Effect of Etidronate and Ibandronate on Cytosolic Ca2+ in HT29 and Parasite Cell Line from Echinococcus Granulosus sensu lato

Background: The bisphosphonates are synthetic analogs of pyrophosphate in which two phosphates are connected through carbon instead of oxygen. They are approved compounds for the treatment of hypercalcemia, bone diseases and they have been proposed to treat infectious diseases. Bisphosphonates’ main mechanisms of action are on calcium metabolism, inhibition of protein prenylation and on ATP synthesis. In a previous work, the antiparasitic activity of bisphosphonates on a cell line from Echinococcus granulosus, sensu lato protoscoleces, 30 µM etidronate and ibandronate have antiproliferative activity after 72 h of incubation, decreasing intracellular ATP and only etidronate increased intracellular total calcium concentration. Objective: This work studied the effect of etidronate and ibandronate on cytoplasmic ionic calcium concentration in parasitic cell line and in HT29, cell line from human colon adenocarcinoma. Methods: Ionic calcium was measured by spectrofluorometric, labeling cells with Fluo-4AM. Cells were suspended in Na+ or K+ rich buffer and two calcium salts were used Cl- or Gluc- , anion permeable and impermeable, respectively. Results: Remarkable differences between cell lines were shown with the effect of bisphosphonates on intracellular ionic calcium concentration in hyperpolarized cells and these differences were smoothed on depolarized cells, in spite of the similar cellular response to calcium salts in absence of bisphosphonates. Conclusion: The bisphosphonates, mainly etidronate, decreased intracellular ionic calcium on parasitic cells explaining other aspects of their antiproliferative effect. Results suggested that other mechanism, such as Cl- and Na+ interchange are differentially affected by bisphosphonates, depending on cell line originFil: Ferrulli, Mariana. Universidad Abierta Interamericana. Secretaría de Investigación. Centro de Altos Estudios En Ciencias Humanas y de la Salud - Sede Buenos Aires; ArgentinaFil: Pérez Rojo, Fernando Gabriel. Universidad Abierta Interamericana. Secretaría de Investigación. Centro de Altos Estudios En Ciencias Humanas y de la Salud - Sede Buenos Aires; ArgentinaFil: Granada Herrera, Lilian Andrea. Universidad Abierta Interamericana. Secretaría de Investigación. Centro de Altos Estudios En Ciencias Humanas y de la Salud - Sede Buenos Aires; ArgentinaFil: Maglioco, Andrea Florencia. Universidad Abierta Interamericana. Secretaría de Investigación. Centro de Altos Estudios En Ciencias Humanas y de la Salud - Sede Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Roldán, Emilio A. J.. Universidad Abierta Interamericana. Secretaría de Investigación. Centro de Altos Estudios En Ciencias Humanas y de la Salud - Sede Buenos Aires; ArgentinaFil: Fuchs, Alicia Graciela. Universidad Abierta Interamericana. Secretaría de Investigación. Centro de Altos Estudios En Ciencias Humanas y de la Salud - Sede Buenos Aires; Argentina. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud "Dr. C. G. Malbrán". Instituto Nacional de Parasitología "Dr. Mario Fatala Chaben"; Argentin

Use of interactive response devices for the improvement of teaching in the degrees of the Faculty of Sciences

La implantación de los nuevos Grados dentro del EEES supone un nuevo enfoque metodológico, pero sobre todo evaluador. El profesor debe esforzarse en ser capaz de valorar no sólo el nivel de conocimientos del alumnado sobre los contenidos, ya que la sociedad actual demanda un perfil de los egresados más completo basado en la formación por competencias. La adquisición de ambas facetas por parte del alumnado se basa principalmente en actividades presenciales y metodologías docentes aplicadas en el desarrollo de las asignaturas, tanto en grupo reducido como en grupo completo. Por tanto, cualquier herramienta adicional que ayude al docente a facilitar esta doble tarea es bien recibida, pues permitirá evaluar el rendimiento académico global del alumnado. Recientemente la Facultad de Ciencias ha puesto en marcha una experiencia piloto mediante la cual un nutrido grupo de profesores ha incorporado en su docencia un sistema de mandos inalámbricos de respuesta. Actualmente, la Facultad de Ciencias dispone de un total de 82 mandos inalámbricos de respuesta y tres antenas receptoras. Esta nueva tecnología ha permitido al docente realizar, de forma interactiva, preguntas colectivas al alumnado y recoger las respuestas individuales de forma inmediata. Los resultados obtenidos en este proyecto nos permiten ser muy optimistas con el uso de esta herramienta y nos animan a continuar en la misma línea. El profesorado participante se ha mostrado dispuesto a continuar empleando esta TIC en su docencia, tratando de abarcar más asignaturas, diversificar el tipo de pruebas, y emplear los mandos de respuesta en grupo completo, cuando el número de alumnos lo permita. La puesta en común de los resultados revela que, de forma general, este tipo de sistemas de respuesta incrementa el nivel de atención del alumnado, ya que se les demanda de forma continuada su participación activa durante la sesión. Se potencia la retención de conceptos, al suministrar en el acto la respuesta correcta a cada pregunta realizada. Permite también al profesorado conocer el nivel previo de conocimientos sobre la materia a impartir, ya que se puede realizar este tipo de preguntas al comienzo de la sesión y enfocar entonces su atención en las debilidades manifestadas. Asimismo se puede testar el grado de adquisición de dichos conocimientos, realizando este tipo de cuestionarios después de la sesión. Además, el tratamiento posterior de los resultados, de forma individualizada, permite gestionar de forma ágil el nivel de conocimientos y adquisición de competencias en lo que es un sistema de evaluación continua, tan necesario en los nuevos enfoques metodológicos nacidos de la implantación del EEES. Por último destacar que el profesorado participante ha considerado que se trata de una herramienta de gran utilidad para la consecución del objetivo de excelencia en la docencia, que además es eficaz y de fácil manejo, y entiende que no debe ser una actividad puntual, sino un proceso transformador en la actividad docente e interacción alumno-profesor, configurándose como una herramienta habitual en los sistemas de enseñanza-aprendizaje.Implementation of the new degrees in the EHEA involve a new methodological approach, but above all evaluation. The teacher should strive to be able to assess not only the level of knowledge of the students on the content, as the current society demands a profile of the most complete graduates based on training by competencies. The acquisition of both facets by students is based mainly on face-to-face activities and teaching methodologies applied in the development of the subjects, both in small group and in whole group. Therefore, any additional tool that helps the teacher to facilitate this double task is well received, since it will allow to evaluate the overall academic performance of the students. Recently the Faculty of Sciences has launched a pilot experience through which a large group of teachers has incorporated into their teaching a system of interactive response devices. Currently, the Faculty of Sciences has a total of 82 wireless response controllers and three receiving antennas. This new technology has enabled the teacher to interact interactively with the students and collect the individual answers immediately. The results obtained in this project allow us to be very optimistic with the use of this tool and encourage us to continue in the same line. The participating teachers have been willing to continue using this ICT in their teaching, trying to cover more subjects, diversify the type of tests, and use the full group response commands, when the number of students allows. The sharing of results reveals that, in a general way, this type of response systems increases the level of attention of the students, since they are continuously demanded their active participation during the session. The retention of concepts is strengthened by providing the correct answer to every question asked. It also allows the faculty to know the previous level of knowledge about the subject to be taught, since this type of questions can be asked at the beginning of the session and then focus their attention on the weaknesses manifested. It is also possible to test the degree of acquisition of this knowledge, performing this type of questionnaire after the session. In addition, the subsequent treatment of the results, in an individualized way, allows to manage in an agile way the level of knowledge and acquisition of competences in what is a system of continuous evaluation, so necessary in the new methodological approaches born from the implantation of the EHEA. Finally, it should be pointed out that the participating teachers have considered that this is a very useful tool for achieving the objective of excellence in teaching, which is also efficient and easy to use and understands that it should not be a specific activity, but a transforming process in the teaching activity and student-teacher interaction, being configured as a habitual tool in the teaching-learning systems

One-year breakthrough SARS-CoV-2 infection and correlates of protection in fully vaccinated hematological patients

The long-term clinical efficacy of SARS-CoV-2 vaccines according to antibody response in immunosuppressed patients such as hematological patients has been little explored. A prospective multicenter registry-based cohort study conducted from December 2020 to July 2022 by the Spanish Transplant and Cell Therapy group, was used to analyze the relationship of antibody response over time after full vaccination (at 3-6 weeks, 3, 6 and 12 months) (2 doses) and of booster doses with breakthrough SARS-CoV-2 infection in 1551 patients with hematological disorders. At a median follow-up of 388 days after complete immunization, 266 out of 1551 (17%) developed breakthrough SARS-CoV-2 infection at median of 86 days (range 7-391) after full vaccination. The cumulative incidence was 18% [95% confidence interval (C.I.), 16-20%]. Multivariate analysis identified higher incidence in chronic lymphocytic leukemia patients (29%) and with the use of corticosteroids (24.5%), whereas female sex (15.5%) and more than 1 year after last therapy (14%) were associated with a lower incidence (p < 0.05 for all comparisons). Median antibody titers at different time points were significantly lower in breakthrough cases than in non-cases. A serological titer cut-off of 250 BAU/mL was predictive of breakthrough infection and its severity. SARS-CoV-2 infection-related mortality was encouragingly low (1.9%) in our series. Our study describes the incidence of and risk factors for COVID-19 breakthrough infections during the initial vaccination and booster doses in the 2021 to mid-2022 period. The level of antibody titers at any time after 2-dose vaccination is strongly linked with protection against both breakthrough infection and severe disease, even with the Omicron SARS-CoV-2 variant

MVA-CoV2-S vaccine candidate confers full protection from SARS-CoV-2 brain infection and damage in susceptible transgenic mice

The protective efficacy of vaccines against SARS-CoV-2 infection in the brain is yet unclear. Here, in the susceptible transgenic K18-hACE2 mouse model of severe COVID-19 disease, we report a detailed spatiotemporal description of the SARS-CoV-2 infection and replication in different areas of the brain. Remarkably, SARS-CoV-2 brain replication occurs primarily in neurons, producing important neuropathological alterations such as neuronal loss, incipient signs of neuroinflammation, and vascular damage in SARS-CoV-2 infected mice. Notably, one or two doses of a modified vaccinia virus Ankara (MVA) vector expressing the SARS-CoV-2 spike (S) protein (MVA-CoV2-S) conferred full protection against SARS-CoV-2 cerebral infection, preventing virus replication in all areas of the brain and its associated damage. This protection was maintained even after SARS-CoV-2 reinfection. To our knowledge, this is the first study of a COVID-19 vaccine candidate showing 100% efficacy against SARS-CoV-2 brain infection and damage, reinforcing the use of MVA-CoV2-S as a promising vaccine candidate against SARS-CoV-2/COVID-19, worth to move forward into clinical trials.The authors thank the Centro de Investigación en Sanidad Animal (CISA)-Instituto Nacional de Investigaciones Agrarias (INIA-CSIC) (Valdeolmos, Madrid, Spain) for the BSL-3 facilities. SARS-CoV-2 MAD6 virus isolate was kindly provided by José M. Honrubia and Dr. Luis Enjuanes (CNB-CSIC, Madrid, Spain). We also thank to Dr. Konstantin L. Levitsky for excellent technical assistance with the confocal acquisition. We thank the Spanish Research Council (CSIC) and the Spanish Ministry of Science and Innovation (MICINN) for continuous support. This research was supported by MCIN/Spanish Research Agency (AEI)/ 10.13039/501100011033 grants: PID2019-105995RB-I00 (J.T.-A. and J.V.), PID2020- 114481RB-I00 (J.G.-A. and M.E.), and PID2019-106410RB-I00 (J.L.-B.). Moreover, this research work was also funded by Red TerCel ISCIII, RD16/0011/0025 (J.T.-A.); Consejería de Salud y Familias, Junta de Andalucía Grant, PECOVID-0078-2020 (R.R.-L. and J.V.); Fondo COVID-19 grant COV20/00151 [Spanish Health Ministry, Instituto de Salud Carlos III (ISCIII)], Fondo Supera COVID-19 (Crue Universidades-Banco Santander) grant and CSIC grant 202120E079 (J.G.-A.); and CSIC grant 2020E84, La CaixaImpulse grant CF01-00008, Ferrovial and MAPFRE donations (M.E.). Additionally, we have also funding from the European Commission-NextGenerationEU, through CSIC's Global Health Platform (PTI Salud Global) (J.G.-A. and M.E.) and the European Research Council (ERC Advanced Grant PRJ201502629) (J.L.-B.).N

Full protection from SARS-CoV-2 brain infection and damage in susceptible transgenic mice conferred by MVA-CoV2-S vaccine candidate

Vaccines against SARS-CoV-2 have been shown to be safe and effective but their protective efficacy against infection in the brain is yet unclear. Here, in the susceptible transgenic K18-hACE2 mouse model of severe coronavirus disease 2019 (COVID-19), we report a spatiotemporal description of SARS-CoV-2 infection and replication through the brain. SARS-CoV-2 brain replication occurs primarily in neurons, leading to neuronal loss, signs of glial activation and vascular damage in mice infected with SARS-CoV-2. One or two doses of a modified vaccinia virus Ankara (MVA) vector expressing the SARS-CoV-2 spike (S) protein (MVA-CoV2-S) conferred full protection against SARS-CoV-2 cerebral infection, preventing virus replication in all areas of the brain and its associated damage. This protection was maintained even after SARS-CoV-2 reinfection. These findings further support the use of MVA-CoV2-S as a promising vaccine candidate against SARS-CoV-2/COVID-19.We thank the CSIC and the Spanish Ministry of Science and Innovation for continuous support. This research was supported by the Spanish Ministry of Science and Innovation/Spanish Research Agency/10.13039/501100011033 grant nos. PID2019-105995RB-I00 (J.J.T.-A. and J.V.), PID2020-114481RB-I00 (J.G.-A. and M.E.), RTI2018-096629-B-I00 (A.P.) and PID2019-106410RB-I00 (J.L.-B.). Moreover, this research was also funded by Red TerCel ISCIII (no. RD16/0011/0025 to J.J.T.-A.), Consejería de Economía, Conocimiento, Empresas y Universidad US-1380891 (to J.J.T.-A. and J.V.), Consejería de Salud y Familias, Junta de Andalucía grant no. PECOVID-0078-2020 (to R.R.-L. and J.V.), Consejería de Educación y Deporte, Junta de Andalucía grant no. PY20_01312 (to A.P.), Fondo COVID-19 grant no. COV20/00151 (Spanish Health Ministry, Instituto de Salud Carlos III), Fondo Supera COVID-19 (Crue Universidades-Banco Santander) grant and CSIC grant no. 202120E079 (J.G.-A.), CSIC grant no. 2020E84, La CaixaImpulse grant no. CF01-00008 and Ferrovial and MAPFRE donations (to M.E.). Additionally, we received funding from the European Commission-NextGenerationEU, through the CSIC’s Global Health Platform (PTI Salud Global) (to J.G.-A. and M.E.) and the European Research Council (ERC Advanced grant no. PRJ201502629) (to J.L.-B.). J.G.-A. and M.E. also acknowledge financial support from the Spanish State Research Agency (no. AEI/10.13039/501100011033) through the ‘Severo Ochoa’ Programme for Centres of Excellence in R&D (nos. SEV-2013-0347 and SEV-2017-0712). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.Peer reviewe

Applicability of probabilistic graphical models for early detection of SARS-CoV-2 reactive antibodies after SARS-CoV-2 vaccination in hematological patients

Prior studies of antibody response after full SARS-CoV-2 vaccination in hematological patients have confirmed lower antibody levels compared to the general population. Serological response in hematological patients varies widely according to the disease type and its status, and the treatment given and its timing with respect to vaccination. Through probabilistic machine learning graphical models, we estimated the conditional probabilities of having detectable anti-SARS-CoV-2 antibodies at 3–6 weeks after SARS-CoV-2 vaccination in a large cohort of patients with several hematological diseases (n= 1166). Most patients received mRNA-based vaccines (97%), mainly Moderna® mRNA-1273 (74%) followed by Pfizer-BioNTech® BNT162b2 (23%). The overall antibody detection rate at 3 to 6 weeks after full vaccination for the entire cohort was 79%. Variables such as type of disease, timing of anti-CD20 monoclonal antibody therapy, age, corticosteroids therapy, vaccine type, disease status, or prior infection with SARS-CoV-2 are among the most relevant conditions influencing SARS-CoV-2-IgG-reactive antibody detection. A lower probability of having detectable antibodies was observed in patients with B-cell non-Hodgkin’s lymphoma treated with anti-CD20 monoclonal antibodies within 6 months before vaccination (29.32%), whereas the highest probability was observed in younger patients with chronic myeloproliferative neoplasms (99.53%). The Moderna® mRNA-1273 compound provided higher probabilities of antibody detection in all scenarios. This study depicts conditional probabilities of having detectable antibodies in the whole cohort and in specific scenarios such as B cell NHL, CLL, MM, and cMPN that may impact humoral responses. These results could be useful to focus on additional preventive and/or monitoring interventions in these highly immunosuppressed hematological patients.REDCap is developed and supported by Vanderbilt Institute for Clinical and Translational Research. We thank the Spanish Society of Hematology (SEHH) for its support on the study. We sincerely want to thanks the invaluable aid of microbiology services for their commitment in SARS-CoV-2-reactive IgG antibody monitoring in these highly immunosuppressed patients from all participating centers. Finally, we also want to thank the patients, nurses, and study coordinators for their foremost contributions in this study.Peer reviewe

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

La renovación de la palabra en el bicentenario de la Argentina : los colores de la mirada lingüística

El libro reúne trabajos en los que se exponen resultados de investigaciones presentadas por investigadores de Argentina, Chile, Brasil, España, Italia y Alemania en el XII Congreso de la Sociedad Argentina de Lingüística (SAL), Bicentenario: la renovación de la palabra, realizado en Mendoza, Argentina, entre el 6 y el 9 de abril de 2010. Las temáticas abordadas en los 167 capítulos muestran las grandes líneas de investigación que se desarrollan fundamentalmente en nuestro país, pero también en los otros países mencionados arriba, y señalan además las áreas que recién se inician, con poca tradición en nuestro país y que deberían fomentarse. Los trabajos aquí publicados se enmarcan dentro de las siguientes disciplinas y/o campos de investigación: Fonología, Sintaxis, Semántica y Pragmática, Lingüística Cognitiva, Análisis del Discurso, Psicolingüística, Adquisición de la Lengua, Sociolingüística y Dialectología, Didáctica de la lengua, Lingüística Aplicada, Lingüística Computacional, Historia de la Lengua y la Lingüística, Lenguas Aborígenes, Filosofía del Lenguaje, Lexicología y Terminología