Computational mapping of regulatory domains of human genes

Das menschliche Genom enthält Millionen von regulatorischen Elementen - Enhancern -, die die Genexpression quantitativ regulieren. Trotz des enormen Fortschritts beim Verständnis, wie Enhancer die Genexpression steuern, fehlt es in diesem Bereich immer noch an einem systematischen, integrativen und zugänglichen Ansatz zur Entdeckung und Dokumentation von cis-regulatorischen Beziehungen im gesamten Genom. Wir haben eine neuartige Methode - reg2gene - entwickelt, die Genexpression~Enhancer-Aktivität modelliert und integriert. reg2gene besteht aus drei Hauptschritten: 1) Datenquantifizierung, 2) Datenmodellierung und Signifikanzbewertung und 3) Datenintegration, die in dem R-Paket reg2gene zusammengefasst sind. Als Ergebnis haben wir zwei Sätze von Enhancer-Gen-Assoziationen (EGAs) identifiziert: den flexiblen Satz von ~230K EGAs (flexibleC) und den stringenten Satz von ~60K EGAs (stringentC). Wir haben große Unterschiede zwischen den bisher veröffentlichten Berechnungsmodellen für Enhancer-Gene-Assoziationen festgestellt, vor allem in Bezug auf die Lage, die Anzahl und die Eigenschaften der definierten Enhancer-Regionen und EGAs. Wir führten ein detailliertes Benchmarking von sieben Sets von rechnerisch modellierten EGAs durch, zeigten jedoch, dass keiner der derzeit verfügbaren Benchmark-Datensätze als "goldener Standard" verwendet werden kann. Wir definierten einen zusätzlichen Benchmark-Datensatz mit positiven und negativen EGAs, mit dem wir zeigten, dass das stringentC-Modell den höchsten positiven Vorhersagewert (PPV) hatte. Wir haben das Potenzial von EGAs zur Identifizierung von Genzielen von nicht-kodierenden SNP-Gene-Assoziationen nachgewiesen. Schließlich führten wir eine funktionelle Analyse durch, um neue Genziele, Enhancer-Pleiotropie und Mechanismen der Enhancer-Aktivität zu ermitteln. Insgesamt bringt diese Arbeit unser Verständnis der durch Enhancer vermittelten Regulierung der Genexpression in Gesundheit und Krankheit voran.Human genome contains millions of regulatory elements - enhancers - that quantitatively regulate gene expression. Multiple experimental and computational approaches were developed to associate enhancers with their gene targets. Despite the tremendous progress in understanding how enhancers tune gene expression, the field still lacks an approach that is systematic, integrative and accessible for discovering and documenting cis-regulatory relationships across the genome. We developed a novel computational approach - reg2gene- that models and integrates gene expression ~ enhancer activity. reg2gene consists of three main steps: 1) data quantification, 2) data modelling and significance assessment, and 3) data integration gathered in the reg2gene R package. As a result we identified two sets of enhancer-gene associations (EGAs): the flexible set of ~230K EGAs (flexibleC), and the stringent set of ~60K EGAs (stringentC). We identified major differences across previously published computational models of enhancer-gene associations; mostly in the location, number and properties of defined enhancer regions and EGAs. We performed detailed benchmarking of seven sets of computationally modelled EGAs, but showed that none of the currently available benchmark datasets could be used as a “golden-standard” benchmark dataset. To account for that observation, we defined an additional benchmark set of positive and negative EGAs with which we showed that the stringentC model had the highest positive predictive value (PPV) across all analyzed computational models. We reviewed the influence of EGA sets on the functional analysis of risk SNPs and demonstrated the potential of EGAs to identify gene targets of non-coding SNP-gene associations. Lastly, we performed a functional analysis to detect novel gene targets, enhancer pleiotropy, and mechanisms of enhancer activity. Altogether, this work advances our understanding of enhancer-mediated gene expression regulation in health and disease.Ljudski genom sadrži milijune regulatornih elemenata - enhancera - koji kvantitativno reguliraju ekspresiju gena. Unatoč ogromnom napretku u razumijevanju načina na koji enhanceri reguliraju ekspresiju gena, području još uvijek nedostaje pristup koji je sustavan, integrativan i dostupan za otkrivanje i dokumentiranje cis-regulatornih odnosa u cijelom genomu. Razvili smo novu računalnu metodu - reg2gene - koja modelira i integrira aktivnost enhancera~ekspresije gena. reg2gene sastoji se od tri glavna koraka: 1) kvantifikacija podataka, 2) modeliranje podataka i procjena značaja, i 3) integracija podataka prikupljenih u reg2gene R paketu. Kao rezultat toga, identificirali smo dva skupa enhancer-gen interakcija (EGA): fleksibilni skup od ~ 230K EGA (flexibleC) i strogi skup od ~ 60K EGA (stringentC). Utvrdili smo velike razlike u prethodno objavljenim računalnim modelima enhancer-gen interakcija; uglavnom u lokaciji, broju i svojstvima definiranih enhancera i EGA. Izveli smo detaljno mjerenje performansi sedam skupova računalno modeliranih EGA-a, ali smo pokazali da se niti jedan od trenutno dostupnih skupova referentnih podataka ne može koristiti kao referentni skup podataka "zlatnI standard". Definirali smo dodatni referentni skup pozitivnih i negativnih EGA -a pomoću kojih smo pokazali da stringentC ima najveću pozitivnu prediktivnu vrijednost (PPV). Pokazali smo potencijal EGA-a za identifikaciju genskih meta nekodirajucih SNP-ova. Proveli smo funkcionalnu analizu kako bismo otkrili nove genske mete, pleiotropiju enhancera i mehanizme aktivnosti enhancera. Ovaj rad poboljšava naše razumijevanje regulacije ekspresije gena posredovane enhancerima

Fault-tolerant gates via homological product codes

A method for the implementation of a universal set of fault-tolerant logical gates is presented using homological product codes. In particular, it is shown that one can fault-tolerantly map between different encoded representations of a given logical state, enabling the application of different classes of transversal gates belonging to the underlying quantum codes. This allows for the circumvention of no-go results pertaining to universal sets of transversal gates and provides a general scheme for fault-tolerant computation while keeping the stabilizer generators of the code sparse.Comment: 11 pages, 3 figures. v2 (published version): quantumarticle documentclass, expanded discussion on the conditions for a fault tolerance threshol

Analysis of Computer Science Communities Based on DBLP

It is popular nowadays to bring techniques from bibliometrics and scientometrics into the world of digital libraries to analyze the collaboration patterns and explore mechanisms which underlie community development. In this paper we use the DBLP data to investigate the author's scientific career and provide an in-depth exploration of some of the computer science communities. We compare them in terms of productivity, population stability and collaboration trends.Besides we use these features to compare the sets of topranked conferences with their lower ranked counterparts.Comment: 9 pages, 7 figures, 6 table

Fiscal Policy as a Stabilisation Device for an Open Economy Inside or Outside EMU

Extending Gali and Monacelli (2004), we build an N-country open economy model, where each economy is subject to sticky wages and prices and, potentially, has access to sales and income taxes as well as government spending as fiscal instruments. We examine an economy either as a small open economy under flexible exchange rates or as a member of a monetary union. In a small open economy when all three fiscal instruments are freely available, we show analytically that the impact of technology and mark-up shocks can be completely eliminated, whether policy acts with discretion or commitment. However, once any one of these fiscal instruments is excluded as a stabilisation tool, costs can emerge. Using simulations, we find that the useful fiscal instrument in this case (in the sense of reducing the welfare costs of the shock) is either income taxes or sales taxes. In contrast, having government spending as an instrument contributes very little. In the case of mark-up shocks tax instruments which can offset the impact of the shock directly are highly effective, while other fiscal instruments are less useful. The results for an individual member of a monetary union facing an idiosyncratic technology shock (where monetary policy in the union does not respond) are very different. First, even with all fiscal instruments freely available, the technology shock will incur welfare costs. Government spending is potentially useful as a stabilisation device, because it can act as a partial substitute for monetary policy. Finally, sales taxes are more effective than income taxes at reducing the costs of a technology shock under monetary union. If all three taxes are available, they can reduce the impact of the technology shock on the union member by around a half, compared to the case where fiscal policy is not used. Finally we consider the robustness of these results to two extensions. Firstly, introducing government debt, such that policy makers take account of the debt consequences of using fiscal instruments as stabilisation devices, and, secondly, introducing implementation lags in the use of fiscal instruments. We find that the need for debt sustainability has very limited impact on the use of fiscal instruments for stabilisation purposes, while implementation lags can reduce, but not eliminate, the gains from fiscal stabilisation.

Distribution channel strategies in a mixed market

This paper studies equilibrium channel strategies in a mixed market with a public firm and a private firm. The public firm is concerned with social welfare, while the private firm aims to maximize its own profit. Each firm decides whether to adopt an integrated or a decentralized channel. We examine two standard market competition modes, Bertrand and Cournot. Within each competition mode, we consider two typical vertical contracts, wholesale-price and two-part tariff contracts. Our results suggest that equilibrium channel structures depend on the market competition mode, the vertical contract form, and the level of product substitutability. Specifically, the channel strategy of the private firm depends mainly on the vertical contract form: under a two-part tariff contract, the private firm always chooses decentralization; under a wholesale-price contract, the private firm chooses integration for most scenarios except for highly substitutable products under Bertrand competition (i.e., under very intense competition). The channel strategy of the public firm depends mainly on the competition mode: under Bertrand competition, the public firm always chooses decentralization; under Cournot competition, the public firm always chooses the opposite of the private firm׳s strategy