Bioinformatics analyses of genomic imprinting

In the present thesis, bioinformatics analyses of genomic DNA sequences identified a number of features that distinguish imprinted genes from normal, biallelically expressed genes. Despite species-specific differences, which particularly complicate identification of functional CpG islands, imprinted genes of human and mouse are enriched in intronic CpG islands and tandem repeats. Together with conserved LINE-1 repeats they might be involved in the establishment of the allele-specific marks in the germ line. Striking in comparison to non-imprinted genes is also the enrichment of CpG-rich motifs as well as a decreased estimated deamination ratio in conserved sequences, which hints at unanticipated effects of differential methylation. Genome-wide analyses showed that highly conserved elements in exons of imprinted genes are less conserved and shorter than those of normal genes. Maternally expressed genes and the proteins encoded by them are more divergent between rodents and other mammals, whereas paternally expressed genes are conserved above average between mouse and rat. The associated opposite patterns of selection suggest that imprinted genes played a role in the evolution of early rodents. The existence of conserved paralogs with similar functions may have facilitated divergence.In der vorliegenden Arbeit wurde durch bioinformatische Untersuchungen von genomischen DNSSequenzen eine Reihe von Merkmalen bestimmt, die elterlich geprägte Gene gegenüber normalen, biallelisch exprimierten Genen auszeichnen. Trotz artenspezifischer Unterschiede, die insbesondere die Identifizierung von funktionalen CpG-Inseln erschweren, besitzen geprägte Gene in Mensch und Maus vermehrt intronische CpG-Inseln und Tandemrepeats. Zusammen mit konservierten LINE-1-Repeats könnten diese zur Einrichtung der allelspezifischen Markierungen in der Keimbahn beitragen. Auffällig im Vergleich zu nicht geprägten Genen sind auch die Anreicherung von CpG-reichen Motiven und eine erniedrigte geschätzte Desaminierungsrate in konservierten Sequenzabschnitten, was auf unvorhergesehene Effekte differentieller Methylierung schließen lässt. Genomweite Analysen ergaben, dass hochkonservierte Elemente in Exons bei geprägten Genen weniger konserviert und kürzer sind als bei normalen Genen. Maternal exprimierte Gene und von ihnen codierte Proteine zeigen erhöhte Divergenz zwischen Nagetieren und anderen Säugetieren, wohingegen paternal exprimierte Gene zwischen Maus und Ratte einen überdurchschnittlich hohen Konservierungsgrad aufweisen. Die damit verbundenen entgegengesetzten Selektionsmuster lassen darauf schließen, dass geprägte Gene eine Rolle in der Evolution früher Nagetiere spielten. Möglicherweise erleichterte die Existenz von konservierten Paralogen mit ähnlicher Funktion die Divergenz

Ab-initio study of model guanine assemblies: The role of pi-pi coupling and band transport

Several assemblies of guanine molecules are investigated by means of first-principle calculations. Such structures include stacked and hydrogen-bonded dimers, as well as vertical columns and planar ribbons, respectively, obtained by periodically replicating the dimers. Our results are in good agreement with experimental data for isolated molecules, isolated dimers, and periodic ribbons. For stacked dimers and columns, the stability is affected by the relative charge distribution of the pi orbitals in adjacent guanine molecules. pi-pi coupling in some stacked columns induces dispersive energy bands, while no dispersion is identified in the planar ribbons along the connections of hydrogen bonds. The implications for different materials comprised of guanine aggregates are discussed. The bandstructure of dispersive configurations may justify a contribution of band transport (Bloch type) in the conduction mechanism of deoxyguanosine fibres, while in DNA-like configurations band transport should be negligible.Comment: 21 pages, 6 figures, 3 tables, to be published in Phys. Rev.

The Rhetoric of Solidarity: Nature and Measurement of Social Cohesion in the Self-representation of Civil Society Organizations

Scholars have called to study how social cohesion is discursively negotiated and produced in communication behavior. However, empirical evidence remains scarce. In this study, we investigate to what extent and how civil society organizations (CSOs), part of the backbone of social integration in modern democracies, make references to social cohesion in their public self-portrayals. We develop a standardized measure for content analyzing the manifestation of social cohesion along three theoretical dimensions: social relations, connectedness, and orientation towards the common good. We apply our innovative content measure to the external communication of an original sample of nearly 800 CSOs in Germany, using their websites. Subsequently, we use data from an accompanying organizational survey of these institutions to investigate whether and how certain organizational features help explain variance in social cohesion rhetoric. Findings suggest that CSOs’ external communications employ themes from all key dimensions of social cohesion, revealing a fair amount of variation on all three subdimensions and a summary index of the overall strength social cohesion rhetoric. These different emphases are contingent upon various organizational characteristics, namely the spheres in which CSOs are primarily active, their locations, and their target groups. Whereas culturally and media-oriented organizations as well as sports clubs are largely reluctant to make references to social cohesion, politically active CSOs and those addressing socially disadvantaged communities tend to push more in this direction. The latter tend to operate in more professionalized structures, indicating that referencing social cohesion legitimizes these groups’ political and social purposes in the public sphere

Genome-Wide Diet-Gene Interaction Analyses for Risk of Colorectal Cancer

Dietary factors, including meat, fruits, vegetables and fiber, are associated with colorectal cancer; however, there is limited information as to whether these dietary factors interact with genetic variants to modify risk of colorectal cancer. We tested interactions between these dietary factors and approximately 2.7 million genetic variants for colorectal cancer risk among 9,287 cases and 9,117 controls from ten studies. We used logistic regression to investigate multiplicative gene-diet interactions, as well as our recently developed Cocktail method that involves a screening step based on marginal associations and gene-diet correlations and a testing step for multiplicative interactions, while correcting for multiple testing using weighted hypothesis testing. Per quartile increment in the intake of red and processed meat were associated with statistically significant increased risks of colorectal cancer and vegetable, fruit and fiber intake with lower risks. From the case-control analysis, we detected a significant interaction between rs4143094 (10p14/near GATA3) and processed meat consumption (OR = 1.17; p = 8.7E-09), which was consistently observed across studies (p heterogeneity = 0.78). The risk of colorectal cancer associated with processed meat was increased among individuals with the rs4143094-TG and -TT genotypes (OR = 1.20 and OR = 1.39, respectively) and null among those with the GG genotype (OR = 1.03). Our results identify a novel gene-diet interaction with processed meat for colorectal cancer, highlighting that diet may modify the effect of genetic variants on disease risk, which may have important implications for prevention. © 2014

Comprehensive molecular characterization of gastric adenocarcinoma

Gastric cancer is a leading cause of cancer deaths, but analysis of its molecular and clinical characteristics has been complicated by histological and aetiological heterogeneity. Here we describe a comprehensive molecular evaluation of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project. We propose a molecular classification dividing gastric cancer into four subtypes: tumours positive for Epstein–Barr virus, which display recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, CD274 (also known as PD-L1) and PDCD1LG2 (also knownasPD-L2); microsatellite unstable tumours, which show elevated mutation rates, including mutations of genes encoding targetable oncogenic signalling proteins; genomically stable tumours, which are enriched for the diffuse histological variant and mutations of RHOA or fusions involving RHO-family GTPase-activating proteins; and tumours with chromosomal instability, which show marked aneuploidy and focal amplification of receptor tyrosine kinases. Identification of these subtypes provides a roadmap for patient stratification and trials of targeted therapies

Drug sensitivity profiling of 3D tumor tissue cultures in the pediatric precision oncology program INFORM

The international precision oncology program INFORM enrolls relapsed/refractory pediatric cancer patients for comprehensive molecular analysis. We report a two-year pilot study implementing ex vivo drug sensitivity profiling (DSP) using a library of 75-78 clinically relevant drugs. We included 132 viable tumor samples from 35 pediatric oncology centers in seven countries. DSP was conducted on multicellular fresh tumor tissue spheroid cultures in 384-well plates with an overall mean processing time of three weeks. In 89 cases (67%), sufficient viable tissue was received; 69 (78%) passed internal quality controls. The DSP results matched the identified molecular targets, including BRAF, ALK, MET, and TP53 status. Drug vulnerabilities were identified in 80% of cases lacking actionable (very) high-evidence molecular events, adding value to the molecular data. Striking parallels between clinical courses and the DSP results were observed in selected patients. Overall, DSP in clinical real-time is feasible in international multicenter precision oncology programs

A thermally self-sustained micro-power plant with integrated micro-solid oxide fuel cells, micro-reformer and functional micro-fluidic carrier

Low temperature micro-solid oxide fuel cell (micro-SOFC) systems are an attractive alternative power source for small-size portable electronic devices due to their high energy efficiency and density. Here, we report a thermally self-sustainable reformer – micro-SOFC assembly. The device consists of a micro-reformer bonded to a silicon chip containing 30 micro-SOFC membranes and a functional glass carrier with gas channels and screen-printed heaters for start-up. Thermal independence of the device from the externally powered heater is achieved by this exothermic reforming reaction above 470 °C. The reforming reaction and the fuel gas flow rate of the n-butane/air gas mixture controls the operation temperature and gas composition on the micro-SOFC membrane. In the temperature range between 505 °C and 570 °C, the gas composition after the micro-reformer consists of 12 vol% to 28 vol% H2. An open-circuit voltage of 1.0 V and maximum power density of 47 mW/cm2 at 565 °C is achieved with the on-chip produced hydrogen at the micro-SOFC membranes