de Salud Carlos III); IDIBAPS fellowship to A.G-M.Peer Reviewe