The 1430s: a cold period of extraordinary internal climate variability during the early Spörer Minimum with social and economic impacts in north-western and central Europe

Changes in climate affected human societies throughout the last millennium. While European cold periods in the 17th and 18th century have been assessed in detail, earlier cold periods received much less attention due to sparse information available. New evidence from proxy archives, historical documentary sources and climate model simulations permit us to provide an interdisciplinary, systematic assessment of an exceptionally cold period in the 15th century. Our assessment includes the role of internal, unforced climate variability and external forcing in shaping extreme climatic conditions and the impacts on and responses of the medieval society in north-western and central Europe. Climate reconstructions from a multitude of natural and anthropogenic archives indicate that the 1430s were the coldest decade in north-western and central Europe in the 15th century. This decade is characterised by cold winters and average to warm summers resulting in a strong seasonal cycle in temperature. Results from comprehensive climate models indicate consistently that these conditions occurred by chance due to the partly chaotic internal variability within the climate system. External forcing like volcanic eruptions tends to reduce simulated temperature seasonality and cannot explain the reconstructions. The strong seasonal cycle in temperature reduced food production and led to increasing food prices, a subsistence crisis and a famine in parts of Europe. Societies were not prepared to cope with failing markets and interrupted trade routes. In response to the crisis, authorities implemented numerous measures of supply policy and adaptation such as the installation of grain storage capacities to be prepared for future food production shortfalls

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

Abstract The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared to information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known non-pathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification. This article is protected by copyright. All rights reserved.Peer reviewe

Impact of infection on proteome-wide glycosylation revealed by distinct signatures for bacterial and viral pathogens

Mechanisms of infection and pathogenesis have predominantly been studied based on differential gene or protein expression. Less is known about posttranslational modifications, which are essential for protein functional diversity. We applied an innovative glycoproteomics method to study the systemic proteome-wide glycosylation in response to infection. The protein site-specific glycosylation was characterized in plasma derived from well-defined controls and patients. We found 3862 unique features, of which we identified 463 distinct intact glycopeptides, that could be mapped to more than 30 different proteins. Statistical analyses were used to derive a glycopeptide signature that enabled significant differentiation between patients with a bacterial or viral infection. Furthermore, supported by a machine learning algorithm, we demonstrated the ability to identify the causative pathogens based on the distinctive host blood plasma glycopeptide signatures. These results illustrate that glycoproteomics holds enormous potential as an innovative approach to improve the interpretation of relevant biological changes in response to infection

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children

Sea urchin Arbacia dufresnei (Blainville 1825) larvae response to ocean acidification

Increased atmospheric CO 2 emissions are inducing changes in seawater carbon chemistry, lowering its pH, decreasing carbonate ion availability and reducing calcium carbonate saturation state. This phenomenon, known as ocean acidification, is happening at a faster rate in cold regions, i.e. polar and sub-polar waters. The larval development of Arbacia dufresnei from a sub-Antarctic population was studied at high (8.0), medium (7.7) and low (7.4) pH waters. The results show that the offspring from sub-Antarctic populations of A. dufresnei are susceptible to a development delay at low pH, with no significant increase in abnormal forms. Larvae were isometric between pH treatments. Even at calcium carbonate (CaCO 3) saturation states (of both calcite and aragonite, used as proxies of the magnesium calcite) <1, skeleton deposition occurred. Polar and sub-polar sea urchin larvae can show a certain degree of resilience to acidification, also emphasizing A. dufresnei potential to poleward migrate and further colonize southern regions. © 2011 Springer-Verlag.IF: 1,445SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Discovery of a New Classical Nova Shell Around a Nova-like Cataclysmic Variable

The morphology and optical spectrum of IPHASX J210204.7+471015, a nebula classified as a possible planetary nebula are, however, strikingly similar to those of AT Cnc, a classical nova shell around a dwarf nova. To investigate its true nature, we have obtained high-resolution narrowband [O iii] and [N ii] images and deep optical spectra. The nebula shows an arc of [N ii]-bright knots notably enriched in nitrogen, while an [O iii]-bright bow shock is progressing throughout the ISM. Diagnostic line ratios indicate that shocks are associated with the arc and bow shock. The central star of this nebula has been identified by its photometric variability. Time-resolved photometric and spectroscopic data of this source reveal a period of 4.26 hr, which is attributed to a binary system. The optical spectrum is notably similar to that of RW Sex, a cataclysmic variable star (CV) of the UX UMa nova-like (NL) type. Based on these results, we propose that IPHASX J210204.7 + 471015 is a classical nova shell observed around a CV-NL system in quiescence.© 2018. The American Astronomical Society. All rights reserved.M.A.G. acknowledges support of the grant AYA 2014-57280-P, cofunded with FEDER funds. L.S. acknowledges support from PAPIIT grant IA-101316 (Mexico). G.T. has been supported by grants PAPIIT IN108316 and CONACyT 166376. G. R.-L. acknowledges support from Universidad de Guadalajara, CONACyT, PRODEP, and SEP (Mexico). AA postdoctoral grant and some computational resources are from CONACyT 2015-CB/254132 and UNAM-DGAPA-PAPIIT-107215 projects. N.J.W. acknowledges an STFC Ernest Rutherford Fellowship. This article is partially based upon observations carried out at the Observatorio Astronomico Nacional on the Sierra San Pedro Martir (OAN SPM), Baja California, Mexico. We thank the daytime and night support staff at the OAN SPM for facilitating and helping obtain our observations. Some of the data presented here were obtained with ALFOSC, which is provided by the Instituto de Astrofisica de Andalucia (IAA) under a joint agreement with the University of Copenhagen and NOTSA. This article is based in part on observations made with the Gran Telescopio Canarias (GTC), installed in the Spanish Observatorio del Roque de los Muchachos of the Instituto de Astrofisica de Canarias, in the island of La Palma. This paper also makes use of data obtained as part of the INT Photometric Ha Survey of the Northern Galactic Plane (IPHAS: http://www.iphas.org) carried out at the Isaac Newton Telescope (INT). The INT is operated on the island of La Palma by the Isaac Newton Group in the Spanish Observatorio del Roque de los Muchachos of the Instituto de Astrofisica de Canarias. All IPHAS data are processed by the Cambridge Astronomical Survey Unit at the Institute of Astronomy in Cambridge. The band-merged DR2 catalog was assembled at the Centre for Astrophysics Research, University of Hertfordshire, supported by STFC grant ST/J001333/1

Primeros pasos docentes en la Facultad de Educación: Red de docentes mentores y acciones formativas en docencia y en investigación (V edición)

La Universidad Complutense de Madrid (UCM) es una de las mayores universidades de España tanto en lo referido a su alumnado como a sus dimensiones físicas, y esto hace que, en ocasiones, resulte complicado crear una identidad que conecte al profesorado y que haga sentir que se forma parte de un mismo proyecto. La acogida y el bienestar en una organización es un elemento esencial para la salud mental, física y emocional de las personas que la componen. Velar por el bienestar de las personas es un elemento indispensable para favorecer el funcionamiento de una institución, en este caso, el presente proyecto plantea como objetivo último velar por el bienestar de los nuevos docentes y conocer y reconocer las consecuencias que esto tiene en el desarrollo de sus funciones, dado que el bienestar, la salud y las competencias personales y profesionales están íntimamente relacionadas con la competencia emocional (Bisquerra y Pérez, 2007). La educación es uno de los pilares del bienestar social de un país y, por tanto, como profesionales universitarios dedicados a la formación de futuros profesionales de la Educación debemos ser conscientes del reto al que nos enfrentamos como responsables de la formación de este alumnado en una universidad como la nuestra. Crear una identidad común como docentes y una pertenencia al centro, ayudará como hilo conductor a la transmisión no solo de conocimientos, sino también de actitudes y valores. En la Facultad de Educación - Centro de Formación del Profesorado, existe una constante entrada de Personal Docente e Investigador (PDI) cada año (como ejemplo cabe decir que durante el primer semestre del curso 2022-2023 se han incorporado 20 profesores y profesoras). Algunos de estos profesionales han tenido una experiencia previa en el entorno, bien como alumnado bien como colaboradores en la Universidad o la Facultad, sin embargo, para otros es la primera vez que tienen contacto tanto con el centro como con la Universidad. Por ello, hace ya cuatro años, un equipo de docentes de la Facultad de Educación-CFP puso en marcha a través de diferentes Proyectos de Innovación (modalidad Innova-Docencia) una propuesta de largo recorrido cuyo objetivo fundamental fuese acompañar a los nuevos docentes desde el inicio de su incorporación a la vida universitaria. Se trataba de ofrecer una primera acogida que les permitiera crear relaciones personales, profesionales e interdepartamentales con todos los miembros que forman parte del centro.Depto. de Investigación y Psicología en EducaciónFac. de EducaciónFALSEsubmitte