Novel casting alloys that retain their mechanical strength at temperatures up to 300 °C are needed in order to improve automotive engine efficiency. The addition of Zr and V is a promising combination as a means of introducing the thermally stable cubic Al3ZrxV1-x nano-precipitates. In this project, the evolution of the Al3ZrxV1-x precipitates in multi-component cast aluminium alloys was characterised in a statistically significant way using small-angle X-ray scattering (SAXS). Unlike established metallurgical techniques, such as transmission electron microscopy (TEM), SAXS measures billions of precipitates in a single experiment. Two Al-6.8Si (wt.%) alloys were employed. One contained 0.30 wt.% Zr and 0.30 wt.% V and the other 0.37 wt.% Zr and 0.34 wt.% V. The alloys were cast and isothermally aged at 400 °C for times ranging from 3 to 50 h. Synchrotron SAXS was undertaken at the Diamond Light Source (DLS). Direct evaluation methods of SAXS spectrum were employed in order to extract information about the average precipitate size, precipitate size distribution and their evolution with ageing time. These results were compared with the results provided via TEM, both validating the methodology, and demonstrating the benefits and drawbacks of SAXS.From the SAXS analysis, the Guinier radius, Rg, was found to increase with ageing time from around 2 nm at 3 h to approximately 9 nm at 50 h. Precipitate volume fraction also increased from 0.11 vol.% to 0.24 vol.% for the lower solute alloy and from 0.14 vol.% to 0.33 vol.% for the higher solute one. In both alloys, the precipitate number density was observed to continuously decrease with ageing time. For the higher solute alloy, the average precipitate radius from the TEM measurements was found to be consistently smaller than Rg. Such a study is important because it extends the experimental SAXS methodology previously used only in simplified alloys to multi-component cast alloys of industrial importance. Moreover, the findings from this investigation suggest that both alloys quickly enter a stage where the precipitate growth and coarsening overlap, and the precipitate number density continuously decreases with time. Finally, this study underlines the importance of preliminary SAXS data treatment and provides an analytical guide in order to successfully characterize low volume fraction of precipitates in multi-component cast alloys.

In the last decade omics technologies enabled detailed and system-wide analysis of complex biological samples. Genomics, transcriptomics and metabolomics all benefited tremendously from technological advances in their respective fields. Proteomics was revolutionised by mass spectrometry, which allowed simultaneous identification of thousands of proteins in cells, tissues and organisms. And this mainly qualitative revolution, quickly turned quantitative. This work had two main objectives. Firstly, to apply the state of the art instrumentation, data analysis and bioinformatics methods to better our understanding of basic cell biology in a model organism Saccharomyces cerevisiae. Specifically, to quantitatively describe the effects of perturbations, such as adverse environmental conditions or chaperone gene deletions, on protein abundances in the cell. Additionally, it was aimed to demonstrate and evaluate the ability of a new timeof-flight mass spectrometer to perform large-scale absolute quantification. First, it was found that yeast cells are remarkably robust to deletions of major chaperone hub proteins (Ssa1p or Ssb1p deletions). This ability was attributed to network structure and redistribution of folding workload among other related chaperones rather than simple functional redundancy. Second, to build on the first set of results, a detailed time resolved description of yeast proteome dynamics in response to heat stress was provided for the wild type and Ssb1p chaperone mutant strains. In this study, for the first time in the literature, temporal expression patterns of many hallmark heat shock proteins were elucidated. Globally, a slow and sustained proteome remodelling or 'buffering' was revealed in both strains. However, it was also shown that the cells knocked out for the Ssb1p chaperone respond to heat in a distinctly different manner to the wild type strain. Finally, consistent and reproducible absolute quantification of multiple yeast proteomes was demonstrated using a new commercial time-of-flight mass spectrometer with ion mobility separation capabilities. The data obtained revealed global differences in cellular protein content between various chaperone prefoldin mutants as well as differential expression of a set of proteins promising to be interesting targets for further investigations.

Quantitative Trait Loci (QTL) mapping has been widely used to identify genetic loci attributable to the variation observed in complex traits. In recent years, gene expression phenotypes have emerged as a new type of quantitative trait for which QTL can be mapped. Locating sequence variation that has an effect on gene expression (eQTL) is thought to be a promising way to elucidate the genetic architecture of quantitative traits. This thesis explores a number of methodological aspects of eQTL mapping (also known as “genetical genomics”) and considers some practical strategies for applying this approach to livestock populations. One of the exciting prospects of genetical genomics is that the combination of expression studies with fine mapping of functional trait loci can guide the reconstruction of gene networks. The thesis begins with an analysis in which correlations between gene expression and meat quality traits in pigs are investigated in relation to a pork meat quality QTL previously identified. The influence on power due to factors including sample size and records of matched subjects is discussed. An efficient experimental design for two-colour microarrays is then put forward, and it is shown to be an effective use of microarrays for mapping additive eQTL in outbred crosses under simulation. However, designs optimised for detecting both additive and dominance eQTL are found to be less effective. Data collected from livestock populations usually have a pedigreed structure. Many family-based association mapping methods are rather computationally intensive, hence are time-consuming when analysing very large numbers of traits. The application of a novel family-based association method is demonstrated; it is shown to be fast, accurate and flexible for genetical genomics. Furthermore, the results show that multiple testing correction alone is not sufficient to control type I errors in genetical genomics and that careful data filtering is essential. While it is important to limit false positives, it is desirable not to miss many true signals. A multi-trait analysis based on grouping of functionally related genes is devised to detect some of the signals overlooked by a univariate analysis. Using an inbred rat dataset, 13 loci are identified with significant linkage to gene sets of various functions defined by Gene Ontology. Applying this method to livestock species is possible, but the current level of annotations is a limiting factor. Finally, the thesis concludes with some current opinions on the development of genetical genomics and its impact on livestock genetics research.

Linkage between markers and genes that affect a phenotype of interest may be determined by examining differences in marker allele frequency in the extreme progeny of a cross between two inbred lines. This strategy is usually employed when pooling is used to reduce genotyping costs. When the cross progeny are asexual the extreme progeny may be selected by multiple generations of asexual reproduction and selection. In this thesis I will analyse this method of measuring phenotype in asexual cross progeny. The aim is to examine the behaviour of marker allele frequency due to selection over many generations, and also to identify statistically significant changes in frequency in the selected population. I will show that stochasticity in marker frequency in the selected population arises due the finite initial population size. For Mendelian traits, the initial population size should be at least in the low to mid hundreds to avoid spurious changes in marker frequency in the selected population. For quantitative traits the length of time selection is applied for, as well as the initial population size, will affect the stochasticity in marker frequency. The longer selection is applied for, the more chance of spurious changes in marker frequency. Also for quantitative traits, I will show that the presence of epistasis can hinder changes in marker frequency at selected loci, and consequently make identification of selected loci more difficult. I also show that it is possible to detect epistasis from the marker frequency by identifying reversals in the direction of marker frequency change. Finally, I develop a maximum likelihood based statistical model that aims to identify significant changes in marker frequency in the selected population. I will show that the power of this statistical model is high for detecting large changes in marker frequency, but very low for detecting small changes in frequency.

Work describes basic quantitative methods and their possible usage in IBM project management, it also substantiates the use of linear optimization software in real project

Social Disorganization Theory (SDT) stated that in poor and unstable neighbourhoods, residents may have difficulty developing and maintaining social order, due to the weaknesses of their social networks and the infrequent exercise of informal control. As a consequence, in those areas criminal victimization tends to be high and persists over time. Latin American poor neighbourhoods are often characterised by high residential stability, dense informal networks, strong social cohesion, and yet they often have high levels of violent crime, which constitutes a challenge for SDT. Studies from new ecological approaches have asserted that even if informal networks are weak, neighbours can engage in actions to prevent crimes when the form of intervention is appropriately targeted and the activity is conducted in a partnership with agencies of public control, such as the police or local authorities. Thereby, the general distrust in police and local authorities, and the weak nexus between those institutions and local communities, which characterize most poor areas of Latin-American cities, represent relevant obstacles for the encouragement of neighbours' involvement in crime prevention initiatives. Despite the low rates of violent crimes in Chile, global figures tend to hide how complex the crime phenomenon is in the country, and particularly in Santiago city. In the capital and largest city of Chile, the distribution of High-Social-Impact crimes is highly unequal with a greater concentration of violent crimes in the most marginalized and poorest districts of the city. In this context is worth asking, to what extent do neighbourhood structural conditions, community-organizational mechanisms and new forms of public control influence the experiences of violent and property victimization in households of Santiago neighbourhoods? And, to what extent do such mechanisms mediate the relationship between structural conditions and the likelihood of being victim of a crime in Santiago neighbourhoods? To address these questions, the present study draws on an integral theoretical framework aimed at providing a holistic multilevel approach to explaining victimization risk across Santiago neighbourhoods. Data for this study are drawn from a community-survey of 5,860 persons (from 15 to 90 years old) who lived in 242 selected neighbourhoods of the Santiago city. The survey was conducted in 2010 by the Centre for Studies on Citizen Security (CESC), based at the University of Chile, in the context of their research project 'Crime and Urban Violence'. The hierarchical structure of the data (incorporating both individual and neighbourhood level measures) and the adaptation of internationally validated measurements, presents an excellent opportunity to evaluate complex hypothesis with advanced statistical tools. The research has shown that in neighbourhoods with a high concentration of poverty and low residential stability the probability of being a victim of violent crime is greater than in rich areas. However, when people manifest positive sentiments toward their neighbourhood, perceive collaboration and social cohesion among neighbours, and have positive perceptions with respect to police responses, this largely mediates the negative effects of structural conditions on household victimization by violent crimes, thereby eliminating these effects. These findings have important policy implications. They suggest that in disadvantaged communities it is imperative that police and local authorities not only try to reduce crime through traditional approaches, but also improve trust and engagement of the public aiming to build sustainable partnerships.

In a heterogeneous environment where temperature influences fitness, individuals must navigate to a thermal optimum to maximize reproductive output and minimize physiological stress. However, the optimal temperature varies among individuals due to genetic and environmental contributions. The neural and genetic basis to such natural variation in behavior has remained elusive in most cases, as the high-throughput genomic, neurodevelopmental, and behavioral techniques were not developed. Using the nematode / 10000-01-01

Since its first experimental implementation in 2005, single-molecule localization microscopy (SMLM) emerged as a versatile and powerful imaging tool for biological structures with nanometer resolution. By now, SMLM has compiled an extensive track-record of novel insights in sub- and inter- cellular organization.\\ Moreover, since all SMLM techniques rely on the analysis of emission patterns from isolated fluorophores, they inherently allocate molecular information $per$ $definitionem$.\\ Consequently, SMLM transitioned from its origin as pure high-resolution imaging instrument towards quantitative microscopy, where the key information medium is no longer the highly resolved image itself, but the raw localization data set.\\ The work presented in this thesis is part of the ongoing effort to translate those $per$ $se$ molecular information gained by SMLM imaging to insights into the structural organization of the targeted protein or even beyond. Although largely consistent in their objectives, the general distinction between global or segmentation clustering approaches on one side and particle averaging or meta-analyses techniques on the other is usually made.\\ During the course of my thesis, I designed, implemented and employed numerous quantitative approaches with varying degrees of complexity and fields of application.\\ \\ In my first major project, I analyzed the localization distribution of the integral protein gp210 of the nuclear pore complex (NPC) with an iterative \textit{k}-means algorithm. Relating the distinct localization statistics of separated gp210 domains to isolated fluorescent signals led, among others, to the conclusion that the anchoring ring of the NPC consists of 8 homo-dimers of gp210.\\ This is of particular significance, both because it answered a decades long standing question about the nature of the gp210 ring and it showcased the possibility to gain structural information well beyond the resolution capabilities of SMLM by crafty quantification approaches.\\ \\ The second major project reported comprises an extensive study of the synaptonemal complex (SNC) and linked cohesin complexes. Here, I employed a multi-level meta-analysis of the localization sets of various SNC proteins to facilitate the compilation of a novel model of the molecular organization of the major SNC components with so far unmatched extend and detail with isotropic three-dimensional resolution.\\ In a second venture, the two murine cohesin components SMC3 and STAG3 connected to the SNC were analyzed. Applying an adapted algorithm, considering the disperse nature of cohesins, led to the realization that there is an apparent polarization of those cohesin complexes in the SNC, as well as a possible sub-structure of STAG3 beyond the resolution capabilities of SMLM.\\ \\ Other minor projects connected to localization quantification included the study of plasma membrane glycans regarding their overall localization distribution and particular homogeneity as well as the investigation of two flotillin proteins in the membrane of bacteria, forming clusters of distinct shapes and sizes.\\ \\ Finally, a novel approach to three-dimensional SMLM is presented, employing the precise quantification of single molecule emitter intensities. This method, named TRABI, relies on the principles of aperture photometry which were improved for SMLM.\\ With TRABI it was shown, that widely used Gaussian fitting based localization software underestimates photon counts significantly. This mismatch was utilized as a $z$-dependent parameter, enabling the conversion of 2D SMLM data to a virtual 3D space. Furthermore it was demonstrated, that TRABI can be combined beneficially with a multi-plane detection scheme, resulting in superior performance regarding axial localization precision and resolution.\\ Additionally, TRABI has been subsequently employed to photometrically characterize a novel dye for SMLM, revealing superior photo-physical properties at the single-molecule level.\\ Following the conclusion of this thesis, the TRABI method and its applications remains subject of diverse ongoing research. / Seit ihrer ersten experimentellen Umsetzung in 2005 hat sich die Einzel-Molekül Lokalisations-Mikroskopie (\textit{engl.} single-molecule localization microscopy (SMLM)) als vielseitig einsetzbares Verfahren in der biologischen Bildgebung etabliert, vor allem aufgrund ihres hohen Auflösungsvermögens im Nanometer Bereich. Bis heute wurde eine Reihe neuer Erkenntnisse bezüglich der sub- und inter- zellulären Organisation durch den Einsatz der SMLM erlangt.\\ Aufgrund der Tatsache, dass alle SMLM Techniken auf dem Prinzip basieren, isolierte Fluorophore zu detektieren und zu analysieren, beinhalten SMLM Daten $per$ $definitionem$ molekulare Informationen.\\ Folgerichtig entwickelte sich das Feld der SMLM vom reinen Bildgebungsinstrument mit Nanometer-Auflösung hin zu quantitativer Mikroskopie, bei welcher der Fokus nicht länger vornehmlich auf dem hochaufgelöstem Bild, sondern vielmehr auf den Lokalisationsdaten liegt.\\ Die vorliegende Arbeit ist als Teil der anhaltenden Bestrebungen zu sehen, aus den $per$ $se$ molekularen Informationen der SMLM weiterführende Erkenntnisse über die strukturelle Organisation der markierten Proteine zu gewinnen. Obwohl mit der gleichen prinzipiellen Zielsetzung versehen, unterscheiden sich hierbei globale oder Segmentierungs- Clusteranalysen von Lokalisations-Meta-Analysen oder so genannten \textit{particle averaging} Ansätzen.\\ Während meiner Doktorarbeit habe ich verschiedene Quantifizierungs Ansätze entworfen, implementiert und angewendet, mit unterschiedlichen Graden an Komplexität und Breite des Anwendungsgebietes.\\ \\ In meinem ersten wesentlichem Projekt analysierte ich mit einem iterativen \textit{k}-means Algorithmus die Lokalisationsverteilung des integralen Proteins gp210, welches Teil des Kernporenkomplexes ist (\textit{engl.} nuclear pore complex (NPC)). Durch den Vergleich der charakteristischen Lokalisations-Statistik von separierten gp210 Domänen mit isolierten Fluoreszenzmarkern konnte unter anderem festgestellt werden, dass der Verankerungsring des NPC aus acht gp210 Homodimeren bestehen muss.\\ Diese Erkenntnis beantwortet zum einen eine jahrzehntealte Frage nach der Zusammensetzung des gp210 Rings und zum anderen liefert sie ein Beispiel dafür, dass durch eine geschickte Analyse der Lokalisationsstatistik strukturelle Informationen erlangt werden können, die jenseits des räumlichen Auflösungsvermögens von SMLM liegen.\\ \\ Das zweite hier vorgestellte wesentliche Projekt beinhaltet eine umfassende Studie des Synaptonemalen Komplexes (\textit{engl.} synaptonemal complex (SNC)) und damit verbundenen Cohesin Komplexen. Um die molekulare Organisation des SNC zu untersuchen, implementierte ich eine multi-level Meta-Analyse der Lokalisationsdaten mehrerer SNC Komponenten. Aus dessen Ergebnissen konnte ein neues drei dimensionales molekulares Modell des SNC erstellt werden.\\ Nachfolgend wurden die beiden murinen Cohesine SMC3 und STAG3 mit adaptierter Methodik untersucht. Hierbei musste die starke intrinsische Dispersion der Cohesin-Signale berücksichtigt werden. Die Analyse ergab deutliche Hinweise auf eine Polarisation der Cohesine innerhalb des SNC. Zudem zeigte sich eine mögliche Substruktur in der Organisation von STAG3, die unterhalb der Auflösungsgrenze von SMLM liegt.\\ \\ Weitere Nebenprojekte im Zusammenhang mit quantitativer Lokalisationsanalyse umfassten die Untersuchung der Lokalisationsverteilung von Plasma-Membran Glykanen, sowie zweier Flotillin Proteine in den Membranen von Bakterien, welche Cluster unterschiedlicher Form und Größe aufzeigten.\\ \\ Schließlich wird ein neuartiger Ansatz für dreidimensionale SMLM vorge-stellt, die auf der genauen Bestimmung von Einzel-Molekül Intensitäten basiert. Diese Methode, genannt TRABI, stützt sich auf die Prinzipien der Apertur Photometrie, welche für die SMLM angepasst und verbessert wurden.\\ Mit TRABI konnte gezeigt werden, dass weit verbreitete Lokalisations-Software, die auf $Gaussian-Fitting$ basiert, die Photonenzahl von Emittern oftmals stark unterschätzt. Diese Diskrepanz kann als $z$-abhängiger Parameter verwendet werden um z.B. einen 2D SMLM Datenatz in einen virtuellen 3D Raum zu überführen. Außerdem wird gezeigt, dass TRABI vorteilhaft mit einem multi-plane Detektionsschema kombiniert werden kann und dabei höhere axiale Lokalisationsgenauigkeiten und Auflösungen er-reicht.\\ Zudem wurde TRABI eingesetzt, um einen neuen Fluoreszenzfarbstoff für SMLM zu charakterisieren und dessen verbesserte photo-physikalische Eigenschaften auf Einzel-Molekül Basis zu demonstrieren.\\ Auch nach Abschluss dieser Arbeit ist die TRABI Methode und deren Anwendung weiterhin Gegenstand diverser Forschungen.

One of the main goals of research in clinical psychology is to enhance the understanding and conceptualization of psychopathology. As such, it is essential that the model used to classify mental illness be as valid as possible. The Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev; DSM-IV-TR, American Psychiatric Association, 2000) provides the current model of psychopathology. However, there has been growing dissatisfaction with the current version of the DSM and there is an increasing view that the DSM taxonomy is scientifically unsound (Brown & Barlow, 2005; Watson & Clark, 2006; Widiger & Samuel, 2005). Quantitative structural models of psychopathology (e.g., Internalizing/Externalizing; Krueger, 1999) have provided an alternative to the DSM model and have greatly advanced the conceptualization of psychopathology. Although these models represent a significant improvement they still have several limitations. First, they exclude many of the "severe" disorders (e.g., psychotic disorders). Second, the placement of some disorders (e.g., OCD and PTSD) in the model has not been consistent. Finally, they are based on categorical diagnoses, which are less valid and reliable than dimensional alternatives (Markon, Chmielewski, & Miller, 2011). Thus, the use of categorical diagnosis as the foundation for empirical models of psychopathology likely results in suboptimal models. Moreover, it has been argued that many diagnoses are excessively heterogeneous, suggesting that analyzing the symptoms that underlie the disorders could result in more fine-grained models that more closely "carves nature at its joints." The current study addresses the limitations of current quantitative models to create an expanded model of psychopathology that likely has increased validity. Structural analyses were conducted at both the syndromal level (to serve as a proxy for dimensional versions of DSM diagnosis) and the symptom level in a large patient sample using both self-report and interview data. A three-factor model, containing Internalizing, Externalizing, and Psychoticism/Oddity dimensions emerged across both sets of analyses The emergence of this model at both the syndromal and symptom level provides strong evidence that a third higher order Psychoticism/Oddity dimension is necessary for a more complete model of psychopathology. The association of these dimensions with normal personality traits and other external correlates also was examined and implications for the conceptualization of psychopathology are discussed.

A significant number of Liberian ex-militants are unemployed and underemployed despite the job skills, formal education, and entrepreneurial training they received as participants in the Formal Disarmament, Demobilization, and Reintegration (DDR) program that was established to reintegrate combatants into civilian society at the end of the two civil wars in Liberia in 2003. The purpose of this study was to examine the strengths and weaknesses of the vocational training offered by the DDR program. Informed by the theories of Human Capital, Peace Building, and Bronfrenbrenner, the research questions for this study assessed the benefits of the educational component of DDR. A phenomenological study design was employed with a purposeful sample of ex-militant participants that included 12 ex-militants and a focus group of 6-ex-militants drawn from the 12 who completed vocational training at the Monrovia Vocational Training Center in Monrovia (MVTC). All data were inductively coded and analyzed using a constant comparative method. Data analysis uncovered five textural themes: motivation for disarmament, hope to rebuild lives through vocational training, dissatisfaction with reintegration, perception of reintegration, and perception of future combat participation. Findings support human capital, peace building, and ecological systems theories in that ex-militants perceived the benefit of education in their transition to peacetime endeavor, but consider themselves only partially reintegrated since all consider themselves unemployed with no means to survive economically. This study is significant because it provides recommendations to policymakers on how such a program can improve the vocational training offered and provide follow-up life-skills counseling.