Accurate and precise quantification of Cu,Zn-SOD in human red blood cells using species-specific double and triple IDMS

Acknowledgements This research was undertaken within the EMRP project HLT05. The EMRP was jointly funded by the EMRP participating countries within EURAMET and the European Union. We gratefully acknowledge support by the Braunschweig International Graduate School of Metrology B-IGSM.Peer reviewedPostprin

Autophagic Flux Failure in Neurodegeneration: Identifying the Defect and Compensating Flux Offset

Protein degradation through autophagy is one of the key pathways that maintain proteostasis and neuronal viability. Dysregulation in autophagy has been associated with a number of major protein aggregation storage disorders that are characterized by increased cellular vulnerability and susceptibility to undergo cell death. Although the molecular machinery, the proteome, and the regulation of the autophagy system are becoming increasingly clear, the specific nature of its dysfunction in the context of neuronal disease pathogenesis remains largely unclear. Moreover, although the intricate network of autophagy regulatory proteins with key metabolic checkpoints is increasingly being revealed, the relationship between autophagy dysfunction, the changing rate of protein degradation in the specific pathology, and the aggregate prone behavior of specific candidate proteins remains less understood. Many questions remain and deserve urgent attention. When does a neuron respond with heightened autophagic activity and When does the system fail to degrade autophagy cargo? This book chapter will focus on some of the main challenges in the field of autophagy research, the identity, and nature of autophagic flux failure in neurodegeneration, current means to discern and measure autophagic flux dysfunction in neuronal tissue, and recent advances in compensating the flux offset. Specifically, the role of both macroautophagy and chaperone‐mediated autophagy in neuronal function and dysfunction and the spatiotemporal changes in their rates of protein degradation will be discussed and their molecular interplay highlighted. Finally, current advances in the use of autophagy modulators to better control autophagy activity will be stressed and contextualized within the framework of re‐establishing neuronal proteostasis to favorably control cellular fate

Complete genome sequences of six measles virus strains

Genetic characterization of wild-type measles virus (MV) strains is a critical component of measles surveillance and molecular epidemiology. We have obtained complete genome sequences of six MV strains belonging to different genotypes, using random-primed next generation sequencing

The extracellular heparan sulfatase SULF2 limits myeloid IFNβ signaling and Th17 responses in inflammatory arthritis

Heparan sulfate (HS) proteoglycans are important regulators of cellular responses to soluble mediators such as chemokines, cytokines and growth factors. We profiled changes in expression of genes encoding HS core proteins, biosynthesis enzymes and modifiers during macrophage polarisation, and found that the most highly regulated gene was Sulf2, an extracellular HS 6-O-sulfatase that was markedly downregulated in response to pro-inflammatory stimuli. We then generated Sulf2+/− bone marrow chimeric mice and examined inflammatory responses in antigen-induced arthritis, as a model of rheumatoid arthritis. Resolution of inflammation was impaired in myeloid Sulf2+/− chimeras, with elevated joint swelling and increased abundance of pro-arthritic Th17 cells in synovial tissue. Transcriptomic and in vitro analyses indicated that Sulf2 deficiency increased type I interferon signaling in bone marrow-derived macrophages, leading to elevated expression of the Th17-inducing cytokine IL6. This establishes that dynamic remodeling of HS by Sulf2 limits type I interferon signaling in macrophages, and so protects against Th17-driven pathology

Complete Genome Sequences of Six Measles Virus Strains.

Genetic characterization of wild-type measles virus (MV) strains is a critical component of measles surveillance and molecular epidemiology. We have obtained complete genome sequences of six MV strains belonging to different genotypes, using random-primed next generation sequencing

Manual de la Escala de Eficacia y Eficiencia Organizacional (OEES): un enfoque sistemático para mejorar los resultados organizacionales

[ES]La Escala de Eficacia y Eficiencia Organizacional (OEES; la Escala) fue desarrollada por el Consorcio Internacional de Investigación sobre Prácticas Basadas en la Evidencia (2013) [International Research Consortium on Evidence-Based Practices] para ayudar a las organizaciones no lucrativas a afrontar la necesidad creciente de ser más eficaces en términos de lograr los resultados buscados, más eficientes en términos de utilización de recursos, y más sostenibles en términos de adaptarse al cambio y proporcionar una serie de oportunidades y prácticas sólidas de prestación de servicios. Estas necesidades son reflejo de los retos de más amplio calado que afrontan las organizaciones no lucrativas de hoy en día. Entre estos retos, los principales son la mayor demanda de servicios y apoyos en un momento en el que los recursos se reducen, un movimiento de estructura organizacional vertical a horizontal, un cambio de servicios generales a apoyos individualizados, la necesidad de alinear los valores con las prácticas de apoyo de los servicios, el foco de interés en prácticas basadas en evidencia, y la necesidad de construir capacidad en cuanto a la autoevaluación organizacional, planificación estratégica y evaluación del rendimiento (Schalock y Verdugo, 2012)

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

From Inception to ConcePTION: Genesis of a Network to Support Better Monitoring and Communication of Medication Safety During Pregnancy and Breastfeeding

In 2019, the Innovative Medicines Initiative (IMI) funded the ConcePTION project—Building an ecosystem for better monitoring and communicating safety of medicines use in pregnancy and breastfeeding: validated and regulatory endorsed workflows for fast, optimised evidence generation—with the vision that there is a societal obligation to rapidly reduce uncertainty about the safety of medication use in pregnancy and breastfeeding. The present paper introduces the set of concepts used to describe the European data sources involved in the ConcePTION project and illustrates the ConcePTION Common Data Model (CDM), which serves as the keystone of the federated ConcePTION network. Based on data availability and content analysis of 21 European data sources, the ConcePTION CDM has been structured with six tables designed to capture data from routine healthcare, three tables for data from public health surveillance activities, three curated tables for derived data on population (e.g., observation time and mother-child linkage), plus four metadata tables. By its first anniversary, the ConcePTION CDM has enabled 13 data sources to run common scripts to contribute to major European projects, demonstrating its capacity to facilitate effective and transparent deployment of distributed analytics, and its potential to address questions about utilization, effectiveness, and safety of medicines in special populations, including during pregnancy and breastfeeding, and, more broadly, in the general population

Impact of 2018 EU Risk Minimisation Measures and Revised Pregnancy Prevention Programme on Utilisation and Prescribing Trends of Medicinal Products Containing Valproate: An Interrupted Time Series Study

Introduction: Due to established teratogenicity of valproates, the EU risk minimisation measures (RMMs) with a pregnancy prevention programme (PPP) for valproate were updated in March 2018. Objectives: To investigate the effectiveness of the 2018 EU RMMs on valproate utilisation in five European countries/regions. Methods: A multi-database, times series study of females of childbearing potential (12–55 years) was conducted using electronic medical records from five countries/regions (01.01.2010–31.12.2020): Denmark, Tuscany (Italy), Spain, the Netherlands, and the UK. Clinical and demographic information from each database was transformed to the ConcePTION Common Data Model, quality checks were conducted and a distributed analysis was performed using common scripts. Incident and prevalent use of valproate, proportion of discontinuers and switchers to alternative medicine, frequency of contraception coverage during valproate use, and occurrence of pregnancies during valproate exposure were estimated per month. Interrupted time series analyses were conducted to estimate the level or trend change in the outcome measures. Results: We included 69,533 valproate users from 9,699,371 females of childbearing potential from the five participating centres. A significant decline in prevalent use of valproates was observed in Tuscany, Italy (mean difference post-intervention −7.7%), Spain (−11.3%), and UK (−5.9%) and a non-significant decline in the Netherlands (−3.3%), but no decline in incident use after the 2018 RMMs compared to the period before. The monthly proportion of compliant valproate prescriptions/dispensings with a contraceptive coverage was low (<25%), with an increase after the 2018 RMMs only in the Netherlands (mean difference post-intervention 12%). There was no significant increase in switching rates from valproates to alternative medicine after the 2018 intervention in any of the countries/regions. We observed a substantial number of concurrent pregnancies during valproate exposure, but with a declining rate after the 2018 RMMs in Tuscany, Italy (0.70 per 1000 valproate users pre- and 0.27 post-intervention), Spain (0.48 and 0.13), the Netherlands (0.34 and 0.00), and an increasing rate in UK (1.13 and 5.07). Conclusion: There was a small impact of the 2018 RMMs on valproate use in the studied European countries/regions. The substantial number of concurrent pregnancies with valproate exposure warrants a careful monitoring of implementation of the existing PPP for valproate in clinical practice in Europe, to see if there is any need for additional measures in the future