eEF1A mediates the nuclear export of SNAG-containing proteins via the exportin5-aminoacyl-tRNA complex

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivative Works License.Exportin5 mediates the nuclear export of double-stranded RNAs, including pre-microRNAs, adenoviral RNAs, and tRNAs. When tRNAs are aminoacylated, the Exportin5-aminoacyl (aa)-tRNA complex recruits and coexports the translation elongation factor eEF1A. Here, we show that eEF1A binds to Snail transcription factors when bound to their main target, the E-cadherin promoter, facilitating their export to the cytoplasm in association with the aa-tRNA-Exportin5 complex. Snail binds to eEF1A through the SNAG domain, a protein nuclear export signal present in several transcription factor families, and this binding is regulated by phosphorylation. Thus, we describe a nuclear role for eEF1A and provide a mechanism for protein nuclear export that attenuates the activity of SNAG-containing transcription factors. © 2013 The Authors.This work was supported by grants from the Spanish Ministry of Science and Innovation (SAF2010-21143 to A.C.; BFU2008-01042 and CONSOLIDER-INGENIO 2010 CSD2007-00023 to M.A.N.; and CDS2007-00017 to A.C. and M.A.N.’s lab) and the Generalitat Valenciana (Prometeo 2008/049 and PROMETEOII/2013/002 to M.A.N.).Peer Reviewe

Snail blocks the cell cycle and confers resistance to cell death

The Snail zinc-finger transcription factors trigger epithelial-mesenchymal transitions (EMTs), endowing epithelial cells with migratory and invasive properties during both embryonic development and tumor progression. During EMT, Snail provokes the loss of epithelial markers, as well as changes in cell shape and the expression of mesenchymal markers. Here, we show that in addition to inducing dramatic phenotypic alterations, Snail attenuates the cell cycle and confers resistance to cell death induced by the withdrawal of survival factors and by pro-apoptotic signals. Hence, Snail favors changes in cell shape versus cell division, indicating that with respect to oncogenesis, although a deregulation/increase in proliferation is crucial for tumor formation and growth, this may not be so for tumor malignization. Finally, the resistance to cell death conferred by Snail provides a selective advantage to embryonic cells to migrate and colonize distant territories, and to malignant cells to separate from the primary tumor, invade, and form metastasis

eEF1A Mediates the Nuclear Export of SNAG-Containing Proteins via the Exportin5-Aminoacyl-tRNA Complex

Erratum: (Cell Reports 5, 727–737; November 14, 2013) In this article, the two lanes in Figure 4E were inadvertently used twice when making the composite. The correct version of Figure 4 appears her

Sequential Induction of Chirality in Helical Polymers: From the Stereocenter to the Achiral Solvent

This is the Accepted Manuscript version of a Published Work that appeared in final form in The Journal of the Physical Chemistry Letters, Copyright © 2018 American Chemical Society after peer review and technical edityng by the publisher. To access the final edited and published work see: https://pubs.acs.org/doi/10.1021/acs.jpclett.8b00519Several steps of chiral induction have been detected in poly(phenylacetylene)s among their different hierarchical levels of chirality by vibrational circular dichroism, namely, (i) from the stereogenic centers to the innermost polyacetylene helical covalent backbone (helixint), (ii) from this to the external helix (helixext) formed by the side phenyl pendants that form a complementary helix or counter-helix, and (iii) from this pendant helix to the helical solvation sphere (helixsolv.), the last one being observed along this work. The pendant to polyene backbone chiral induction determines the helical structure adopted by the polymer and therefore the solvation helix. This helical structure is promoted by two mechanisms: steric effects and hydrogen bonding. An important finding concerns the demonstration by VCD of how an achiral solvent becomes chirally organized owing to the template effect of the covalent polymer helices, an effect that is silent to other structural techniques such as ECD or AFM and that hence significantly broadens the scope of these previous analysesFinancial support from Ministerio de Ciencia e Innovación [CTQ2014-61470-EXP, CTQ2015- 69391-P, FPI (R. Rodríguez), FPU (S. Medina), Juan de la Cierva postdoctoral Fellowship FJCI- 2015-23531 (B.Nieto-Ortega)], Xunta de Galicia (GRC2014/040, Centro singular de investigación de Galicia accreditation 2016-2019, ED431G/09) and the European Regional Development Fund (ERDF) is gratefully acknowledgedS

Rac2 GTPase activation by angiotensin II is modulated by Ca2+/calcineurin and mitogen-activated protein kinases in human neutrophils

Angiotensin II (Ang II) highly stimulates superoxide anion production by neutrophils. The G-protein Rac2 modulates the activity of NADPH oxidase in response to various stimuli. Here, we describe that Ang II induced both Rac2 translocation from the cytosol to the plasma membrane and Rac2 GTP-binding activity. Furthermore, Clostridium difficile toxin A, an inhibitor of the Rho-GTPases family Rho, Rac and Cdc42, prevented Ang II-elicited O2/ROS production, phosphorylation of the mitogen-activated protein kinases (MAPKs) p38, extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase 1/2, and Rac2 activation. Rac2 GTPase inhibition by C. difficile toxin A was accompanied by a robust reduction of the cytosolic Ca2+ elevation induced by Ang II in human neutrophils. Furthermore, SB203580 and PD098059 act as inhibitors of p38MAPK and ERK1/2 respectively, wortmannin, an inhibitor of phosphatidylinositol-3-kinase, and cyclosporin A, a calcineurin inhibitor, hindered both translocation of Rac2 from the cytosol to the plasma membrane and enhancement of Rac2 GTP-binding elicited by Ang II. These results provide evidence that the activation of Rac2 by Ang II is exerted through multiple signalling pathways, involving Ca2+/calcineurin and protein kinases, the elucidation of which should be insightful in the design of new therapies aimed at reversing the inflammation of vessel walls found in a number of cardiovascular diseases.This work was financed by grants from the Ministerio de Educación y Ciencia (BFU2006-13802), and the Consejería de Innovación, Ciencia y Empresa (P06-CTS-1936), Junta de Andalucía, Spain, awarded to F S

Folic acid deficiency induces premature hearing loss through mechanisms involving cochlear oxidative stress and impairment of homocysteine metabolism

Nutritional imbalance is emerging as a causative factor of hearing loss (HL). Epidemiological studies have linked HL to elevated plasma homocysteine (pHcy) and folate deficiency, and showed that folate supplementation lowers pHcy levels potentially ameliorating age-related HL. The purpose of this study was to address the potential impact of folate deficiency in HL and to unveil the underlying mechanisms. For this purpose, two-month old C57BL/6J-mice (Animalia Chordata Mus musculus) were randomly divided in two groups (n=65 each) that were fed folate-deficient or standard diets for 8 weeks. HPLC analysis demonstrated 7-fold decline in serum folate and 3-fold increase in pHcy levels. Auditory brainstem recordings showed that only folate-deficient mice exhibited severe HL and cochlear TUNEL+-apoptotic cells. RTqPCR and Western-blotting showed reduced levels of enzymes involved in Hcy production and recycling, together with 30% increased protein homocysteinylation. Redox stress was evidenced by decreased expression of Cat, Gpx4 and Gss genes, increased levels of the proteins MnSOD and the NOX-complex adaptor p22phox, and elevated concentrations of glutathione species. Altogether, our findings show for the first time that the relationship between folate-induced hyperhomocysteinemia and premature HL involves impairment of cochlear Hcy metabolism and associated oxidative stress

Plantas silvestres consumidas como tés recreativos por grupos de rancheros en Baja California Sur, México

Background and Aims: Recreational teas are herbal beverages prepared by infusion/boiling, consumed in a social or food context, generally considered healthy and with medicinal uses but without being the unique purpose of consumption. In Mexico, recreational teas are not commonly mentioned in ethnobotanical studies. This research describes the ethnobotanical uses, phenolics content and antioxidant activity of wild plants used to prepare recreational teas in two ranch communities in Baja California Sur, Mexico: the Sierra La Laguna Biosphere Reserve and San Blas-Cacachilas.Methods: Ethnobotanical information was obtained through semi-structured surveys and stays with the ranchers of both communities. The percentage of citations, preferences and cultural value of each species was calculated; moreover, their medicinal uses were described. The phenolic content and antioxidant activity was determined by colorimetric methods, and they were correlated with ethnobotanical parameters.Key results: Twelve taxa of wild plants were recorded as recreational tea material, 11 in Sierra La Laguna and six in San Blas-Las Cacachilas. Damiana (Turnera diffusa) had the highest cultural value (71.2%), followed by margarita (Aloysia barbata) (41.1%) and wild anise (Tagetes filifolia / T. micrantha) (21.5%). The main medicinal uses of the recreational teas were as anti-flu/ antitussives and as general relaxants. The antioxidant content had a negative correlation with the percentage of citations and the preference. The medicinal uses for A. barbata and the peyote fern (Pellaea ternifolia) are described for the first time, and new uses for damiana and cherry (Prunus serotina) are documented.Conclusions: Ranchers from Baja California Sur have a high affinity for the consumption of recreational teas of wild plants, and those used to treat common ailments such as flu/cough or stress are preferred. This is the first ethnobotanical study about recreational teas in Mexico.Antecedentes y Objetivos: Los tés recreativos son bebidas preparadas, por infusión/ebullición, de diferentes partes de plantas que se consumen en un entorno social/alimenticio. Se consideran generalmente saludables y con usos medicinales, aunque ese no es su único propósito de consumo. En México, los tés recreativos prácticamente no se mencionan en los estudios etnobotánicos. Este estudio describe la etnobotánica, contenido de fenólicos y actividad antioxidante de plantas silvestres empleadas como tés recreativos en dos rancherías de las zonas montañosas de la región de Los Cabos, Baja California Sur, México: Reserva de la Biosfera Sierra La Laguna y comunidad San Blas-Cacachilas.Métodos: La información etnobotánica se obtuvo mediante encuestas semi-estructuradas y estancias con los rancheros de ambas comunidades. Se calculó el porcentaje de citas, preferencia y valor cultural de cada especie registrada, además de describir sus usos medicinales adicionales. El contenido de fenólicos y actividad antioxidante se determinó por métodos colorimétricos y fueron correlacionados con parámetros etnobotánicos.Resultados clave: Se registraron 12 taxa de plantas silvestres para elaborar tés recreativos, 11 en Sierra La Laguna y seis en San Blas-Las Cacachilas. La damiana (Turnera diffusa) obtuvo el mayor valor cultural (71.2%), seguido de margarita (Aloysia barbata) (41.1%) y anís silvestre (Tagetes filifolia/T. micrantha) (21.5%). Los tés recreativos tuvieron sus principales usos medicinales como antigripales/antitusivos y relajantes generales. El contenido de antioxidantes presentó correlación negativa con el porcentaje de citas y la preferencia. Los usos etnofarmacológicos de A. barbata y el helecho peyote (Pellaea ternifolia) son descritos por primera vez, y se documentaron nuevos usos para la damiana y el cerezo (Prunus serotina).Conclusiones: Los rancheros de Baja California Sur tienen gran afinidad por el consumo de tés recreativos de plantas silvestres, y aquellos usados para tratar padecimientos comunes como gripe/tos o estrés son los preferidos. El presente es el primer estudio etnobotánico específico para tés recreativos en México

Procedimiento y sistema para detectar queratocono subclínico

Número de publicación: 2 564 397 Número de solicitud: 201431361Procedimiento y sistema para detectar queratocono subclínico, donde el sistema comprende: - un topógrafo corneal configurado para proporcionar un primer (1) y un segundo conjunto (2) de datos espaciales normalizados asociados a la superficie anterior y posterior de la córnea, y un valor de distancia (8) representativo de la separación entre ambas superficies y; - unos medios de procesamiento configurados para generar una primera (3) y una segunda superficie (4) a partir del primer (1) y segundo conjunto de datos (2), y generar un modelo (7) tridimensional que proporciona al menos un primer parámetro (p1) con información de una primera medida de desviación (16) correspondiente a la distancia existente entre el punto de mayor altura (14) de la segunda superficie (4) respecto de un eje axial (12), y donde los medios de procesamiento están además configurados para detectar un posible queratocono subclínico a partir de la medida proporcionada.Universidad Politécnica de CartagenaUniversidad de Murci

Cell free circulating tumor DNA in cerebrospinal fluid detects and monitors central nervous system involvement of B-cell lymphomas

The levels of cell free circulating tumor DNA (ctDNA) in plasma correlate with treatment response and outcome in systemic lymphomas. Notably, in brain tumors, the levels of ctDNA in the cerebrospinal fluid (CSF) are higher than in plasma. Nevertheless, their role in central nervous system (CNS) lymphomas remains elusive. We evaluated the CSF and plasma from 19 patients: 6 restricted CNS lymphomas, 1 systemic and CNS lymphoma, and 12 systemic lymphomas. We performed whole exome sequencing or targeted sequencing to identify somatic mutations of the primary tumor, then variant-specific droplet digital polymerase chain reaction was designed for each mutation. At time of enrollment, we found ctDNA in the CSF of all patients with restricted CNS lymphoma but not in patients with systemic lymphoma without CNS involvement. Conversely, plasma ctDNA was detected in only 2 out of 6 patients with restricted CNS lymphoma with lower variant allele frequencies than CSF ctDNA. Moreover, we detected CSF ctDNA in one patient with CNS lymphoma in complete remission and in one patient with systemic lymphoma, 3 and 8 months before CNS relapse was confirmed, indicating that CSF ctDNA might detect CNS relapse earlier than conventional methods. Finally, in two cases with CNS lymphoma, CSF ctDNA was still detected after treatment even though no tumoral cells were observed by flow cytometry (FC), indicating that CSF ctDNA detected residual disease better than FC. In conclusion, CSF ctDNA can detect CNS lesions better than plasma ctDNA and FC. In addition, CSF ctDNA predicted CNS relapse in CNS and systemic lymphomas

Cell free circulating tumor DNA in cerebrospinal fluid detects and monitors central nervous system involvement of B-cell lymphomas

Limfoma no Hodgkin agressiu; Limfoma del SNCLinfoma no Hodgkin agresivo; Linfoma del SNCAggressive Non-Hodgkin's Lymphoma; CNS lymphomaThe levels of cell free circulating tumor DNA (ctDNA) in plasma correlated with treatment response and outcome in systemic lymphomas. Notably, in brain tumors, the levels of ctDNA in the cerebrospinal fluid (CSF) are higher than in plasma. Nevertheless, their role in central nervous system (CNS) lymphomas remains elusive. We evaluated the CSF and plasma from 19 patients: 6 restricted CNS lymphomas, 1 systemic and CNS lymphoma, and 12 systemic lymphomas. We performed whole exome sequencing or targeted sequencing to identify somatic mutations of the primary tumor, then variant-specific droplet digital PCR was designed for each mutation. At time of enrolment, we found ctDNA in the CSF of all patients with restricted CNS lymphoma but not in patients with systemic lymphoma without CNS involvement. Conversely, plasma ctDNA was detected in only 2/6 patients with restricted CNS lymphoma with lower variant allele frequencies than CSF ctDNA. Moreover, we detected CSF ctDNA in 1 patient with CNS lymphoma in complete remission and in 1 patient with systemic lymphoma, 3 and 8 months before CNS relapse was confirmed; indicating CSF ctDNA might detect CNS relapse earlier than conventional methods. Finally, in 2 cases with CNS lymphoma, CSF ctDNA was still detected after treatment even though a complete decrease in CSF tumor cells was observed by flow cytometry (FC), indicating CSF ctDNA better detected residual disease than FC. In conclusion, CSF ctDNA can better detect CNS lesions than plasma ctDNA and FC. In addition, CSF ctDNA predicted CNS relapse in CNS and systemic lymphomas.This work was supported by research funding from Fundación Asociación Española contra el Cáncer (AECC) (to JS, MC and PA); FERO (to JS), laCaixa (to JS), BBVA (CAIMI) (to JS), the Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias (PI16/01278 to JS; PI17/00950 to MC; PI17/00943 to FB) cofinanced by the European Regional Development Fund (ERDF) and Gilead Fellowships (GLD16/00144, GLD18/00047, to FB). MC holds a contract from Ministerio de Ciencia, Innovación y Universidades (RYC-2012-12018). SB received funding from Fundación Alfonso Martin Escudero. LE received funding from the Juan de la Cierva fellowship. We thank CERCA Programme / Generalitat de Catalunya for institutional support