GENCODE: producing a reference annotation for ENCODE.

BACKGROUND: The GENCODE consortium was formed to identify and map all protein-coding genes within the ENCODE regions. This was achieved by a combination of initial manual annotation by the HAVANA team, experimental validation by the GENCODE consortium and a refinement of the annotation based on these experimental results. RESULTS: The GENCODE gene features are divided into eight different categories of which only the first two (known and novel coding sequence) are confidently predicted to be protein-coding genes. 5' rapid amplification of cDNA ends (RACE) and RT-PCR were used to experimentally verify the initial annotation. Of the 420 coding loci tested, 229 RACE products have been sequenced. They supported 5' extensions of 30 loci and new splice variants in 50 loci. In addition, 46 loci without evidence for a coding sequence were validated, consisting of 31 novel and 15 putative transcripts. We assessed the comprehensiveness of the GENCODE annotation by attempting to validate all the predicted exon boundaries outside the GENCODE annotation. Out of 1,215 tested in a subset of the ENCODE regions, 14 novel exon pairs were validated, only two of them in intergenic regions. CONCLUSION: In total, 487 loci, of which 434 are coding, have been annotated as part of the GENCODE reference set available from the UCSC browser. Comparison of GENCODE annotation with RefSeq and ENSEMBL show only 40% of GENCODE exons are contained within the two sets, which is a reflection of the high number of alternative splice forms with unique exons annotated. Over 50% of coding loci have been experimentally verified by 5' RACE for EGASP and the GENCODE collaboration is continuing to refine its annotation of 1% human genome with the aid of experimental validation.

The origins, evolution, and functional potential of alternative splicing in vertebrates.

Alternative splicing (AS) has the potential to greatly expand the functional repertoire of mammalian transcriptomes. However, few variant transcripts have been characterized functionally, making it difficult to assess the contribution of AS to the generation of phenotypic complexity and to study the evolution of splicing patterns. We have compared the AS of 309 protein-coding genes in the human ENCODE pilot regions against their mouse orthologs in unprecedented detail, utilizing traditional transcriptomic and RNAseq data. The conservation status of every transcript has been investigated, and each functionally categorized as coding (separated into coding sequence [CDS] or nonsense-mediated decay [NMD] linked) or noncoding. In total, 36.7% of human and 19.3% of mouse coding transcripts are species specific, and we observe a 3.6 times excess of human NMD transcripts compared with mouse; in contrast to previous studies, the majority of species-specific AS is unlinked to transposable elements. We observe one conserved CDS variant and one conserved NMD variant per 2.3 and 11.4 genes, respectively. Subsequently, we identify and characterize equivalent AS patterns for 22.9% of these CDS or NMD-linked events in nonmammalian vertebrate genomes, and our data indicate that functional NMD-linked AS is more widespread and ancient than previously thought. Furthermore, although we observe an association between conserved AS and elevated sequence conservation, as previously reported, we emphasize that 30% of conserved AS exons display sequence conservation below the average score for constitutive exons. In conclusion, we demonstrate the value of detailed comparative annotation in generating a comprehensive set of AS transcripts, increasing our understanding of AS evolution in vertebrates. Our data supports a model whereby the acquisition of functional AS has occurred throughout vertebrate evolution and is considered alongside amino acid change as a key mechanism in gene evolution.

Comparative analysis of the transcriptome across distant species.

The transcriptome is the readout of the genome. Identifying common features in it across distant species can reveal fundamental principles. To this end, the ENCODE and modENCODE consortia have generated large amounts of matched RNA-sequencing data for human, worm and fly. Uniform processing and comprehensive annotation of these data allow comparison across metazoan phyla, extending beyond earlier within-phylum transcriptome comparisons and revealing ancient, conserved features. Specifically, we discover co-expression modules shared across animals, many of which are enriched in developmental genes. Moreover, we use expression patterns to align the stages in worm and fly development and find a novel pairing between worm embryo and fly pupae, in addition to the embryo-to-embryo and larvae-to-larvae pairings. Furthermore, we find that the extent of non-canonical, non-coding transcription is similar in each organism, per base pair. Finally, we find in all three organisms that the gene-expression levels, both coding and non-coding, can be quantitatively predicted from chromatin features at the promoter using a 'universal model' based on a single set of organism-independent parameters.

Modules d'endo-permutation

Dans la th´eorie des repr´esentations modulaires des groupes finis, les modules d?endo-permutation occupent une place importante. En e_et, c?est le r?ole jou´e par ces modules dans l?analyse de la structure de certains modules simples pour des groupes finis p-nilpotents, qui a amen´e E. Dade `a en introduire le concept, en 1978. Quelques ann´ees plus tard, L. Puig a d´emontr´e que la source de n?importe quel module simple pour un groupe fini p-r´esoluble quelconque est un module d?endo-permutation. Plus r´ecemment, on s?est rendu compte que ces modules interviennent aussi dans l?analyse locale des cat´egories d´eriv´ees et dans l?´etude des syst`emes de fusion. La situation que l?on consid`ere est la suivante. On se donne un nombre premier p, un p-groupe fini P, un corps alg´ebriquement clos k de caract´eristique p et on veut d´eterminer tous les kP-modules d?endo-permutation couverts ind´ecomposables de type fini, c?est-`a-dire tous les kP-modules ind´ecomposables de type fini, tels que leur alg`ebre d?endomorphismes est un kP-module de permutation ayant un facteur direct trivial. On d´efinit une relation d?´equivalence sur l?ensemble de ces kP-modules et le produit tensoriel des modules induit une structure de groupe ab´elien sur l?ensemble des classes d?´equivalence. On appelle ce groupe, le groupe de Dade de P. Ainsi, classifier les modules d?endo-permutation couverts revient `a d´eterminer le groupe de Dade de P. Le groupe de Dade d?un p-groupe fini arbitraire est encore inconnu, bien qu?E. Dade, en 1978, ´etait d´ej`a parvenu `a la classification dans le cas o`u P est ab´elien. La premi`ere partie de ce travail de th`ese est consacr´ee au probl`eme de la classification dans le cas g´en´eral et r´esoud la question dans le cas de deux familles de p-groupes finis, `a savoir celle des p-groupes m´etacycliques, pour un nombre premier p impair, et celle des 2-groupes extrasp´eciaux, de la forme D8 _ · · · _ D8. Ces deux choix ont ´et´e motiv´es par le fait que ces groupes sont "presque" ab´eliens. De plus, certains r´esultats sur la structure du groupe de Dade d?un p-groupe fini quelconque rendent le groupe de Dade des groupes de ces deux familles plus simple `a ´etudier. Dans un deuxi`eme temps, nous nous sommes int´eress´es `a deux occurrences de ces modules dans la th´eorie de la repr´esentation des groupes finis, c?est-`a-dire `a deux raisons qui motivent leur ´etude. Ainsi, nous avons r´ealis´e des modules d?endo-permutation comme sources de modules simples. En particulier, il s?av`ere que, dans le cas d?un nombre premier p impair, tout module d?endo-permutation ind´ecomposable dont la classe est un ´el´ement de torsion dans le groupe de Dade est la source d?un module simple. Finalement, nous avons d´etermin´e, parmi tous les modules d?endo-permutation connus actuellement, lesquels poss`edent une r´esolution de permutation endo-scind´ee. Nous sommes arriv´es `a la conclusion que les seuls modules d?endo-permutation qui n?ont pas de r´esolution de permutation endo-scind´ee sont les modules "exceptionnels" apparaissant pour un 2-groupe de quaternions g´en´eralis´es.<br/><br/>In modular representation theory, endo-permutation modules occupy an important position. Indeed, the role that these modules play, in the analysis of the structure of some particular simple modules for finite p-nilpotent groups, induced E. Dade, in 1978, to give them their current name. A few years later, L. Puig proved that the source of any simple module for any finite psolvable group is an endo-permutation module. More recently, the occurrence of endo-permutation modules has also been noticed in the local analysis of splendid equivalences between derived categories and in the study of fusion systems. We consider the following situation. Given a prime number p, a finite pgroup P and an algebraically closed field k of characteristic p, we are looking for all finitely generated indecomposable capped endo-permutation kP-modules. That is, all finitely generated indecomposable kP-modules such that their endomorphism algebra is a permutation kP-module having a trivial direct summand. Then, we define an equivalence relation on the set of all isomorphism classes of such modules, and it turns out that the tensor product (over k) induces a structure of abelian group on this set. We call this group the Dade group of P. Hence, classifying all indecomposable finitely generated capped endo-permutation kPmodules is equivalent to determining the Dade group of P. At present, the Dade group of an arbitrary finite p-group is still unknown. However, E. Dade computed the Dade group of all finite abelian p-groups, in 1978 already. The first part of this doctoral thesis is concerned with the problem of the classification in the general case and solve it in the case of two families of finite p-groups, namely the metacyclic p-groups, for an odd prime number p, and the extraspecial 2-groups of the shape D8 _· · ·_D8. These two choices have been motivated by the fact that these groups are not far from being abelian. Moreover, some general results concerning the Dade group of arbitrary finite p-groups suggest that the Dade group of the groups belonging to these two families is easier to study. In the second part of this thesis, we have been looking at two particular occurrences of these modules in representation theory of finite groups which motivate the interest of their classification. Thus, we realised endo-permutation modules as sources of simple modules. In particular, it turns out that, in case p is an odd prime, any indecomposable module whose class in the Dade group is a torsion element is the source of some simple module. Finally, we considered all the modules we know at present and determined which ones have an endo-split permutation resolution. We could then conclude that all but the "exceptionnal" modules occurring in the generalized quaternion case have an endo-split permutation resolution.<br/><br/>"Module d?endo-permutation" n?est pas le nom d?une maladie exotique contagieuse (du moins pas `a ma connaissance), comme vous pourriez peut-?etre l?imaginer si vous faites partie des personnes qui croient que le titre de docteur n?est destin´e qu?aux m´edecins. Dans ce cas, il se peut que le sujet dont il est question ici vous cause quelques naus´ees et r´eveille de douloureux souvenirs d?´ecole, car un module d?endo-permutation est un objet math´ematique, alg´ebrique, plus pr´ecis´ement. Ce concept a ´et´e introduit il y a un quart de si`ecle, de l?autre c?ot´e de l?Atlantique, et il s?est r´ev´el´e su_samment int´eressant pour qu?aujourd?hui il ait franchi bien des fronti`eres, celles de l?alg`ebre y compris. Mais de quoi s?agit-il ? Si vous entendez le terme "endo-permutation" probablement pour la premi`ere fois, ce n?est certainement pas le cas pour celui de "module". Cependant, sa d´efinition dans le pr´esent contexte ne co¨ýncide avec aucune de celles figurant dans les dictionnaires ordinaires. Les personnes qui ont d´ej`a entendu parler de Frobenius, Burnside, Schur, ou encore Brauer, pourront vous dire qu?un module est une repr´esentation. "De quoi ?" vous demanderezvous. "Un spectacle de marionnettes, peut-?etre ?" Bien s?ur que non ! Un module d?endo-permutation est une repr´esentation particuli`ere de certains groupes finis, o`u un groupe n?est pas un groupe de rock, comme vous pouvez vous en douter, mais d´esigne un objet math´ematique connu par tous les ´etudiants en sciences au terme de leur premi`ere ann´ee universitaire (en th´eorie, du moins). La "popularit´e" de la notion de groupe, fini ou non, est due au fait que les groupes sont fr´equemment utilis´es, aussi bien dans le domaine abstrait des math´ematiques, que dans le monde r´eel des physiciens, chimistes et autres biologistes (pour ne citer qu?eux). "Mais comment peut-on utiliser concr`etement ces objets invisibles ?" vous demanderez-vous alors. Et bien, justement, en les consid´erant par l?interm´ediaire de leurs repr´esentations, c?est-`a-dire en leur associant des matrices, de fa¸con plus ou moins naturelle. Or, comme il y a "beaucoup trop" de matrices pour un groupe donn´e, elles sont classifi´ees selon certaines de leurs propri´et´es, ce qui permet de les r´epertorier dans diverses familles (celle des modules d?endo-permutation, par exemple). Un groupe est ainsi rendu "concret", car les donn´ees matricielles sont manipulables par tous les scienti- fiques (et leurs ordinateurs), qui peuvent alors les utiliser dans leurs recherches, afin de contribuer au progr`es de la science. En toute franchise, c?est bien loin de ces soucis terre-`a-terre que ce travail de th`ese sur la classification des modules d?endo-permutation a ´et´e accompli. En fait, quitte `a choquer certaines ?ames sensibles, sa r´ealisation est surtout due au caract`ere ´epicure de son auteur, qui, avouons-le, en a ´et´e pleinement satisfait !

Zins-Spreads als Einnahmequelle für Kantone : Die Abhängigkeit des Passivzinssatzes von den Bruttoschulden und damit einhergehende Renditemöglichkeiten am Kapitalmarkt

Über eine längere Zeitdauer betrachtet, weisen staatliche Schulden tendenziell tiefere Zinssätze respektive Renditen auf als andere auf dem Markt gehandelte papiere, was teilweise durch das geringere Risiko erklärt werden kann (Mehra & Prescott, 2003: S.892). Indem die Abhängigkeit der Schuldzinssätze von den Schuldenquoten der Schweizer Kantone modelliert und in Beziehung zu einer adäquaten Marktrendite gebracht wird, zeigt diese Arbeit, welches Einnahmepotential sich aus diesem Zins-Spread für die Schweizer Kantone ergibt. Zur Schätzung der Zinskurve wird vom Marktgleichgewicht ausgegangen, bei welchem die investoren mit einem Default Premium für einen möglichen Ausfall des Kantons als Schuldner, im Vergleich zu einer risikolosen Anlage, abgegolten werden müssen (Bayoumi, Goldstein und Woglom, 1995: S. 1048-1051). Dazu werden die für den Schweizer Kontext spezifischen Determinanten für die Ausfallswahrscheinlichkeit identifiziert (Daldoss und Foraita, 2003: S. 87). Empirisch überprüft wird dieses Modell anhand eines quantitativen Ansatzes, wobei in erster Linie die Generalisierte Momenten-Methode (GMM) angewandt wird. Als Datenbasis dient hauptsächlich die Finanzstatistik der Eidgenössischen Finanzverwaltung (EFV), wobei alle 26 Schweizer Kantone im Zeitraum von 1981 bis 2011 betrachtet werden. Als Marktrendite wird die durchschnittliche Rendite der Schweizer Pensionskassen verwendet. Mit den verwendeten Daten und Modellen kann die Form der Zinskurve jedoch nicht eindeutig bestimmt werden, was grösstenteils auf die Endogenitätsproblematik zurückzuführen ist. Diese kann aufgrund ungenügender und mangelhafter Instrumente ohne zusätzliche Daten nicht überwunden werden. Folglich kann auch keine optimale Schuldenquote bestimmt werden. Die quantitativen Resultate deuten dennoch auf ein gewisses Einnahmepotential hin. Wie das Fallbeispiel Kanton Aargau zeigt, kann dieses punktuell auch gebraucht werden und findet in der Praxis Anwendung (Anonymer Interviewpartner, 2013).

Mikrozystisches Makulaödem bei Optikusatrophie: eine Fallserie Microcystic Macular Edema in Optic Nerve Atrophy: A Case Series.

Background:Microcystic macular edema can occur after optic neuropathies of various etiologies, and is easily demonstrated by OCT. We report a cohort of patients with microcystic macular edema. Patients and Methods: All patients with optic neuropathy and microcystic macular edema were enrolled. Demographics, visual function, retinal angiographies and OCT parameters were studied. Results: Nineteen patients (23 eyes) exhibited microcystic macular edema: 10 men/9 women, aged 17-91 years. Etiologies of optic nerve atrophy were compressive (5), inflammatory (4), glaucoma (3), ischemic (3), trauma (2), degenerative (1), and hereditary (1). Median visual acuity was 4/10 (NLP-12/10). Fluorescein angiography showed no leakage. Topography of the microcystic macular edema correlated with near infrared images but with visual field defects in only 26 %. OCT parameters were all abnormal. Conclusions: Microcystic macular edema is a non-specific manifestation from an optic neuropathy of any etiology. The precise mechanism leading to microcystic macular edema remains unknown but trans-synaptic retrograde degeneration with Müller cells dysfunction is likely. Zusammenfassung Hintergrund: Das mikrozystische Makulaödem kann im Rahmen einer Optikusatrophie jeglicher Ätiologie auftreten und ist leicht mit dem OCT zu erkennen. Wir berichten über eine Patientenkohorte mit mikrozystischem Makulaödem. Patienten und Methoden: Alle Patienten mit einer Optikusneuropathie und einem mikrozystischen Makulaödem wurden in diese Studie eingeschlossen. Die Demografie, die Sehfunktion, die Netzhautangiografie und die OCT-Parameter wurden untersucht. Ergebnisse: Neunzehn Patienten (23 Augen) hatten ein mikrozystisches Makulaödem: 10 Männer/9 Frauen im Alter von 17 bis 91 Jahren. Die Ursachen der Optikusatrophie waren Kompressionen (5), Entzündungen (4), Glaukom (3), Ischämien (3), Traumata (2), Degenerationen (1) und genetisch (1). Der mittlere Visus war 0,4 (keine Lichtwahrnehmung 1,2). In der Fluoreszenzangiografie fand sich keine Leckage. Das OCT des mikrozystischen Makulaödems korrelierte immer mit den Infrarot-Bildern (Nahaufnahme), jedoch nur in 26 % mit den Gesichtsfelddefekten. Alle OCT-Parameter waren abnormal. Schlussfolgerungen: Das mikrozystische Makulaödem ist eine unspezifische Manifestation einer Optikusneuropathie jeglicher Ätiologie. Der genaue Mechanismus, der zu einem mikrozystischen Makulaödem führt, ist unbekannt, eine trans-synaptische retrograde Degeneration mit Dysfunktion der Müller-Zellen ist jedoch wahrscheinlich.

Fast generation of spin-squeezed states in bosonic Josephson junctions

We describe methods for the fast production of highly coherent-spin-squeezed many-body states in bosonic Josephson junctions. We start from the known mapping of the two-site Bose-Hubbard (BH) Hamiltonian to that of a single effective particle evolving according to a Schrödinger-like equation in Fock space. Since, for repulsive interactions, the effective potential in Fock space is nearly parabolic, we extend recently derived protocols for shortcuts to adiabatic evolution in harmonic potentials to the many-body BH Hamiltonian. A comparison with current experiments shows that our methods allow for an important reduction in the preparation times of highly squeezed spin states.

rDock: A Fast, Versatile and Open Source Program for Docking Ligands to Proteins and Nucleic Acids

Identification of chemical compounds with specific biological activities is an important step in both chemical biology and drug discovery. When the structure of the intended target is available, one approach is to use molecular docking programs to assess the chemical complementarity of small molecules with the target; such calculations provide a qualitative measure of affinity that can be used in virtual screening (VS) to rank order a list of compounds according to their potential to be active. rDock is a molecular docking program developed at Vernalis for high-throughput VS (HTVS) applications. Evolved from RiboDock, the program can be used against proteins and nucleic acids, is designed to be computationally very efficient and allows the user to incorporate additional constraints and information as a bias to guide docking. This article provides an overview of the program structure and features and compares rDock to two reference programs, AutoDock Vina (open source) and Schrodinger's Glide (commercial). In terms of computational speed for VS, rDock is faster than Vina and comparable to Glide. For binding mode prediction, rDock and Vina are superior to Glide. The VS performance of rDock is significantly better than Vina, but inferior to Glide for most systems unless pharmacophore constraints are used; in that case rDock and Glide are of equal performance. The program is released under the Lesser General Public License and is freely available for download, together with the manuals, example files and the complete test sets, at http://rdock.sourceforge.net/

Thermische Modellierung einer Mehrlagenplatine

In der Leistungselektronik spielt die Kenntnis des Wärmevrhaltens einer Platine eine sehr große Rolle. Die immer größeren Leistungsdichten unterstreichen die Wichtigkeit des Kenntnisses des Wärmeverhaltens. In der Platine funktionieren die Leistungskomponenten und Kupferlagen die große Ströme tragen als Leistungsquellen. Das Isolationsmaterial zwischen den Kupferlagen limitiert die maximale Temperatur der Platine. Dieses bringt eine Grentzung für den maximalen Strom der durch die Platine geführt werden kann. In dieser Arbeit wurden die maximalen Stromdichten im Worst-Case-Szenario einer Platine untersucht. Dafür wurde eine Testplatine entworfen und für die Testplatine ein thermisches Modell konstruiert. Die Effekte von Kühlung wurden auch untersucht. Die Bestimmtheit des Modells wurde mit Messungen überprüft.

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