Molecular characterization of autophagic and apoptotic signaling induced by sorafenib in liver cancer cells

Sorafenib is the unique accepted molecular targeted drug for the treatment of patients in advanced stage of hepatocellular carcinoma. The current study evaluated cell signaling regulation of endoplasmic reticulum (ER) stress, c-Jun-N-terminal kinase (JNK), Akt, and 5′AMP-activated protein kinase (AMPK) leading to autophagy and apoptosis induced by sorafenib. Sorafenib induced early (3–12 hr) ER stress characterized by an increase of Ser51P-eIF2α/eIF2α, C/EBP homologous protein (CHOP), IRE1α, and sXBP1, but a decrease of activating transcription factor 6 expression, overall temporally associated with the increase of Thr183,Tyr185P-JNK1/2/JNK1/2, Thr172P-AMPKα, Ser413P-Foxo3a, Thr308P-AKt/AKt and Thr32P-Foxo3a/Foxo3a ratios, and reduction of Ser2481P-mammalian target of rapamycin (mTOR)/mTOR and protein translation. This pattern was related to a transient increase of tBid, Bim EL, Beclin-1, Bcl-xL, Bcl-2, autophagy markers, and reduction of myeloid cell leukemia-1 (Mcl-1) expression. The progressive increase of CHOP expression, and reduction of Thr308P-AKt/AKt and Ser473P-AKt/AKt ratios were associated with the reduction of autophagic flux and an additional upregulation of Bim EL expression and caspase-3 activity (24 hr). Small interfering-RNA (si-RNA) assays showed that Bim, but not Bak and Bax, was involved in the induction of caspase-3 in sorafenib-treated HepG2 cells. Sorafenib increased autophagic and apoptotic markers in tumor-derived xenograft model. In conclusion, the early sorafenib-induced ER stress and regulation of JNK and AMPK-dependent signaling were related to the induction of survival autophagic process. The sustained drug treatment induced a progressive increase of ER stress and PERK-CHOP-dependent rise of Bim EL, which was associated with the shift from autophagy to apoptosis. The kinetic of Bim EL expression profile might also be related to the tight balance between AKt- and AMPK-related signaling leading to Foxo3a-dependent BIM EL upregulation.Ministerio de Economía y Competitividad BFU2016‐75352‐PInstituto de Salud Carlos III PI15/00034, PI13/ 00021, PI16/00090, PI14/01349Ministerio de Educación FPU16/05127, FPU12/01433, FPU13/01237Junta de Andalucía CTS-6264, PI-00025-2013, PI-0127-2013, PI-0198-201

Assessment of feedback devices for performance monitoring in master’s swimmers

In recent years, new portable performance monitoring devices have appeared in swimming. The study aims to establish the current validity of the FORM Goggles, Finis Stopwatch, and the Garmin Swim 2 Watch, for the partial and total times and stroke count (experiment 1; n = 17) and to compare the effect of the devices considered as valid in monitoring the pace of master swimmers (experiment 2; n = 10). The FORM Goggles and the Finis Stopwatch showed good level of agreement and accuracy (Bland Altman plots showed homoscedasticity and in most cases Lin’s concordance correlation coefficient were>0.95, and the error magnitude<0.2 seconds). These systems allow better pace control compared to Garmin Swim 2, with a difference between target and actual time below 1.5 %. However, the results showed that the concurrent feedback provided by FORM Smart Swim Goggles could offer greater advantages than the traditional feedback provided via the Finis Stopwatch at the end of each series, as swimmers were closer to the target time (p < 0.05). In conclusion both the FORM Goggles and the Finis Stopwatch, showed a good validity and could serve for performance monitoring in swimming, allowing the Form Goggles better pace control.CTS-527Agencia de Innovación y Desarollo de Andalucía [B- SEJ-164-UGR20 “SWIM FOR LIFE”

Management of coastal dunes affected by shrub encroachment: are rabbits an ally or an enemy of restoration?

In coastal dunes, shrub encroachment disrupts natural disturbance, and reduces habitat heterogeneity and species composition. In this paper, we implemented a pilot scale trial aimed at restoring coastal dunes affected by the encroachment by the shrub Retama monosperma (hereinafter Retama) as well as strengthening the populations of Thymus carnosus (regionally cataloged as ‘Critically Endangered’). A total 3 ha of Retama shrub was clearcut in two sites with different Retama cover (54 and 72%). The effect of rabbits on vegetation recovery was assessed by placing exclosures both in treated and untreated plots in Spring, 2015. Plant composition, species richness and diversity were evaluated two years after treatments (with and without Retama clearing, and with and without rabbit exclusion). Retama clearing alone did not allow the recovery of plant composition typical of gray dunes two-years after treatments, but resulted in a biodiversity loss within the Retama understorey when rabbits were present. However, Retama clearing resulted in a significant vigor improvement of T. carnosus in the site with the highest density of Retama. Rabbit exclusion significantly increased species richness and Shannon-Wiener diversity index, and allowed the recovery of plant composition typical of gray dunes. The results suggest that shrub encroachment caused by Retama has a long-lasting negative impact on dune vegetation and that periodic clearing should be combined with rabbit exclusion at least during early restoration stages of dune vegetation. To recover the population of T. carnosus, Retama should be prevented from reaching high cover and periodic clearing without rabbit exclusion is suggested

Immunometabolism is a key factor for the persistent spontaneous elite control of HIV-1 infection

Approximately 25% of elite controllers (ECs) lose their virological control by mechanisms that are only partially known. Recently, immunovirological and proteomic factors have been associated to the loss of spontaneous control. Our aim was to perform a metabolomic approach to identify the underlying mechanistic pathways and potential biomarkers associated with this loss of control. Methods: Plasma samples from EC who spontaneously lost virological control (Transient Controllers, TC, n=8), at two and one year before the loss of control, were comparedwith a control group of ECwho persistently maintained virological control during the same follow-up period (Persistent Controllers, PC, n=8). The determination of metabolites and plasma lipids was performed by GC-qTOF and LC-qTOF using targeted and untargeted approaches. Metabolite levels were associated with the polyfunctionality of HIV-specific CD8+T-cell response. Findings: Our data suggest that, before the loss of control, TCs showed a specific circulating metabolomic profile characterized by aerobic glycolytic metabolism, deregulated mitochondrial function, oxidative stress and increased immunological activation. In addition, CD8+ T-cell polyfunctionality was strongly associated with metabolite levels. Finally, valine was the main differentiating factor between TCs and PCs. Interpretation: All these metabolomic differences should be considered not only as potential biomarkers but also as therapeutic targets in HIV infection.Instituto Carlos III PI10/02635 PI13/00796 PI16/00503 PI12/02283 PI16/00684 CPII014/00025 FI14/00431 FI17/00186 INT11/240 INT12/282 INT15/226Fondos Europeos para el Desarrollo Regional PI10/02635 PI13/00796 PI16/00503 PI12/02283 PI16/00684 CPII014/00025 FI14/00431 FI17/00186FEDER PI10/02635 PI13/00796 PI16/00503 PI12/02283 PI16/00684 CPII014/00025 FI14/00431 FI17/00186FEDER PI10/02635 PI13/00796 PI16/00503 PI12/02283 PI16/00684 CPII014/00025 FI14/00431 FI17/00186Programa de Suport als Grups de Recerca 2017SGR948 2014SGR250Gilead Fellowship Program GLD14/293 GLD17/00299Red de Investigación en Sida RD12/0017/0005 RD16/0025/0006 RD12/0017/0029 RD16/0025/0020Junta de Andalucía C-0032/17Generalitat de Catalunya PERIS SLT002/16/0010

Monozygotic twins discordant for common variable immunodeficiency reveal impaired DNA demethylation during naı¨ve-to-memory B-cell transition

Common variable immunodeficiency (CVID), the most frequent primary immunodeficiency characterized by loss of B-cell function, depends partly on genetic defects, and epigenetic changes are thought to contribute to its aetiology. Here we perform a high-throughput DNA methylation analysis of this disorder using a pair of CVID-discordant MZ twins and show predominant gain of DNA methylation in CVID B cells with respect to those from the healthy sibling in critical B lymphocyte genes, such as PIK3CD, BCL2L1, RPS6KB2, TCF3 and KCNN4. Individual analysis confirms hypermethylation of these genes. Analysis in naive, unswitched and switched memory B cells in a CVID patient cohort shows impaired ability to demethylate and upregulate these genes in transitioning from naive to memory cells in CVID. Our results not only indicate a role for epigenetic alterations in CVID but also identify relevant DNA methylation changes in B cells that could explain the clinical manifestations of CVID individuals

The Deleterious Influence of Tenofovir-Based Therapies on the Progression of Atherosclerosis in HIV-Infected Patients

We investigated the potential differential effects of antiretroviral therapies on unbalanced chemokine homeostasis and on the progression of atherosclerosis in HIV-infected patients. A two-year prospective study was performed in 67 consecutive HIV-infected patients initiating antiretroviral therapy with abacavir/lamivudine or tenofovir/emtricitabine. Circulating levels of inflammatory biomarkers, progression of subclinical atherosclerosis and expression levels of selected chemokines genes in circulating leukocytes were assessed. Control subjects showed significantly lower plasma concentrations of CRP, tPA, IL-6, and MCP-1 than HIV-infected patients at a baseline. After two years of followup, the observed decreases in plasma inflammatory biomarker levels were only significant for MCP-1, tPA, and IL-6. The decrease in plasma MCP-1 concentration was associated with the progression of atherosclerosis, and this effect was negligible only in patients receiving TDF-based therapy. Multivariate analysis confirmed that treatment with TDF was positively and significantly associated with a higher likelihood of subclinical atherosclerosis progression. However, the expression levels of selected genes in blood cells only showed associations with the viral load and total and HDL-cholesterol levels. Current antiretroviral treatments may partially attenuate the influence of HIV infection on certain inflammatory pathways, though patients receiving TDF therapy must be carefully monitored with respect to the presence and/or progression of atherosclerosis

Impacto de las nuevas tecnologías en los niveles de actividad física y sedentarismo en el alumnado de Educación Secundaria Obligatoria: Diagnóstico y plan de acción

Actualmente las nuevas tecnologías están integradas en la sociedad y son una parte importante y significativa en la vida de los más jóvenes. Estas nuevas tecnologías en algunas ocasiones están relacionadas con un comportamiento sedentario que ha desembocado en la reducción de los niveles de actividad física de los niños, factor que está directamente relacionado con un incremento de la obesidad infantil. Se pretende buscar un nuevo enfoque en el que las nuevas tecnologías no supongan un cese de la actividad física, sino que la incrementen y ayuden a mejorar la motivación del alumnado hacia esta. Éstas se consideran como una oportunidad para incluir la actividad física en la vida de los alumnos, por lo que se trata de aprovechar la parte tan importante que estas suponen en su día a día y los niveles de atención que les suscitan para integrarlos en la asignatura de Educación Física

Efectos adversos de las vacunas frente al SARS-CoV-2 en farmacéuticos comunitarios de Pontevedra

Objetivo: analizar los registros de sospechas de efectos adversos (EA) de las vacunas frente al SARSCoV-2 administradas a farmacéuticos comunitarios (FC) y personal auxiliar. Métodos. Diseño: estudio observacional transversal, en febrero-abril de 2021. Sujetos: farmacéuticos, técnicos y auxiliares de la provincia de Pontevedra que ejercen en contacto con los pacientes, vacunados con la primera dosis frente al SARS-CoV-2. Variables: número, tipo y frecuencia de EA, características demográficas. Procedimiento: se habilitó un formulario en la web del Colegio de Farmacéuticos de Pontevedra. Se anunció a los FC colegiados de la provincia su existencia y la conveniencia de cumplimentarlo. Resultados: 167 participantes, de los que 153 manifestaron síntomas compatibles con reactividad a la vacuna, 122 (93,1 %) mujeres y 31 (86,1 %) hombres. 146 (95,4 %) habían recibido Vaxzevria®, 116(79,4 %) mujeres y 30 (20,6 %) hombres, y 7 (4,6 %) Comirnaty®, 6 (85,7 %) mujeres y 1 (14,3 %) hombre. Se comunicaron 823 EA, 811 (5,3 DE=2,8 EA, 0-12 por paciente) con Vaxzevria® y 12 (0,9 DE=1,0 EA, 0-3 por paciente) con Comirnaty®. EA más frecuentes: dolor en punto de inyección, 128 (87,7 %); escalofríos, 107 (73,3 %); dolor muscular, 106 (72,6 %). En los tres casos, mayor proporción de mujeres (p<0,01). El número máximo de EA manifestados por un participante fue 12. 132 (86,3 %) vacunados que refirieron EA, 106 (86,9 %) mujeres y 26 (83,9 %) hombres, necesitaron medicamentos para aliviar los síntomas. 77 (46,1 %) no pudieron desarrollar sus actividades diarias y 47 (28,1 %) no pudieron trabajar el día siguiente. Conclusiones: el número de EA comunicados por farmacéuticos y personal auxiliar vacunados fue alto. Aunque no fueron graves, afectaron de manera considerable a su actividad diaria y laboral

Biomarkers and inorganic proxies in the paleoenvironmental reconstruction of mires: The importance of landscape in Las Conchas (Asturias, Northern Spain)

We determined the lipid distributions (n-alkanes, n-alkan-2-ones, n-alkanoic acids), total organic carbon (TOC), total nitrogen (TN), Ca/Mg and ash content in Las Conchas mire, a 3.2 m deep bryophyte-dominated mire in Northern Spain covering 8000 cal yr BP. Bog conditions developed in the bottom 20 cm of the profile, and good preservation of organic matter (OM) was inferred from n-alkanoic acid distribution, with the exception of the uppermost 20 cm (last ca. 200 yr). Microbial synthesis of long chain saturated fatty acids from primary OM likely produced a dominance of short chain n-alkanoic acids with a bimodal distribution, as well as the lack of correspondence between the n-alkane and n-alkanoic acid profiles in the upper 20 cm. This was accompanied by an increase in ash content, a decrease in TOC and variation in n-alkane ratios, thereby suggesting significant changes in the mire, namely drainage and transformation to a meadow, in the last ca. 200 yr. The distribution of n-alkan-2-ones indicated an increase in bacterial source from the bottom of the record to 94 cm, whereas their distribution in the upper part could be attributed mainly to plant input and/or the microbial oxidation of n-alkanes. The different n-alkane proxies showed variations, which we interpreted in terms of changes in vegetation (Sphagnum vs. non-Sphagnum dominated phases) during the last 8000 cal yr BP. C23 was the most abundant homolog throughout most of the record, thereby suggesting dominant humid conditions alternating with short drier phases. However, such humid conditions were not linked to paleoclimatic variation but rather to geomorphological characteristics: Las Conchas mire, at the base of the Cuera Range, receives continuous runoff—even during drier periods—which is not necessarily accompanied by additional mineral input to peat, producing the development of Sphagnum moss typical of waterlogged ecotopes and damp habitats. Thus, although geochemical proxies indicated an ombrotrophic regime in the mire, geomorphological characteristics may make a considerable contribution to environmental conditions

Evaluación de la calidad en el servicio: una aplicación práctica en un establecimiento de Café

Service quality evaluation has become a very powerful tool for organizations to achieve, among other purposes, customer loyalty and competitiveness. In a particular context, this article offers a quantitative study of customer perception of the service quality provided by a coffeehouse chain located in Hermosillo, Sonora. The general objective is to evaluate the quality of the service, through the Servperf methodology, in the coffee houses of a recognized brand. Consequently, a survey of 750 clients was required to determine that the validity and internal consistency tests of the scale were satisfactory, with a Cronbach's alpha at the level of 0.977. To investigate the underlying structure of the 25 items that made up the survey, a Varimax rotation in Principal Component Analysis (PCA) was used, revealing the existence of two variables that explain 70.999 % of the variance.&nbsp; As part of the main results, it can be concluded that the adapted survey, based on the Servperf methodology, allowed for a successful evaluation of the quality of service provided by the coffeehouse chain and the level of overall customer satisfaction, as determined by Spearman's Rho correlation coefficient, with a high percentage of correlation (74.3%) between both variables. Finally, the confidence and responsiveness dimension had a higher correlation (0.578) than the empathy and tangible dimension (0.410).La evaluación de la calidad en el servicio se ha convertido en una herramienta muy poderosa para que las organizaciones logren, entre otros propósitos, fidelizar a los clientes y ser más competitivas. En un contexto particular; este artículo ofrece un estudio de carácter cuantitativo sobre la percepción de los clientes en torno a la calidad en el servicio brindado por una cadena de café localizada en Hermosillo, Sonora. El objetivo general es hacer esta evaluación a través de la metodología Servperf, en los establecimientos de café de una marca reconocida. Con este objetivo, fue necesario aplicar una encuesta a 750 clientes a fin de determinar que las pruebas de validez y consistencia interna de la escala fueron satisfactorias, con un alfa de Cronbach a nivel de 0.977. Para indagar sobre la estructura subyacente de los 25 ítems que integraron la encuesta, se empleó el análisis de componentes principales con rotación Varimax, que reveló la existencia de dos variables que explican el 70.999 % de la varianza. Como parte de los resultados principales, se concluye que la encuesta adaptada a partir de la metodología Servperf permitió evaluar de forma exitosa la calidad en el servicio otorgado por la cadena de café y el nivel de satisfacción global del cliente; así lo determinó el coeficiente de correlación Rho de Spearman, con un alto porcentaje de correlación (74.3 %) entre ambas variables. Por último, la dimensión que centró la confianza y la capacidad de respuesta fue la que obtuvo una mayor correlación (0.578), con respecto a la dimensión de empatía y tangibles (0.410)