Untersuchung zur Rolle der Profilaggrin-Peptide FLG91-122 und FLG87-197 in der kutanen Abwehr

Die menschliche Haut ist als große Kontaktfläche zur Umwelt ständig einer Vielzahl von Bakterien, Viren und Pilzen ausgesetzt. Dennoch treten bei gesunden Menschen nur selten Hautinfektionen auf. An dieser natürliche Resistenz ist neben einer physikalischen Barriere auch eine "chemische Barriere" beteiligt. Zusätzlich zu ihrem "Säureschutzmantel" (pH ca. 5,0) verfügt die Haut mit der Produktion von antimikrobiellen Peptiden über wirkungsvolle Mechanismen gegen das Eindringen von Mikroorganismen. In vorangegangenen Untersuchungen unserer Arbeitsgruppe konnten in antimikrobiell aktiven HPLC-Fraktionen von Proteinextrakten des Stratum corneums gesunder Menschen unter anderem N-terminal lokalisierte Fragmente von Profilaggrin nachgewiesen werden. Ziel dieser Arbeit war es nun, die Rolle der Fragmente FLG 91-122 (PFLG-3) und FLG 87-197 (PFLG-4) im Rahmen der kutanen Abwehr zu klären. Dazu wurden diese Fragmente als nicht-toxisches Fusionsprotein rekombinant in Escherichia coli exprimiert, vom Fusionsabschnitt abgespalten, aufgereinigt und auf antimikrobielle Eigenschaften getestet. Für PFLG-4 konnte im radialen Plattendiffusionstest antimikrobielle Aktivität gegen das Gram-positive Bakterium Staphylococcus aureus, für die Gram-negativen Bakterien Escherichia coli und Pseudomonas aeruginosa sowie die Hefe Candida albicans nachgewiesen werden. PFLG-3 zeigte gegen die genannten Mikroorganismen keine Aktivität. Neben den bereits bekannten Funktionen des Profilaggrin-Proteins konnte in dieser Arbeit erstmalig nachgewiesen werden, dass ein definierter in der Haut nachweisbarer N-terminaler Abschnitt von Profilaggrin antimikrobielle Eigenschaften aufweist und somit möglicherweise einen direkten Beitrag zur kutanen Abwehr von Mikroorganismen leistet

Phase Space Description of the Leading Order Quark and Gluon Production from a Space-Time Dependent Chromofield

We derive source terms for the production of quarks and gluons from the QCD vacuum in the presence of a space-time dependent external chromofield A_{cl} to the order of S^{(1)}. We found that the source terms for the parton production processes A_{cl} -> q\bar{q} and A_{cl},A_{cl}A_{cl} -> gg also include the annihilation processes q\bar{q} -> A_{cl} and gg -> A_{cl},A_{cl}A_{cl}. The source terms we derive are applicable for the description of the production of partons with momentum p larger rhan gA which itself must be larger than \Lambda_{QCD}. We observe that these source terms for the production of partons from a space-time dependent chromofield can be used to study the production and equilibration of the quark-gluon plasma during the very early stages of an ultrarelativistic heavy-ion collision.Comment: 30 pages latex (single spaced), 7 eps figures, Revised Version, To appear in Physical Review

Genomic basis of a social polymorphism in a halictid bee

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Tango Controls and data pipeline for petawatt laser experiments

The Centre for Advanced Laser Applications in Garching, Germany, is home to the ATLAS-3000 multi-petawatt laser, dedicated to research on laser particle acceleration and its applications. A control system based on Tango Controls is implemented for both the laser and four experimental areas. The device server approach features high modularity, which, in addition to the hardware control, enables a quick extension of the system and allows for automated data acquisition of the laser parameters and experimental data for each laser shot. In this paper we present an overview of our implementation of the control system, as well as our advances in terms of experimental operation, online supervision and data processing. We also give an outlook on advanced experimental supervision and online data evaluation – where the data can be processed in a pipeline – which is being developed on the basis of this infrastructure

Genomic and transcriptomic changes complement each other in the pathogenesis of sporadic Burkitt lymphoma

Burkitt lymphoma (BL) is the most common B-cell lymphoma in children. Within the International Cancer Genome Consortium (ICGC), we performed whole genome and transcriptome sequencing of 39 sporadic BL. Here, we unravel interaction of structural, mutational, and transcriptional changes, which contribute to MYC oncogene dysregulation together with the pathognomonic IG-MYC translocation. Moreover, by mapping IGH translocation breakpoints, we provide evidence that the precursor of at least a subset of BL is a B-cell poised to express IGHA. We describe the landscape of mutations, structural variants, and mutational processes, and identified a series of driver genes in the pathogenesis of BL, which can be targeted by various mechanisms, including IG-non MYC translocations, germline and somatic mutations, fusion transcripts, and alternative splicing

The genomic and transcriptional landscape of primary central nervous system lymphoma

Primary lymphomas of the central nervous system (PCNSL) are mainly diffuse large B-cell lymphomas (DLBCLs) confined to the central nervous system (CNS). Molecular drivers of PCNSL have not been fully elucidated. Here, we profile and compare the whole-genome and transcriptome landscape of 51 CNS lymphomas (CNSL) to 39 follicular lymphoma and 36 DLBCL cases outside the CNS. We find recurrent mutations in JAK-STAT, NFkB, and B-cell receptor signaling pathways, including hallmark mutations in MYD88 L265P (67%) and CD79B (63%), and CDKN2A deletions (83%). PCNSLs exhibit significantly more focal deletions of HLA-D (6p21) locus as a potential mechanism of immune evasion. Mutational signatures correlating with DNA replication and mitosis are significantly enriched in PCNSL. TERT gene expression is significantly higher in PCNSL compared to activated B-cell (ABC)-DLBCL. Transcriptome analysis clearly distinguishes PCNSL and systemic DLBCL into distinct molecular subtypes. Epstein-Barr virus (EBV)+ CNSL cases lack recurrent mutational hotspots apart from IG and HLA-DRB loci. We show that PCNSL can be clearly distinguished from DLBCL, having distinct expression profiles, IG expression and translocation patterns, as well as specific combinations of genetic alterations

Sex differences in oncogenic mutational processes.

Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research

Analyses of non-coding somatic drivers in 2,658 cancer whole genomes

The discovery of drivers of cancer has traditionally focused on protein-coding genes1–4. Here we present analyses of driver point mutations and structural variants in non-coding regions across 2,658 genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium5 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). For point mutations, we developed a statistically rigorous strategy for combining significance levels from multiple methods of driver discovery that overcomes the limitations of individual methods. For structural variants, we present two methods of driver discovery, and identify regions that are significantly affected by recurrent breakpoints and recurrent somatic juxtapositions. Our analyses confirm previously reported drivers6,7, raise doubts about others and identify novel candidates, including point mutations in the 5′ region of TP53, in the 3′ untranslated regions of NFKBIZ and TOB1, focal deletions in BRD4 and rearrangements in the loci of AKR1C genes. We show that although point mutations and structural variants that drive cancer are less frequent in non-coding genes and regulatory sequences than in protein-coding genes, additional examples of these drivers will be found as more cancer genomes become available

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe