Haematopoietic stem cell-derived immune cells have reduced X chromosome inactivation skewing in systemic lupus erythematosus.

OBJECTIVES: Systemic lupus erythematosus (SLE) shows a marked female bias in prevalence. X chromosome inactivation (XCI) is the mechanism which randomly silences one X chromosome to equalise gene expression between 46, XX females and 46, XY males. Though XCI is expected to result in a random pattern of mosaicism across tissues, some females display a significantly skewed ratio in immune cells, termed XCI-skew. We tested whether XCI was abnormal in females with SLE and hence contributes to sexual dimorphism. METHODS: We assayed XCI in whole blood DNA in 181 female SLE cases, 796 female healthy controls and 10 twin pairs discordant for SLE. Using regression modelling and intra-twin comparisons, we assessed the effect of SLE on XCI and combined clinical, cellular and genetic data via a polygenic score to explore underlying mechanisms. RESULTS: Accommodating the powerful confounder of age, XCI-skew was reduced in females with SLE compared with controls (p=1.3×10-5), with the greatest effect seen in those with more severe disease. Applying an XCI threshold of >80%, we observed XCI-skew in 6.6% of SLE cases compared with 22% of controls. This difference was not explained by differential white cell counts, medication or genetic susceptibility to SLE. Instead, XCI-skew correlated with a biomarker for type I interferon-regulated gene expression. CONCLUSIONS: These results refute current views on XCI-skew in autoimmunity and suggest, in lupus, XCI patterns of immune cells reflect the impact of disease state, specifically interferon signalling, on the haematopoietic stem cells from which they derive.

The changing profile of infective endocarditis: A multi-year retrospective study for dentists.

BACKGROUND: Infective endocarditis (IE) has high morbidity and mortality and is often attributed to dental procedures. AIM: This study characterized variables related to paediatric IE in a paediatric hospital cohort. DESIGN: A retrospective review of medical records, from January 1, 2008, to January 1, 2020, to examine demographic, medical and dental history, and risk factors associated with children diagnosed with IE at Nationwide Children's Hospital. RESULTS: Of the 242 patients who were admitted with tentative IE diagnoses, 67 met the inclusion criteria: 46 (69%) had underlying cardiac conditions and 21 (31%) had not. One-third had an infection with S. aureus and viridans streptococci. Age was significantly associated with intracardiac devices in children with IE. Mean hospitalization was 25 days, and the mortality was 6 (9%); 41(61%) required surgery for causative defects, and 24 (32%) had dental consultation during admission. CONCLUSION: Although cardiac-related conditions were present in most cases, IE occurred in patients without cardiac factors.

Cross-selective Deoxygenative Coupling of Aliphatic Alcohols: Installation of Methyl Groups including Isotopic Labels by Nickel Catalysis.

Nickel-catalyzed cross-electrophile coupling reactions of two aliphatic alcohol derivatives remain a challenge. Herein, we report a nickel-catalyzed reductive methylation reaction of aliphatic mesylates with methyl tosylate. This reaction provides straightforward access to compounds bearing aliphatic methyl groups from alkyl alcohol derivatives. Isotopically labelled substrates and reagents can be employed in the reaction to provide perdeuterated and 13C-labelled products. This transformation can be achieved by employing stoichiometric Mn reductant or electrochemically. Additionally, mechanistic experiments show that alkyl iodides are key intermediates in the transformation which undergo a stereoablative reaction via radical intermediates.