Gene expression signature of cerebellar hypoplasia in a mouse model of Down syndrome during postnatal development

Background Down syndrome is a chromosomal disorder caused by the presence of three copies of chromosome 21. The mechanisms by which this aneuploidy produces the complex and variable phenotype observed in people with Down syndrome are still under discussion. Recent studies have demonstrated an increased transcript level of the three-copy genes with some dosage compensation or amplification for a subset of them. The impact of this gene dosage effect on the whole transcriptome is still debated and longitudinal studies assessing the variability among samples, tissues and developmental stages are needed. Results We thus designed a large scale gene expression study in mice (the Ts1Cje Down syndrome mouse model) in which we could measure the effects of trisomy 21 on a large number of samples (74 in total) in a tissue that is affected in Down syndrome (the cerebellum) and where we could quantify the defect during postnatal development in order to correlate gene expression changes to the phenotype observed. Statistical analysis of microarray data revealed a major gene dosage effect: for the three-copy genes as well as for a 2 Mb segment from mouse chromosome 12 that we show for the first time as being deleted in the Ts1Cje mice. This gene dosage effect impacts moderately on the expression of euploid genes (2.4 to 7.5% differentially expressed). Only 13 genes were significantly dysregulated in Ts1Cje mice at all four postnatal development stages studied from birth to 10 days after birth, and among them are 6 three-copy genes. The decrease in granule cell proliferation demonstrated in newborn Ts1Cje cerebellum was correlated with a major gene dosage effect on the transcriptome in dissected cerebellar external granule cell layer. Conclusion High throughput gene expression analysis in the cerebellum of a large number of samples of Ts1Cje and euploid mice has revealed a prevailing gene dosage effect on triplicated genes. Moreover using an enriched cell population that is thought responsible for the cerebellar hypoplasia in Down syndrome, a global destabilization of gene expression was not detected. Altogether these results strongly suggest that the three-copy genes are directly responsible for the phenotype present in cerebellum. We provide here a short list of candidate genes

Maternal outcomes and risk factors for COVID-19 severity among pregnant women.

Pregnant women may be at higher risk of severe complications associated with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which may lead to obstetrical complications. We performed a case control study comparing pregnant women with severe coronavirus disease 19 (cases) to pregnant women with a milder form (controls) enrolled in the COVI-Preg international registry cohort between March 24 and July 26, 2020. Risk factors for severity, obstetrical and immediate neonatal outcomes were assessed. A total of 926 pregnant women with a positive test for SARS-CoV-2 were included, among which 92 (9.9%) presented with severe COVID-19 disease. Risk factors for severe maternal outcomes were pulmonary comorbidities [aOR 4.3, 95% CI 1.9-9.5], hypertensive disorders [aOR 2.7, 95% CI 1.0-7.0] and diabetes [aOR2.2, 95% CI 1.1-4.5]. Pregnant women with severe maternal outcomes were at higher risk of caesarean section [70.7% (n = 53/75)], preterm delivery [62.7% (n = 32/51)] and newborns requiring admission to the neonatal intensive care unit [41.3% (n = 31/75)]. In this study, several risk factors for developing severe complications of SARS-CoV-2 infection among pregnant women were identified including pulmonary comorbidities, hypertensive disorders and diabetes. Obstetrical and neonatal outcomes appear to be influenced by the severity of maternal disease

The SIB Swiss Institute of Bioinformatics' resources: focus on curated databases

The SIB Swiss Institute of Bioinformatics (www.isb-sib.ch) provides world-class bioinformatics databases, software tools, services and training to the international life science community in academia and industry. These solutions allow life scientists to turn the exponentially growing amount of data into knowledge. Here, we provide an overview of SIB's resources and competence areas, with a strong focus on curated databases and SIB's most popular and widely used resources. In particular, SIB's Bioinformatics resource portal ExPASy features over 150 resources, including UniProtKB/Swiss-Prot, ENZYME, PROSITE, neXtProt, STRING, UniCarbKB, SugarBindDB, SwissRegulon, EPD, arrayMap, Bgee, SWISS-MODEL Repository, OMA, OrthoDB and other databases, which are briefly described in this article

Down syndrome gene dosage imbalance on cerebellum development

Down syndrome (DS) is a chromosomal disorder whereby genes on chromosome 21 are present in three copies. This gene copy imbalance is thought to be responsible for a number of debilitating conditions experienced by individuals with DS. Amongst these is a reduced cerebellar volume, or cerebellar hypoplasia, which is believed to contribute to the perturbation of fine motor control. Mouse models of DS (such as Ts65Dn, Ts1Cje, Tc1) exhibit a cerebellar phenotype similar to that of individuals with DS and which primarily manifests as a disruption of the density of the granule cell layer. Dissecting which of the three-copy genes are responsible for this phenotype (the primary gene dosage effect) has been a task undertaken by researchers working with various segmental trisomies and transgenic mice. It is generally agreed that, when expressed, three-copy genes of trisomic mice are expressed at around 1.5 times that of the same genes in euploid (wild-type) mice. However, amongst these studies there does not appear to be a consensus on the nature and extent of differential expression of two-copy genes in trisomic mice—the secondary dosage effect. Much of this variation may have to do with the stage of development investigated and the nature and complexity of the tissue (i.e. whole brain versus the cerebellum). The recent discovery that trisomic granule cell precursors are less sensitive to sonic hedgehog-induced proliferation has opened up another avenue for the identification of three-copy genes responsible for the cerebellar phenotype. It is hoped that further investigation of this phenomenon, together with new mouse segmental trisomies and transgenics, will reveal the cause of the proliferation deficit and allow for potential treatment

Clathrin-dependent APP endocytosis and Abeta secretion are highly sensitive to the level of plasma membrane cholesterol

Several lines of evidence support a strong relationship between cholesterol and Alzheimer's disease pathogenesis. Membrane cholesterol is known to modulate amyloid precursor protein (APP) endocytosis and amyloid-β (Aβ) secretion. Here we show in a human cell line model of endocytosis (HEK293 cells) that cholesterol exerts these effects in a dose-dependent and linear manner, over a wide range of concentrations (-40% to + 40% variations of plasma membrane cholesterol induced by methyl-beta-cyclodextrin (MBCD) and MBCD-cholesterol complex respectively). We found that the gradual effect of cholesterol is inhibited by small interference RNA-mediated downregulation of clathrin. Modulation of clathrin-mediated APP endocytosis by cholesterol was further demonstrated using mutants of proteins involved in the formation of early endosomes (dynamin2, Eps15 and Rab5). Importantly we show that membrane proteins other than APP are not affected by cholesterol to the same extent. Indeed clathrin-dependent endocytosis of transferrin and cannabinoid1 receptors as well as internalization of surface proteins labelled with a biotin derivative (sulfo-NHS-SS-biotin) were not sensitive to variations of plasma membrane cholesterol from -40% to 40%. In conclusion clathrin-dependent APP endocytosis appears to be very sensitive to the levels of membrane cholesterol. These results suggest that cholesterol increase in AD could be responsible for the enhanced internalization of clathrin-, dynamin2-, Eps15- and Rab5-dependent endocytosis of APP and the ensuing overproduction of Aβ. Copyright © 2010 Elsevier B.V. All rights reserved

New chemistry involving 1,2,4-trioxanes related to Qinghaosu

The 1,2,4-trioxane ring is a poorly studied hetcrocycle. Not many derivatives are known. However, the sole example found in nature, artemisinin (Qinghaosu), commands attention on account of its potent anti -malarial properties. We discuss new methodology for preparing a variety of 1,2,4-trioxanes. The basis of the method is the capture of zwitterionic peroxides by aldehydes. Precursors such as allylic hydroperoxides, peroxides, and 1,2- dioxetanes behave similarly and can be captured by aldehydes and ketones in intramolecular and intermolecular processes. The structures of many of the 1,2,4-trioxanes so obtained have been established by X-ray ana lysis. In addition, the chemistry of the trioxane ring is discussed, in particular the formation of 1,2-diol monoesters.</p