Enhanced Gene Delivery Triggered by Dual pH/Redox Responsive Host-Guest Dimerization of Cyclooligosaccharide Star Polycations

A robust strategy is reported to build perfectly monodisperse star polycationscombining a trehalose-based cyclooligosaccharide (cyclotrehalan, CT) centralcore onto which oligoethyleneimine radial arms are installed. Thearchitectural perfection of the compounds is demonstrated by a variety ofphysicochemical techniques, including NMR, MS, DLS, TEM, and GPC. Key tothe strategy is the possibility of customizing the cavity size of the macrocyclicplatform to enable/prevent the inclusion of adamantane motifs. Theseproperties can be taken into advantage to implement sequential levels ofstimuli responsiveness by combining computational design, precisionchemistry and programmed host-guest interactions. Specifically, it is shownthat supramolecular dimers implying a trimeric CT-tetraethyleneimine starpolycation and purposely designed bis-adamantane guests are preorganizedto efficiently complex plasmid DNA (pDNA) into transfection-competentnanocomplexes. The stability of the dimer species is responsive to theprotonation state of the cationic clusters, resulting in dissociation at acidicpH. This process facilitates endosomal escape, but reassembling can takeplace in the cytosol then handicapping pDNA nuclear import. By equippingthe ditopic guest with a redox-sensitive disulfide group, recapturingphenomena are prevented, resulting in drastically improved transfectionefficiencies both in vivo and in vitro.Ministerio de Ciencia e Innovación y Agencia Estatal de Investigación, de España-MCIN/AEI/10.13039/501100011033Fondo Europeo de Desarrollo Regional de la Unión Europea-RTI2018-097609-B-C21, RTI2018-097609-B-C22, PID2019-105858RB-I00 y PID2020-118384GB-I00Junta de Andalucía-P20_0016

Identificación y determinación estructural de un sesquiterpeno de las hojas de Tessaria integrifolia Ruiz & Pav. y evaluación de su actividad Leishmanicida

Objetivos. Identificar y determinar la estructura del fitoconstituyente de hojas de Tessaria integrifolia Ruiz Pav con efecto leishmanicida. Materiales y métodos. Se preparó un extracto fluido de hojas de Tessaria integrifolia Ruiz Pav. que fue concentrado a extracto blando y se utilizó para evaluar la actividad leishmanicida en Mesocricetus auratus con leishmaniasis experimental, administrando vía intramuscular la dosis de 250 mg/kg del extracto blando por 15 días. El extracto fue fraccionado en columna cromatográfica de 45 cm, con un diámetro de 2,5 cm que contiene silicagel G-60, de 70-230 mesh (Sigma-Aldrich®), las nueve fracciones obtenidas fueron evaluadas sobre macrófagos infectados con Leishmania sp para determinar la fracción activa y aislar el compuesto activo, mediante separación, purificación y cristalización, siendo analizado por resonancia magnética nuclear (RMN) de 1H, 13C, y cromatografía líquida acoplada a espectroscopía de masas (LC/MS). Resultados. El extracto fluido de las hojas de Tessaria integrifolia Ruiz Pav. presenta actividad leishmanicida en Mesocricetus auratus y la fracción F8 es activa sobre macrófagos infectados a dosis de 14 μg/mL. Se elucidó en esa fracción un sesquiterpeno tipo eudesmano ((4aS, 5R,6R,8aR)-6-hidroxi-5,8a-dimetil-3- (1-metiletiliden) octahidronaftalen-2(1H)-ona), según análisis de RMN 1H, 13C, y LC/MS. Conclusiones. El extracto fluido de hojas de Tessaria integrifolia Ruiz Pav. presenta actividad leishmanicida sobre Mesocricetus auratus. La fracción F8 presenta actividad leishmanicida sobre macrófagos infectados a dosis de 14 μg/mL. Se elucidó en la fracción activa un sesquiterpeno tipo eudesmano según los análisis de RMN 1H, 13C, y LC/MS

Trifaceted Mickey Mouse Amphiphiles for Programmable Self-Assembly, DNA Complexation and Organ-Selective Gene Delivery

Instilling segregated cationic and lipophilic domains with an angular disposition in a trehalose-based trifaceted macrocyclic scaffold allows engineering patchy molecular nanoparticles leveraging directional interactions that emulate those controlling self-assembling processes in viral capsids. The resulting trilobular amphiphilic derivatives, featuring a Mickey Mouse architecture, can electrostatically interact with plasmid DNA (pDNA) and further engage in hydrophobic contacts to promote condensation into transfectious nanocomplexes. Notably, the topology and internal structure of the cyclooligosaccharide/pDNA co-assemblies can be molded by fine-tuning the valency and characteristics of the cationic and lipophilic patches, which strongly impacts the transfection efficacy in vitro and in vivo. Outstanding organ selectivities can then be programmed with no need of incorporating a biorecognizable motif in the formulation. The results provide a versatile strategy for the construction of fully synthetic and perfectly monodisperse nonviral gene delivery systems uniquely suited for optimization schemes by making cyclooligosaccharide patchiness the focus.Peer reviewe

Profundización en metodologías y espacios docentes innovadores

Fac. de FilologíaFALSEsubmitte

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Shrubs influence arbuscular mycorrhizal fungi communities in a semi-arid environment

Interactions between arbuscular mycorrhizal fungi (AMF) and plants are essential components of ecosystem functioning; however, they remain poorly known in dry ecosystems. We examined the relationship between seven shrub species and their associated AMF community in a semi-arid plant community in southern Spain. Soil characteristics and plant physiological status were measured and related to AMF community composition and genetic diversity by multivariate statistics. We found differences in AMF communities in soils under shrubs and in gaps among them, whereas no differences were detected among AMF communities colonizing roots. Soil nutrients content drove most of the spatial variations in the AMF community and genetic diversity. AMF communities were more heterogeneous in fertile islands with low nitrogen-to-phosphorus ratio and vice versa. AMF genetic diversity increased in soils limited by phosphorus and with high soil organic matter content, while AMF genetic diversity increased in roots growing in soil not limited by phosphorus. Overall, we could not find a clear link between plant performance and the associated AMF community. Our findings show that different shrub species generate islands of fertility which differ in nutrient content and, therefore, support different AMF communities, increasing AMF diversity at the landscape level

Trifaceted Mickey Mouse Amphiphiles for Programmable Self‐Assembly, DNA Complexation and Organ‐Selective Gene Delivery

Instilling segregated cationic and lipophilic domains with an angular disposition in a trehalose-based trifaceted macrocyclic scaffold allows engineering patchy molecular nanoparticles leveraging directional interactions that emulate those controlling self-assembling processes in viral capsids. The resulting trilobular amphiphilic derivatives, featuring a Mickey Mouse architecture, can electrostatically interact with plasmid DNA (pDNA) and further engage in hydrophobic contacts to promote condensation into transfectious nanocomplexes. Notably, the topology and internal structure of the cyclooligosaccharide/pDNA co-assemblies can be molded by fine-tuning the valency and characteristics of the cationic and lipophilic patches, which strongly impacts the transfection efficacy in vitro and in vivo. Outstanding organ selectivities can then be programmed with no need of incorporating a biorecognizable motif in the formulation. The results provide a versatile strategy for the construction of fully synthetic and perfectly monodisperse nonviral gene delivery systems uniquely suited for optimization schemes by making cyclooligosaccharide patchiness the focus.Peer reviewe

Anuario del Centro de Estudios Martianos (Vol. 1 1978)

El Anuario del Centro de Estudios Martianos es la publicación insignia de esta institución y heredera directa del Anuario Martiano de la Biblioteca Nacional José Martí, que se publicó entre 1969 y 1977, bajo la dirección del poeta y ensayista Cintio Vitier. Desde que salió a la luz su primera entrega, en 1978, se han publicado treinta y cinco números, en los que aparecen artículos y ensayos de importantes estudiosos de la vida y obra del Apóstol, en Cuba y el resto del mundo. En sus secciones fijas (Otros textos de José Martí, Documentos, Estudios y aproximaciones, Vigencias, Publicaciones, Bibliografía, Constante) y los apartados especiales, los lectores pueden conocer disímiles temas del quehacer martiano internacional, en el año que termina además de mantenerse al tanto de las últimas contribuciones de los promotores e investigadores de la obra martiana en el orbe