Topological aspects of the human protein interaction network

It is currently widely accepted that the understanding of complex cell functions depends on an integrated network theoretical approach and not on an isolated view of the different molecular agents. Aim of this thesis was the examination of topological properties that mirror known biological aspects by depicting the human protein network with methods from graph- and network theory. The presented network is a partial human interactome of 9222 proteins and 36324 interactions, consisting of single interactions reliably extracted from peer-reviewed scientific publications. In general, one can focus on intra- or intermodular characteristics, where a functional module is defined as "a discrete entity whose function is separable from those of other modules". It is found that the presented human network is also scale-free and hierarchically organised, as shown for yeast networks before. The interactome also exhibits proteins with high betweenness and low connectivity which are biologically analyzed and interpreted here as shuttling proteins between organelles (e.g. ER to Golgi, internal ER protein translocation, peroxisomal import, nuclear pores import/export) for the first time. As an optimisation for finding proteins that connect modules, a new method is developed here based on proteins located between highly clustered regions, rather than regarding highly connected regions. As a proof of principle, the Mediator complex is found in first place, the prime example for a connector complex. Focusing on intramodular aspects, the measurement of k-clique communities discriminates overlapping modules very well. Twenty of the largest identified modules are analysed in detail and annotated to known biological structures (e.g. proteasome, the NFκB-, TGF-β complex). Additionally, two large and highly interconnected modules for signal transducer and transcription factor proteins are revealed, separated by known shuttling proteins. These proteins yield also the highest number of redundant shortcuts (by calculating the skeleton), exhibit the highest numbers of interactions and might constitute highly interconnected but spatially separated rich-clubs either for signal transduction or for transcription factors. This design principle allows manifold regulatory events for signal transduction and enables a high diversity of transcription events in the nucleus by a limited set of proteins. Altogether, biological aspects are mirrored by pure topological features, leading to a new view and to new methods that assist the annotation of proteins to biological functions, structures and subcellular localisations. As the human protein network is one of the most complex networks at all, these results will be fruitful for other fields of network theory and will help understanding complex network functions in general.

Mathematical aspects of Feynman integrals

In the present dissertation we consider Feynman integrals in the framework of dimensional regularization. As all such integrals can be expressed in terms of scalar integrals, we focus on this latter kind of integrals in their Feynman parametric representation and study their mathematical properties, partially applying graph theory, algebraic geometry and number theory. The three main topics are the graph theoretic properties of the Symanzik polynomials, the termination of the sector decomposition algorithm of Binoth and Heinrich and the arithmetic nature of the Laurent coefficients of Feynman integrals.rnrnThe integrand of an arbitrary dimensionally regularised, scalar Feynman integral can be expressed in terms of the two well-known Symanzik polynomials. We give a detailed review on the graph theoretic properties of these polynomials. Due to the matrix-tree-theorem the first of these polynomials can be constructed from the determinant of a minor of the generic Laplacian matrix of a graph. By use of a generalization of this theorem, the all-minors-matrix-tree theorem, we derive a new relation which furthermore relates the second Symanzik polynomial to the Laplacian matrix of a graph.rnrnStarting from the Feynman parametric parameterization, the sector decomposition algorithm of Binoth and Heinrich serves for the numerical evaluation of the Laurent coefficients of an arbitrary Feynman integral in the Euclidean momentum region. This widely used algorithm contains an iterated step, consisting of an appropriate decomposition of the domain of integration and the deformation of the resulting pieces. This procedure leads to a disentanglement of the overlapping singularities of the integral. By giving a counter-example we exhibit the problem, that this iterative step of the algorithm does not terminate for every possible case. We solve this problem by presenting an appropriate extension of the algorithm, which is guaranteed to terminate. This is achieved by mapping the iterative step to an abstract combinatorial problem, known as Hironaka's polyhedra game. We present a publicly available implementation of the improved algorithm. Furthermore we explain the relationship of the sector decomposition method with the resolution of singularities of a variety, given by a sequence of blow-ups, in algebraic geometry.rnrnMotivated by the connection between Feynman integrals and topics of algebraic geometry we consider the set of periods as defined by Kontsevich and Zagier. This special set of numbers contains the set of multiple zeta values and certain values of polylogarithms, which in turn are known to be present in results for Laurent coefficients of certain dimensionally regularized Feynman integrals. By use of the extended sector decomposition algorithm we prove a theorem which implies, that the Laurent coefficients of an arbitrary Feynman integral are periods if the masses and kinematical invariants take values in the Euclidean momentum region. The statement is formulated for an even more general class of integrals, allowing for an arbitrary number of polynomials in the integrand.

Nuclear structure studies in the xenon and radon region and the discovery of a new radon isotope by Penning trap mass spectrometry

Heutzutage gewähren hochpräzise Massenmessungen mit Penning-Fallen tiefe Einblicke in die fundamentalen Eigenschaften der Kernmaterie. Zu diesem Zweck wird die freie Zyklotronfrequenz eines Ions bestimmt, das in einem starken, homogenen Magnetfeld gespeichert ist. Am ISOLTRAP-Massenspektrometer an ISOLDE / CERN können die Massen von kurzlebigen, radioaktiven Nukliden mit Halbwertszeiten bis zu einigen zehn ms mit einer Unsicherheit in der Größenordnung von 10^-8 bestimmt werden. ISOLTRAP besteht aus einem Radiofrequenz-Quadrupol zum akkumulieren der von ISOLDE gelieferten Ionen, sowie zwei Penning-Fallen zum säubern und zur Massenbestimmung der Ionen. Innerhalb dieser Arbeit wurden die Massen von neutronenreichen Xenon- und Radonisotopen (138-146Xe und 223-229Rn) gemessen. Für elf davon wurde zum ersten Mal die Masse direkt bestimmt; 229Rn wurde im Zuge dieses Experimentes sogar erstmalig beobachtet und seine Halbwertszeit konnte zu ungefähr 12 s bestimmt werden. Da die Masse eines Nuklids alle Wechselwirkungen innerhalb des Kerns widerspiegelt, ist sie einzigartig für jedes Nuklid. Eine dieser Wechselwirkungen, die Wechselwirkung zwischen Protonen und Neutronen, führt zum Beispiel zu Deformationen. Das Ziel dieser Arbeit ist eine Verbindung zwischen kollektiven Effekten, wie Deformationen und Doppeldifferenzen von Bindungsenergien, sogenannten deltaVpn-Werten zu finden. Insbesondere in den hier untersuchten Regionen zeigen deltaVpn-Werte ein sehr ungewöhnliches Verhalten, das sich nicht mit einfachen Argumenten deuten lässt. Eine Erklärung könnte das Auftreten von Oktupoldeformationen in diesen Gebieten sein. Nichtsdestotrotz ist eine quantitative Beschreibung von deltaVpn-Werten, die den Effekt von solchen Deformationen berücksichtigt mit modernen Theorien noch nicht möglich.

Le opere di urbanizzazione a scomputo degli oneri

Le considerazioni sviluppate in questo scritto si pongono come obiettivo quello di fare chiarezza sul delicato tema delle opere di urbanizzazione a scomputo. La normativa concernente la realizzazione delle opere pubbliche a scomputo totale o parziale degli oneri di urbanizzazione è stata oggetto di svariate modifiche e interpretazioni giurisprudenziali, che si sono susseguite dopo l'importante pronuncia della Corte di Giustizia Europea. E' con questa sentenza che i Giudici del Kirchberg introducono un particolare obbligo procedurale a carico dei privati: nel caso in cui singole opere superino i valori di rilevanza europea, esse devono essere affidate, applicando le procedure di gara previste dalla direttiva 37/93/CEE. Va precisato che sino a quel momento l'affidamento diretto delle opere al privato costituiva nell'ottica del Legislatore lo strumento per realizzare le infrastrutture necessarie per consentire gli insediamenti edilizi che la pubblica amministrazione spesso non era in grado di effettuare. In questo panorama legislativo la sentenza della Corte di Giustizia, appare del tutto dirompente. Infatti, introducendo il principio secondo cui anche la realizzazione diretta delle opere di urbanizzazione da parte del privato deve sottostare alle regole delle procedure europee in materia di appalti, mette inevitabilmente a confronto due normative, quella degli appalti pubblici e quella dell'urbanistica, che sino a quel momento erano riuscite a viaggiare in modo parallelo, senza dar luogo a reciproche sovrapposizioni. Il Legislatore nazionale ha, con molta fatica, recepito il principio comunitario ed è stato negli anni quasi costretto, attraverso una serie di modifiche legislative, ad ampliarne la portata. La presente ricerca, dopo aver analizzato i vari correttivi apportati al Codice degli appalti pubblici vuole, quindi, verificare se l'attuale quadro normativo rappresenti un vero punto di equilibrio tra le contrapposte esigenze di pianificazione del territorio e di rispetto dei principi comunitari di concorrenza nella scelta del contraente.

Measurement of the elastic electron-proton cross section and separation of the electric and magnetic form factor in the Q 2 range from 0.004 to 1 (GeV/c) 2

The electromagnetic form factors of the proton are fundamental quantities sensitive to the distribution of charge and magnetization inside the proton. Precise knowledge of the form factors, in particular of the charge and magnetization radii provide strong tests for theory in the non-perturbative regime of QCD. However, the existing data at Q^2 below 1 (GeV/c)^2 are not precise enough for a hard test of theoretical predictions.rnrnFor a more precise determination of the form factors, within this work more than 1400 cross sections of the reaction H(e,e′)p were measured at the Mainz Microtron MAMI using the 3-spectrometer-facility of the A1-collaboration. The data were taken in three periods in the years 2006 and 2007 using beam energies of 180, 315, 450, 585, 720 and 855 MeV. They cover the Q^2 region from 0.004 to 1 (GeV/c)^2 with counting rate uncertainties below 0.2% for most of the data points. The relative luminosity of the measurements was determined using one of the spectrometers as a luminosity monitor. The overlapping acceptances of the measurements maximize the internal redundancy of the data and allow, together with several additions to the standard experimental setup, for tight control of systematic uncertainties.rnTo account for the radiative processes, an event generator was developed and implemented in the simulation package of the analysis software which works without peaking approximation by explicitly calculating the Bethe-Heitler and Born Feynman diagrams for each event.rnTo separate the form factors and to determine the radii, the data were analyzed by fitting a wide selection of form factor models directly to the measured cross sections. These fits also determined the absolute normalization of the different data subsets. The validity of this method was tested with extensive simulations. The results were compared to an extraction via the standard Rosenbluth technique.rnrnThe dip structure in G_E that was seen in the analysis of the previous world data shows up in a modified form. When compared to the standard-dipole form factor as a smooth curve, the extracted G_E exhibits a strong change of the slope around 0.1 (GeV/c)^2, and in the magnetic form factor a dip around 0.2 (GeV/c)^2 is found. This may be taken as indications for a pion cloud. For higher Q^2, the fits yield larger values for G_M than previous measurements, in agreement with form factor ratios from recent precise polarized measurements in the Q2 region up to 0.6 (GeV/c)^2.rnrnThe charge and magnetic rms radii are determined as rn⟨r_e⟩=0.879 ± 0.005(stat.) ± 0.004(syst.) ± 0.002(model) ± 0.004(group) fm,rn⟨r_m⟩=0.777 ± 0.013(stat.) ± 0.009(syst.) ± 0.005(model) ± 0.002(group) fm.rnThis charge radius is significantly larger than theoretical predictions and than the radius of the standard dipole. However, it is in agreement with earlier results measured at the Mainz linear accelerator and with determinations from Hydrogen Lamb shift measurements. The extracted magnetic radius is smaller than previous determinations and than the standard-dipole value.

Genetic dynamics across early life stages in the tropical tree Prunus africana (Rosaceae)

In many plant species, the genetic template of early life-stages is formed by animal-mediated pollination and seed dispersal and has profound impact on further recruitment and population dynamics. Understanding the impact of pollination and seed dispersal on genetic patterns is a central issue in plant population biology. In my thesis, I investigated (i) contemporary dispersal and gene flow distances as well as (ii) genetic diversity and spatial genetic structure (SGS) across subsequent recruitment stages in a population of the animal-pollinated and dispersed tree Prunus africana in Kakamega Forest, West Kenya. Using microsatellite markers and parentage analyses, I inferred distances of pollen dispersal (father-to-mother), seed dispersal/maternal gene flow (mother-to-offspring) as well as paternal gene flow (father-to-offspring) for four early life stages of the species (seeds and fruits, current year seedlings, seedlings ≤ 3yr, seedlings > 3yr). Distances of pollen and seed dispersal as well as paternal gene flow were significantly shorter than expected from the spatial arrangement of trees and sampling plots. They were not affected by the density of conspecific trees in the surrounding. At the propagule stage, mean pollen dispersal distances were considerably (23-fold) longer than seed dispersal distances, and paternal gene flow distances exceeded maternal gene flow by a factor of 25. Seed dispersal distances were remarkably restricted, potentially leading to a strong initial SGS. The initial genetic template created by pollination and seed dispersal was extensively altered during later recruitment stages. Potential Janzen-Connell effects led to markedly increasing distances between offspring and both parental trees in older life stages. This showed that distance and density-dependent mortality factors are not exclusively related to the mother tree, but also to the father. Across subsequent recruitment stages, the pollen to seed dispersal ratio and the paternal to maternal gene flow ratio dropped to 2.1 and 3.4, respectively, in seedlings > 3yr. The relative changes in effective pollen dispersal, seed dispersal, and paternal gene flow distances across recruitment stages elucidate the mechanisms affecting the contribution of the two processes pollen and seed dispersal to overall gene flow. Using the same six microsatellite loci, I analyzed genetic diversity and SGS across five life stages, from seed rain to adults. Levels of genetic diversity within the studied P. africana population were comparable to other Prunus species and did not vary across life stages. In congruence with the short seed dispersal distances, I found significant SGS in all life stages. SGS decreased from seed and early seedling stages to older juvenile stages, and it was higher in adults than in late juveniles of the next generation. A comparison of the data with direct assessments of contemporary gene flow patterns indicate that distance- or density-dependent mortality, potentially due to Janzen-Connell effects, led to the initial decrease in SGS. Intergeneration variation in SGS could have been driven by variation in demographic processes, the effect of overlapping generations, and local selection processes. Overall, my study showed that complex sequential processes during recruitment contribute to the spatial genetic structure of tree populations. It highlights the importance of a multistage perspective for a comprehensive understanding of the impact of animal-mediated pollen and seed dispersal on spatial population dynamics and genetic patterns of trees.

Development, degeneration and neural network of the bodily self

The question addressed by this dissertation is how the human brain builds a coherent representation of the body, and how this representation is used to recognize its own body. Recent approaches by neuroimaging and TMS revealed hints for a distinct brain representation of human body, as compared with other stimulus categories. Neuropsychological studies demonstrated that body-parts and self body-parts recognition are separate processes sub-served by two different, even if possibly overlapping, networks within the brain. Bodily self-recognition is one aspect of our ability to distinguish between self and others and the self/other distinction is a crucial aspect of social behaviour. This is the reason why I have conducted a series of experiment on subjects with everyday difficulties in social and emotional behaviour, such as patients with autism spectrum disorders (ASD) and patients with Parkinson’s disease (PD). More specifically, I studied the implicit self body/face recognition (Chapter 6) and the influence of emotional body postures on bodily self-processing in TD children as well as in ASD children (Chapter 7). I found that the bodily self-recognition is present in TD and in ASD children and that emotional body postures modulate self and others’ body processing. Subsequently, I compared implicit and explicit bodily self-recognition in a neuro-degenerative pathology, such as in PD patients, and I found a selective deficit in implicit but not in explicit self-recognition (Chapter 8). This finding suggests that implicit and explicit bodily self-recognition are separate processes subtended by different mechanisms that can be selectively impaired. If the bodily self is crucial for self/other distinction, the space around the body (personal space) represents the space of interaction and communication with others. When, I studied this space in autism, I found that personal space regulation is impaired in ASD children (Chapter 9).

Komparative Analyse der humanen Chromosomenregion 11p15.3 um die Gene LMO1,TUB und der orthologen Region in der Maus

Ziel der vorliegenden Arbeit war die vergleichende Sequenzierung und nachfolgende Analyse des syntänen chromosomalen Abschnitts auf dem kurzen Arm des humanen Chromosoms 11 in der Region 11p15.3 mit den Genen LMO1, TUB und dem orthologen Genomabschnitt der Maus auf Chromosom 7 F2. Die im Rahmen dieser Arbeit durchgeführte Kartierung dieser beiden chromosomalen Bereiche ermöglichte die Komplettierung einer genomischen Karte auf insgesamt über eine Megabase, die im Kooperationssequenzierprojekt der Universitäts-Kinderklinik und dem Institut für Molekulargenetik in Mainz erstellt wurde. Mit Hilfe von 28 PAC- und Cosmid-Klonen konnten in dieser Arbeit 383 kb an genomischer DNA des Menschen und mit sechs BAC- und PAC-Klonen 412 kb an genomischer DNA der Maus dargestellt werden. Dies ermöglichte erstmals die exakte Festlegung der Reihenfolge der in diesem chromosomalen Abschnitt enthaltenen Gene und die genaue Kartierung von acht STS-Markern des Menschen, bzw. vier STS-Sonden der Maus. Es zeigte sich dabei, dass die chromosomale Orientierung telomer-/centromerwärts des orthologen Bereichs in der Maus im Vergleich zum Menschen in invertierter Ausrichtung vorliegt. Die Sequenzierung von drei humanen Klonen ermöglichte die Bestimmung von 319.119 bp an zusammenhängender genomischer DNA. Dadurch konnte die genaue Lokalisation und Strukturaufklärung der Gene LMO1, ein putatives Tumorsuppressorgen, das mit der Entstehung von Leukämien assoziiert ist, und TUB, ein Transkriptionsmodulator, der in die Fettstoffwechselregulation involviert ist, vorgenommen werden. Für das murine Genom wurden 412.827 bp an neuer DNA-Sequenz durch Sequenzierung von ebenfalls drei Klonen generiert. Der im Vergleich zum Menschen ca. 100 kb größere Genombereich beinhaltete zudem die neuen Gene Stk33 und Eif3. Es handelte sich dabei um zwei Gene, die erst im Rahmen dieser Arbeit entdeckt und charakterisiert wurden. Die parallele Bearbeitung beider Genombereiche ermöglichte eine umfassende komparative Analyse nach kodierenden, funktionellen und strukturgebenden Sequenzabschnitten in beiden Spezies. Es konnten dabei für beide Organismen die Exon-Intron-Strukturen der Gene LMO1/Lmo1 und TUB/Tub geklärt. Zudem konnten vier neue Exons und zwei neue speziesspezifischer Spleißvarianten für TUB/Tub beschrieben werden. Die Identifizierung dieser neuen Spleißvarianten offenbart neue Möglichkeiten für alternative Regulation und Funktion, oder für eine veränderte Proteinstruktur, die weitere Erklärungsansätze für die Entstehung der mit diesen Genen assoziierten Erkrankungen zulässt. In der sequenzierten, größeren Genomsequenz der Maus konnte in den flankierenden, nicht mit der sequenzierten Humansequenz überlappenden Bereich das neue Gen Eif3 in seiner Exon-Intron-Struktur und die beiden letzten Exons 11 und 12 des Gens Stk33 kartiert und charakterisiert werden. Die umfangreiche Sequenzanalyse beider sequenzierter Genombereiche ergab für den Abschnitt des Menschen insgesamt 229 potentielle Exonsequenzen und für den Bereich der Maus 527 mögliche Exonbereiche. Davon konnten beim Menschen explizit 21 Exons und bei der Maus 31 Exons als exprimierte Bereiche identifiziert und experimentell mittels RT-PCR, bzw. durch cDNA-Sequenzierung verifiziert werden. Diese Abschnitte beschrieben nicht nur die Exonbereiche der oben genannten vier Gene, sondern konnten auch neuen nicht weiter definierten EST-Sequenzen zugeordnet werden. Mittels des Interspeziesvergleiches war darüber hinaus auch die Analyse der nichtkodierenden Intergen-Bereiche möglich. So konnten beispielsweise im ersten Intron des LMO1/Lmo1 sieben Sequenzbereiche mit Konservierungen von ca. 90% bestimmt werden. Auch die Charakterisierung von Promotor- und putativ regulatorischen Sequenzabschnitten konnte mit Hilfe unterschiedlicher bioinformatischer Analyse-Tools durchgeführt werden. Die konservierten Sequenzbereiche der DNA zeigen im Durchschnitt eine Homologie von mehr als 65% auf. Auch die Betrachtung der Genomorganisation zeigte Gemeinsamkeiten, die sich meist nur in ihrer graduellen Ausprägung unterschieden. So weist ein knapp 80 kb großer Bereich proximal zum humanen TUB-Gen einen deutlich erhöhten AT-Gehalt auf, der ebenso im murinen Genom nur in verkürzter Version und schwächer ausgeprägt in Erscheinung tritt. Die zusätzliche Vergleichsanalyse mit einer weiteren Spezies, den orthologen Genomabschnitten von Fugu, zeigte, dass es sich bei den untersuchten Genen LMO1 und TUB um sehr konservierte und evolutiv alte Gene handelt, deren genomisches Organisationsmuster sich auch bei den paralogen Genfamilienmitglieder innerhalb derselben Spezies wiederfindet. Insgesamt konnte durch die Kartierung, Sequenzierung und Analyse eine umfassende Datenbasis für die betrachtete Genomregion und die beschriebenen Gene generiert werden, die für zukünftige Untersuchungen und Fragestellungen wertvolle Informationen bereithält.