The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has made it clear that combating coronavirus outbreaks benefits from a combination of vaccines and therapeutics. A... Show moreThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has made it clear that combating coronavirus outbreaks benefits from a combination of vaccines and therapeutics. A promising drug target common to all coronaviruses-including SARS-CoV, MERS-CoV, and SARS-CoV-2-is the papain-like protease (PLpro). PLpro cleaves part of the viral replicase polyproteins into non-structural protein subunits, which are essential to the viral replication cycle. Additionally, PLpro can cleave both ubiquitin and the ubiquitin-like protein ISG15 from host cell substrates as a mechanism to evade innate immune responses during infection. These roles make PLpro an attractive antiviral drug target. Here we demonstrate that ubiquitin variants (UbVs) can be selected from a phage-displayed library and used to specifically and potently block SARS-CoV-2 PLpro activity. A crystal structure of SARS-CoV-2 PLpro in complex with a representative UbV reveals a dimeric UbV bound to PLpro at a site distal to the catalytic site. Yet, the UbV inhibits the essential cleavage activities of the protease in vitro and in cells, and it reduces viral replication in cell culture by almost five orders of magnitude.Author summaryIn the last 3 years, it has become clear that emerging coronaviruses still pose a significant threat to human health. Despite the vaccines that are now available in many countries against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), vaccine scarcity or the inability to gain proper protection from immunization due to an immunocompromised status still leaves various people that will benefit from the administration of potent and safe antiviral agents. In this research, we have developed ubiquitin variants (UbVs), small proteins that resemble a natural component of human cells called ubiquitin, that are able to bind a part of the virus that is essential for its survival, with high affinity and selectivity. This way, these UbVs are able to inhibit the production of new viral particles after infection, thus preventing the virus from spreading from cell to cell and wreaking havoc on the body. Show less
We present the first near-IR scattered light detection of the transitional disk associated with the Herbig Ae star MWC 758 using data obtained as part of the Strategic Exploration of Exoplanets... Show moreWe present the first near-IR scattered light detection of the transitional disk associated with the Herbig Ae star MWC 758 using data obtained as part of the Strategic Exploration of Exoplanets and Disks with Subaru, and 1.1 {$μ$}m Hubble Space Telescope/NICMOS data. While submillimeter studies suggested there is a dust-depleted cavity with r = 0.''35, we find scattered light as close as 0.''1 (20-28 AU) from the star, with no visible cavity at H, K', or K$_s$ . We find two small-scaled spiral structures that asymmetrically shadow the outer disk. We model one of the spirals using spiral density wave theory, and derive a disk aspect ratio of h ~{} 0.18, indicating a dynamically warm disk. If the spiral pattern is excited by a perturber, we estimate its mass to be 5$^{+3}$ $_{- 4}$ M$_J$ , in the range where planet filtration models predict accretion continuing onto the star. Using a combination of non-redundant aperture masking data at L' and angular differential imaging with Locally Optimized Combination of Images at K' and K$_s$ , we exclude stellar or massive brown dwarf companions within 300 mas of the Herbig Ae star, and all but planetary mass companions exterior to 0.''5. We reach 5{$σ$} contrasts limiting companions to planetary masses, 3-4 M$_J$ at 1.''0 and 2 M$_J$ at 1.''55, using the COND models. Collectively, these data strengthen the case for MWC 758 already being a young planetary system. Show less
Grady, C.; Muto, T.; Hashimoto, J.; Fukagawa, M.; Currie, T.; Biller, B.; ... ; Tamura, M. 2013
We present the first near-IR scattered light detection of the transitional disk associated with the Herbig Ae star MWC 758 using data obtained as part of the Strategic Exploration of Exoplanets and... Show moreWe present the first near-IR scattered light detection of the transitional disk associated with the Herbig Ae star MWC 758 using data obtained as part of the Strategic Exploration of Exoplanets and Disks with Subaru, and 1.1 {$μ$}m Hubble Space Telescope/NICMOS data. While submillimeter studies suggested there is a dust-depleted cavity with r = 0.''35, we find scattered light as close as 0.''1 (20-28 AU) from the star, with no visible cavity at H, K', or K$_s$ . We find two small-scaled spiral structures that asymmetrically shadow the outer disk. We model one of the spirals using spiral density wave theory, and derive a disk aspect ratio of h ~{} 0.18, indicating a dynamically warm disk. If the spiral pattern is excited by a perturber, we estimate its mass to be 5$^{+3}$ $_{- 4}$ M$_J$ , in the range where planet filtration models predict accretion continuing onto the star. Using a combination of non-redundant aperture masking data at L' and angular differential imaging with Locally Optimized Combination of Images at K' and K$_s$ , we exclude stellar or massive brown dwarf companions within 300 mas of the Herbig Ae star, and all but planetary mass companions exterior to 0.''5. We reach 5{$σ$} contrasts limiting companions to planetary masses, 3-4 M$_J$ at 1.''0 and 2 M$_J$ at 1.''55, using the COND models. Collectively, these data strengthen the case for MWC 758 already being a young planetary system. Show less
Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide... Show moreGenome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 x 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis. Show less
We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association... Show moreWe undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 x 10(-8)). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease. Show less
