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Institute
We have discovered a new mechanism of monoallelic gene expression that links antigenic variation, cell cycle, and development in the model parasite Trypanosoma brucei. African trypanosomes possess hundreds of variant surface glycoprotein (VSG) genes, but only one is expressed from a telomeric expression site (ES) at any given time. We found that the expression of a second VSG alone is sufficient to silence the active VSG gene and directionally attenuate the ES by disruptor of telomeric silencing-1B (DOT1B)-mediated histone methylation. Three conserved expression-site-associated genes (ESAGs) appear to serve as signal for ES attenuation. Their depletion causes G1-phase dormancy and reversible initiation of the slender-to-stumpy differentiation pathway. ES-attenuated slender bloodstream trypanosomes gain full developmental competence for transformation to the tsetse fly stage. This surprising connection between antigenic variation and developmental progression provides an unexpected point of attack against the deadly sleeping sickness.
Der Knochenmann
(2011)
Es handelt sich um eine mittelschwere Klausur auf Examensniveau. Neben Standardwissen zu gängigen Delikten wird vom Bearbeiter problembewusstes Transferdenken in ungewohnten, aber mit fundierter juristischer Arbeitstechnik gut lösbaren Problemkreisen erwartet. Der Fall wurde im Sommersemester 2009 im Rahmen des Examensklausurenkurses der Juristischen Fakultät gestellt. Der Notendurchschnitt betrug 5,68 Punkte, die Durchfallquote 21 %.
Internet der Zukunft
(2010)
Wie kaum eine andere technische Neuerung hat das Internet das tägliche Leben von Millionen von Menschen verändert. Quasi im Gegenzug verändern mittlerweile aber auch Millionen von Menschen ihrerseits das Internet. Aus dem einfachen User wurde der Creator. Diese Entwicklung wird vielerorts unter den Begriff des Web 2.0 gefasst, das vor allem als Schlagwort die veränderte Rollenverteilung im Web beschreibt. Das Web 2.0 lässt sich aber auch typologisch begreifen, als Zusammenfassung vieler Ein-zelphänomene, die den Typus Web 2.0 charakterisieren. Diese Phänomene befinden sich aber (wie auch das Web selbst) in einem stetigen Wandel und Weiterentwicklungs-prozess, sodass sie sowohl dem Web 2.0 als auch dem Internet der Zukunft zugehörig zu sein scheinen: Während die Potentiale des Cloud Computing und der Augmented Reality wohl noch in den Kinderschuhen stecken, haben soziale Netzwerke, ubiquitäres Computing und Mashups die Medienlandschaft bereits grundlegend verändert. Eine stetige technische und ökonomische Weiterentwicklung dieser Phänomene kann allerdings nur auf den geleiteten Bahnen des Rechts stattfinden. Fraglich ist aber gerade – wie es im Bereich der neuen Medien so oft der Fall ist -, ob das Recht über die nötigen Rahmenbedingungen verfügt, um den besagten Entwicklungen entgegenzutreten. Das Memorandum Internet der Zukunft zeigt diese rechtlichen Hintergründe für die wichtigsten aktuellen IT-Erscheinungen auf und beleuchtet die besagten Phänomene aus technischer und ökonomischer Sicht, was letztlich auch dem interdisziplinären Charakter der Rechtsinformatik Rechnung trägt.
An expanded evaluation of protein function prediction methods shows an improvement in accuracy
(2016)
Background
A major bottleneck in our understanding of the molecular underpinnings of life is the assignment of function to proteins. While molecular experiments provide the most reliable annotation of proteins, their relatively low throughput and restricted purview have led to an increasing role for computational function prediction. However, assessing methods for protein function prediction and tracking progress in the field remain challenging.
Results
We conducted the second critical assessment of functional annotation (CAFA), a timed challenge to assess computational methods that automatically assign protein function. We evaluated 126 methods from 56 research groups for their ability to predict biological functions using Gene Ontology and gene-disease associations using Human Phenotype Ontology on a set of 3681 proteins from 18 species. CAFA2 featured expanded analysis compared with CAFA1, with regards to data set size, variety, and assessment metrics. To review progress in the field, the analysis compared the best methods from CAFA1 to those of CAFA2.
Conclusions
The top-performing methods in CAFA2 outperformed those from CAFA1. This increased accuracy can be attributed to a combination of the growing number of experimental annotations and improved methods for function prediction. The assessment also revealed that the definition of top-performing algorithms is ontology specific, that different performance metrics can be used to probe the nature of accurate predictions, and the relative diversity of predictions in the biological process and human phenotype ontologies. While there was methodological improvement between CAFA1 and CAFA2, the interpretation of results and usefulness of individual methods remain context-dependent.
Unique features of a global human ectoparasite identified through sequencing of the bed bug genome
(2016)
The bed bug, Cimex lectularius, has re-established itself as a ubiquitous human ectoparasite throughout much of the world during the past two decades. This global resurgence is likely linked to increased international travel and commerce in addition to widespread insecticide resistance. Analyses of the C. lectularius sequenced genome (650 Mb) and 14,220 predicted protein-coding genes provide a comprehensive representation of genes that are linked to traumatic insemination, a reduced chemosensory repertoire of genes related to obligate hematophagy, host–symbiont interactions, and several mechanisms of insecticide resistance. In addition, we document the presence of multiple putative lateral gene transfer events. Genome sequencing and annotation establish a solid foundation for future research on mechanisms of insecticide resistance, human–bed bug and symbiont–bed bug associations, and unique features of bed bug biology that contribute to the unprecedented success of C. lectularius as a human ectoparasite.
For persistent infections of the mammalian host, African trypanosomes limit their population size by quorum sensing of the parasite-excreted stumpy induction factor (SIF), which induces development to the tsetse-infective stumpy stage. We found that besides this cell density-dependent mechanism, there exists a second path to the stumpy stage that is linked to antigenic variation, the main instrument of parasite virulence. The expression of a second variant surface glycoprotein (VSG) leads to transcriptional attenuation of the VSG expression site (ES) and immediate development to tsetse fly infective stumpy parasites. This path is independent of SIF and solely controlled by the transcriptional status of the ES. In pleomorphic trypanosomes varying degrees of ES-attenuation result in phenotypic plasticity. While full ES-attenuation causes irreversible stumpy development, milder attenuation may open a time window for rescuing an unsuccessful antigenic switch, a scenario that so far has not been considered as important for parasite survival.
The protein density in biological membranes can be extraordinarily high, but the impact of molecular crowding on the diffusion of membrane proteins has not been studied systematically in a natural system. The diversity of the membrane proteome of most cells may preclude systematic studies. African trypanosomes, however, feature a uniform surface coat that is dominated by a single type of variant surface glycoprotein (VSG). Here we study the density-dependence of the diffusion of different glycosylphosphatidylinositol-anchored VSG-types on living cells and in artificial membranes. Our results suggest that a specific molecular crowding threshold (MCT) limits diffusion and hence affects protein function. Obstacles in the form of heterologous proteins compromise the diffusion coefficient and the MCT. The trypanosome VSG-coat operates very close to its MCT. Importantly, our experiments show that N-linked glycans act as molecular insulators that reduce retarding intermolecular interactions allowing membrane proteins to function correctly even when densely packed.
Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.