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- Cruz, Raquel, et al.
(författare)
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Novel genes and sex differences in COVID-19 severity
- 2022
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Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 31:22, s. 3789-3806
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Tidskriftsartikel (refereegranskat)abstract
- Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P < 5 × 10−8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P = 1.3 × 10−22 and P = 8.1 × 10−12, respectively), and for variants in 9q21.32 near TLE1 only among females (P = 4.4 × 10−8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P = 2.7 × 10−8) and ARHGAP33 (P = 1.3 × 10−8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P = 4.1 × 10−8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.
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- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Forskningsöversikt (refereegranskat)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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- Buselli, Irene, et al.
(författare)
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Natural language processing for aviation safety : Extracting knowledge from publicly-available loss of separation reports
- 2022
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Ingår i: Open Research Europe. - : F1000 Research Ltd. - 2732-5121. ; , s. 1-39
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Tidskriftsartikel (refereegranskat)abstract
- Background: The air traffic management (ATM) system has historicallycoped with a global increase in traffic demand ultimately leading toincreased operational complexity.When dealing with the impact of this increasing complexity on systemsafety it is crucial to automatically analyse the losses of separation(LoSs) using tools able to extract meaningful and actionableinformation from safety reports.Current research in this field mainly exploits natural languageprocessing (NLP) to categorise the reports,with the limitations that theconsidered categories need to be manually annotated by experts andthat general taxonomies are seldom exploited.Methods: To address the current gaps,authors propose to performexploratory data analysis on safety reports combining state-of-the-arttechniques like topic modelling and clustering and then to develop analgorithm able to extract the Toolkit for ATM Occurrence Investigation(TOKAI) taxonomy factors from the free-text safety reports based onsyntactic analysis.TOKAI is a tool for investigation developed by EUROCONTROL and itstaxonomy is intended to become a standard and harmonisedapproach to future investigations.Results: Leveraging on the LoS events reported in the publicdatabases of the Comisi n de Estudio y An lisis de Notificaciones deIncidentes de Tr nsito A reo and the United Kingdom AirproxBoard,authors show how their proposal is able to automaticallyextract meaningful and actionable information from safetyreports,other than to classify their content according to the TOKAItaxonomy.The quality of the approach is also indirectly validated by checking theconnection between the identified factors and the main contributor ofthe incidents.Conclusions: Authors' results are a promising first step toward the fullautomation of a general analysis of LoS reports supported by resultson real-world data coming from two different sources.In the future,authors' proposal could be extended to othertaxonomies or tailored to identify factors to be included in the safetytaxonomies.KeywordsATM, Safety, Resilience, Natural Language Processing, Losses ofSeparation, Safety Reports, TOKAI
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