This essay analyzes why John Gower set the "Tale of the Three Questions," the concluding story in Book I of the Confessio Amantis, in Spain. Written during a time of intense parliamentary concerns over money apparently wasted by Richard II's uncles on military campaigns against Castille-Leon, the tale argues tar the relevance of Spain to England and for the relevance of poetic counsel in domestic politics. The question of Spain in English politics in the 1380s offered Gower a way into debates among the magnates and parliaments of England by evoking past and present Anglo-Castilian relationships. He imagines a situation in which the strategy of good counsel works, suggesting a more acceptable set of choices: alliance and realignment instead of the absolutism of either conquest or avoidance.
Defining the principles that apply to resolving conflicts between individuals in The Wife of Bath 's Tale and comparing them to parallel conflicts in Gower's "Tale of Florent," one discovers that The Wife of Bath 's Tale foregrounds appeals to political, social, religious, and ethical authority -all of which are questioned, discussed, and negotiated. In the "Tale of Florent," on the other hand, conflict tends to be internal rather than between individuals. Florent's conflicts are resolved by himself alone thinking about the obligations he has accepted in his various covenants, and then behaving in such a way that he does not lie or cheat or break his pledge. Conflict resolution in Gower depends upon absolute commitment to principle, the culturally sanctioned rules that govern human behavior. Conflicts in the "Tale of Florent" are not resolved through argument, debate, negotiation with an adversary as in Chaucer's text.
This article explores the connections between the views of Love and Fortune in the Confessio Amantis and in works by Guillaume de Machaut. lt demonstrates Machaut's anti-Boethian views that the worthy lover may escape Fortune's control through the exercise of virtue and applies those views to Gower's presentation of both love and political fortunes. In the Prologue and Book I, in particular, Gower establishes Love and Fortune as essentially interchangeable, preparing the reader to understand each as the product of reciprocal relationships between people, rather than the result of Fortune or Love capriciously turning a wheel. The Confessio thus aims to enable readers to adopt virtuous behaviors, not to court love but rather to court good fortune more broadly.
In each instance that John Gower uses the term "Saracen" in his Confessio Amantis to characterize the enemies of Christendom, Juan de Cuenca' s prose Castilian translation, the Confisyon del Amante, employs alternative language -language that predominantly downplays rather than exacerbates scenes of religious conflict. This essay analyzes these divergent representations of difference to argue that such comparative analysis of English and Spanish texts makes legible each writer's differing investments in narratives of Christianity's violence and pacifism, its anxieties about its religious neighbors and its belief in its own triumphant ascendancy. Understanding the interpretive nuances of these differences between Gower and Cuenca carries implications for our understanding of the political, historical, and literary transactions between England and Castile and Leon in the late middle ages.
DREAM, a neuronal calcium sensor protein, has multiple cellular roles including the regulation of Ca2+ and protein homeostasis. We recently showed that reduced DREAM expression or blockade of DREAM activity by repaglinide is neuroprotective in Huntington's disease (HD). Here we used structure-based drug design to guide the identification of IQM-PC330, which was more potent and had longer lasting effects than repaglinide to inhibit DREAM in cellular and in vivo HD models. We disclosed and validated an unexplored ligand binding site, showing Tyr118 and Tyr130 as critical residues for binding and modulation of DREAM activity. IQM-PC330 binding de-repressed c-fos gene expression, silenced the DREAM effect on KV4.3 channel gating and blocked the ATF6/DREAM interaction. Our results validate DREAM as a valuable target and propose more effective molecules for HD treatment. ; PC was the recipient of a postgraduate FPI fellowship from the Spanish Ministry de Economy, Industry and Competitivity (MINECO). P.C. also thanks the Spanish Society of Therapeutic Chemistry (SEQT) for a Jassen-Cilag Award for young researchers (XVIII Edition, 2016). T.G. holds a Ramón y Cajal contract. D.A.P. holds a CSIC contract. This work was funded by the Spanish Ministery of Economy, Industry and Competitivity (AEI-FEDER, EU grants): BFU2015-67284-R (to M.G.R., R.H.), SAF2017-89554-R (to J.R.N.), SAF2016-75021-R (to C.V.) and SAF2015-66275-C2-2-R (to M.M.M.); the Instituto de Salud Carlos III CIBERNED and CIBERCV programs (to J.R.N. and to C.V., respectively) and the Madrid regional government/Neurodegmodels (to J.R.N.); CSIC grant PIE201880E109 (to M.G.R., R.H. and M.M.M.) and PIE201820E104 (to C.V.). ; Peer reviewed
Downstream Regulatory Element Antagonist Modulator (DREAM)/KChIP3/calsenilin is a neuronal calcium sensor (NCS) with multiple functions, including the regulation of A-type outward potassium currents (I A). This effect is mediated by the interaction between DREAM and KV4 potassium channels and it has been shown that small molecules that bind to DREAM modify channel function. A-type outward potassium current (I A) is responsible of the fast repolarization of neuron action potentials and frequency of firing. Using surface plasmon resonance (SPR) assays and electrophysiological recordings of KV4.3/DREAM channels, we have identified IQM-266 as a DREAM ligand. IQM-266 inhibited the KV4.3/DREAM current in a concentration-, voltage-, and time-dependent-manner. By decreasing the peak current and slowing the inactivation kinetics, IQM-266 led to an increase in the transmembrane charge ( QKV4.3/DREAM ) at a certain range of concentrations. The slowing of the recovery process and the increase of the inactivation from the closed-state inactivation degree are consistent with a preferential binding of IQM-266 to a pre-activated closed state of KV4.3/DREAM channels. Finally, in rat dorsal root ganglion neurons, IQM-266 inhibited the peak amplitude and slowed the inactivation of I A. Overall, the results presented here identify IQM-266 as a new chemical tool that might allow a better understanding of DREAM physiological role as well as modulation of neuronal I A in pathological processes. ; PC was the recipient of a postgraduate FPI fellowship from the Spanish Ministry of Economy, Industry and Competitivity (MINECO). This work was funded by the Spanish Ministry of Economy, Industry and Competitivity (Ministerio de Economía y Competitividad; AEI-FEDER, EU grants): SAF2012-32209 and BFU2015-67284-R (to MG-R), SAF2014-53412-R and SAF2017- 89554-R (to JN), SAF2013-45800-R, SAF2016-75021-R (to CV) and SAF2015-66275-C2-2-R (to MM-M); Universidad Complutense de Madrid (UCM) grant: PR75/18-21593 (to AA); the Instituto de Salud Carlos III CIBERNED and CIBERCV programs (to JN and to CV, respectively) and the Madrid regional government/Neurodegmodels (to JN); Consejo Superior de Investigaciones Científicas (CSIC) grants: PIE 201820E104 (to CV) and 201880E109 (to MG-R and MM-M). ; We acknowledge support of the publication fee by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI). ; Peer reviewed
Deregulated protein and Ca2+ homeostasis underlie synaptic dysfunction and neurodegeneration in Huntington disease (HD); however, the factors that disrupt homeostasis are not fully understood. Here, we determined that expression of downstream regulatory element antagonist modulator (DREAM), a multifunctional Ca2+-binding protein, is reduced in murine in vivo and in vitro HD models and in HD patients. DREAM downregulation was observed early after birth and was associated with endogenous neuroprotection. In the R6/2 mouse HD model, induced DREAM haplodeficiency or blockade of DREAM activity by chronic administration of the drug repaglinide delayed onset of motor dysfunction, reduced striatal atrophy, and prolonged life span. DREAM-related neuroprotection was linked to an interaction between DREAM and the unfolded protein response (UPR) sensor activating transcription factor 6 (ATF6). Repaglinide blocked this interaction and enhanced ATF6 processing and nuclear accumulation of transcriptionally active ATF6, improving prosurvival UPR function in striatal neurons. Together, our results identify a role for DREAM silencing in the activation of ATF6 signaling, which promotes early neuroprotection in HD. ; A. De la Cruz holds a RECAVA contract, A. Prieto and P. Cercós hold FPI fellowships, and T. González holds a Ramón y Cajal contract. J. Casado-Vela holds a JAE-DOC (CSIC) from the Spanish Ministerio de Economía y Competitividad (MINECO), cofunded by the European Social Fund. This work was funded by the Instituto de Salud Carlos III/CIBERNED (to J.R. Naranjo, B. Mellström, and A. Rábano), FISS-RIC RD12/0042/0019 (to C. Valenzuela), Madrid regional government/Neurodegmodels (to J.R. Naranjo), MINECO grants SAF2010-21784 and SAF2014-53412-R (to J.R. Naranjo), SAF2012-32209 (to M. Gutierrez-Rodriguez), SAF2010-14916 and SAF2013-45800-R (to C. Valenzuela), and a grant from the Swedish Research Council (J.Y. Li). ; Peer Reviewed
