A Duplication CNV That Conveys Traits Reciprocal to Metabolic Syndrome and Protects against Diet-Induced Obesity in Mice and Men

The functional contribution of CNV to human biology and disease pathophysiology has undergone limited exploration. Recent observations in humans indicate a tentative link between CNV and weight regulation. Smith-Magenis syndrome (SMS), manifesting obesity and hypercholesterolemia, results from a deletion CNV at 17p11.2, but is sometimes due to haploinsufficiency of a single gene, RAI1. The reciprocal duplication in 17p11.2 causes Potocki-Lupski syndrome (PTLS). We previously constructed mouse strains with a deletion, Df(11)17, or duplication, Dp(11)17, of the mouse genomic interval syntenic to the SMS/PTLS region. We demonstrate that Dp(11)17 is obesity-opposing; it conveys a highly penetrant, strain-independent phenotype of reduced weight, leaner body composition, lower TC/LDL, and increased insulin sensitivity that is not due to alteration in food intake or activity level. When fed with a high-fat diet, Dp(11)17/+ mice display much less weight gain and metabolic change than WT mice, demonstrating that the Dp(11)17 CNV protects against metabolic syndrome. Reciprocally, Df(11)17/+ mice with the deletion CNV have increased weight, higher fat content, decreased HDL, and reduced insulin sensitivity, manifesting a bona fide metabolic syndrome. These observations in the deficiency animal model are supported by human data from 76 SMS subjects. Further, studies on knockout/transgenic mice showed that the metabolic consequences of Dp(11)17 and Df(11)17 CNVs are not only due to dosage alterations of Rai1, the predominant dosage-sensitive gene for SMS and likely also PTLS. Our experiments in chromosome-engineered mouse CNV models for human genomic disorders demonstrate that a CNV can be causative for weight/metabolic phenotypes. Furthermore, we explored the biology underlying the contribution of CNV to the physiology of weight control and energy metabolism. The high penetrance, strain independence, and resistance to dietary influences associated with the CNVs in this study are features distinct from most SNP–associated metabolic traits and further highlight the potential importance of CNV in the etiology of both obesity and MetS as well as in the protection from these traits

Morphology and wall ultrastructure of the megaspore Lagenicula (Triletes) mixta (Winslow 1962) comb. nov from the Carboniferous (Early Mississippian: mid Tournaisian) of Ohio, USA

Megaspores assigned to Lagenicula (Triletes) mixta (Winslow, M., 1962. Plant Spores and Other Microfossils from Upper Devonian and Lower Mississippian Rocks of Ohio. Geol. Surv., Prof. Paper 364,1-93.) comb. nov.. from the Carboniferous (Early Mississippian: mid Tournaisian) of northeastern Ohio, USA, have been analysed using light microscopy (LM), scanning electron microscopy (SEM) and transmission electron microscopy (TEM). These studies provide new information on morphology, gross structure and wall ultrastructure. This taxon has a confused taxonomic history, and the new morphological information allows recognition as a distinct species that can be placed with the genus Lagenicula as a new combination. Morphological/ultrastructural studies confirm the lycopsid affinities of this megaspore and it is suggested that it probably derived from an arborescent lycopsid that belonged with the Lepidocarpaceae. Thus it is an early example of a megaspore derived from an arborescent lycopsid of the type that went on to dominate the Euramerican Coal Measure forests. The Ohio Tournaisian megaspore assemblage is surprisingly diverse revealing an interesting insight into vegetation ecology at this poorly understood time in plant history. (C) 2008 Elsevier B.V. All rights reserved

Maternal uniparental disomy of chromosome 20: a novel imprinting disorder of growth failure

PURPOSE: Maternal uniparental disomy of chromosome 20 (UPD(20)mat) has been reported in only four patients, three of whom also had mosaicism for complete or partial trisomy of chromosome 20. We sought to evaluate the clinical significance of isolated UPD(20)mat in eight individuals. METHODS: We evaluated phenotypic and genomic findings of a series of eight new patients with UPD(20)mat. RESULTS: All eight individuals with UPD(20)mat had intrauterine growth restriction, short stature, and prominent feeding difficulties with failure to thrive. As a common feature, they often required gastric tube feeds. Genomic data in most patients are indicative of UPD as a result of trisomy rescue after meiosis II nondisjunction. CONCLUSION: We describe the first natural history of the disorder and the results of therapeutic interventions, including the frequent requirement of direct gastric feedings only during the first few years of life, and propose that growth hormone supplementation is probably safe and effective for this condition. We suggest that UPD(20)mat can be regarded as a new imprinting disorder and its identification requires specialized molecular testing, which should be performed in patients with early-onset idiopathic isolated growth failure.Genet Med advance online publication 06 August 2015Genetics in Medicine (2015); doi:10.1038/gim.2015.103

Response to pegylated interferon in a COVID‐19 positive male with metastatic jejunal neuroendocrine tumor treated with everolimus

A 61‐year‐old male on everolimus had chronic SARS‐CoV‐2 infection. Addition of pegylated interferon cleared viral RNA and supports combination therapy with everolimus plus interferon for COVID‐19