Liposomal Drug Delivery to the Central Nervous System

Central nervous system diseases represent a huge world of burden of human suffering with negative economic results. Most therapeutic compounds cannot attain the brain because of the blood-brain barrier and its expression of efflux transporters. Among them, the P-glycoprotein plays a significant role leading to failure of various clinical treatments. A non-invasive strategy to circumvent the blood-brain barrier and P-glycoprotein emphasizes on the encapsulation and therefore masking of therapeutic compounds in drug delivery systems. Up to now, liposomes are the most widely studied drug delivery systems due to their biocompatibility, biodegradability, and less toxicity. The incorporation of polyethylene glycol-lipid derivatives within the bilayer of conventional liposomes significantly prolongs liposomal cargo half-life by steric stabilization. Interestingly, an increased brain accumulation of liposomal cargo is achieved by coupling targeting moieties on liposomes surface. These targeting moieties such as peptides or monoclonal antibodies recognize the biochemical transport systems at the blood-brain barrier and mediate the transport of liposomes and their cargo across this barrier. Moreover, stimuli-sensitive liposomes are programmed for cargo release when exposed to a particular microenvironment. Hence, this chapter highlights the potential liposomal applications for delivery of therapeutic compounds as well as diagnostic tools or both, in major central nervous system diseases

La gobernabilidad democrática global y las reformas de algunas instituciones internacionales

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Vectorisation de molécules thérapeutiques aux tissus cérébraux

Although the P-glycoprotein (P-gp) represents an obstacle in several central nervous system (CNS) pharmacotherapies, the P-gp also protects the brain from intoxication by endogenous and exogenous harmful lipophilic compounds that otherwise could penetrate the blood-brain barrier (BBB) by simple diffusion. Therefore, any modulation of the efflux transporter has to consider the potential neurotoxicity of such modulation. Early studies showed that elacridar and tariquidar, two third-generation P-gp modulators, increase the distribution of several P-gp substrates in the brain. Unfortunately, recent studies suggest the use of high doses of elacridar and tariquidar to efficiently modulate the P-gp at the BBB. Nevertheless, when co-administered with P-gp substrates, these high doses may be associated with pharmacokinetic interactions and toxic profiles, thus limiting the use of these compounds.Hence, this thesis aimed to attain a transient but efficient modulation of the P-gp at the BBB using elacridar and tariquidar but avoiding the use of large doses of these compounds. For this purpose we took advantage of the possible in vivo intravenous co-administration of low but therapeutic doses of elacridar and tariquidar, under their free form or co-encapsulated in liposomes. The brain distribution of free loperamide was determined as an in vivo probe of full inhibition of the P-gp activity at the BBB.The concurrent administration of both free P-gp modulators does not modify their plasma concentrations or those of the P-gp substrate but significantly increased the brain uptake of loperamide as a result of their non-competitive modulatory activity. Moreover, the co-encapsulation of elacridar and tariquidar in targeted sterically stabilized immunoliposomes improved the half-lives and brain distribution of both compounds. Consequently, the brain uptake of free loperamide was significantly enhanced without any modification of its pharmacokinetics or tissue distribution. Moreover, the partial impairment of the modulatory activity of tariquidar by empty liposomes, supports the use of this nanocarrier as a bio-detoxifying approach for the treatment of tariquidar overdoses.In summary, this thesis proposes different approaches for full exploitation of elacridar and tariquidar. The findings described in this manuscript should open interesting avenues to achieve an efficient overcoming of the P-gp at the BBB and succeed CNS pharmacotherapies.La présence de la glycoprotéine P (P-gp) dans la barrière hémato-encéphalique (BHE) conduit à l’échec de nombreuses thérapies ciblant le système nerveux central (SNC). Cependant la P-gp protège aussi le cerveau contre des composés nocifs, essentiellement lipophiles, endogènes et exogènes susceptibles de passer la BHE par diffusion simple. Par conséquent, toute inhibition de la P-gp qui vise à améliorer la distribution des agents pharmacologiques dans le cerveau doit prendre en compte la neurotoxicité potentielle de cette inhibition. Les premiers travaux ont montré que l’elacridar et le tariquidar, deux modulateurs de la P-gp de troisième génération, augmentaient la distribution dans le cerveau de plusieurs de ses substrats. Malheureusement, d’autres études plus récentes, suggèrent l’utilisation de doses élevées de l’elacridar et du tariquidar pour moduler efficacement l’activité de la P-gp dans la BHE. Néanmoins, ces doses élevées en co-administration avec des substrats de la P-gp peuvent être associées à des interactions pharmacocinétiques et à des profils toxiques, limitant ainsi l'utilisation de ces inhibiteurs.Dans ce contexte, l’objectif principal de cette thèse est d’obtenir une modulation transitoire mais efficace de la P-gp dans la BHE par administration intraveineuse de doses faibles mais thérapeutiques de l’elacridar et du tariquidar sous leur forme libre ou co-encapsulé dans les liposomes. Le lopéramide, substrat de la P-gp, a été également administré sous sa forme libre comme une preuve in vivo d’une inhibition efficace de la P-gp dans la BHE.L'administration simultanée de ces deux modulateurs de la P-gp n’a pas modifié leurs concentrations plasmatiques ou celles du lopéramide, mais a entraîné une importante distribution du lopéramide dans le cerveau en raison de leur activité inhibitrice non- compétitive. De plus, la co-encapsulation de l’elacridar et du tariquidar dans des immunoliposomes stabilisées stériquement a amélioré la demi-vie et la distribution dans le cerveau des ceux deux composés. Par conséquent, la distribution dans le cerveau du lopéramide a été considérablement augmentée, sans aucune modification de sa pharmacocinétique ou distribution tissulaire. Par ailleurs, la diminution partielle de l'activité inhibitrice du tariquidar par des liposomes vides suggère l’utilisation de ce nanovecteur comme une approche de bio-détoxification pour le traitement des surdoses de tariquidar. En résumé, cette thèse propose différentes approches pour exploiter pleinement l’elacridar et le tariquidar. Les résultats décrits dans ce manuscrit devraient ouvrir des pistes intéressantes pour atteindre une inhibition efficace de la P-gp dans la BHE et pour réussir des thérapies ciblant le système nerveux centra

Monedas virtuales y locales: las paramonedas, ¿nuevas formas de dinero?

Artículo de revistaEl fenómeno de las monedas virtuales y locales, a las que denominaremos en este trabajo «paramonedas», no es nuevo. Sin embargo, en los últimos años los nuevos avances tecnológicos han favorecido su desarrollo y extensión a escala global. Esta creciente expansión y su potencial efecto sustitutivo del dinero han originado que los reguladores y los supervisores hayan comenzado a prestar una especial atención a ambas figuras. En la actualidad, a pesar de las pretensiones sustitutorias del dinero que pudieran tener inicialmente, ni cabe considerarlas dinero, ni es previsible que en un futuro vayan a reemplazarlo. No obstante, la creciente popularidad de las paramonedas podría conducir a un aumento de los riesgos para el sistema financiero. Por el momento, los riesgos identificados en relación con la estabilidad del sistema financiero son limitados, como consecuencia de su reducido tamaño y escasa conexión con él. Sin embargo, los riesgos para los consumidores no son nada desdeñables, incluso en un ámbito de utilización limitado como el actual. Los esfuerzos de los supervisores y de los reguladores se centran hasta la fecha en la evaluación del fenómeno y en el seguimiento de dichos riesgos, con el objetivo de valorar la adopción de medidas enfocadas a mitigarlos, así como la conveniencia o no de desarrollar un marco normativo específico para las paramonedas

Rethinking the Xylella fastidiosa scenario in the Balearic Islands: what epidemiological, phylogenetic and dendrochronological data tell us

Trabajo presentado en la 2nd European conference on Xylella fastidiosa (how research can support solutions), celebrada en Ajaccio el 29 y 30 de octubre de 2019.The emergence of Xylella fastidiosa(Xf) in Europe has been dealt as relatively recent introductions from the American continent. While this seems accurate for highly virulent genotypes such as thestrain currently causing the quick olive decline syndrome in Apulia since ca. 2013, less virulent Xf genotypes might have gone undetected for a long time, being confused with drought or fungal disease symptoms under Mediterranean climatic conditions. Indeed, the current widespread incidence and severity of the Pierce’s disease (PD) and Almond Leaf Scorch Disease (ALSD) in Mallorca Island can only be understood in this context of a 20-year introduction scenario. Our current epidemiological, phylogenetic anddendrochronological data onXf strains belonging to subsp. fastidiosaST1, and Xf subsp. multiplexST81, causing Pierce’s disease (PD) and ALSD, respectively, strongly suggest that they were overlooked for decades. Both subspecies were very likely transported from California to Mallorca with infected almond scions around 1995 and subsequently spread throughout the island by the local vector Philaenus spumarius. Our phylogenetic analysis based on WGS of isolates of both subspecies from Mallorca supports their Californian origin. Congruent with this, Xf DNA was consistently detected in the growing rings of infected almond trees from 2006 to the present and occasionally as far back as 1998. In the main focus in Son Carrió more than 50% of the almond trees diedand 90% of trees showed symptoms compatible with ALSD in 2012, but the aetiology of this problem was attributed to fungal trunk diseases, drought or field abandonment. We hypothesise that during the last 20 years, Xf subsp. multiplexST81 isolates have adapted to wild olive trees, widespread on the island, causing a mild dieback, and later on reaching the island of Menorca very likely on infected P. spumariustransported as a hitchhiker on ships moving between the islands.This research was funded by project E-RTA2017-00004-C06 from AEI-INIA Spain and FEDER and received financial support from the Ministry of Agriculture, Fishery and Food (Dirección General de la Sanidad de la Producción Agrària) of Spain and from ‘Govern de les Illes Balears’

Continuous Cultivation as a Tool Toward the Rational Bioprocess Development With Pichia Pastoris Cell Factory

The methylotrophic yeast Pichia pastoris (Komagataella phaffii) is currently considered one of the most promising hosts for recombinant protein production (RPP) and metabolites due to the availability of several tools to efficiently regulate the recombinant expression, its ability to perform eukaryotic post-translational modifications and to secrete the product in the extracellular media. The challenge of improving the bioprocess efficiency can be faced from two main approaches: the strain engineering, which includes enhancements in the recombinant expression regulation as well as overcoming potential cell capacity bottlenecks; and the bioprocess engineering, focused on the development of rational-based efficient operational strategies. Understanding the effect of strain and operational improvements in bioprocess efficiency requires to attain a robust knowledge about the metabolic and physiological changes triggered into the cells. For this purpose, a number of studies have revealed chemostat cultures to provide a robust tool for accurate, reliable, and reproducible bioprocess characterization. It should involve the determination of key specific rates, productivities, and yields for different C and N sources, as well as optimizing media formulation and operating conditions. Furthermore, studies along the different levels of systems biology are usually performed also in chemostat cultures. Transcriptomic, proteomic and metabolic flux analysis, using different techniques like differential target gene expression, protein description and 13 C-based metabolic flux analysis, are widely described as valued examples in the literature. In this scenario, the main advantage of a continuous operation relies on the quality of the homogeneous samples obtained under steady-state conditions, where both the metabolic and physiological status of the cells remain unaltered in an all-encompassing picture of the cell environment. This contribution aims to provide the state of the art of the different approaches that allow the design of rational strain and bioprocess engineering improvements in Pichia pastoris toward optimizing bioprocesses based on the results obtained in chemostat cultures. Interestingly, continuous cultivation is also currently emerging as an alternative operational mode in industrial biotechnology for implementing continuous process operations

A review of deep learning applications for the next generation of cognitive networks

Intelligence capabilities will be the cornerstone in the development of next-generation cognitive networks. These capabilities allow them to observe network conditions, learn from them, and then, using prior knowledge gained, respond to its operating environment to optimize network performance. This study aims to offer an overview of the current state of the art related to the use of deep learning in applications for intelligent cognitive networks that can serve as a reference for future initiatives in this field. For this, a systematic literature review was carried out in three databases, and eligible articles were selected that focused on using deep learning to solve challenges presented by current cognitive networks. As a result, 14 articles were analyzed. The results showed that applying algorithms based on deep learning to optimize cognitive data networks has been approached from different perspectives in recent years and in an experimental way to test its technological feasibility. In addition, its implications for solving fundamental challenges in current wireless networks are discussed

Specific growth rate governs AOX1 gene expression, affecting the production kinetics of Pichia pastoris (Komagataella phaffii) P-driven recombinant producer strains with different target gene dosage

The P-based expression system is the most widely used for producing recombinant proteins in the methylotrophic yeast Pichia pastoris (Komagataella phaffii). Despite relevant recent advances in regulation of the methanol utilization (MUT) pathway have been made, the role of specific growth rate (µ) in AOX1 regulation remains unknown, and therefore, its impact on protein production kinetics is still unclear. The influence of heterologous gene dosage, and both, operational mode and strategy, on culture physiological state was studied by cultivating the two P-driven Candida rugosa lipase 1 (Crl1) producer clones. Specifically, a clone integrating a single expression cassette of CRL1 was compared with one containing three cassettes over broad dilution rate and µ ranges in both chemostat and fed-batch cultivations. Chemostat cultivations allowed to establish the impact of µ on the MUT-related MIT1 pool which leads to a bell-shaped relationship between µ and P-driven gene expression, influencing directly Crl1 production kinetics. Also, chemostat and fed-batch cultivations exposed the favorable effects of increasing the CRL1 gene dosage (up to 2.4 fold in q ) on Crl1 production with no significant detrimental effects on physiological capabilities. P-driven gene expression and Crl1 production kinetics in P. pastoris were successfully correlated with µ. In fact, µ governs MUT-related MIT1 amount that triggers P-driven gene expression-heterologous genes included-, thus directly influencing the production kinetics of recombinant protein

Formulación y evaluación in vitro de un sistema conjugado "quitosano - enrofloxacino" como alternativa en el tratamiento de endometritis subclínica en vacas

La endometritis, inflamación del endometrio usualmente debido a la persistencia de una infección o al retraso en la involución uterina, es uno de los principales factores que afectan la eficiencia reproductiva del vacuno lechero retrasando el retorno de la vaca en sus actividades reproductivas. En ausencia de signos clínicos de endometritis, las modificaciones del endometrio uterino pueden ser definidas como endometritis subclínicas (ES) que se caracterizan por la presencia y aumento de Polimorfo Nucleares Neutrófilos (PMN) en el lumen uterino sin descargas purulentas.Trabajo de investigació

¿COVID-19 la pandemia y que sabemos de ella? Y como la afronta el Perú.

The novel coronavirus disease 2019 or COVID-19, had been reported for the first time in December 2019, in Wuhan China. To date, around 6 777 435 cases of COVID-19 were confirmed and 395 597 deaths worldwide. The COVID-19 outbreak is the largest in the past decades and is caused by a newly discovered coronavirus (SARS-CoV-2). On March 11th, 2020, the world Health Organization (WHO) has declared the COVID-19 a “Pandemic” with high rate of morbidity and mortality. This review synthesizes the scientific evidence and reports in the literature. The content of this manuscript presents the opinions of specialists and we present our interpretation and recommendations to the Peruvian government.La enfermedad del coronavirus o COVID-19, fue reportada por la primera vez en diciembre del 2019, en la ciudad de Wuhan China. A la fecha más de 6 777 435 casos de COVID-19 y 395 597muertes han sido reportadas globalmente. El brote del COVID-19 es causado por el virus SARS-CoV-2, siendo el brote más grande de las últimas décadas. Por lo cual la Organización Mundial de Salud (OMS) declaró al COVID-19 como pandemia (marzo 11, 2020), asociada con una importante morbilidad y mortalidad. Esta síntesis bibliográfica recapitula las evidencias científicas y los reportes publicados en revistas médicas. El contenido de este manuscrito recoge las opiniones y experiencias de especialistas. Y presentamos nuestra interpretación y recomendaciones a gobierno peruano