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BACKGROUND: Chronic obstructive pulmonary disease (COPD) patients are at increased risk of poor outcome from Coronavirus disease (COVID-19). Early data suggest elevated Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) receptor angiotensin converting enzyme 2 (ACE2) expression, but relationships to disease phenotype and downstream regulators of inflammation in the Renin-Angiotensin system (RAS) are unknown. We aimed to determine the relationship between RAS gene expression relevant to SARS-CoV-2 infection in the lung with disease characteristics in COPD, and the regulation of newly identified SARS-CoV-2 receptors and spike-cleaving proteases, important for SARS-CoV-2 infection. METHODS: We quantified gene expression using RNA sequencing of epithelial brushings and bronchial biopsies from 31 COPD and 37 control subjects. RESULTS: ACE2 gene expression (log2-fold change (FC)) was increased in COPD compared to ex-smoking (HV-ES) controls in epithelial brushings (0.25, p = 0.042) and bronchial biopsies (0.23, p = 0.050), and correlated with worse lung function (r = - 0.28, p = 0.0090). ACE2 was further increased in frequent exacerbators compared to infrequent exacerbators (0.51, p = 0.00045) and associated with use of ACE inhibitors (ACEi) (0.50, p = 0.0034), having cardiovascular disease (0.23, p = 0.048) or hypertension (0.34, p = 0.0089), and inhaled corticosteroid use in COPD subjects in bronchial biopsies (0.33, p = 0.049). Angiotensin II receptor type (AGTR)1 and 2 expression was decreased in COPD bronchial biopsies compared to HV-ES controls with log2FC of -0.26 (p = 0.033) and - 0.40, (p = 0.0010), respectively. However, the AGTR1:2 ratio was increased in COPD subjects compared with HV-ES controls, log2FC of 0.57 (p = 0.0051). Basigin, a newly identified potential SARS-CoV-2 receptor was also upregulated in both brushes, log2FC of 0.17 (p = 0.0040), and bronchial biopsies, (log2FC of 0.18 (p = 0.017), in COPD vs HV-ES. Transmembrane protease, serine (T

Genome-wide association studies have uncovered thousands of common variants associated with human disease, but the contribution of rare variants to common disease remains relatively unexplored. The UK Biobank contains detailed phenotypic data linked to medical records for approximately 500,000 participants, offering an unprecedented opportunity to evaluate the effect of rare variation on a broad collection of traits1,2. Here we study the relationships between rare protein-coding variants and 17,361 binary and 1,419 quantitative phenotypes using exome sequencing data from 269,171 UK Biobank participants of European ancestry. Gene-based collapsing analyses revealed 1,703 statistically significant gene-phenotype associations for binary traits, with a median odds ratio of 12.4. Furthermore, 83% of these associations were undetectable via single-variant association tests, emphasizing the power of gene-based collapsing analysis in the setting of high allelic heterogeneity. Gene-phenotype associations were also significantly enriched for loss-of-function-mediated traits and approved drug targets. Finally, we performed ancestry-specific and pan-ancestry collapsing analyses using exome sequencing data from 11,933 UK Biobank participants of African, East Asian or South Asian ancestry. Our results highlight a significant contribution of rare variants to common disease. Summary statistics are publicly available through an interactive portal ( http://azphewas.com/ ).

Insight into a species’ native and introduced range is essential in understanding the invasion process. Genetic diversity, propagule pressure and environmental conditions all have been recognised as playing a determinant role in invasion success. Here, we aimed to investigate the genetic diversity and population genetic structure (using the COI mtDNA gene region and 22 nDNA microsatellite markers) of the Asian green mussel Perna viridis within its potential native range in Asia and at introduced locations in the USA and the Caribbean. We also analyse genetic data from vessel intercepts and an incursion. By doing so, we aimed to identify genetic signatures that could allow to track vessel samples to their source and provide further insight into potential high-risk invasive populations or areas. Three top hierarchical clusters were identified using the individual-based Bayesian clustering method in STRUCTURE, corresponding to populations in three world regions: (1) USA and Caribbean, (2) India and (3) Southeast Asia. Within Southeast Asia, additional analysis indicate a shallow genetic differentiation of three subgroups consisting of (3a) Thailand, (3b) Taiwan and Hong-Kong, and (3c) a cluster of Singapore–Indonesia samples. Overall, the population structure found in this study suggests that the markers used could be useful in identifying source populations, particularly between the three mains world regions. Most surprisingly however, this study shows that the genetic diversity of samples collected from vessel intercepts and incursions did not differ significantly from established populations in Southeast Asia. In this region, in addition to the high vessel connectivity and number of P. viridis transported, all sampled populations are likely to pose a comparable risk in terms of genetic diversity. The present work represents the most comprehensive population genetic study of P. viridis, and the first to address the potential genetic introduction risk posed by populat

Insight into a species’ native and introduced range is essential in understanding the invasion process. Genetic diversity, propagule pressure and environmental conditions all have been recognised as playing a determinant role in invasion success. Here, we aimed to investigate the genetic diversity and population genetic structure (using the COI mtDNA gene region and 22 nDNA microsatellite markers) of the Asian green mussel Perna viridis within its potential native range in Asia and at introduced locations in the USA and the Caribbean. We also analyse genetic data from vessel intercepts and an incursion. By doing so, we aimed to identify genetic signatures that could allow to track vessel samples to their source and provide further insight into potential high-risk invasive populations or areas. Three top hierarchical clusters were identified using the individual-based Bayesian clustering method in STRUCTURE, corresponding to populations in three world regions: (1) USA and Caribbean, (2) India and (3) Southeast Asia. Within Southeast Asia, additional analysis indicate a shallow genetic differentiation of three subgroups consisting of (3a) Thailand, (3b) Taiwan and Hong-Kong, and (3c) a cluster of Singapore–Indonesia samples. Overall, the population structure found in this study suggests that the markers used could be useful in identifying source populations, particularly between the three mains world regions. Most surprisingly however, this study shows that the genetic diversity of samples collected from vessel intercepts and incursions did not differ significantly from established populations in Southeast Asia. In this region, in addition to the high vessel connectivity and number of P. viridis transported, all sampled populations are likely to pose a comparable risk in terms of genetic diversity. The present work represents the most comprehensive population genetic study of P. viridis, and the first to address the potential genetic introduction risk posed by populat

Introduced Marine Pests (IMP, = non-indigenous marine species) prevention, early detection and risk-based management strategies have become the priority for biosecurity operations worldwide, in recognition of the fact that, once established, the effective management of marine pests can rapidly become cost prohibitive or impractical. In Western Australia (WA), biosecurity management is guided by the “Western Australian Prevention List for Introduced Marine Pests” which is a policy tool that details species or genera as being of high risk to the region. This list forms the basis of management efforts to prevent introduction of these species, monitoring efforts to detect them at an early stage, and rapid response should they be detected. It is therefore essential that the species listed can be rapid and confidently identified and discriminated from native species by a range of government and industry stakeholders. Recognising that identification of these species requires very specialist expertise which may be in short supply and not readily accessible in a regulatory environment, and the fact that much publicly available data is not verifiable or suitable for regulatory enforcement, the WA government commissioned the current project to collate a reference collection of these marine pest specimens. In this work, we thus established collaboration with researchers worldwide in order to source representative specimens of the species listed. Our main objective was to build a reference collection of taxonomically vouchered specimens and subsequently to generate species-specific DNA barcodes suited to supporting their future identification. To date, we were able to obtain specimens of 75 species (representative of all but four of the pests listed) which have been identified by experts and placed with the WA Government Department of Fisheries and, where possible, in accessible museums and institutions in Australasia. The reference collection supports the fast and reliable taxo

Introduced Marine Pests (IMP, = non-indigenous marine species) prevention, early detection and risk-based management strategies have become the priority for biosecurity operations worldwide, in recognition of the fact that, once established, the effective management of marine pests can rapidly become cost prohibitive or impractical. In Western Australia (WA), biosecurity management is guided by the “Western Australian Prevention List for Introduced Marine Pests” which is a policy tool that details species or genera as being of high risk to the region. This list forms the basis of management efforts to prevent introduction of these species, monitoring efforts to detect them at an early stage, and rapid response should they be detected. It is therefore essential that the species listed can be rapid and confidently identified and discriminated from native species by a range of government and industry stakeholders. Recognising that identification of these species requires very specialist expertise which may be in short supply and not readily accessible in a regulatory environment, and the fact that much publicly available data is not verifiable or suitable for regulatory enforcement, the WA government commissioned the current project to collate a reference collection of these marine pest specimens. In this work, we thus established collaboration with researchers worldwide in order to source representative specimens of the species listed. Our main objective was to build a reference collection of taxonomically vouchered specimens and subsequently to generate species-specific DNA barcodes suited to supporting their future identification. To date, we were able to obtain specimens of 75 species (representative of all but four of the pests listed) which have been identified by experts and placed with the WA Government Department of Fisheries and, where possible, in accessible museums and institutions in Australasia. The reference collection supports the fast and reliable taxo

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It is unclear whether habitat degradation correlates with tolerance of marine invertebrates to abiotic stress. We therefore tested whether resistance to climate change-related stressors differs between populations of the green mussel Perna viridis from a heavily impacted and a mostly pristine site in West Java, Indonesia. In laboratory experiments, we compared their oxygen consumption and mortality under lowered salinity (-13 and -18 units, both responses), hypoxia (0.5 mg/l, mortality only) and thermal stress (+7 degrees C, mortality only). Mussels from the eutrophied and polluted Jakarta Bay showed a significantly smaller deviation from their normal oxygen consumption and higher survival rates when stressed than their conspecifics from the unaffected Lada Bay. This shows that human induced habitat degradation correlates with mussel tolerance to environmental stress. We discuss possible mechanisms - e.g. the selection of tolerant genotypes or habitat-specific differences in the nutritional status of the mussels - that could explain our observation.

It is unclear whether habitat degradation correlates with tolerance of marine invertebrates to abiotic stress. We therefore tested whether resistance to climate change-related stressors differs between populations of the green mussel Perna viridis from a heavily impacted and a mostly pristine site in West Java, Indonesia. In laboratory experiments, we compared their oxygen consumption and mortality under lowered salinity (-13 and -18 units, both responses), hypoxia (0.5 mg/l, mortality only) and thermal stress (+7 degrees C, mortality only). Mussels from the eutrophied and polluted Jakarta Bay showed a significantly smaller deviation from their normal oxygen consumption and higher survival rates when stressed than their conspecifics from the unaffected Lada Bay. This shows that human induced habitat degradation correlates with mussel tolerance to environmental stress. We discuss possible mechanisms - e.g. the selection of tolerant genotypes or habitat-specific differences in the nutritional status of the mussels - that could explain our observation.

This paper discusses technical issues and implementation of a generic interface to import a Functional Mock-up Unit (FMU) into Modelica simulators, specifically the Open- Modelica environment. Whereas other approaches for importing the FMUs rely on functionality specific to the simulator environment, this approach tries to provide a generic Modelica interface for embedding an FMU to be imported into a Modelica model. In this way any FMU conforming to the Functional Mock-up Interface (FMI) for Model Exchange v1.0 Specification for model exchange from MODELISAR can be imported into any Modelica simulator. When importing an FMU into a model, the resulting Modelica model can be used just like any pure Modelica models. Hence, a better reusability and interoperability for both sides, namely the external models provided via FMI and the Modelica environment, are achieved.