Anglo-Iberian Relations 1150-1280: A Diplomatic History

This thesis examines the political relations between England and the Iberian Peninsula, from the accession of Henry II of England to the death of Alfonso X of León-Castile, an episode in diplomatic history that remains largely unexplored. This period, spanning over a century and a half, was punctuated by a series of key political events. The study of these sheds light upon the diplomatic complexities of the period. Chapter One explores the historiography and the particularities of Spanish documentary sources. Chapter Two analyses the use of the word Hispania in thirteenth-century chronicles and charters, in an attempt to discover how the term was used and to whom it referred. Chapters Three examines the close relations between the crown of Aragón and the vicomté of Béarn in the twelfth century, while the following chapter looks at the unification of Catalonia and Aragón and the implications of the marriage between Eleanor of England and Alfonso VIII of Castile. Chapter Five explores the impact of Richard I and John’s alliances with Navarre. As León-Castile consolidated is power in the Peninsula, there was a shift of alliances, reflected on Anglo-Iberian relations. Chapter Six explores the particular circumstances that brought about the treaty of 1254 between Henry III of England and Alfonso X of Castile. No study of the political relations of the period would be complete without examination of the impact of the imperial controversy and interregnum upon relations between Henry III of England (the brother of a claimant) and Alfonso X of Castile (a claimant in his own right). Finally, Chapter Eight studies the failed marriage of the infante Sancho of Castile and Gilhelme (Willemina), the younger daughter of the vicomte of Béarn, Gaston VII. This involved negotiations between Edward I of England, Philip III of France and Alfonso X of Castile

Sistema de seguridad y salud en el trabajo según la Ley 29783 para reducir el nivel de riesgo laboral en la empresa SV2 Contratistas Generales S.R.L. – Trujillo

El propósito de esta investigación es aplicar el sistema de seguridad y salud en el trabajo según la Ley 29783 para reducir el nivel de riesgo laboral en la empresa SV2 Contratistas generales S.R.L– Trujillo, esto permitirá a minimizar los niveles de riesgo y por ende proteger la integridad de sus trabajadores. El proyecto pertenece al tipo de investigación aplicada, con nivel de investigación descriptiva y diseño de investigación no experimental – transversal. Se utiliza una serie de técnicas y herramientas, como el análisis documental y la observación directa. La investigación tiene dos momentos, los cuales están diseñados en un antes y después de aplicar el sistema. Para poder indicar la situación actual que presenta la empresa se determinó un valor de 71.23% del no cumplimento de los lineamientos, además se analizó la empresa mediante una matriz FODA, la cual permitió conocer sus fortaleces y oportunidades que permitirán contrarrestar sus amenazas y mejorar sus debilidades. Para tener un control más fino en el proceso de construcción de torres de alta tensión de aplicó la matriz IPERC, la cual ayudó a determinar los peligros y proponer medidas de control, se identificó 22 riesgos con nivel intolerables con un valor promedio de 20.37% y 27 riesgos con nivel importante con un promedio del 25%, estos valores se mitigaron en el segundo momento de la aplicación con resultados de a 0% y 0.93% en los niveles Intolerable e importante respectivamente, además de pasar a un 30.56% en nivel tolerable. Cabe resultar que también se inició el control del nivel trivial con un 1.85% lo que indica que nuestro sistema propuesto es eficiente. Como indicador final se analizó un estudio del B/C, lo cual al aplicar el sistema propuesto se tiene valor de 1.05 mostrando un resultado rentable para la entidad.The purpose of this research is to apply the occupational health and safety system according to Law 29783 to reduce the level of occupational risk in the company SV2 General Contractors SRL - Trujillo, this will allow to minimize the risk levels and therefore protect the integrity of its workers. The project belongs to the type of applied research, with a descriptive research level and a non-experimental - crosssectional research design. A series of techniques and tools are used, such as documentary analysis and direct observation. The investigation has two moments, which are designed before and after applying the system. To indicate the current situation that the company presents, a value of 71.23% of non-compliance with the guidelines was determined, in addition, the company was analyzed through a SWOT matrix, which will improve knowing its strengths and opportunities that will allow to counteract its threats and improve its weaknesses. To have finer control in the process of construction of high voltage towers, the IPERC matrix was applied, which helped to determine the dangers and propose control measures, 22 risks with intolerable levels were identified with an average value of 20.37% and 27 risks with an important level with an average of 25%, these values were mitigated in the second moment of the application with results of 0% and 0.93% in the Intolerable and important levels respectively, in addition to going to 30.56% in the tolerable level. It may turn out that the control of the trivial level also began with 1.85%, which indicates that our proposed system is efficient. As a final indicator, a study of the B / C was analyzed, which when applying the proposed system has a value of 1.05, showing a profitable result for the entity.Tesi

Estradiol Activates β-Catenin Dependent Transcription in Neurons

Estradiol may fulfill a plethora of functions in neurons, in which much of its activity is associated with its capacity to directly bind and dimerize estrogen receptors. This hormone-protein complex can either bind directly to estrogen response elements (ERE's) in gene promoters, or it may act as a cofactor at non-ERE sites interacting with other DNA-binding elements such as AP-1 or c-Jun. Many of the neuroprotective effects described for estrogen have been associated with this mode of action. However, recent evidence suggests that in addition to these “genomic effects”, estrogen may also act as a more general “trophic factor” triggering cytoplasmic signals and extending the potential activity of this hormone. We demonstrated that estrogen receptor alpha associates with β-catenin and glycogen synthase kinase 3 in the brain and in neurons, which has since been confirmed by others. Here, we show that the action of estradiol activates β-catenin transcription in neuroblastoma cells and in primary cortical neurons. This activation is time and concentration-dependent, and it may be abolished by the estrogen receptor antagonist ICI 182780. The transcriptional activation of β-catenin is dependent on lymphoid enhancer binding factor-1 (LEF-1) and a truncated-mutant of LEF-1 almost completely blocks estradiol TCF-mediated transcription. Transcription of a TCF-reporter in a transgenic mouse model is enhanced by estradiol in a similar fashion to that produced by Wnt3a. In addition, activation of a luciferase reporter driven by the engrailed promoter with three LEF-1 repeats was mediated by estradiol. We established a cell line that constitutively expresses a dominant-negative LEF-1 and it was used in a gene expression microarray analysis. In this way, genes that respond to estradiol or Wnt3a, sensitive to LEF-1, could be identified and validated. Together, these data demonstrate the existence of a new signaling pathway controlled by estradiol in neurons. This pathway shares some elements of the insulin-like growth factor-1/Insulin and Wnt signaling pathways, however, our data strongly suggest that it is different from that of both these ligands. These findings may reveal a set of new physiological roles for estrogens, at least in the Central Nervous System (CNS)

A risk-organised model for clinically significant prostate cancer early detection

Prostate cancer; Risk‐organised modelCàncer de pròstata; Model organitzat de riscCáncer de próstata; Modelo organizado de riesgoThe Instituto de Salut Carlos III (SP) and European Union financed this project, ref. PI20/01666

La decisión sobre relocalización: ¿alternativa rentable o amenaza de supervivencia? Estudio de caso empresa: muelles y frenos Rincón Ltda

En el presente estudio de caso se analizará la empresa Muelles y llantas Rincón Ltda. cuya actividad principal se basa en el servicio de mantenimiento preventivo y correctivo de vehículos de carga, realizando un análisis sobre los aspectos que le impactarían la decisión que pueda tomar el gerente de la compañía al decidir sobre la ubicación actual de su empresa.En el mes de agosto del año 2017, el  señor Rincón  recibe una llamada del dueño de la Bodega donde está funcionando la empresa Muelles y frenos Rincón Ltda, la cual tiene rentada, en dicha llamada se le solicita la entrega del inmueble antes del 31 de Diciembre del mismo año, bodega  que  estaba arrendada por el señor Rincón por más de 19 años y donde ha ejercido su actividad por el mismo tiempo, al señor Rincón esta noticia le preocupa ya que en esta bodega  fue donde surgió su empresa Muelles y frenos Rincón Ltda y donde con mucho esfuerzo compro sus primeras herramientas para operar y construir así su capital. Adicionalmente le preocupa el futuro de sus trabajadores ya que son 10 familias que prácticamente dependen económicamente de la empresa.El señor Rincon enfrenta una disyuntiva que consiste en decidir cuál va a ser el futuro de su empresa y definir la nueva ubicación y los impactos que puede traer su decisión

Metagenomic Mining for Esterases in the Microbial Community of Los Rueldos Acid Mine Drainage Formation

Acid mine drainage (AMD) systems are extremely acidic and are metal-rich formations inhabited by relatively low-complexity communities of acidophiles whose enzymes remain mostly uncharacterized. Indeed, enzymes from only a few AMD sites have been studied. The low number of available cultured representatives and genome sequences of acidophiles inhabiting AMDs makes it difficult to assess the potential of these environments for enzyme bioprospecting. In this study, using naïve and in silico metagenomic approaches, we retrieved 16 esterases from the α/β-hydrolase fold superfamily with the closest match from uncultured acidophilic Acidobacteria, Actinobacteria (Acidithrix, Acidimicrobium, and Ferrimicrobium), Acidiphilium, and other Proteobacteria inhabiting the Los Rueldos site, which is a unique AMD formation in northwestern Spain with a pH of ∼2. Within this set, only two polypeptides showed high homology (99.4%), while for the rest, the pairwise identities ranged between 4 and 44.9%, suggesting that the diversity of active polypeptides was dominated not by a particular type of protein or highly similar clusters of proteins, but by diverse non-redundant sequences. The enzymes exhibited amino acid sequence identities ranging from 39 to 99% relative to homologous proteins in public databases, including those from other AMDs, thus indicating the potential novelty of proteins associated with a specialized acidophilic community. Ten of the 16 hydrolases were successfully expressed in Escherichia coli. The pH for optimal activity ranged from 7.0 to 9.0, with the enzymes retaining 33–68% of their activities at pH 5.5, which was consistent with the relative frequencies of acid residues (from 54 to 67%). The enzymes were the most active at 30–65°C, retaining 20–61% of their activity under the thermal conditions characterizing Los Rueldos (13.8 ± 0.6°C). The analysis of the substrate specificity revealed the capacity of six hydrolases to efficiently degrade (up to 1,652 ± 75 U/g at pH 8.0 and 30°C) acrylic- and terephthalic-like [including bis(2-hydroxyethyl)-terephthalate, BHET] esters, and these enzymes could potentially be of use for developing plastic degradation strategies yet to be explored. Our assessment uncovers the novelty and potential biotechnological interest of enzymes present in the microbial populations that inhibit the Los Rueldos AMD system

Cellular Senescence Is Immunogenic and Promotes Antitumor Immunity

Senescencia celular; Inmunidad antitumoralSenescència cel·lular; Immunitat antitumoralCellular senescence; Antitumor immunityCellular senescence is a stress response that activates innate immune cells, but little is known about its interplay with the adaptive immune system. Here, we show that senescent cells combine several features that render them highly efficient in activating dendritic cells (DC) and antigen-specific CD8 T cells. This includes the release of alarmins, activation of IFN signaling, enhanced MHC class I machinery, and presentation of senescence-associated self-peptides that can activate CD8 T cells. In the context of cancer, immunization with senescent cancer cells elicits strong antitumor protection mediated by DCs and CD8 T cells. Interestingly, this protection is superior to immunization with cancer cells undergoing immunogenic cell death. Finally, the induction of senescence in human primary cancer cells also augments their ability to activate autologous antigen-specific tumor-infiltrating CD8 lymphocytes. Our study indicates that senescent cancer cells can be exploited to develop efficient and protective CD8-dependent antitumor immune responses. Significance: Our study shows that senescent cells are endowed with a high immunogenic potential—superior to the gold standard of immunogenic cell death. We harness these properties of senescent cells to trigger efficient and protective CD8-dependent antitumor immune responses.We are grateful to Maria Isabel Muñoz for assistance with the animal protocols; to Kevin Kovalchik for help with data sharing; to Francesca Castoldi for help in total RNA extraction for B16F10 and IMR-90 cells; to Fredrik Fagerstrom-Billai, Susann Fält, Anastasios Damdimopoulos, and David Brodin at Bioinformatics and Expression Analysis Core Facility, Karolinska Institute (KI), for assistance in RNA-seq and analysis; to the IRB core facilities (Functional Genomics, Biostatistics/Bioinformatics and Histopathology); and to the PCB (Animal House) for general research support. I. Marin was the recipient of an FPI fellowship from the Spanish Ministry of Science (PRE2018-083381). O. Boix was the recipient of an FPI-AGAUR fellowship from the Generalitat de Catalunya. A. Garcia-Garijo was supported by a PERIS grant (SLT017/20/000131) from the Generalitat de Catalunya. J.A. López-Domínguez and M. Kovatcheva were supported by a fellowship from the Spanish Association Against Cancer (AECC). Work in the laboratory of E. Caron was funded by the Fonds de recherche du Québec – Santé (FRQS), the Cole Foundation, CHU Sainte-Justine, the Charles-Bruneau Foundation, the Canada Foundation for Innovation, the National Sciences and Engineering Research Council (#RGPIN-2020-05232), and the Canadian Institutes of Health Research (#174924). E. Garralda received funding from the Comprehensive Program of Cancer Immunotherapy and Immunology II (CAIMI-II) supported by the BBVA Foundation (grant 53/2021). The M. Abad lab received funding from the Spanish Ministry of Science and Innovation (RTI2018-102046-B-I00A and RTC-2017-6123-1) and the AECC (PRYCO211023SERR). M. Abad was the recipient of a Ramón y Cajal contract from the Spanish Ministry of Science and Innovation (RYC-2013-14747). A. Gros received funding from the Spanish Ministry of Science cofunded by the European Regional Development Fund (ERDF; RTC-2017-6123-1), from the Instituto de Salud Carlos III (MS15/00058), and from CAIMI-II (grant 53/2021) supported by the BBVA Foundation. The work in the laboratory of F. Pietrocola is supported by a KI Starting Grant, a Starting Grant from the Swedish Research Council (2019_02050_3), and grants from the Harald Jeanssons Foundation, the Loo and Hans Osterman Foundation, and Cancerfonden (21 1637 Pj). Work in the laboratory of M. Serrano was funded by the IRB and La Caixa Foundation, and by grants from the Spanish Ministry of Science cofunded by the European Regional Development Fund (SAF-2017-82613-R, RTC-2017-6123-1), the European Research Council (ERC-2014-AdG/669622), Secretaria d'Universitats i Recerca del Departament d'Empresa i Coneixement of Catalonia (Grup de Recerca consolidat 2017 SGR 282), and the AECC (PRYCO211023SERR). The publication costs of this article were defrayed in part by the payment of publication fees. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734

A Clinically Significant Prostate Cancer Predictive Model Using Digital Rectal Examination Prostate Volume Category to Stratify Initial Prostate Cancer Suspicion and Reduce Magnetic Resonance Imaging Demand

Magnetic resonance imaging; Predictive model; Prostate cancerImágenes por resonancia magnética; Modelo predictivo; Cáncer de próstataImatges per ressonància magnètica; Model predictiu; Càncer de pròstataA predictive model including age, PCa family history, biopsy status (initial vs repeat), DRE (normal vs abnormal), serum prostate-specific antigen (PSA), and DRE prostate volume ca-tegory was developed to stratify initial PCa suspicion in 1486 men with PSA > 3 ng/mL and/or abnormal DRE, in whom mpMRI followed; 2- to 4-core TRUS-guided biopsies where Prostate Imaging Report and Data System (PI-RADS) > 3 lesions and/or 12-core TRUS systematic biopsies were performed in one academic institution between 1 January 2016–31 December 2019. The csPCa detection rate, defined as International Society of Uro-Pathology grade group 2 or higher, was 36.9%. An external validation of designed BCN-RC 1 was carried out on 946 men from two other institutions in the same metropolitan area, using the same criteria of PCa suspicion and diagnostic approach, yielded a csPCa detection rate of 40.8%. The areas under the receiver operating characteristic curves of BCN-RC 1 were 0.823 (95% CI: 0.800–0.846) in the development cohort and 0.837 (95% CI: 0.811–0.863) in the validation cohort (p = 0.447). In both cohorts, BCN-RC 1 exhibited net benefit over performing mpMRI in all men from 8 and 12% risk thresholds, respectively. At 0.95 sensitivity of csPCa, the specificities of BCN-RC 1 were 0.24 (95% CI: 0.22–0.26) in the development cohort and 0.34 (95% CI: 0.31–0.37) in the validation cohort (p < 0.001). The percentages of avoided mpMRI scans were 17.2% in the development cohort and 22.3% in the validation cohort, missing between 1.8% and 2% of csPCa among men at risk of PCa. In summary, BCN-RC 1 can stratify initial PCa suspicion, reducing the demand of mpMRI, with an acceptable loss of csPCa.This research was funded by Instituto de Salut Carlos III (SP) and European Union, grant number PI20/01666

A risk-organised model for clinically significant prostate cancer early detection

Prostate cancer; Risk‐organised modelCàncer de pròstata; Model organitzat de riscCáncer de próstata; Modelo organizado de riesgoThe Instituto de Salut Carlos III (SP) and European Union financed this project, ref. PI20/01666