Maternal Exposure to Bisphenol-A During Pregnancy Increases Pancreatic β-Cell Growth During Early Life in Male Mice Offspring

Alterations during development of metabolic key organs such as the endocrine pancreas affect the phenotype later in life. There is evidence that in utero or perinatal exposure to bisphenol-A (BPA) leads to impaired glucose metabolism during adulthood. However, how BPA exposure during pregnancy affects pancreatic β-cell growth and function in offspring during early life has not been explored. We exposed pregnant mice to either vehicle (control) or BPA (10 and 100 μg/kg·d, BPA10 and BPA100) and examined offspring on postnatal days (P) P0, P21, P30, and P120. BPA10 and BPA100 mice presented lower birth weight than control and subsequently gained weight until day 30. At that age, concentration of plasma insulin, C-peptide, and leptin were increased in BPA-exposed animals in the nonfasting state. Insulin secretion and content were diminished in BPA10 and maintained in BPA100 compared with control. A global gene expression analysis indicated that genes related with cell division were increased in islets from BPA-treated animals. This was associated with an increase in pancreatic β-cell mass at P0, P21, and P30 together with increased β-cell proliferation and decreased apoptosis. On the contrary, at P120, BPA-treated animals presented either equal or decreased β-cell mass compared with control and altered fasting glucose levels. These data suggest that in utero exposure to environmentally relevant doses of BPA alters the expression of genes involved in β-cell growth regulation, incrementing β-cell mass/area, and β-cell proliferation during early life. An excess of insulin signaling during early life may contribute to impaired glucose tolerance during adulthood

Antidiabetic Actions of an Estrogen Receptor β Selective Agonist

The estrogen receptor β (ERβ) is emerging as an important player in the physiology of the endocrine pancreas. We evaluated the role and antidiabetic actions of the ERβ selective agonist WAY200070 as an insulinotropic molecule. We demonstrate that WAY200070 enhances glucose-stimulated insulin secretion both in mouse and human islets. In vivo experiments showed that a single administration of WAY200070 leads to an increase in plasma insulin levels with a concomitant improved response to a glucose load. Two-week treatment administration increased glucose-induced insulin release and pancreatic β-cell mass and improved glucose and insulin sensitivity. In addition, streptozotocin-nicotinamide–induced diabetic mice treated with WAY200070 exhibited a significant improvement in plasma insulin levels and glucose tolerance as well as a regeneration of pancreatic β-cell mass. Studies performed in db/db mice demonstrated that this compound restored first-phase insulin secretion and enhanced pancreatic β-cell mass. We conclude that ERβ agonists should be considered as new targets for the treatment of diabetes.This work was supported by Generalitat Valenciana grant PROMETEO/2011/080, Ministerio de Economia y Competitividad BFU2011-28358, and Ministerio de Economía y Competitividad BFU2010-21773 and BFU2008-1942; the Swedish Cancer Fund; the Emerging Technology Fund of Texas; and the Robert A. Welch Foundation (E-0004)

Organic distributed feedback laser for label-free biosensing of ErbB2 protein biomarker

The human epidermal growth factor receptor 2 (ErbB2) protein plays an important role in human malignancies. Its overexpression has been recognized as a feature of a malignant cancerous phenotype in breast cancer cell lines, and has become one of the most widely investigated clinical indicators of breast, ovarian, gastrointestinal and lung cancers. In this work a vertically emitting organic distributed feedback (DFB) laser has been used to detect the ErbB2 protein. This DFB laser consists of a polystyrene (PS) film containing a perylenediimide laser dye, deposited over a second-order one dimensional grating fabricated on fused silica by thermal-nanoimprint lithography and subsequent reactive ion etching processes. Specificity of the system to ErbB2 protein biomarker, achieved by functionalizing the PS with anti-ErbB2 monoclonal antibodies, is demonstrated. A concentration limit of detection for ErbB2 protein of 14 ng/mL has been obtained, and no cross-reactivity has been observed with bovine serum albumin (BSA) and tumor necrosis factor alpha (TNFα) proteins. These findings open the possibility of using this type of biosensors in clinical applications.This work was supported by the Spanish Government (MINECO) and the European Community (FEDER) through grant no. MAT-2011–28167-C02. This work was partially funded by the Basque Government within the framework of the Etortek Program (Grant No. IE13-360). M. Morales-Vidal has been partly supported by a MINECO FPI fellowship (no. BES-2009-020747)

Biomarker candidates for progression and clinical management of COVID-19 associated pneumonia at time of admission

COVID-19 pathophysiology is currently not fully understood, reliable prognostic factors remain elusive, and few specific therapeutic strategies have been proposed. In this scenario, availability of biomarkers is a priority. MS-based Proteomics techniques were used to profile the proteome of 81 plasma samples extracted in four consecutive days from 23 hospitalized COVID-19 associated pneumonia patients. Samples from 10 subjects that reached a critical condition during their hospital stay and 10 matched non-severe controls were drawn before the administration of any COVID-19 specific treatment and used to identify potential biomarkers of COVID-19 prognosis. Additionally, we compared the proteome of five patients before and after glucocorticoids and tocilizumab treatment, to assess the changes induced by the therapy on our selected candidates. Forty-two proteins were differentially expressed between patients' evolution groups at 10% FDR. Twelve proteins showed lower levels in critical patients (fold-changes 1.20-3.58), of which OAS3 and COG5 found their expression increased after COVID-19 specific therapy. Most of the 30 proteins over-expressed in critical patients (fold-changes 1.17-4.43) were linked to inflammation, coagulation, lipids metabolism, complement or immunoglobulins, and a third of them decreased their expression after treatment. We propose a set of candidate proteins for biomarkers of COVID-19 prognosis at the time of hospital admission. The study design employed is distinctive from previous works and aimed to optimize the chances of the candidates to be validated in confirmatory studies and, eventually, to play a useful role in the clinical practice

Antiretroviral therapy duration and immunometabolic state determine efficacy of ex vivo dendritic cell-based treatment restoring functional HIV-specific CD8+ T cells in people living with HIV.

Dysfunction of CD8+ T cells in people living with HIV-1 (PLWH) receiving anti-retroviral therapy (ART) has restricted the efficacy of dendritic cell (DC)-based immunotherapies against HIV-1. Heterogeneous immune exhaustion and metabolic states of CD8+ T cells might differentially associate with dysfunction. However, specific parameters associated to functional restoration of CD8+ T cells after DC treatment have not been investigated. We studied association of restoration of functional HIV-1-specific CD8+ T cell responses after stimulation with Gag-adjuvant-primed DC with ART duration, exhaustion, metabolic and memory cell subsets profiles. HIV-1-specific CD8+ T cell responses from a larger proportion of PLWH on long-term ART (more than 10 years; LT-ARTp) improved polyfunctionality and capacity to eliminate autologous p24+ infected CD4+ T cells in vitro. In contrast, functional improvement of CD8+ T cells from PLWH on short-term ART (less than a decade; ST-ARTp) after DC treatment was limited. This was associated with lower frequencies of central memory CD8+ T cells, increased co-expression of PD1 and TIGIT and reduced mitochondrial respiration and glycolysis induction upon TCR activation. In contrast, CD8+ T cells from LT-ARTp showed increased frequencies of TIM3+ PD1- cells and preserved induction of glycolysis. Treatment of dysfunctional CD8+ T cells from ST-ARTp with combined anti-PD1 and anti-TIGIT antibodies plus a glycolysis promoting drug restored their ability to eliminate infected CD4+ T cells. Together, our study identifies specific immunometabolic parameters for different PLWH subgroups potentially useful for future personalized DC-based HIV-1 vaccines. NIH (R21AI140930), MINECO/FEDER RETOS (RTI2018-097485-A-I00) and CIBERINF grants.NIH (R21AI140930), MINECO/FEDER RETOS (RTI2018-097485-A-I00) and CIBERINF grants. We would like to thank the NIH AIDS Reagent Pro- gram, Division of AIDS, NIAID, NIH for providing HIV-1 PTE Gag Peptide Pool from NIAID, DAIDS (cat #11057) for the study. We would also like to thank Alvaro Serrano Navarro, for his help on adapting the lin- ear mixed model previously described by Martin- C ofreces N. et al83 to our data. Graphical schematic rep- resentations were created with BioRender.com. EMG was supported by the NIH R21 program (R21AI140930), the Ramón y Cajal Program (RYC2018- 024374-I), the MINECO/FEDER RETOS program (RTI2018-097485-A-I00), by Comunidad de Madrid Talento Program (2017-T1/BMD-5396) and by Gilead becas de investigaci on (GLD19/00168). EMG and IDS are supported by Centro de Investigación Biomédica en Red (CIBERINF) de Enfermedades Infecciosas (CB21/ 13/00107). MCM was supported by NIH R21 program (R21AI140930), “La Caixa Banking Foundation (H20- 00218) and Gilead becas de investigaci on (GLD19/ 00168). MJB is supported by the Miguel Servet program funded by the Spanish Health Institute Carlos III (CP17/00179), the MINECO/FEDER RETOS program (RTI2018-101082-B-100), and Fundació La Marat o TV3 (201805-10FMTV3). EMG and MJB are both funded by “La Caixa Banking Foundation (H20-00218) and by REDINCOV grant from Fundació La Marat o TV3. FSM was supported by SAF2017-82886-R and PDI-2020- 120412RB-I00 grants from the Ministerio de Ciencia e Innovaci on, and HR17-00016 grant from “La Caixa Banking Foundation. HF was funded by PI21/01583 grant from Ministerio de Ciencia e Innovación, Instituto de Salud Carlos III. MJC was supported by PID2019- 104406RB-I00 from Ministerio de Ciencia e Innovación. ISC was funded by the CM21/00157 Rio- Hortega grant. IT was supported by grant for the pro- motion of research studies master-UAM 2021.S

ERK5 Is a major determinant of chemical sarcomagenesis: implications in human pathology

Sarcomas are a heterogeneous group of tumors in which the role of ERK5 is poorly studied. To clarify the role of this MAPK in sarcomatous pathology, we used a murine 3-methyl-cholanthrene (3MC)-induced sarcoma model. Our data show that 3MC induces pleomorphic sarcomas with muscle differentiation, showing an increased expression of ERK5. Indeed, this upregulation was also observed in human sarcomas of muscular origin, such as leiomyosarcoma or rhabdomyosarcoma. Moreover, in cell lines derived from these 3MC-induced tumors, abrogation of Mapk7 expression by using specific shRNAs decreased in vitro growth and colony-forming capacity and led to a marked loss of tumor growth in vivo. In fact, transcriptomic profiling in ERK5 abrogated cell lines by RNAseq showed a deregulated gene expression pattern for key biological processes such as angiogenesis, migration, motility, etc., correlating with a better prognostic in human pathology. Finally, among the various differentially expressed genes, Klf2 is a key mediator of the biological effects of ERK5 as indicated by its specific interference, demonstrating that the ERK5–KLF2 axis is an important determinant of sarcoma biology that should be further studied in human pathology.This work has been supported with Grant RTI2018-094093-B-I00 funded by MCIN/AEI/10.13039/501100011033, “ERDF A way of making Europe” to RSP. Also supported with funds from Fundación Leticia Castillejo Castillo, Roche España and ACEPAIN to RSP and MJRH. RSP and MJRH’s Research Institute and the work carried out in their laboratory, received partial support from the European Community through the FEDER. JJ and EAL hold a predoctoral research contract cofounded by the European Social Fund and UCLM. OR holds a contract for accessing the Spanish System of Science, Technology, and Innovation (SECTI) funded by the University of Castilla-La Mancha (UCLM) and received partial support from the European Social Fund (FSE) through its Operative Program for Castilla-La Mancha (2007–2013)

ERK5 Is a Major Determinant of Chemical Sarcomagenesis : Implications in Human Pathology

Sarcoma is a heterogeneous group of tumors poorly studied with few therapeutic opportunities. Interestingly, the role of MAPKs still remains unclear in sarcomatous pathology. Here, we describe for the first time the critical role of ERK5 in the biology of soft tissue sarcoma by using in vitro and in vivo approaches in a murine experimental model of chemical sarcomagenesis. Indeed, our observations were extrapolated to a short series of human leiomyosarcoma and rhabdomyosarcomas. Furthermore, transcriptome analysis allows us to demonstrate the critical role of KLF2 in the biological effects of ERK5. Therefore, the data presented here open new windows in the diagnosis and therapy of soft tissue sarcomas. Sarcomas are a heterogeneous group of tumors in which the role of ERK5 is poorly studied. To clarify the role of this MAPK in sarcomatous pathology, we used a murine 3-methyl-cholanthrene (3MC)-induced sarcoma model. Our data show that 3MC induces pleomorphic sarcomas with muscle differentiation, showing an increased expression of ERK5. Indeed, this upregulation was also observed in human sarcomas of muscular origin, such as leiomyosarcoma or rhabdomyosarcoma. Moreover, in cell lines derived from these 3MC-induced tumors, abrogation of Mapk7 expression by using specific shRNAs decreased in vitro growth and colony-forming capacity and led to a marked loss of tumor growth in vivo. In fact, transcriptomic profiling in ERK5 abrogated cell lines by RNAseq showed a deregulated gene expression pattern for key biological processes such as angiogenesis, migration, motility, etc., correlating with a better prognostic in human pathology. Finally, among the various differentially expressed genes, Klf2 is a key mediator of the biological effects of ERK5 as indicated by its specific interference, demonstrating that the ERK5-KLF2 axis is an important determinant of sarcoma biology that should be further studied in human pathology

Estrategias de motivación en el aula: Aplicación del modelo TARGET en asignaturas del Grado y Máster en Ingeniería Química

La titulación en Ingeniería Química ostenta una larga tradición en la Universidad Complutense, que se ha constituido como un referente a nivel nacional en la implantación de nuevos planes de estudio dentro de esta disciplina. En el año 1944 se implantaron por primera vez los estudios de Doctorado en Química Industrial, que incluían asignaturas de especialización en el área de Ingeniería Química. En 1960 se pone en marcha la especialidad de Química Industrial en los dos últimos cursos de la Licenciatura en Ciencias Químicas, cuyo plan de estudios se modificó posteriormente en el año 1970. Finalmente, en 1992 comenzó a impartirse el título de Ingeniero Químico, que se ha mantenido hasta la reciente implantación del Grado en Ingeniería Química, conforme a las directrices del Espacio Europeo de Educación Superior (EEES). Asimismo, los estudios de Posgrado a nivel de Máster se comenzaron a impartir en el año 2006, obteniendo el Programa Oficial de Posgrado en ese mismo año la Mención de Calidad. Actualmente muchos profesores universitarios hemos detectado en el aula una elevada falta de motivación e interés por parte del alumnado, independientemente de la materia o titulación de la que se trate. En muchas ocasiones, nos vemos en la obligación de hablarles en el aula de forma repetitiva e incansable acerca de la importancia del compromiso y la responsabilidad de, por ejemplo, entregar un trabajo en tiempo y forma y sobre la responsabilidad y seriedad que deben ejercer a la hora de ser parte de un grupo de trabajo. Por tanto, en este sentido, la motivación en el aula universitaria se erige como una necesidad pedagógica. Mediante las estrategias propuestas en este proyecto (siguiendo el modelo TARGET), se pretende motivar al alumno, orientándolo en la dirección correcta en el desarrollo de diversas actividades, pero haciéndolo partícipe y responsable de sus propios resultados y metas, haciendo especial hincapié en el reconocimiento del esfuerzo personal. Así, la utilización de recursos digitales y material multimedia, así como el desarrollo de actividades que promueven la participación del alumno (metodologías activas para el aprendizaje) cobra especial relevancia en los estudios de Máster, dado el carácter autónomo que se pretende imprimir a este alumnado, además de la frecuente simultaneidad que se ejerce de los estudios con la actividad profesional. El desarrollo de actividades que promuevan la participación y, como consecuencia, fortalezcan la entidad y autonomía del estudiante en su aprendizaje es el leitmotiv de este Proyecto de Innovación Educativa. Se trata de seguir los pasos necesarios para optimizar el vínculo entre la enseñanza y el aprendizaje, consiguiendo un aprendizaje eficaz. Mediante la aplicación del modelo TARGET se va a incentivar el reconocimiento del alumno -no basado exclusivamente en el resultado final-, lo que favorece la generación de autoestima, la autorrealización del alumno y, por tanto, la motivación. Se prevé, además, que esto redundará en otro beneficio de suma importancia, la reducción en la tasa de abandono durante los primeros cursos, consecuencia directa de la falta de motivación por parte del estudiante y de la necesidad de tener una valoración estable y sensación de pertenencia que no encuentra en el aula. Se ha publicado recientemente que España se consolida como el país de la Unión Europea con mayor tasa de abandono de los estudios (17,9%) entre los jóvenes de 18 a 24 años. La situación es de tal gravedad que muchos de ellos no tienen ni estudios superiores a la Educación Secundaria Obligatoria (ESO). Asimismo, según un estudio publicado por el informe U-Ranking de la Fundación BBVA, 1 de cada 3 alumnos abandona el sistema universitario sin haber terminado la carrera que inició. En este sentido, los analistas educativos, como Francesca Borgonovi, analista de la Organización para la Cooperación y el Desarrollo Económicos (OCDE) refrendan que para mejorar esta circunstancia se deben “potenciar las fortalezas de carácter: autoconfianza, la asertividad, la capacidad de esfuerzo, los altos niveles de motivación interna para el logro del éxito y la ambición de sus aspiraciones de futuro”

Formas de Hispanidad

Este texto presenta estudios sobre las múltiples formas de hispanidad, desarrollados en los últimos años por destacados investigadores del mundo hispánico que, poco a poco, han estado construyendo un nuevo espacio de investigación para una creciente y activa comunidad científica. En este libro el lector encontrará estudios con enfoques desde la ciencia política, la teoría política, la historia, la filosofía, la sociología, la economía, los estudios literarios y culturales, entre otras perspectivas académicas. Los aportes de cada aproximación teórica y disciplinar están orientados al logro de una meta común: la de reconstruir y reinterpretar la tradición histórica hispánica, desmantelando prejuicios ideológicamente provocados, con el fin de comprender los fenómenos políticos que la caracterizan. Por las mismas razones este libro se sitúa en el debate sobre las formas de escritura de la historia, que no es sólo un debate de teoría de la historia sino también de filosofía de lo histórico

New insights into the pathogenesis and transmission of Brucella pinnipedialis: systemic infection in two bottlenose dolphins ( Tursiops truncatus)

The emergence of Brucella infections in marine mammals is a growing concern. The present study reports two cases of systemic Brucella pinnipedialis infection detected in bottlenose dolphins (Tursiops truncatus) pair stranded together in the Cantabrian coast of Spain. Both animals showed systemic lesions associated with the Brucella infection, more severe in the younger dolphin, considered the likely offspring of the other individual. Real-time PCR, bacterial culture, and whole-genome sequencing were used to detect and characterize the Brucella strains involved in both dolphins. The phylogenetic analysis performed on the Brucella genomes retrieved revealed that the species involved was B. pinnipedialis (ST25). Both animals resulted seropositive in a commercial multispecies blocking ELISA but tested negative in the standard Rose Bengal test. To the best of our knowledge, this is the first report of a systemic infection resulting in various lesions associated with Brucella pinnipedialis (ST25) in two bottlenose dolphins. It is also the initial isolation of Brucella in the milk of a non-pregnant or non-aborting female cetacean likely stranded with its offspring. These findings provide new insights into the epidemiology and clinical impact of B. pinnipedialis infection in cetaceans and underscore the importance of continued diagnostic surveillance to gain better understanding of brucellosis effects and transmission in marine mammal populations.Este trabajo ha contado con el apoyo de un convenio de colaboración entre la Fundación Oceanogràfic (Valencia), la Consejería de Medio Rural, Ganadería, Pesca, Alimentación y Medio Ambiente del Gobierno de Cantabria y el Centro de Vigilancia Sanitaria Veterinaria (VISAVET) de la Universidad Complutense de Madrid. Este convenio permite la recogida de muestras de cadáveres de cetáceos varados y aporta fondos para la realización de estudios post-mortem. Ignacio Vargas-Castro es beneficiario de una beca FPU del Ministerio de Ciencia, Innovación y Universidades. El trabajo del CITA fue apoyado por el Gobierno de Aragón (Grupo de Investigación A21_23R). André E. Moura recibió el apoyo del Centro Nacional de Ciencia de Polonia (beca de investigación Sonata 2018/31/D/NZ8/02835) y de la Agencia Nacional Polaca de Intercambio Académico (programa NAWA Ulam PPN/ ULM/2019/1/00162).milkBrucella pinnipedialisbottlenose dolphinmarine mammalssystemic infectionhealth surveillancetransmissionwhole-genome sequencingPublishe