SK Channel Modulators as Drug Candidates and Pharmacological Tools

The small- and intermediate-conductance Ca2+ activated K + (SK/IK) channels play a fundamental role in the regulation of neurons in the central nervous system. In animal models, SK/IK channel positive modulators have been shown to be effective in reducing the symptoms of neurological diseases such as ataxia. Ataxia is a lethal neurological rare disease characterized by lack of balance and incoordination of muscle movements, often as a result of cerebellar or spinocerebellar neurodegeneration. SK/IK channel modulators have been developed over the past few decades. Currently available modulators are often weak in potency. Lack of knowledge about the binding site for the compounds is the main reason hindering the development of more potent and effective therapeutics targeting SK channels. Dr. Zhang and his colleagues recently discovered the binding pocket for these positive modulators of SK/IK channels. This pocket is located at the interface between the channel and calmodulin. Dr. Zhang and his colleagues performed screening of a large number of compounds in silico, to find those fitting into the binding pocket. I performed electrophysiological recordings to evaluate the efficacy and the potency of these modulators on SK2 channels. We discovered a correlation between the total binding energy values calculated from the structures and the potencies determined from electrophysiological recording

Genetic Mutations of K\u3csub\u3eCa\u3c/sub\u3e2.3 and K\u3csub\u3eCa\u3c/sub\u3e3.1 Channels Affect Ca2+ Sensitivity

The Ca2+-activated potassium channels KCa channels are a unique family of potassium channels activated by intracellular calcium. KCa channels are critical for maintaining K+ homeostasis and modulate several physiological processes, from the firing properties of neurons to the control of the transmitter release. The Ca2+ sensitivity of these channels allows intracellular Ca2+ to regulate the electrical activity of the cell membrane. Increased Ca2+ sensitivity of KCa channels caused by gain of function mutations (GOF) in the KCNN genes results in a broad spectrum of human channelopathies, including Zimmermann- Laband syndrome (ZLS), idiopathic non-cirrhotic portal hypertension (INCPH), and hereditary xerocytosis (HX). The impact of dysfunctional KCa2.3/KCa3.1 channels on human health has not been well documented. In this dissertation, I used inside-out patch clamp recordings to measure the apparent Ca2+ sensitivity of KCa2.3 and KCa3.1 heterologously expressed in HEK293 cells. Wild-type KCa2.3 channels have a Ca2+ EC50 value of ∼0.3 μM, while the apparent Ca2+ sensitivity of wild-type KCa3.1 channels is ∼0.27 μM. The equivalent mutations related to the ZLS and INCPH in the S45A/S45B helices increased the apparent Ca2+ sensitivity of both KCa2.3 & KCa3.1 channel subtypes. However, the equivalent mutations related to the HX in HA/HB helices of KCa2.3 and KCa3.1 affected their apparent Ca2+ sensitivity differently. AP14145 reduced the apparent Ca2+ sensitivity of the hypersensitive mutant KCa2.3 channels. The results of my Ph.D. project would suggest the potential therapeutic usefulness of negative gating modulators as a novel target in these channelopathy-causing mutations. At the same time would guide us to design more potent and subtype-selective positive modulators targeting these channels

Tragic Choices: Autonomy and Emotional Responses to Medical Decisions

We investigate how making highly consequential, highly undesirable decisions affects emotions and preference for autonomy. We examine individuals facing real or hypothetical decisions to discontinue their infants' life support who either choose personally or have physicians choose for them. Findings from a multidisciplinary approach consisting of a qualitative analysis of in-depth interviews and three laboratory studies reveal that perceived personal causality for making tragic decisions generates more negative feelings than having the same choices externally made. Tragic decisions also undermine coping abilities, weakening the desire for autonomy. Consequently, participants disliked making decisions but also resented relinquishing their option to choose

Aspectos sociales y espirituales de los sefardíes de Ragusa a través de la documentación testamentaria (siglos XVI-XVI)

In this study, we will learn about the spiritual life and religious attitudes of the Sephardim of Ragusa, during the sixteenth and seventeenth centuries, by examiningJewish wills preserved in the Historical Archives of Dubrovnik. These wills were drafted by Christian notaries and later deposited in the local registry. While some of the wills are lengthy and others succinct, they all attest to the importance of these bequests in their dual role as spiritual and economic documents. The bequests and legacies, with their emphasis on donations to charitable causes and on bringing order to one’s worldly possessions, reveal much about the donor’s social-spiritual world, about his economic status and his spiritual priorities. We learn, for example, about the importance of preserving unison within the family and about the special connection to the Land of Israel. Reflected as well in these documents is the influence of the Catholic cultural milieu.A partir de testamentos que se conservan en el Archivo Histórico de Dubrovnik, este estudio intenta dar a conocer aspectos de la vida espiritual y de la actitud religiosa de los sefardíes de Ragusa en los siglos XVI y XVI. Se trata de testamentos judíos, otorgados ante notarios cristianos que luego los consignan en el registro local. Aunque su extensión es desigual, confirman todos ellos la importancia del legado testamentario en su doble vertiente espiritual y económica. Las mandas y legados de carácter moral, asistencial y crematístico dejan entrever el mundo socio-espiritual de los causantes, su nivel económicco y sus prioridades espirituales así como la cohesión familiar y la relación con la Tierra de Israel, reflejando también la influencia del medio cultural católico circundante

De Iudaicis erroribus ex Talmut : tratado apologético de Jeronónimo de Santa Fe

Tesis Univ. Complutense. Madrid.ProQuestDepto. de Lingüística, Estudios Árabes, Hebreos y de Asia OrientalFac. de FilologíaTRUEpu

El testamento de Benveniste Nansi de Ragusa (1571) y su nulidad halájica según R. Samuel de Medina

This article deals with the appeal which took place to assess the validity of the will of the Jew Benveniste Nansi, a confessed murderer a co-religionist of the Sephardi community of Ragusa (Dubrovnik), who was sentenced to death and executed by the local Christian authorities. In this unique trial for murder among Jews in that small community, the will had been drawn up in the presence of a gentile scribe and the executioner, a circumstance that could make the will invalid from the point of view of halakhah. The appeal, which was judged by one of the illustrious Sephardi authorities of Thessaloniki, R. Samuel de Medina, demonstrates the application of the Hispano-Jewish method of Talmudic speculation and jurisprudence that he learned in the rabbinical schools of two of the eminent teachers expelled from Spain. It also casts light on his personal reasons for judging the will invalid, due to the negative image he had of both the Republic of Ragusa and its juridical and legal institutions.En el caso aquí tratado se estudia la impugnación del testamento del judío Benveniste Nansi, asesino confeso de otro correligionario suyo de la comunidad sefardí de Ragusa (Dubrovnik) y, sentenciado a la pena capital, fue ejecutado por las autoridades cristianas locales. En este único juicio de asesinato entre judíos en aquella pequeña comunidad, el testamento del reo fue redactado ante un escribano gentil y el verdugo, circunstancia que de por sí podría ilegitimar el testamento desde el punto de vista de la halajá. El análisis de la impugnación realizado por una de las ilustres autoridades sefardíes de Salónica, R. Samuel de Medina, demuestra no solo la aplicación del método de especulación talmúdica y jurisprudencial hispanohebrea que aprendió en las escuelas rabínicas de dos de los eminentes maestros de los expulsados de España, sino también sus razones personales para ilegitimar el testamento a causa y debido a la negativa imagen que tenía tanto de la república de Ragusa como de sus instituciones jurídicas y legales

Motives inhibitors of the use of Moodle in higher education teachers

El propósito de este estudio ha sido identificar cual son los principales motivos por los cuales los docentes no usan el Moodle o lo usan muy poco, con fines pedagógicos. Se ha realizado una encuesta a una población de 640 docentes, de una institución de educación superior técnico profesional de Chile. Entre los motivos identificados se destaca la falta de formación en la aplicación pedagógica de las herramientas que el Moodle presenta y la opinión común de que la principal utilidad de la plataforma es para el trabajo de gestión. Se concluye que el grado de uso de las TIC en el aula de clase, junto al manejo instrumental, responde a múltiple factores, entre los cuales destacamos las habilidades pedagógicas y la frecuencia de uso. Se evidencia la importancia de analizar el uso pedagógico del Moodle con foco multifactorial