Carl Gustav Carus Institute

Niefern-Oschelbronn, Germany

Carl Gustav Carus Institute

Niefern-Oschelbronn, Germany
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Buschmann T.,Carl Gustav Carus Institute | Bystrykh L.V.,University of Groningen
BMC Bioinformatics | Year: 2013

Background: High-throughput sequencing technologies are improving in quality, capacity and costs, providing versatile applications in DNA and RNA research. For small genomes or fraction of larger genomes, DNA samples can be mixed and loaded together on the same sequencing track. This so-called multiplexing approach relies on a specific DNA tag or barcode that is attached to the sequencing or amplification primer and hence appears at the beginning of the sequence in every read. After sequencing, each sample read is identified on the basis of the respective barcode sequence.Alterations of DNA barcodes during synthesis, primer ligation, DNA amplification, or sequencing may lead to incorrect sample identification unless the error is revealed and corrected. This can be accomplished by implementing error correcting algorithms and codes. This barcoding strategy increases the total number of correctly identified samples, thus improving overall sequencing efficiency. Two popular sets of error-correcting codes are Hamming codes and Levenshtein codes.Result: Levenshtein codes operate only on words of known length. Since a DNA sequence with an embedded barcode is essentially one continuous long word, application of the classical Levenshtein algorithm is problematic. In this paper we demonstrate the decreased error correction capability of Levenshtein codes in a DNA context and suggest an adaptation of Levenshtein codes that is proven of efficiently correcting nucleotide errors in DNA sequences. In our adaption we take the DNA context into account and redefine the word length whenever an insertion or deletion is revealed. In simulations we show the superior error correction capability of the new method compared to traditional Levenshtein and Hamming based codes in the presence of multiple errors.Conclusion: We present an adaptation of Levenshtein codes to DNA contexts capable of correction of a pre-defined number of insertion, deletion, and substitution mutations. Our improved method is additionally capable of recovering the new length of the corrupted codeword and of correcting on average more random mutations than traditional Levenshtein or Hamming codes.As part of this work we prepared software for the flexible generation of DNA codes based on our new approach. To adapt codes to specific experimental conditions, the user can customize sequence filtering, the number of correctable mutations and barcode length for highest performance. © 2013 Buschmann and Bystrykh; licensee BioMed Central Ltd.

Cheng L.E.,University of California at San Francisco | Hartmann K.,University of Cologne | Roers A.,Carl Gustav Carus Institute | Krummel M.F.,University of California at San Francisco | Locksley R.M.,Howard Hughes Medical Institute
Immunity | Year: 2013

Mast cells are tissue-resident immune cells that play a central role in allergic disease. These contributions are largely dependent on the acquisition of antigen-specific immunoglobulin E (IgE). Despite this requirement, studies of mast cell and IgE interactions have overlooked the mechanism by which mast cells acquire IgE from the blood. To address this gap, we developed reporter IgE molecules and employed imaging techniques to study mast cell function in situ. Our data demonstrate that skin mast cells exhibit selective uptake of IgE based on perivascular positioning. Furthermore, perivascular mast cells acquire IgE by extending cell processes across the vessel wall to capture luminal IgE. These data demonstrate how tissue mast cells acquire IgE and reveal a strategy by which extravascular cells monitor blood contents to capture molecules central to cellular function. © 2013 Elsevier Inc.

Suckale J.,Carl Gustav Carus Institute | Solimena M.,Carl Gustav Carus Institute | Solimena M.,Max Planck Institute of Molecular Cell Biology and Genetics
Trends in Endocrinology and Metabolism | Year: 2010

The insulin granule was previously thought of as merely a container, but accumulating evidence suggests that it also acts as a signaling node. Regulatory pathways intersect at but also originate from the insulin granule membrane. Examples include the small G-proteins Rab3a and Rab27a, which influence granule movement, and the transmembrane proteins (tyrosine phosphatase receptors type N) PTPRN and PTPRN2, which upregulate β-cell transcription and proliferation. In addition, many cosecreted compounds possess regulatory functions, often related to energy metabolism. For instance, ATP and γ-amino butyric acid (GABA) modulate insulin and glucagon secretion, respectively; C-peptide protects β-cells and kidney cells; and amylin reduces gastric emptying and food intake via the brain. In this paper, we review the current knowledge of the insulin granule proteome and discuss its regulatory functions. © 2010 Elsevier Ltd.

Winters T.,Carl Gustav Carus Institute | McNicoll F.,Carl Gustav Carus Institute | Jessberger R.,Carl Gustav Carus Institute
EMBO Journal | Year: 2014

The cohesin complex is essential for mitosis and meiosis. The specific meiotic roles of individual cohesin proteins are incompletely understood. We report in vivo functions of the only meiosis-specific STAG component of cohesin, STAG3. Newly generated STAG3-deficient mice of both sexes are sterile with meiotic arrest. In these mice, meiotic chromosome architecture is severely disrupted as no bona fide axial elements (AE) form and homologous chromosomes do not synapse. Axial element protein SYCP3 forms dot-like structures, many partially overlapping with centromeres. Asynapsis marker HORMAD1 is diffusely distributed throughout the chromatin, and SYCP1, which normally marks synapsed axes, is largely absent. Centromeric and telomeric sister chromatid cohesion are impaired. Centromere and telomere clustering occurs in the absence of STAG3, and telomere structure is not severely affected. Other cohesin proteins are present, localize throughout the STAG3-devoid chromatin, and form complexes with cohesin SMC1β. No other deficiency in a single meiosis-specific cohesin causes a phenotype as drastic as STAG3 deficiency. STAG3 emerges as the key STAG cohesin involved in major functions of meiotic cohesin. © 2014 The Authors.

Linn J.,Carl Gustav Carus Institute
Clinical Neuroradiology | Year: 2015

Cerebral microbleeds (CMBs) are defined as small, rounded, or ovoid, homogeneous hypointense lesions on T2*-weighted gradient-echo and other susceptibility-sensitive magnetic resonance imaging (MRI) sequences. They must be differentiated from other causes of focal hypointensities on these sequences. Although CMBs can be caused by a variety of diseases, they are most frequently associated with different forms of cerebral small vessel diseases. This review summarizes the MRI characteristics of CMBs including methodological considerations, as well as prevalence, differential diagnosis, mimics, and clinical relevance of CMBs. © 2015, Springer-Verlag Berlin Heidelberg.

McNicoll F.,Carl Gustav Carus Institute | Stevense M.,Carl Gustav Carus Institute | Jessberger R.,Carl Gustav Carus Institute
Current Topics in Developmental Biology | Year: 2013

Sister chromatid cohesion depends on cohesin, a tripartite complex that forms ring structures to hold sister chromatids together in mitosis and meiosis. Meiocytes feature a multiplicity of distinct cohesin proteins and complexes, some meiosis specific, which serve additional functions such as supporting synapsis of two pairs of sister chromatids and determining the loop-axis architecture of prophase I chromosomes. Despite considerable new insights gained in the past few years into the localization and function of some cohesin proteins, and the recent identification of yet another meiosis-specific cohesin subunit, a plethora of open questions remains, which concern not only fundamental germ cell biology but also the consequences of cohesin impairment for human reproductive health. © 2013 Elsevier Inc.

Dumke R.,Carl Gustav Carus Institute | Jacobs E.,Carl Gustav Carus Institute
Journal of Clinical Microbiology | Year: 2014

Four commercial real-time PCR assays to detect Mycoplasma pneumoniae were tested, and the results were compared with the results for an in-house approach. Despite differences of crossing threshold values of up to 4, assays were able to detect at least 20 CFU/5 μl (52 fg DNA/5 μl) of sample with the Diagenode kit showing the best clinical sensitivity. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Jessberger R.,Carl Gustav Carus Institute
Genes and Development | Year: 2010

Humans suffer a steep increase in aneuploidies when oocytes age, and deterioration of cohesin was suggested recently as a prominent cause. In the November 15, 2010, issue of Genes & Development, Tachibana-Konwalski and colleagues (pp. 2505-2516) answered a question central to this hypothesis: Can cohesin be reloaded onto mouse oocyte chromosomes long after birth? They found that it cannot, or at least not with an efficiency adequate to rescue cohesin deficiency. With no chance for sufficient replenishment, age-related loss of sister chromatid cohesion seems unavoidable. © 2010 by Cold Spring Harbor Laboratory Press.

Pearce G.,Carl Gustav Carus Institute | Audzevich T.,Carl Gustav Carus Institute | Jessberger R.,Carl Gustav Carus Institute
Blood | Year: 2011

B-cell migration into and within lymphoid tissues is not only central to the humoral immune response but also for the development of malignancies and autoimmunity. We previously demonstrated that SWAP-70, an F-actin-binding, Rho GTPase-interacting protein strongly expressed in activated B cells, is necessary for normal B-cell migration in vivo. SWAP-70 regulates integrin-mediated adhesion and cell attachment. Here we show that upon B-cell activation, SWAP-70 is extensively posttranslationally modified and becomes tyrosine phosphorylated by SYK at position 517. This phosphorylation inhibits binding of SWAP-70 to Factin. Phospho-site mutants of SWAP-70 disrupt B-cell polarization in a dominant-negative fashion in vitro and impair migration in vivo. After CXCL12 stimulation of B cells SYK becomes activated and SWAP-70 is phosphorylated in a SYK-dependent manner. Use of the highly specific SYK inhibitor BAY61-3606 showed SYK activity is necessary for normal chemotaxis and B-cell polarization in vitro and for entry of B cells into lymph nodes in vivo. These findings demonstrate a novel requirement for SYK in migration and polarization of naive recirculating B cells and show that SWAP-70 is an important target of SYK in this pathway. © 2011 by The American Society of Hematology.

Behrendt R.,Carl Gustav Carus Institute | Roers A.,Carl Gustav Carus Institute
Clinical and Experimental Immunology | Year: 2014

Aicardi-Goutières syndrome (AGS) is a hereditary autoimmune disease which overlaps clinically and pathogenetically with systemic lupus erythematosus (SLE), and can be regarded as a monogenic variant of SLE. Both conditions are characterized by chronic activation of anti-viral type I interferon (IFN) responses. AGS can be caused by mutations in one of several genes encoding intracellular enzymes all involved in nucleic acid metabolism. Mouse models of AGS-associated defects yielded distinct phenotypes and reproduced important features of the disease. Analysis of these mutant mouse lines stimulated a new concept of autoimmunity caused by intracellular accumulations of nucleic acids, which trigger a chronic cell-intrinsic antiviral type I IFN response and thereby autoimmunity. This model is of major relevance for our understanding of SLE pathogenesis. Findings in gene-targeted mice deficient for AGS associated enzymes are summarized in this review. © 2013 British Society for Immunology.

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