Pentamidine Is Not a Permeant but a Nanomolar Inhibitor of the Trypanosoma brucei Aquaglyceroporin-2

The chemotherapeutic arsenal against human African trypanosomiasis, sleeping sickness, is limited and can cause severe, often fatal, side effects. One of the classic and most widely used drugs is pentamidine, an aromatic diamidine compound introduced in the 1940s. Recently, a genome-wide loss-of-function screen and a subsequently generated trypanosome knockout strain revealed a specific aquaglyceroporin, TbAQP2, to be required for high-affinity uptake of pentamidine. Yet, the underlying mechanism remained unclear. Here, we show that TbAQP2 is not a direct transporter for the di-basic, positively charged pentamidine. Even though one of the two common cation filters of aquaglyceroporins, i.e. the aromatic/arginine selectivity filter, is unconventional in TbAQP2, positively charged compounds are still excluded from passing the channel. We found, instead, that the unique selectivity filter layout renders pentamidine a nanomolar inhibitor of TbAQP2 glycerol permeability. Full, non-covalent inhibition of an aqua(glycero)porin in the nanomolar range has not been achieved before. The remarkable affinity derives from an electrostatic interaction with Asp265 and shielding from water as shown by structure-function evaluation and point mutation of Asp265. Exchange of the preceding Leu264 to arginine abolished pentamidine-binding and parasites expressing this mutant were pentamidine-resistant. Our results indicate that TbAQP2 is a high-affinity receptor for pentamidine. Taken together with localization of TbAQP2 in the flagellar pocket of bloodstream trypanosomes, we propose that pentamidine uptake is by endocytosis

EL INFIERNO AL REVÉS O EL INFIERNO DECADENTISTA EN «EL SUEÑO DE RAPIÑA» DE CARLOS REYLES

El decadentismo es un movimiento estético que surge a finales del siglo XIX en Francia y de allí se extiende a diversos países, incluidos los de América Latina. En la literatura, el decadentismo propone «invertir el orden», pervertir la forma y el contenido. Las obras decadentistas giran en torno a la metáfora del ocaso: el ocaso del día o del siglo, el ocaso de un personaje (fisiológico e intelectual) o de la sociedad y de sus Instituciones, por tanto, lo decadente está estrechamente relacionado con lo oscuro, lo macabro y lo abyecto. En este sentido, proponemos una relectura y reinterpretación del cuento «El sueño de Rapiña» del escritor modernista Carlos Reyles a fin de demostrar cómo se reelabora el tema de lo infernal, de la tentación y de la expiación desde la estética decadentista. Ello, no sin dejar de destacar la recurrencia de ciertos elementos descriptivos, como topois y cuadros de imágenes prototípicas del Infierno que contribuyen a la configuración del motivo del viaje al Averno y que, sin duda alguna, remiten al lector a las diferentes representaciones que la literatura griega, latina, medieval y renacentista han hecho del Infierno. ABSTRACT The Decadent Movement was a late 19th- century aesthetic movement flourished in France which spread out to different countries, including some of Latin America. In the literature, the Decadent Movement suggests «to invert the order», «to distort shape and content». Decadent papers revolve around the metaphor of the sunset: the sunset of the day or of the century, the sunset of a character (physiologically and intellectually speaking) or the sunset of the society and its institutions, therefore, the Decadent feature is intimately related to darkness, death and vileness. In this sense, we pose a rereading and a reinterpretation of the story El sueño de Rapiña of the Modernist writer Carlos Reyles to demonstrate how the infernal feature, the temptation and the expiation are reformulated from the Decadent aesthetics’ point of view, always taking into account and highlighting the recurrence of some descriptive elements like topois and some pictures of prototypical images of hell which contribute to the configuration of the reason of the travel to the Avernus and which, without any question, guide readers to the different representations that Greek, Latin, Medieval and Renaissance Literatures have done of Hell.&nbsp

Corrección en el artículo de B. Vera et al. « Un portal de cálculo para la evaluación de la vulnerabilidad sísmica de estructuras aporticadas mediante elementos finitos »

Peer Reviewe

Un portal de cálculo para la evaluación de la vulnerabilidad sísmica de estructuras aporticadas mediante elementos finitos

This paper describes a computing portal called “Portal de Pórticos” that contain a finite element program for the dynamic, nonlinear analysis of framed reinforced concrete structures. The program is based on Lumped Damage Mechanics which describes the behaviour of this type of structure. To access the “Portal de Pórticos” it is only necessary to have a personal computer with Internet connection through a commercial browser (explorer, Mozilla firefox, etc). To show the accuracy in the results of the program Portal de Pórticos, some numerical simulations of experimental tests are presented

Síntesis y caracterización de los derivados N-carbamoilo e hidantoina de la L-prolina.

CONTENIDO Editorial La posición de Venezuela en el Ranking Iberoamericano de Instituciones de Investigación en el área de química. Lárez Velásquez, Cristóbal Artículos científicos Síntesis y caracterización de los derivados N-carbamoilo e hidantoina de la L-prolina. Seijas, Luis E.; Delgado, Gerzon; Mora, Asiloé J.; Bahsas B., Alí H. y Uzcátegui, Jorge Nueva estrategia de síntesis del 2-amino-1-ciclopentencarboditioato de propilo y de los proligandos derivados tipo [N2S2]2- Contreras, Ricardo Rafael; Fontal, Bernardo; Bahsas B., Alí H.; Reyes, Marisela del C.; Bellandi, Fernando; Suárez B., Trino; Romero C., Isolda; Contreras, A. y Cancines, Pedro I. Artículos divulgativos Quitina y quitosano: materiales del pasado para el presente y el futuro. Lárez Velásquez, Cristó[email protected]@[email protected]@ula.veNivel analíticosemestra

Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance.

We report that eight heterozygous missense mutations in TUBB3, encoding the neuron-specific beta-tubulin isotype III, result in a spectrum of human nervous system disorders that we now call the TUBB3 syndromes. Each mutation causes the ocular motility disorder CFEOM3, whereas some also result in intellectual and behavioral impairments, facial paralysis, and/or later-onset axonal sensorimotor polyneuropathy. Neuroimaging reveals a spectrum of abnormalities including hypoplasia of oculomotor nerves and dysgenesis of the corpus callosum, anterior commissure, and corticospinal tracts. A knock-in disease mouse model reveals axon guidance defects without evidence of cortical cell migration abnormalities. We show that the disease-associated mutations can impair tubulin heterodimer formation in vitro, although folded mutant heterodimers can still polymerize into microtubules. Modeling each mutation in yeast tubulin demonstrates that all alter dynamic instability whereas a subset disrupts the interaction of microtubules with kinesin motors. These findings demonstrate that normal TUBB3 is required for axon guidance and maintenance in mammals