Maximising the Potential of Longitudinal Cohorts for Research in Neurodegenerative Diseases: A Community Perspective

Despite a wealth of activity across the globe in the area of longitudinal population cohorts, surprisingly little information is available on the natural biomedical history of a number of age-related neurodegenerative diseases (ND), and the scope for intervention studies based on these cohorts is only just beginning to be explored. The Joint Programming Initiative on Neurodegenerative Disease Research (JPND) recently developed a novel funding mechanism to rapidly mobilise scientists to address these issues from a broad, international community perspective. Ten expert Working Groups, bringing together a diverse range of community members and covering a wide ND landscape (Alzheimer’s, Parkinson’s, frontotemporal degeneration, amyotrophic lateral sclerosis, Lewy-body and vascular dementia) were formed to discuss and propose potential approaches to better exploiting and coordinating cohort studies. The purpose of this work is to highlight the novel funding process along with a broad overview of the guidelines and recommendations generated by the ten groups, which include investigations into multiple methodologies such as cognition/functional assessment, biomarkers and biobanking, imaging, health and social outcomes, and pre-symptomatic ND. All of these were published in reports that are now publicly available online.The EU Joint Programming Initiative on Neurodegenerative Disease Research (JPND) supported the ten Working Groups described in this manuscript with funding from the following: The Canadian Institutes of Health Research (CIHR), French National Research Agency (ANR), German Federal Ministry of Education and Research (BMBF), Innovation Fund Denmark, Italian Ministry of Health (IT-MOH), Luxembourg National Research Fund (FNR), Netherlands Organisation for Health Research and Development (ZonMw), Research Council of Norway, Swedish Research Council for Health, Working Life and Welfare, and UK Medical Research Council (MRC)

Meeting report : GBIF hackathon-workshop on Darwin Core and sample data (22-24 May 2013)

© The Author(s), 2014. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Standards in Genomic Sciences 9 (2014): 585-598, doi:10.4056/sigs.4898640.The workshop-hackathon was convened by the Global Biodiversity Information Facility (GBIF) at its secretariat in Copenhagen over 22-24 May 2013 with additional support from several projects (RCN4GSC, EAGER, VertNet, BiSciCol, GGBN, and Micro B3). It assembled a team of experts to address the challenge of adapting the Darwin Core standard for a wide variety of sample data. Topics addressed in the workshop included 1) a review of outstanding issues in the Darwin Core standard, 2) issues relating to publishing of biodiversity data through Darwin Core Archives, 3) use of Darwin Core Archives for publishing sample and monitoring data, 4) the case for modifying the Darwin Core Text Guide specification to support many-to-many relations, and 5) the generalization of the Darwin Core Archive to a “Biodiversity Data Archive”. A wide variety of use cases were assembled and discussed in order to inform further developments.We gratefully acknowledge support from the Global Biodiversity Information Facility (GBIF), from the Global Genome Biodiversity Network (GGBN), from the EU 7FP Biodiversity, Bioinformatics, Biotechnology project (Micro B3), and from the US National Science Foundation (NSF) through the following grants: DBI-0840989 [Research Coordination Network for the Ge-nomic Standards Consortium (RCN4GSC)], IIS-1255035 [EAGER: An Interoperable Information Infrastructure for Biodiversity Research (I3BR)], ABI Development: Collaborative Research: VertNet, a New Model for Bio-diversity Networks (DBI-1062193), and Collaborative Research: BiSciCol Tracker: Towards a tagging and tracking infrastructure for biodiversity science collec-tions (DBI-0956426)

Meeting Report: GBIF hackathon-workshop on Darwin Core and sample data (22-24 May 2013)

This is the published version, also available at http://dx.doi.org/10.4056/sigs.4898640.The workshop-hackathon was convened by the Global Biodiversity Information Facility (GBIF) at its secretariat in Copenhagen over 22-24 May 2013 with additional support from several projects (RCN4GSC, EAGER, VertNet, BiSciCol, GGBN, and Micro B3). It assembled a team of experts to address the challenge of adapting the Darwin Core standard for a wide variety of sample data. Topics addressed in the workshop included 1) a review of outstanding issues in the Darwin Core standard, 2) issues relating to publishing of biodiversity data through Darwin Core Archives, 3) use of Darwin Core Archives for publishing sample and monitoring data, 4) the case for modifying the Darwin Core Text Guide specification to support many-to-many relations, and 5) the generalization of the Darwin Core Archive to a “Biodiversity Data Archive”. A wide variety of use cases were assembled and discussed in order to inform further developments

Meeting Report: GBIF hackathon-workshop on Darwin Core and sample data (22-24 May 2013)

This is the published version, also available at http://dx.doi.org/10.4056/sigs.4898640.The workshop-hackathon was convened by the Global Biodiversity Information Facility (GBIF) at its secretariat in Copenhagen over 22-24 May 2013 with additional support from several projects (RCN4GSC, EAGER, VertNet, BiSciCol, GGBN, and Micro B3). It assembled a team of experts to address the challenge of adapting the Darwin Core standard for a wide variety of sample data. Topics addressed in the workshop included 1) a review of outstanding issues in the Darwin Core standard, 2) issues relating to publishing of biodiversity data through Darwin Core Archives, 3) use of Darwin Core Archives for publishing sample and monitoring data, 4) the case for modifying the Darwin Core Text Guide specification to support many-to-many relations, and 5) the generalization of the Darwin Core Archive to a “Biodiversity Data Archive”. A wide variety of use cases were assembled and discussed in order to inform further developments

Meeting Report: GBIF hackathon-workshop on Darwin Core and sample data (22-24 May 2013)

This is the published version, also available at http://dx.doi.org/10.4056/sigs.4898640.The workshop-hackathon was convened by the Global Biodiversity Information Facility (GBIF) at its secretariat in Copenhagen over 22-24 May 2013 with additional support from several projects (RCN4GSC, EAGER, VertNet, BiSciCol, GGBN, and Micro B3). It assembled a team of experts to address the challenge of adapting the Darwin Core standard for a wide variety of sample data. Topics addressed in the workshop included 1) a review of outstanding issues in the Darwin Core standard, 2) issues relating to publishing of biodiversity data through Darwin Core Archives, 3) use of Darwin Core Archives for publishing sample and monitoring data, 4) the case for modifying the Darwin Core Text Guide specification to support many-to-many relations, and 5) the generalization of the Darwin Core Archive to a “Biodiversity Data Archive”. A wide variety of use cases were assembled and discussed in order to inform further developments

Meeting Report: GBIF hackathon-workshop on Darwin Core and sample data (22-24 May 2013)

This is the published version, also available at http://dx.doi.org/10.4056/sigs.4898640.The workshop-hackathon was convened by the Global Biodiversity Information Facility (GBIF) at its secretariat in Copenhagen over 22-24 May 2013 with additional support from several projects (RCN4GSC, EAGER, VertNet, BiSciCol, GGBN, and Micro B3). It assembled a team of experts to address the challenge of adapting the Darwin Core standard for a wide variety of sample data. Topics addressed in the workshop included 1) a review of outstanding issues in the Darwin Core standard, 2) issues relating to publishing of biodiversity data through Darwin Core Archives, 3) use of Darwin Core Archives for publishing sample and monitoring data, 4) the case for modifying the Darwin Core Text Guide specification to support many-to-many relations, and 5) the generalization of the Darwin Core Archive to a “Biodiversity Data Archive”. A wide variety of use cases were assembled and discussed in order to inform further developments

Meeting Report: GBIF hackathon-workshop on Darwin Core and sample data (22-24 May 2013)

This is the published version, also available at http://dx.doi.org/10.4056/sigs.4898640.The workshop-hackathon was convened by the Global Biodiversity Information Facility (GBIF) at its secretariat in Copenhagen over 22-24 May 2013 with additional support from several projects (RCN4GSC, EAGER, VertNet, BiSciCol, GGBN, and Micro B3). It assembled a team of experts to address the challenge of adapting the Darwin Core standard for a wide variety of sample data. Topics addressed in the workshop included 1) a review of outstanding issues in the Darwin Core standard, 2) issues relating to publishing of biodiversity data through Darwin Core Archives, 3) use of Darwin Core Archives for publishing sample and monitoring data, 4) the case for modifying the Darwin Core Text Guide specification to support many-to-many relations, and 5) the generalization of the Darwin Core Archive to a “Biodiversity Data Archive”. A wide variety of use cases were assembled and discussed in order to inform further developments

Low-density granulocytes are related to shorter pregnancy duration but not to interferon alpha protein blood levels in systemic lupus erythematosus

BACKGROUND: An increased risk of pregnancy complications is seen in women with systemic lupus erythematosus (SLE), but the specific immunopathological drivers are still unclear. Hallmarks of SLE are granulocyte activation, type I interferon (IFN) overproduction, and autoantibodies. Here we examined whether low-density granulocytes (LDG) and granulocyte activation increase during pregnancy, and related the results to IFNα protein levels, autoantibody profile, and gestational age at birth. METHODS: Repeated blood samples were collected during pregnancy in trimesters one, two, and three from 69 women with SLE and 27 healthy pregnant women (HC). Nineteen of the SLE women were also sampled late postpartum. LDG proportions and granulocyte activation (CD62L shedding) were measured by flow cytometry. Plasma IFNα protein concentrations were quantified by single molecule array (Simoa) immune assay. Clinical data were obtained from medical records. RESULTS: Women with SLE had higher LDG proportions and increased IFNα protein levels compared to HC throughout pregnancy, but neither LDG fractions nor IFNα levels differed during pregnancy compared to postpartum in SLE. Granulocyte activation status was higher in SLE relative to HC pregnancies, and it was increased during pregnancy compared to after pregnancy in SLE. Higher LDG proportions in SLE were associated with antiphospholipid positivity but not to IFNα protein levels. Finally, higher LDG proportions in trimester three correlated independently with lower gestational age at birth in SLE. CONCLUSION: Our results suggest that SLE pregnancy results in increased peripheral granulocyte priming, and that higher LDG proportions late in pregnancy are related to shorter pregnancy duration but not to IFNα blood levels in SLE

Genetic variations in A20 DUB domain provide a genetic link to citrullination and neutrophil extracellular traps in systemic lupus erythematosus

Objectives: Genetic variations in TNFAIP3 (A20) de-ubiquitinase (DUB) domain increase the risk of systemic lupus erythematosus (SLE) and rheumatoid arthritis. A20 is a negative regulator of NF-κB but the role of its DUB domain and related genetic variants remain unclear. We aimed to study the functional effects of A20 DUB-domain alterations in immune cells and understand its link to SLE pathogenesis. Methods: CRISPR/Cas9 was used to generate human U937 monocytes with A20 DUB-inactivating C103A knock-in (KI) mutation. Whole genome RNA-sequencing was used to identify differentially expressed genes between WT and C103A KI cells. Functional studies were performed in A20 C103A U937 cells and in immune cells from A20 C103A mice and genotyped healthy individuals with A20 DUB polymorphism rs2230926. Neutrophil extracellular trap (NET) formation was addressed ex vivo in neutrophils from A20 C103A mice and SLE-patients with rs2230926. Results: Genetic disruption of A20 DUB domain in human and murine myeloid cells did not give rise to enhanced NF-κB signalling. Instead, cells with C103A mutation or rs2230926 polymorphism presented an upregulated expression of PADI4, an enzyme regulating protein citrullination and NET formation, two key mechanisms in autoimmune pathology. A20 C103A cells exhibited enhanced protein citrullination and extracellular trap formation, which could be suppressed by selective PAD4 inhibition. Moreover, SLE-patients with rs2230926 showed increased NETs and increased frequency of autoantibodies to citrullinated epitopes. Conclusions: We propose that genetic alterations disrupting the A20 DUB domain mediate increased susceptibility to SLE through the upregulation of PADI4 with resultant protein citrullination and extracellular trap formation

Complement C4 Copy Number Variation is Linked to SSA/Ro and SSB/La Autoantibodies in Systemic Inflammatory Autoimmune Diseases

Objective Copy number variation of the C4 complement components, C4A and C4B, has been associated with systemic inflammatory autoimmune diseases. This study was undertaken to investigate whether C4 copy number variation is connected to the autoimmune repertoire in systemic lupus erythematosus (SLE), primary Sjögren's syndrome (SS), or myositis. Methods Using targeted DNA sequencing, we determined the copy number and genetic variants of C4 in 2,290 well-characterized Scandinavian patients with SLE, primary SS, or myositis and 1,251 healthy controls. Results A prominent relationship was observed between C4A copy number and the presence of SSA/SSB autoantibodies, which was shared between the 3 diseases. The strongest association was detected in patients with autoantibodies against both SSA and SSB and 0 C4A copies when compared to healthy controls (odds ratio [OR] 18.0 [95% confidence interval (95% CI) 10.2–33.3]), whereas a weaker association was seen in patients without SSA/SSB autoantibodies (OR 3.1 [95% CI 1.7–5.5]). The copy number of C4 correlated positively with C4 plasma levels. Further, a common loss-of-function variant in C4A leading to reduced plasma C4 was more prevalent in SLE patients with a low copy number of C4A. Functionally, we showed that absence of C4A reduced the individuals’ capacity to deposit C4b on immune complexes. Conclusion We show that a low C4A copy number is more strongly associated with the autoantibody repertoire than with the clinically defined disease entities. These findings may have implications for understanding the etiopathogenetic mechanisms of systemic inflammatory autoimmune diseases and for patient stratification when taking the genetic profile into account.publishedVersio