769-6 Inhibitory Effect of Lovastatin on Human Coronary Smooth Muscle Cell Proliferation

Longterm administration of lipid lowering agents has been shown to cause regression of coronary atherosclerosis. To evaluate the mechanism of such regression, we studied the effect of Lovastatin (HMG coenzyme A reductase inhibitor) on the smooth muscle cells cultured from atherosclerotic plaque obtained from 5 human coronary arteries undergoing directional coronary atherectomy for de novo lesions. Arterial smooth muscle cell lines were created by 3–5 passages. These cells were then placed at a density of 3000 cells/ml in M-199 medium with 10% fetal bovine serum. They were exposed to Lovastatin at varying concentrations between 10-9 to 10-4 M. The coronary arterial smooth muscle cells were inhibited in a dose dependent manner. The table below shows the actual cell counts at various concentrations of Lovastatin in the 5 patients.Effect of Lovastatin on smooth muscle cell proliferationPTControlMitogen10-910-810-710-610-510-4MJ.B.25755216432538753320297525751901M.P28794390412539793629309820951971I.H.23893613336831532841222120061696M.L.29005938481739093199272920721092W.C.2830372932102710209317731292934Mean27154581396935253016255920081519ConclusionHMG Coenzyme A reductase inhibitor Lovastatin has a strong antiporliferative effect on human coronary smooth muscle cells. These observations suggest that antiproliferative effect of Lovastatin may be responsible for causing regression of atherosclerotic lesions in addition to its lipid lowering effects

Germline mutations in the oncogene EZH2 cause Weaver syndrome and increased human height.

The biological processes controlling human growth are diverse, complex and poorly understood. Genetic factors are important and human height has been shown to be a highly polygenic trait to which common and rare genetic variation contributes. Weaver syndrome is a human overgrowth condition characterised by tall stature, dysmorphic facial features, learning disability and variable additional features. We performed exome sequencing in four individuals with Weaver syndrome, identifying a mutation in the histone methyltransferase, EZH2, in each case. Sequencing of EZH2 in additional individuals with overgrowth identified a further 15 mutations. The EZH2 mutation spectrum in Weaver syndrome shows considerable overlap with the inactivating somatic EZH2 mutations recently reported in myeloid malignancies. Our data establish EZH2 mutations as the cause of Weaver syndrome and provide further links between histone modifications and regulation of human growth

Increased Adhesive Potential of Antiphospholipid Syndrome Neutrophils Mediated by β2 Integrin Macâ 1

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153125/1/art41057.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153125/2/art41057_am.pd

New Strong Gravitational Lenses from the DESI Legacy Imaging Surveys Data Release 9

We have conducted a search for strong gravitational lensing systems in the Dark Energy Spectroscopic Instrument (DESI) Legacy Imaging Surveys Data Release 9. This is the third paper in a series (following Huang et al. 2020; Huang et al. 2021, Paper I & II, respectively). These surveys together cover $\sim$ 19,000 deg$^2$ visible from the northern hemisphere, reaching a z-band AB magnitude of $\sim$ 22.5. We use a deep residual neural network, trained on a compilation of known lensing systems and candidates as well as non-lenses in the same footprint. After applying our trained neural networks to the survey data, we visually inspect and rank images with probabilities above a threshold. We have found 1895 lens candidates. Out of these, 1512 are identified for the first time. Combining the discoveries from this work, Paper I (335) and II (1210), the total number of strong lens candidates from the Legacy Surveys that we have discovered is 3057.Comment: 19 pages, 10 figures, 4 tables. arXiv admin note: text overlap with arXiv:2005.0473

New Insights Into the Clinical and Molecular Spectrum of the Novel CYFIP2-Related Neurodevelopmental Disorder and Impairment of the WRC-Mediated Actin Dynamics

Purpose: A few de novo missense variants in the cytoplasmic FMRP-interacting protein 2 (CYFIP2) gene have recently been described as a novel cause of severe intellectual disability, seizures, and hypotonia in 18 individuals, with p.Arg87 substitutions in the majority. Methods: We assembled data from 19 newly identified and all 18 previously published individuals with CYFIP2 variants. By structural modeling and investigation of WAVE-regulatory complex (WRC)-mediated actin polymerization in six patient fibroblast lines we assessed the impact of CYFIP2 variants on the WRC. Results: Sixteen of 19 individuals harbor two previously described and 11 novel (likely) disease-associated missense variants. We report p.Asp724 as second mutational hotspot (4/19 cases). Genotype–phenotype correlation confirms a consistently severe phenotype in p.Arg87 patients but a more variable phenotype in p.Asp724 and other substitutions. Three individuals with milder phenotypes carry putative loss-of-function variants, which remain of unclear pathogenicity. Structural modeling predicted missense variants to disturb interactions within the WRC or impair CYFIP2 stability. Consistent with its role in WRC-mediated actin polymerization we substantiate aberrant regulation of the actin cytoskeleton in patient fibroblasts. Conclusion: Our study expands the clinical and molecular spectrum of CYFIP2-related neurodevelopmental disorder and provides evidence for aberrant WRC-mediated actin dynamics as contributing cellular pathomechanism

Biallelic TMEM260 variants cause truncus arteriosus, with or without renal defects

Only two families have been reported with biallelic TMEM260 variants segregating with structural heart defects and renal anomalies syndrome (SHDRA). With a combination of genome, exome sequencing and RNA studies, we identified eight individuals from five families with biallelic TMEM260 variants. Variants included one multi-exon deletion, four nonsense/frameshifts, two splicing changes and one missense change. Together with the published cases, analysis of clinical data revealed ventricular septal defects (12/12), mostly secondary to truncus arteriosus (10/12), elevated creatinine levels (6/12), horse-shoe kidneys (1/12) and renal cysts (1/12) in patients. Three pregnancies were terminated on detection of severe congenital anomalies. Six patients died between the ages of 6 weeks and 5 years. Using a range of stringencies, carrier frequency for SHDRA was estimated at 0.0007–0.007 across ancestries. In conclusion, this study confirms the genetic basis of SHDRA, expands its known mutational spectrum and clarifies its clinical features. We demonstrate that SHDRA is a severe condition associated with substantial mortality in early childhood and characterised by congenital cardiac malformations with a variable renal phenotype

A restricted spectrum of missense KMT2D variants cause a multiple malformations disorder distinct from Kabuki syndrome

Purpose: To investigate if specific exon 38 or 39 KMT2D missense variants (MVs) cause a condition distinct from Kabuki syndrome type 1 (KS1). Methods: Multiple individuals, with MVs in exons 38 or 39 of KMT2D that encode a highly conserved region of 54 amino acids flanked by Val3527 and Lys3583, were identified and phenotyped. Functional tests were performed to study their pathogenicity and understand the disease mechanism. Results: The consistent clinical features of the affected individuals, from seven unrelated families, included choanal atresia, athelia or hypoplastic nipples, branchial sinus abnormalities, neck pits, lacrimal duct anomalies, hearing loss, external ear malformations, and thyroid abnormalities. None of the individuals had intellectual disability. The frequency of clinical features, objective software-based facial analysis metrics, and genome-wide peripheral blood DNA methylation patterns in these patients were significantly different from that of KS1. Circular dichroism spectroscopy indicated that these MVs perturb KMT2D secondary structure through an increased disordered to ɑ-helical transition. Conclusion: KMT2D MVs located in a specific region spanning exons 38 and 39 and affecting highly conserved residues cause a novel multiple malformations syndrome distinct from KS1. Unlike KMT2D haploinsufficiency in KS1, these MVs likely result in disease through a dominant negative mechanism.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.16-17/10/Newlife - The Charity for Disabled Children FS/13/32/30069/BHF_/British Heart Foundation/United Kingdom 72160007/Chile's National Commission for Scientific and Technological Research MR/K011154/1/MRC_/Medical Research Council/United Kingdom WT_/Wellcome Trust/United Kingdompre-prin