A similar proportion of patients with and without rheumatic disease were hospitalised (23 (44%) vs 42 (40%)), p=0.50) but those with rheumatic disease required intensive care admission and mechanical ventilation more often (11 (48%) vs 7 (18%), multivariable OR 3.11 (95% CI 1.07 to 9.05)). Mortality was similar between the two groups (3 (6%) vs 4 (4%), p=0.69). Conclusions Patients with rheumatic disease and COVID-19 infection were more likely to require mechanical ventilation but had similar clinical features and hospitalisation rates as those without rheumatic disease. These findings have important implications for patients with rheumatic disease but require further validation.Nonstructural protein 5B (NS5B) is theviral RNA-dependent RNA polymerase thatcatalyzes the replication of the hepatitis C virusgenome. It is a major target for antiviral drugs,including nucleotide analogs (NAs) such as theprodrugs mericitabine and sofosbuvir, which getmetabolized to 2'-fluoro-2'-C-methylcytidine-5'-triphosphate and 2'fluoro-2'-C-methyluridine-5'-triphosphate, respectively. These analogs act aschain terminators after they are incorporated duringviral RNA synthesis. Recently, it has been shownthat NS5B can efficiently remove chain terminatorsby a nucleotide-mediated excision reaction thatrescues RNA synthesis. Importazole compound library inhibitor In this study, we usedtransient-state kinetics to study the efficiency ofNS5B inhibition by five NAs. We show that NS5Breadily incorporates CTP analogs into a growingprimer, but that these analogs are also efficientlyexcised. In contrast, although UMP analogs weremore slowly incorporated, UMP excision was alsoslow and inefficient, and modifications to the 2'Cof the UTP ribose ring further decreased excisionrates to an undetectable level. Taken together, theseresults suggest that the greater clinical effectivenessof the UMP analog sofosbuvir is largely due to itbeing intractable to nucleotide-mediated excisioncompared with similar NAs such as mericitabine.Poly(A)-specific ribonuclease (PARN) is a 3' exoribonuclease that plays an important role in regulating the stability and maturation of RNAs. Recently, PARN has been found to regulate the maturation of the human telomerase RNA component (hTR), a non-coding RNA required for telomere elongation. Specifically, PARN cleaves the 3' end of immature, polyadenylated hTR to form the mature, non-polyadenylated template. Despite PARN's critical role in mediating telomere maintenance, little is known about how PARN's function is regulated by post-translational modifications. In this study, using shRNA- and CRISPR/Cas9-mediated gene silencing and knockout approaches, along with 3' exoribonuclease activity assays and additional biochemical methods, we examined whether PARN is post-translationally modified by acetylation and what effect acetylation has on PARN's activity. We found PARN is primarily acetylated by the acetyltransferase p300 at Lys-566 and deacetylated by sirtuin1 (SIRT1). We also revealed how acetylation of PARN can decrease its enzymatic activity both in vitro, using a synthetic RNA probe, and in vivo, by quantifying endogenous levels of adenylated hTR. Furthermore, we also found that SIRT1 can regulate levels of adenylated hTR through PARN. The findings of our study uncover a mechanism by which PARN acetylation and deacetylation regulate its enzymatic activity as well as levels of mature hTR. Thus, PARN's acetylation status may play a role in regulating telomere length.In humans, cobalamin or vitamin B12 is delivered to two target enzymes via a complex intracellular trafficking pathway comprising transporters and chaperones. CblC (or MMACHC) is a processing chaperone that catalyzes an early step in this trafficking pathway. CblC removes the upper axial ligand of cobalamin derivatives, forming an intermediate in the pathway that is subsequently converted to the active cofactor derivatives. Mutations in the cblC gene lead to methylmalonic aciduria and homocystinuria. Here, we report that nitrosylcobalamin (NOCbl), which was developed as an antiproliferative reagent, and is purported to cause cell death by virtue of releasing nitric oxide, is highly unstable in air and is rapidly oxidized to nitrocobalamin (NO2Cbl). We demonstrate that CblC catalyzes the glutathione-dependent denitration of NO2Cbl forming 5-coordinate cob(II)alamin, which had one of two fates. It could be oxidized to aquo-cob(III)alamin or enter a futile thiol oxidase cycle forming glutathione disulfide. Arg-161 in the active site of CblC suppressed the NO2Cbl-dependent thiol oxidase activity whereas the disease-associated R161G variant stabilized cob(II)alamin and promoted futile cycling. We also report that CblC exhibits nitrite reductase activity, converting cob(I)alamin and nitrite to NOCbl. Finally, the denitration activity of CblC supported cell proliferation in the presence of NO2Cbl, which can serve as a cobalamin source. The newly described nitrite reductase and denitration activities of CblC extend its catalytic versatility, adding to its known decyanation and dealkylation activities. In summary, upon exposure to air, NOCbl is rapidly converted to NO2Cbl, which is a substrate for the B12-trafficking enzyme CblC.Lyme borreliosis is the most common vectorborne disease in the northern hemisphere. It usually begins with erythema migrans; early disseminated infection particularly causes multiple erythema migrans or neurologic disease, and late manifestations predominantly include arthritis in North America, and acrodermatitis chronica atrophicans (ACA) in Europe. Diagnosis of Lyme borreliosis is based on characteristic clinical signs and symptoms, complemented by serological confirmation of infection once an antibody response has been mounted. Manifestations usually respond to appropriate antibiotic regimens, but the disease can be followed by sequelae, such as immune arthritis or residual damage to affected tissues. A subset of individuals reports persistent symptoms, including fatigue, pain, arthralgia, and neurocognitive symptoms, which in some people are severe enough to fulfil the criteria for post-treatment Lyme disease syndrome. The reported prevalence of such persistent symptoms following antimicrobial treatment varies considerably, and its pathophysiology is unclear.