Proteasome inhibition by new dual warhead containing peptido vinyl sulfonyl fluorides

The success of inhibition of the proteasome by formation of covalent bonds is a major victory over the long held-view that this would lead to binding the wrong targets and undoubtedly lead to toxicity. Great challenges are now found in uncovering ensembles of new moieties capable of forming long lasting ties. We have introduced peptido sulfonyl fluorides for this purpose. Tuning the reactivity of this electrophilic trap may be crucial for modulating the biological action. Here we describe incorporation of a vinyl moiety into a peptido sulfonyl fluoride backbone, which should lead to a combined attack of the proteasome active site threonine on the double bond and the sulfonyl fluoride. Although this led to strong proteasome inhibitors, in vitro studies did not unambiguously demonstrate the formation of the proposed seven-membered ring structure. Possibly, formation of a seven-membered covalent adduct with the proteosomal active site threonine can only be achieved within the context of the enzyme. Nevertheless, this dual warhead concept may provide exclusive possibilities for duration and selectivity of proteasome inhibition

Perceived Reportability of Intimate Partner Violence against Women to the Police and Help-seeking: A National Survey

The literature has consistently found that victims of intimate partner violence (IPV) against women are reluctant to make their situation visible and report it to the police. Whether victims perceive and define IPV behaviors as reportable is key to understanding in which cases the police are seen as potential providers of help or whether other potential sources of help (family, friends, professionals, etc.) are preferred. The purpose of the present study was to analyze the influence of perceived reportability of IPV on women’s selection of the police as a source of help compared to not seeking help or selecting other sources of help. Structural equation modeling was applied to data from 479 female participants drawn from a nationally representative sample of 1,112 male and female Chilean adolescents and young adults conducted by the National Youth Institute of Chile. The results showed that perceived reportability was a significant predictor of choosing the police as a source of help compared to other informal sources of help, such as family and friends. However, perceived reportability did not affect help-seeking choices between the police and other formal help sources (psychologists, public services). Participants’ IPV victimization and attitudes toward IPV also played a specific role in selecting the police as a source of help. These findings highlight the complexity of the visibility of women’s IPV victimization to the police and the need to examine its explanatory mechanisms. Las publicaciones científicas señalan sistemáticamente la reticencia de las víctimas de violencia de pareja contra las mujeres a hacer visible su situación y denunciarla ante la policía. El hecho de que las víctimas perciban y definan las conductas de violencia de pareja como denunciables es clave para comprender en qué casos se considera a la policía como posible proveedora de ayuda o si se prefieren otros potenciales proveedores de ayuda (familiares, amigos, especialistas, etc.). El objetivo de la presente investigación ha sido analizar la influencia de la percepción de la capacidad de denunciar la violencia de pareja en la selección de la policía como proveedora de ayuda por parte de las mujeres, en comparación con la falta de búsqueda de ayuda o la selección de otros proveedores de la misma. Se han analizado los datos de 479 mujeres participantes en el estudio de una muestra representativa nacional de 1,112 adolescentes y jóvenes chilenos de ambos sexos realizado por el Instituto Nacional de la Juventud de Chile. Los resultados mostraron que la capacidad de denuncia percibida predice la selección de la policía como proveedor de ayuda en comparación con otras fuentes informales de ayuda, como la familia o los amigos. Sin embargo, no pareció tener efecto en la selección de la búsqueda de ayuda comparar a la policía con otras fuentes formales de ayuda (psicólogos, servicios públicos). La victimización y las actitudes hacia la violencia de pareja también desempeñan un papel específico en la selección de la policía como proveedora de ayuda. Los resultados demuestran la complejidad de la visibilidad para la policía de la violencia en la pareja contra las mujeres y la necesidad de examinar sus mecanismos explicativos

Ellipsometric characterization of Bi and Al2O3 coatings for plasmon excitation in an optical fiber sensor

The authors present the results of the ellipsometric characterization of thin layers of bismuth and aluminum oxide deposited over the waist of a tapered optical fiber by pulsed laser deposition. The characteristics of the deposits are studied by spectroscopic ellipsometry. From the effective thicknesses determined by the ellipsometric characterization, it is shown by simulations that surface plasmon resonances (SPRs) can occur in the fiber device, and it is demonstrated experimentally. These results show the feasibility of employing bismuth as a plasmonic material in SPR fiber sensors based on doubly-deposited uniform-waist tapered optical fibers, which show excellent performance and versatility

Policy Coherence for Development in the Basque Country: diagnosis and proposals

Resumen ejecutivo en euskera, inglés y español. Informe completo en españolEl texto que aquí se presenta es un resumen del Informe encargado a Hegoa, Instituto de Estudios sobre Desarrollo y Cooperación Internacional (Universidad del País Vasco, UPV/EHU) por la Agencia Vasca de Cooperación para el Desarrollo, relativo al análisis de la Coherencia de Políticas para el Desarrollo (CPD) en Euskadi. El trabajo fue realizado entre los meses de abril y septiembre de 2014, y su realización estuvo a cargo del Grupo de Investigación sobre Políticas de Desarrollo y Cooperación. El encargo se enmarca en la creciente importancia concedida al tema de la CPD en el ámbito internacional y tiene que ver asimismo con la necesidad, planteada desde hace ya algún tiempo en el Consejo Vasco de Cooperación para el Desarrollo, de acometer un diagnóstico específico sobre la situación y las posibilidades de avance existentes en Euskadi en este terrenoGobierno Vasc

Innovación docente y creación de recursos educativos en abierto para Psicometría.

El objetivo del proyecto es el desarrollo de un banco de recursos educativos en abierto para dar soporte a metodologías docentes innovadoras en la asignatura de Psicometría y fomentar el papel activo del alumnado en su proceso de aprendizaje.Depto. de Psicobiología y Metodología en Ciencias del ComportamientoFac. de PsicologíaFALSEsubmitte

Position paper on screening for breast cancer by the European Society of Breast Imaging (EUSOBI) and 30 national breast radiology bodies from Austria, Belgium, Bosnia and Herzegovina, Bulgaria, Croatia, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Israel, Lithuania, Moldova, The Netherlands, Norway, Poland, Portugal, Romania, Serbia, Slovakia, Spain, Sweden, Switzerland and Turkey.

UNLABELLED: EUSOBI and 30 national breast radiology bodies support mammography for population-based screening, demonstrated to reduce breast cancer (BC) mortality and treatment impact. According to the International Agency for Research on Cancer, the reduction in mortality is 40 % for women aged 50-69 years taking up the invitation while the probability of false-positive needle biopsy is <1 % per round and overdiagnosis is only 1-10 % for a 20-year screening. Mortality reduction was also observed for the age groups 40-49 years and 70-74 years, although with "limited evidence". Thus, we firstly recommend biennial screening mammography for average-risk women aged 50-69 years; extension up to 73 or 75 years, biennially, is a second priority, from 40-45 to 49 years, annually, a third priority. Screening with thermography or other optical tools as alternatives to mammography is discouraged. Preference should be given to population screening programmes on a territorial basis, with double reading. Adoption of digital mammography (not film-screen or phosphor-plate computer radiography) is a priority, which also improves sensitivity in dense breasts. Radiologists qualified as screening readers should be involved in programmes. Digital breast tomosynthesis is also set to become "routine mammography" in the screening setting in the next future. Dedicated pathways for high-risk women offering breast MRI according to national or international guidelines and recommendations are encouraged. KEY POINTS: • EUSOBI and 30 national breast radiology bodies support screening mammography. • A first priority is double-reading biennial mammography for women aged 50-69 years. • Extension to 73-75 and from 40-45 to 49 years is also encouraged. • Digital mammography (not film-screen or computer radiography) should be used. • DBT is set to become "routine mammography" in the screening setting in the next future

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

Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation.

GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84-0.87; P=1.7 × 10(-43)) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology