Somatic mutations acquired in healthy tissues as we age are major determinants of cancer risk. Whether variants confer a fitness advantage or rise to detectable frequencies by change remains largely unknown. Blood sequencing data from ∼50,000 individuals reveals how mutation, genetic drift and fitness shape the genetic diversity of healthy blood (clonal hematopoiesis). We show that positive selection, not drift, is the major force shaping clonal hematopoiesis, provide bounds on the number of hematopoietic stem...
Objective To assess over 3 years of follow-up, the effects of maintaining or switching to ocrelizumab (OCR) therapy on clinical and MRI outcomes and safety measures in the open-label extension (OLE) phase of the pooled OPERA studies in relapsing multiple sclerosis. Methods After 2 years of double-blind, controlled treatment, patients continued OCR (600 mg infusions every 24 weeks) or switched from interferon (IFN) β-1a (44 μg 3 times weekly) to OCR when entering the OLE...
Inflammatory osteolysis is governed by exacerbated osteoclastogenesis. Ample evidence points to central role of NF-kB in such pathologic responses, yet the precise mechanisms underpinning specificity of these responses remain unclear. We propose that motifs of the scaffold protein IKKg/NEMO partly facilitate such functions. As proof-of-principle, we used site-specific mutagenesis to examine the role of NEMO in mediating RANKL-induced signaling in bone marrow macrophages, known as osteoclast precursors. We identified lysine (K)270 as a target regulating...
Mutation of CFAP57, a protein required for the asymmetric targeting of a subset of inner dynein arms in Chlamydomonas, causes primary ciliary dyskinesiaSusan Dutcher, Ximena Bustamante-Marin, Amjad Horani, Mihaela Stoyanova, Wu-Lin Charng, Mathieu Bottier, Patrick Sears, Wei-Ning Yin, Leigh Anne Daniels, Hailey Bowen, Donald Conrad, Michael Knowles, Lawrence Ostrowski & Maimoona Zariwala
Primary ciliary dyskinesia (PCD) is characterized by chronic airway disease, reduced fertility, and randomization of the left/right body axis. It is caused by defects of motile cilia and sperm flagella. We screened a cohort of affected individuals that lack an obvious axonemal defect for pathogenic variants using whole exome capture, next generation sequencing, and bioinformatic analysis assuming an autosomal recessive trait. We identified one subject with an apparently homozygous nonsense variant [(c.1762C>T), p.(Arg588*)] in the...
Objective. To characterize lesion evolution and neurodegeneration in retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) using multimodal MRI. Methods: We prospectively performed MRI and cognitive testing in RVCL-S and healthy control cohorts. Gray and white matter volume and disruption of white matter microstructure were quantified. Asymmetric spin echo acquisition permitted voxel-wise oxygen extraction fraction (OEF) calculation as an in vivo marker of microvascular ischemia. The RVCL-S cohort was included in a longitudinal analysis...
REV-ERBalpha mediates complement expression and circadian regulation of microglial synaptic phagocytosisErik Musiek
The circadian clock has been shown to regulate various aspects of brain health including microglial and astrocyte activation. Here we report that deletion of the master clock protein BMAL1 induces robust increases in the expression of complement genes such as C3, C4b and C1q in the hippocampus. Loss of downstream REV-ERBa-mediated transcriptional repression led to increases in C4b in neurons and astrocytes as well as C3 protein in microglia and astrocytes. REV-ERBa deletion induced complement...
Objective. To determine whether years of education and the ε4 risk allele at APOE influence β-amyloid pathology similarly in asymptomatic individuals with a family history of sporadic Alzheimer’s disease (AD) and pre-symptomatic autosomal dominant AD mutation carriers. Methods. We analyzed cross-sectional data from 106 asymptomatic individuals with a parental history of sporadic AD (PREVENT-AD cohort; age=67.28±4.72 years) and 117 pre-symptomatic autosomal dominant AD mutation carriers (DIAN cohort; age=34.00±9.43 years). All participants underwent structural MRI and...
We characterized gene expression profiles in founder cells isolated from Drosophila embryos.
Washington University in St. Louis School of Medicine8
Washington University in St. Louis2
University of Pennsylvania1
University of North Carolina1
University of Cambridge1
Genetec (United States)1
University of California, Berkeley1