Proceedings of the National Academy of Sciences of the United States of America
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Proc. Natl. Acad. Sci. U.S.A. · Sep 2020
Multiplexed conditional genome editing with Cas12a in Drosophila.
CRISPR-Cas genome engineering has revolutionized biomedical research by enabling targeted genome modification with unprecedented ease. In the popular model organism Drosophila melanogaster, gene editing has so far relied exclusively on the prototypical CRISPR nuclease Cas9. Additional CRISPR systems could expand the genomic target space, offer additional modes of regulation, and enable the independent manipulation of genes in different cells of the same animal. ⋯ We also test a variant of LbCas12a with a D156R point mutation and show that it has substantially higher activity and outperforms a state-of-the-art Cas9 system in identifying essential genes. Cas12a gene editing expands the genome-engineering toolbox in Drosophila and will be a powerful method for the functional annotation of the genome. This work also presents a fully genetically encoded Cas12a system in an animal, laying out principles for the development of similar systems in other genetically tractable organisms for multiplexed conditional genome engineering.
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Proc. Natl. Acad. Sci. U.S.A. · Sep 2020
Comparative StudyBroad host range of SARS-CoV-2 predicted by comparative and structural analysis of ACE2 in vertebrates.
The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of COVID-19. The main receptor of SARS-CoV-2, angiotensin I converting enzyme 2 (ACE2), is now undergoing extensive scrutiny to understand the routes of transmission and sensitivity in different species. Here, we utilized a unique dataset of ACE2 sequences from 410 vertebrate species, including 252 mammals, to study the conservation of ACE2 and its potential to be used as a receptor by SARS-CoV-2. ⋯ Extending this analysis to human population data, we found only rare (frequency <0.001) variants in 10/25 binding sites. In addition, we found significant signals of selection and accelerated evolution in the ACE2 coding sequence across all mammals, and specific to the bat lineage. Our results, if confirmed by additional experimental data, may lead to the identification of intermediate host species for SARS-CoV-2, guide the selection of animal models of COVID-19, and assist the conservation of animals both in native habitats and in human care.
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Proc. Natl. Acad. Sci. U.S.A. · Sep 2020
The effect of big-city news on rural America during the COVID-19 pandemic.
Can "urban-centric" local television news coverage of the COVID-19 pandemic affect the behavior of rural residents with lived experiences so different from their "local" news coverage? Leveraging quasi-random geographic variation in media markets for 771 matched rural counties, we show that rural residents are more likely to practice social distancing if they live in a media market that is more impacted by COVID-19. Individual-level survey responses from residents of these counties confirm county-level behavioral differences and help attribute the differences we identify to differences in local television news coverage-self-reported differences only exist among respondents who prefer watching local news, and there are no differences in media usage or consumption across media markets. Although important for showing the ability of local television news to affect behavior despite urban-rural differences, the media-related effects we identify are at most half the size of the differences related to partisan differences.
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Proc. Natl. Acad. Sci. U.S.A. · Sep 2020
Characterizing superspreading events and age-specific infectiousness of SARS-CoV-2 transmission in Georgia, USA.
It is imperative to advance our understanding of heterogeneities in the transmission of SARS-CoV-2 such as age-specific infectiousness and superspreading. To this end, it is important to exploit multiple data streams that are becoming abundantly available during the pandemic. In this paper, we formulate an individual-level spatiotemporal mechanistic framework to integrate individual surveillance data with geolocation data and aggregate mobility data, enabling a more granular understanding of the transmission dynamics of SARS-CoV-2. ⋯ Our results improve our understanding of the natural history and transmission dynamics of SARS-CoV-2. More importantly, we reveal the roles of age-specific infectiousness and characterize systematic variations and associated risk factors of superspreading. These have important implications for the planning of relaxing social distancing and, more generally, designing optimal control measures.
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Proc. Natl. Acad. Sci. U.S.A. · Sep 2020
IL-6 trans-signaling induces plasminogen activator inhibitor-1 from vascular endothelial cells in cytokine release syndrome.
Cytokine release syndrome (CRS) is a life-threatening complication induced by systemic inflammatory responses to infections, including bacteria and chimeric antigen receptor T cell therapy. There are currently no immunotherapies with proven clinical efficacy and understanding of the molecular mechanisms of CRS pathogenesis is limited. Here, we found that patients diagnosed with CRS from sepsis, acute respiratory distress syndrome (ARDS), or burns showed common manifestations: strikingly elevated levels of the four proinflammatory cytokines interleukin (IL)-6, IL-8, monocyte chemotactic protein-1 (MCP-1), and IL-10 and the coagulation cascade activator plasminogen activator inhibitor-1 (PAI-1). ⋯ Tocilizumab treatment decreased the PAI-1 levels and alleviated critical illness in severe COVID-19 patients. Our findings suggest that distinct levels of cytokine production are associated with CRS induced by bacterial infection and COVID-19, but both CRS types are accompanied by endotheliopathy through IL-6 trans-signaling. Thus, the present study highlights the crucial role of IL-6 signaling in endothelial dysfunction during bacterial infection and COVID-19.