La última prisión de Quevedo. Documentos atribuidos, atribuibles y apócrifos

El autor manifiesta sus dudas sobre algunas obras atribuidas a Quevedo y tenidas por auténticas. Repasa diversos documentos relativos a la prisión de 1639: la Carta del arzobispo de Granada a Felipe IV (6 de diciembre de 1639), el memorial de Quevedo al Conde-Duque “Si no es la esperanza...”, el “primer” memorial de Quevedo a Felipe IV “Señor: Don Francisco de Quevedo ha tres años y más...”, las cuatro epístolas escritas “A imitación de las de Séneca” y el testamento y codicilo fechados el 25 de abril de 1645. The author shows his doubts about some works attributed to Quevedo and generally thought as authentic. He examines differents documents refering to the prision of 1639: A letter of the archbishop to the king Felipe IV (December, the 6th, 1639), Quevedo’s memorial addressed to the Conde-Duque “Si no es la esperanza...”, and the “first” memorial to the king Felipe IV “Señor: Don Francisco de Quevedo ha tres años y más...”, the four letters written “A imitación de las de Séneca” and the testament and codicil dated 25 April, 1645

Cuarenta y dos cartas de Quevedo a dos jesuitas distinguidos

Examen detenido basado en la documentación original coetánea de lo que ya sabemos de las relaciones de Quevedo con los jesuitas, y de las noticias que aportan una serie de cartas desconocidas de Quevedo. Lo que sabemos se somete a una revisión a fondo; en las cartas desconocidas el satírico ventila, con el acostumbrado ingenio y atrevimiento, su experiencia, su intelecto, su habilidad literaria y su sentido del humor. This article is a detailed exam based on contemporary documents about the relationship of Quevedo with the jesuits and new information provided by some letters unknown of Quevedo. What we know is revised thoroughly; in the new letters, Quevedo examines his experience, his know ledge, his literary skills and his sense of humour, with his ingenuity and fearlessness

"Más he querido atreverme que engañarme": Quevedo frente al dilema de hablar o callarse en Los sueños

Entre «hablar» y «callarse» parece haberse debatido Quevedo, obedeciendo ya a uno, ya a otro impulso, pero no por vacilación ni irresolución. Dicha postura retórica y las decisiones que tomó al respecto entre 1603 y 1631, si no más tarde, eran de índole personal y política; personal porque se trataba del impulso por expresarse que siente profundamente cualquier escritor, y política porque en la España del siglo XVII «hablar» traía a colación el riego de la intervención del Estado y de la Inquisición («callar»). Caught between «speaking out» and «silencing himself», Quevedo seems to have complied with now one and now the other of these two impulses, but not in vacillation nor irresolution. This rhetorical posture and the decisions that he took in this respect between 1603 and 1631, if not later on, were of a personal and political character. Personal because they involved the impulse to express oneself which every writer feels in a profound way, and political because in seventeenth-century Spain, «speaking out» carried the risk of intervention by the State or the Inquisition («silencing himself»)

A causative relationship exists between eosinophils and the development of allergic pulmonary pathologies in the mouse

Asthma and mouse models of allergic respiratory inflammation are invariably associated with a pulmonary eosinophilia; however, this association has remained correlative. In this report, a causative relationship between eosinophils and allergen-provoked pathologies was established using eosinophil adoptive transfer. Eosinophils were transferred directly into the lungs of either naive or OVA-treated IL-5-/- mice. This strategy resulted in a pulmonary eosinophilia equivalent to that observed in OVA-treated wild-type animals. A concomitant consequence of this eosinophil transfer was an increase in Th2 bronchoalveolar lavage cytokine levels and the restoration of intracellular epithelial mucus in OVA-treated IL-5-/- mice equivalent to OVA-treated wild-type levels. Moreover, the transfer also resulted in the development of airway hyperresponsiveness. These pulmonary changes did not occur when eosinophils were transferred into naive IL-5-/- mice, eliminating nonspecific consequences of the eosinophil transfer as a possible explanation. Significantly, administration of OVA-treated IL-5-/- mice with GK1.5 (anti-CD4) Abs abolished the increases in mucus accumulation and airway hyperresponsiveness following adoptive transfer of eosinophils. Thus, CD4+ T cell-mediated inflammatory signals as well as signals derived from eosinophils are each necessary, yet alone insufficient, for the development of allergic pulmonary pathology. These data support an expanded view of T cell and eosinophil activities and suggest that eosinophil effector functions impinge directly on lung function

Anti-cancer effects and mechanism of actions of aspirin analogues in the treatment of glioma cancer

INTRODUCTION: In the past 25 years only modest advancements in glioma treatment have been made, with patient prognosis and median survival time following diagnosis only increasing from 3 to 7 months. A substantial body of clinical and preclinical evidence has suggested a role for aspirin in the treatment of cancer with multiple mechanisms of action proposed including COX 2 inhibition, down regulation of EGFR expression, and NF-κB signaling affecting Bcl-2 expression. However, with serious side effects such as stroke and gastrointestinal bleeding, aspirin analogues with improved potency and side effect profiles are being developed. METHOD: Effects on cell viability following 24 hr incubation of four aspirin derivatives (PN508, 517, 526 and 529) were compared to cisplatin, aspirin and di-aspirin in four glioma cell lines (U87 MG, SVG P12, GOS – 3, and 1321N1), using the PrestoBlue assay, establishing IC50 and examining the time course of drug effects. RESULTS: All compounds were found to decrease cell viability in a concentration and time dependant manner. Significantly, the analogue PN517 (IC50 2mM) showed approximately a twofold increase in potency when compared to aspirin (3.7mM) and cisplatin (4.3mM) in U87 cells, with similar increased potency in SVG P12 cells. Other analogues demonstrated similar potency to aspirin and cisplatin. CONCLUSION: These results support the further development and characterization of novel NSAID derivatives for the treatment of glioma

Evolution of Assortative Mating in a Population Expressing Dominance

In this article, we study the influence of dominance on the evolution of assortative mating. We perform a population-genetic analysis of a two-locus two-allele model. We consider a quantitative trait that is under a mixture of frequency-independent stabilizing selection and density- and frequency-dependent selection caused by intraspecific competition for a continuum of resources. The trait is determined by a single (ecological) locus and expresses intermediate dominance. The second (modifier) locus determines the degree of assortative mating, which is expressed in females only. Assortative mating is based on similarities in the quantitative trait (‘magic trait’ model). Analytical conditions for the invasion of assortment modifiers are derived in the limit of weak selection and weak assortment. For the full model, extensive numerical iterations are performed to study the global dynamics. This allows us to gain a better understanding of the interaction of the different selective forces. Remarkably, depending on the size of modifier effects, dominance can have different effects on the evolution of assortment. We show that dominance hinders the evolution of assortment if modifier effects are small, but promotes it if modifier effects are large. These findings differ from those in previous work based on adaptive dynamics

Models of <i>KPTN</i>-related disorder implicate mTOR signalling in cognitive and overgrowth phenotypes

KPTN-related disorder is an autosomal recessive disorder associated with germline variants in KPTN (previously known as kaptin), a component of the mTOR regulatory complex KICSTOR. To gain further insights into the pathogenesis of KPTN-related disorder, we analysed mouse knockout and human stem cell KPTN loss-of-function models. Kptn -/- mice display many of the key KPTN-related disorder phenotypes, including brain overgrowth, behavioural abnormalities, and cognitive deficits. By assessment of affected individuals, we have identified widespread cognitive deficits (n = 6) and postnatal onset of brain overgrowth (n = 19). By analysing head size data from their parents (n = 24), we have identified a previously unrecognized KPTN dosage-sensitivity, resulting in increased head circumference in heterozygous carriers of pathogenic KPTN variants. Molecular and structural analysis of Kptn-/- mice revealed pathological changes, including differences in brain size, shape and cell numbers primarily due to abnormal postnatal brain development. Both the mouse and differentiated induced pluripotent stem cell models of the disorder display transcriptional and biochemical evidence for altered mTOR pathway signalling, supporting the role of KPTN in regulating mTORC1. By treatment in our KPTN mouse model, we found that the increased mTOR signalling downstream of KPTN is rapamycin sensitive, highlighting possible therapeutic avenues with currently available mTOR inhibitors. These findings place KPTN-related disorder in the broader group of mTORC1-related disorders affecting brain structure, cognitive function and network integrity.</p

Control of Alzheimer's Amyloid Beta Toxicity by the High Molecular Weight Immunophilin FKBP52 and Copper Homeostasis in Drosophila

FK506 binding proteins (FKBPs), also called immunophilins, are prolyl-isomerases (PPIases) that participate in a wide variety of cellular functions including hormone signaling and protein folding. Recent studies indicate that proteins that contain PPIase activity can also alter the processing of Alzheimer's Amyloid Precursor Protein (APP). Originally identified in hematopoietic cells, FKBP52 is much more abundantly expressed in neurons, including the hippocampus, frontal cortex, and basal ganglia. Given the fact that the high molecular weight immunophilin FKBP52 is highly expressed in CNS regions susceptible to Alzheimer's, we investigated its role in Aβ toxicity. Towards this goal, we generated Aβ transgenic Drosophila that harbor gain of function or loss of function mutations of FKBP52. FKBP52 overexpression reduced the toxicity of Aβ and increased lifespan in Aβ flies, whereas loss of function of FKBP52 exacerbated these Aβ phenotypes. Interestingly, the Aβ pathology was enhanced by mutations in the copper transporters Atox1, which interacts with FKBP52, and Ctr1A and was suppressed in FKBP52 mutant flies raised on a copper chelator diet. Using mammalian cultures, we show that FKBP52 (−/−) cells have increased intracellular copper and higher levels of Aβ. This effect is reversed by reconstitution of FKBP52. Finally, we also found that FKBP52 formed stable complexes with APP through its FK506 interacting domain. Taken together, these studies identify a novel role for FKBP52 in modulating toxicity of Aβ peptides