Genome-wide screening reveals the genetic basis of mammalian embryonic eye development.

BACKGROUND: Microphthalmia, anophthalmia, and coloboma (MAC) spectrum disease encompasses a group of eye malformations which play a role in childhood visual impairment. Although the predominant cause of eye malformations is known to be heritable in nature, with 80% of cases displaying loss-of-function mutations in the ocular developmental genes OTX2 or SOX2, the genetic abnormalities underlying the remaining cases of MAC are incompletely understood. This study intended to identify the novel genes and pathways required for early eye development. Additionally, pathways involved in eye formation during embryogenesis are also incompletely understood. This study aims to identify the novel genes and pathways required for early eye development through systematic forward screening of the mammalian genome. RESULTS: Query of the International Mouse Phenotyping Consortium (IMPC) database (data release 17.0, August 01, 2022) identified 74 unique knockout lines (genes) with genetically associated eye defects in mouse embryos. The vast majority of eye abnormalities were small or absent eyes, findings most relevant to MAC spectrum disease in humans. A literature search showed that 27 of the 74 lines had previously published knockout mouse models, of which only 15 had ocular defects identified in the original publications. These 12 previously published gene knockouts with no reported ocular abnormalities and the 47 unpublished knockouts with ocular abnormalities identified by the IMPC represent 59 genes not previously associated with early eye development in mice. Of these 59, we identified 19 genes with a reported human eye phenotype. Overall, mining of the IMPC data yielded 40 previously unimplicated genes linked to mammalian eye development. Bioinformatic analysis showed that several of the IMPC genes colocalized to several protein anabolic and pluripotency pathways in early eye development. Of note, our analysis suggests that the serine-glycine pathway producing glycine, a mitochondrial one-carbon donator to folate one-carbon metabolism (FOCM), is essential for eye formation. CONCLUSIONS: Using genome-wide phenotype screening of single-gene knockout mouse lines, STRING analysis, and bioinformatic methods, this study identified genes heretofore unassociated with MAC phenotypes providing models to research novel molecular and cellular mechanisms involved in eye development. These findings have the potential to hasten the diagnosis and treatment of this congenital blinding disease

Erwartungsbildung über den Wahlausgang und ihr Einfluss auf die Wahlentscheidung

Erwartungen über den Wahlausgang haben einen festen Platz sowohl in Rational-Choice-Theorien des Wählerverhaltens als auch in stärker sozialpsychologisch orientierten Ansätzen. Die Bildung von Erwartungen und ihr Einfluss auf die Wahlentscheidung ist dabei jedoch ein noch relativ unerforschtes Gebiet. In diesem Beitrag werden anhand von Wahlstudien für Belgien, Österreich und Deutschland verschiedene Fragen der Erwartungsbildung und ihrer Auswirkungen untersucht. Zunächst wird die Qualität der Gesamterwartungen analysiert und verschiedene Faktoren identifiziert, die einen systematischen Einfluss auf die Erwartungsbildung haben. Im zweiten Schritt wenden wir uns den Einzelerwartungen über verschiedene Parteien und Koalitionen zu und finden eine moderate Verzerrung zugunsten der präferierten Parteien und Koalitionen. Dabei kann gezeigt werden, dass der Effekt des Wunschdenkens mit dem politischen Wissen und dem Bildungsgrad abnimmt. Schließlich werden in einem letzten Schritt zwei unterschiedliche Logiken für die Auswirkungen von Erwartungen getestet, das rationale Kalkül des koalitionsstrategischen Wählens zur Vermeidung der Stimmenvergeudung sowie der sozialpsychologisch begründete Bandwagon-Effekt. Das Ausmaß an politischem Wissen scheint dabei eine zentrale vermittelnde Variable zwischen den beiden Logiken zu sein

The transport mechanism of the mitochondrial ADP/ATP carrier

The mitochondrial ADP/ATP carrier imports ADP from the cytosol and exports ATP from the mitochondrial matrix, which are key transport steps for oxidative phosphorylation in eukaryotic organisms. The transport protein belongs to the mitochondrial carrier family, a large transporter family in the inner membrane of mitochondria. It is one of the best studied members of the family and serves as a paradigm for the molecular mechanism of mitochondrial carriers. Structurally, the carrier consists of three homologous domains, each composed of two transmembrane α-helices linked with a loop and short α-helix on the matrix side. The transporter cycles between a cytoplasmic and matrix state in which a central substrate binding site is alternately accessible to these compartments for binding of ADP or ATP. On both the cytoplasmic and matrix side of the carrier are networks consisting of three salt bridges each. In the cytoplasmic state, the matrix salt bridge network is formed and the cytoplasmic network is disrupted, opening the central substrate binding site to the intermembrane space and cytosol, whereas the converse occurs in the matrix state. In the transport cycle, tighter substrate binding in the intermediate states allows the interconversion of conformations by lowering the energy barrier for disruption and formation of these networks, opening and closing the carrier to either side of the membrane in an alternating way. Conversion between cytoplasmic and matrix states might require the simultaneous rotation of three domains around a central translocation pathway, constituting a unique mechanism among transport proteins. This article is part of a Special Issue entitled: Mitochondrial Channels edited by Pierre Sonveaux, Pierre Maechler and Jean-Claude Martinou

Whole genome assessment of the retinal response to diabetes reveals a progressive neurovascular inflammatory response

<p>Abstract</p> <p>Background</p> <p>Despite advances in the understanding of diabetic retinopathy, the nature and time course of molecular changes in the retina with diabetes are incompletely described. This study characterized the functional and molecular phenotype of the retina with increasing durations of diabetes.</p> <p>Results</p> <p>Using the streptozotocin-induced rat model of diabetes, levels of retinal permeability, caspase activity, and gene expression were examined after 1 and 3 months of diabetes. Gene expression changes were identified by whole genome microarray and confirmed by qPCR in the same set of animals as used in the microarray analyses and subsequently validated in independent sets of animals. Increased levels of vascular permeability and caspase-3 activity were observed at 3 months of diabetes, but not 1 month. Significantly more and larger magnitude gene expression changes were observed after 3 months than after 1 month of diabetes. Quantitative PCR validation of selected genes related to inflammation, microvasculature and neuronal function confirmed gene expression changes in multiple independent sets of animals.</p> <p>Conclusion</p> <p>These changes in permeability, apoptosis, and gene expression provide further evidence of progressive retinal malfunction with increasing duration of diabetes. The specific gene expression changes confirmed in multiple sets of animals indicate that pro-inflammatory, anti-vascular barrier, and neurodegenerative changes occur in tandem with functional increases in apoptosis and vascular permeability. These responses are shared with the clinically documented inflammatory response in diabetic retinopathy suggesting that this model may be used to test anti-inflammatory therapeutics.</p

Strategic and Sincere Voting in a One-Sided Election: The Canadian Federal Election of 1997

We are interested in whether and how voters make strategic decisions in a race that is, according to the polls, expected to be very one sided. Looking specifically at the choices available to ideologically right-of-center voters in the 1997 Canadian federal election, we argue that strategic considerations will be filtered by voters' assessments of the competitiveness of the race both locally and nationally. Copyright (c) 2005 by the Southwestern Social Science Association.

Electoral Systems, Party competition, and strength of partisan attachment: evidence from three countries. by Shaun Bowler, David J. Lanoue and Paul Savoie

This article brings together the literatures on individual voting behavior and on the effect of electoral systems. Evidence from Australia, Canada and Germany

Democratization, political institutions, and ethnic conflict: A pooled time-series analysis, 1985-1998

Although there has been much debate about whether democratization causes ethnic conflict, and many comparativists have argued about which kinds of political institutions are best for managing communal strife, little large-N work has addressed these issues. The authors apply a theory of ethnic conflict - the ethnic security dilemma - to derive predictions about the impact of democratization and political institutions on ethnic unrest. They then test these predictions by performing a series of pooled time-series analyses covering all ethnic groups in the Minorities at Risk data set from 1985 to 1998. The authors find that democratization, federalism, and presidentialism may not be as problematic as some argue and that proportional representation tends to reduce severe ethnic violence. They conclude by suggesting some directions for future research