Multivalent interactions drive nucleosome binding and efficient chromatin deacetylation by SIRT6

The protein deacetylase SIRT6 maintains cellular homeostasis through multiple pathways that include the deacetylation of histone H3 and repression of transcription. Prior work suggests that SIRT6 is associated with chromatin and can substantially reduce global levels of H3 acetylation, but how SIRT6 is able to accomplish this feat is unknown. Here, we describe an exquisitely tight interaction between SIRT6 and nucleosome core particles, in which a 2:1 enzyme:nucleosome complex assembles via asymmetric binding with distinct affinities. While both SIRT6 molecules associate with the acidic patch on the nucleosome, we find that the intrinsically disordered SIRT6 C-terminus promotes binding at the higher affinity site through recognition of nucleosomal DNA. Together, multivalent interactions couple productive binding to efficient deacetylation of histones on endogenous chromatin. Unique among histone deacetylases, SIRT6 possesses the intrinsic capacity to tightly interact with nucleosomes for efficient activity

Identification of and Molecular Basis for SIRT6 Loss-of-Function Point Mutations in Cancer

SummaryChromatin factors have emerged as the most frequently dysregulated family of proteins in cancer. We have previously identified the histone deacetylase SIRT6 as a key tumor suppressor, yet whether point mutations are selected for in cancer remains unclear. In this manuscript, we characterized naturally occurring patient-derived SIRT6 mutations. Strikingly, all the mutations significantly affected either stability or catalytic activity of SIRT6, indicating that these mutations were selected for in these tumors. Further, the mutant proteins failed to rescue sirt6 knockout (SIRT6 KO) cells, as measured by the levels of histone acetylation at glycolytic genes and their inability to rescue the tumorigenic potential of these cells. Notably, the main activity affected in the mutants was histone deacetylation rather than demyristoylation, pointing to the former as the main tumor-suppressive function for SIRT6. Our results identified cancer-associated point mutations in SIRT6, cementing its function as a tumor suppressor in human cancer

Association of Genetic Variants With Primary Open-Angle Glaucoma Among Individuals With African Ancestry.

Importance:Primary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders. Objectives:To perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma. Design, Settings, and Participants:A 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14 917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma. Exposures:Genetic variants associated with primary open-angle glaucoma. Main Outcomes and Measures:Presence of primary open-angle glaucoma. Genome-wide significance was defined as P < 5 × 10-8 in the discovery stage and in the meta-analysis of combined discovery and validation data. Results:A total of 2320 individuals with primary open-angle glaucoma (mean [interquartile range] age, 64.6 [56-74] years; 1055 [45.5%] women) and 2121 individuals without primary open-angle glaucoma (mean [interquartile range] age, 63.4 [55-71] years; 1025 [48.3%] women) were included in the discovery GWAS. The GWAS discovery meta-analysis demonstrated association of variants at amyloid-β A4 precursor protein-binding family B member 2 (APBB2; chromosome 4, rs59892895T>C) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P = 2 × 10-8). The association was validated in an analysis of an additional 6937 affected individuals and 14 917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P < .001). Each copy of the rs59892895*C risk allele was associated with increased risk of primary open-angle glaucoma when all data were included in a meta-analysis (OR, 1.19 [95% CI, 1.14-1.25]; P = 4 × 10-13). The rs59892895*C risk allele was present at appreciable frequency only in African ancestry populations. In contrast, the rs59892895*C risk allele had a frequency of less than 0.1% in individuals of European or Asian ancestry. Conclusions and Relevance:In this genome-wide association study, variants at the APBB2 locus demonstrated differential association with primary open-angle glaucoma by ancestry. If validated in additional populations this finding may have implications for risk assessment and therapeutic strategies

Implementation of rapid genomic sequencing in safety-net neonatal intensive care units: protocol for the VIrtual GenOme CenteR (VIGOR) proof-of-concept study.

INTRODUCTION: Rapid genomic sequencing (rGS) in critically ill infants with suspected genetic disorders has high diagnostic and clinical utility. However, rGS has primarily been available at large referral centres with the resources and expertise to offer state-of-the-art genomic care. Critically ill infants from racial and ethnic minority and/or low-income populations disproportionately receive care in safety-net and/or community settings lacking access to state-of-the-art genomic care, contributing to unacceptable health equity gaps. VIrtual GenOme CenteR is a \u27proof-of-concept\u27 implementation science study of an innovative delivery model for genomic care in safety-net neonatal intensive care units (NICUs). METHODS AND ANALYSIS: We developed a virtual genome centre at a referral centre to remotely support safety-net NICU sites predominantly serving racial and ethnic minority and/or low-income populations and have limited to no access to rGS. Neonatal providers at each site receive basic education about genomic medicine from the study team and identify eligible infants. The study team enrols eligible infants (goal n of 250) and their parents and follows families for 12 months. Enrolled infants receive rGS, the study team creates clinical interpretive reports to guide neonatal providers on interpreting results, and neonatal providers return results to families. Data is collected via (1) medical record abstraction, (2) surveys, interviews and focus groups with neonatal providers and (3) surveys and interviews with families. We aim to examine comprehensive implementation outcomes based on the Proctor Implementation Framework using a mixed methods approach. ETHICS AND DISSEMINATION: This study is approved by the institutional review board of Boston Children\u27s Hospital (IRB-P00040496) and participating sites. Participating families are required to provide electronic written informed consent and neonatal provider consent is implied through the completion of surveys. The results will be disseminated via peer-reviewed publications and data will be made accessible per National Institutes of Health (NIH) policies. TRIAL REGISTRATION NUMBER: NCT05205356/clinicaltrials.gov

The Main Belt Comets and ice in the Solar System

We review the evidence for buried ice in the asteroid belt; specifically the questions around the so-called Main Belt Comets (MBCs). We summarise the evidence for water throughout the Solar System, and describe the various methods for detecting it, including remote sensing from ultraviolet to radio wavelengths. We review progress in the first decade of study of MBCs, including observations, modelling of ice survival, and discussion on their origins. We then look at which methods will likely be most effective for further progress, including the key challenge of direct detection of (escaping) water in these bodies

Watch, Imagine, Attempt: Motor Cortex Single-Unit Activity Reveals Context-Dependent Movement Encoding in Humans With Tetraplegia

Planning and performing volitional movement engages widespread networks in the human brain, with motor cortex considered critical to the performance of skilled limb actions. Motor cortex is also engaged when actions are observed or imagined, but the manner in which ensembles of neurons represent these volitional states (VoSs) is unknown. Here we provide direct demonstration that observing, imagining or attempting action activates shared neural ensembles in human motor cortex. Two individuals with tetraplegia (due to brainstem stroke or amyotrophic lateral sclerosis, ALS) were verbally instructed to watch, imagine, or attempt reaching actions displayed on a computer screen. Neural activity in the precentral gyrus incorporated information about both cognitive state and movement kinematics; the three conditions presented overlapping but unique, statistically distinct activity patterns. These findings demonstrate that individual neurons in human motor cortex reflect information related to sensory inputs and VoS in addition to movement features, and are a key part of a broader network linking perception and cognition to action

"A Sort of Rathmines Version of a Dior Design": Maeve Brennan, Self-Fashioning, and the Uses of Style

This article explores the politics of style in the writing of Maeve Brennan. Brennan's concern with style, subjectivity and power is strikingly visible in her short stories and ‘Talk of the Town’ essays for the New Yorker. While in some of her short stories published in the New Yorker in the 1950s, Brennan seems to offer an extended critique of dandyism, elsewhere in her writing self-fashioning takes on an altogether more positive value and is steeped in the political as well as literary commitments of her work. The article argues that Brennan's interest in the politics of style, both personally and in her writing, is informed by the different strategies she deployed as an Irish woman writer establishing her place amongst a New York literary elite in the mid twentieth century.This work began as a conversation with Neil Sammells about Irish women's writing and self-fashioning, and his encouragement and insightful responses to ideas in development were invaluable to the progress of the research. I am also very grateful to Maureen O'Connor and Caitríona Clear, whose work on the Irish woman writer and dandyism, and women and magazine culture, lays an all-important foundation for the arguments developed here. Archival research for the article was made possible by a Fulbright Scholarship in the Humanities (September 2012—January 2013), and I am most grateful to my host institution, Fordham University in New York. I would like to thank the literary estate of Maeve Brennan for kind permission to cite from Maeve Brennan's letters and unpublished material held in the Special Collections at the University of Delaware and the Manuscripts and Archives Division of the New York Public Library. The work was completed with the assistance of a Moore Institute Visiting Fellowship to the National University of Ireland, Galway in 2015, which provided a valuable opportunity to present work in progress as part of the seminar series hosted by the Centre for Irish Studies. Finally, I am grateful to the anonymous peer reviewers and editors at Women: A Cultural Review for their thorough and expert responses to the article