ORCID Profile
0000-0002-2080-1804
Current Organisation
Paul-Ehrlich-Institut
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Oxford University Press (OUP)
Date: 21-02-2012
Abstract: High-throughput sequencing and genotyping methods are dramatically increasing the number of observable genetic intraspecies differences that can be exploited as genetic markers. In addition, automated phenotyping platforms and “omics” profiling technologies further enlarge the set of quantifiable macroscopic and molecular traits at an ever-increasing pace. Combined, both lines of technological advances create unparalleled opportunities to identify candidate gene regions and, ideally, even single genes responsible for observed variations in a particular trait via association studies. However, as of yet, this new potential is not sufficiently matched by enabling software solutions to easily exploit this wealth of genotype henotype information. We have developed Matapax, a Web-based platform to address this need. Initially, we built the infrastructure to support association studies in Arabidopsis (Arabidopsis thaliana) based on several genotyping efforts covering up to 1,375 Arabidopsis accessions. Based on the user-supplied trait information, associated single-nucleotide polymorphism markers and single-nucleotide polymorphism-harboring or -neighboring genes are identified using both the GAPIT and EMMA libraries developed for R. Additional interrogation is facilitated by displaying candidate regions and genes in a genome browser and by providing relevant annotation information. In the future, we plan to broaden the scope of organisms to other plant species as more genotype henotype information becomes available. Matapax is freely available at matapax.mpimp-golm.mpg.de and can be accessed using any internet browser.
Publisher: Public Library of Science (PLoS)
Date: 06-05-2015
Publisher: Mary Ann Liebert Inc
Date: 06-2022
Abstract: Since first proposed as a new tool for gene targeting and genome editing, CRISPR technology has quickly advanced into the clinical stage. Initial studies highlight the potential for CRISPR-Cas9-mediated therapeutic approaches in human medicine to correct incurable genetic diseases and enhance cell-based therapeutic approaches. While acknowledging the opportunities this technology brings for the treatment of patients with severe diseases, timely development of these innovative medicinal products requires regulatory oversight and adaptation of regulatory requirements to ensure the safety and efficacy of medicinal products based on CRISPR technology. We briefly present the current regulatory framework applicable for CRISPR-Cas-based developments as advanced therapy medicinal products. Moreover, scientific- and regulatory-driven considerations relevant for advancing product development toward clinical trial applications in Germany are highlighted by discussing the key aspects of quality and nonclinical and clinical development requirements.
Publisher: Elsevier BV
Date: 09-2009
Publisher: American Society of Hematology
Date: 20-05-2021
Abstract: Aberrant B-cell receptor/NF-κB signaling is a hallmark feature of B-cell non-Hodgkin lymphomas, especially in diffuse large B-cell lymphoma (DLBCL). Recurrent mutations in this cascade, for ex le, in CD79B, CARD11, or NFKBIZ, and also in the Toll-like receptor pathway transducer MyD88, all deregulate NF-κB, but their differential impact on lymphoma development and biology remains to be determined. Here, we functionally investigate primary mouse lymphomas that formed in recipient mice of Eµ-myc transgenic hematopoietic stem cells stably transduced with naturally occurring NF-κB mutants. Although most mutants supported Myc-driven lymphoma formation through repressed apoptosis, CARD11- or MyD88-mutant lymphoma cells selectively presented with a macrophage-activating secretion profile, which, in turn, strongly enforced transforming growth factor β (TGF-β)-mediated senescence in the lymphoma cell compartment. However, MyD88- or CARD11-mutant Eµ-myc lymphomas exhibited high-level expression of the immune-checkpoint mediator programmed cell death ligand 1 (PD-L1), thus preventing their efficient clearance by adaptive host immunity. Conversely, these mutant-specific dependencies were therapeutically exploitable by anti–programmed cell death 1 checkpoint blockade, leading to direct T-cell–mediated lysis of predominantly but not exclusively senescent lymphoma cells. Importantly, mouse-based mutant MyD88- and CARD11-derived signatures marked DLBCL subgroups exhibiting mirroring phenotypes with respect to the triad of senescence induction, macrophage attraction, and evasion of cytotoxic T-cell immunity. Complementing genomic subclassification approaches, our functional, cross-species investigation unveils pathogenic principles and therapeutic vulnerabilities applicable to and testable in human DLBCL subsets that may inform future personalized treatment strategies.
Publisher: Oxford University Press (OUP)
Date: 13-04-2010
Abstract: The wide application of high-throughput transcriptomics using microarrays has generated a plethora of technical platforms, data repositories, and sophisticated statistical analysis methods, leaving the in idual scientist with the problem of choosing the appropriate approach to address a biological question. Several software applications that provide a rich environment for microarray analysis and data storage are available (e.g. GeneSpring, EMMA2), but these are mostly commercial or require an advanced informatics infrastructure. There is a need for a noncommercial, easy-to-use graphical application that aids the lab researcher to find the proper method to analyze microarray data, without this requiring expert understanding of the complex underlying statistics, or programming skills. We have developed Robin, a Java-based graphical wizard application that harnesses the advanced statistical analysis functions of the R/BioConductor project. Robin implements streamlined workflows that guide the user through all steps of two-color, single-color, or Affymetrix microarray analysis. It provides functions for thorough quality assessment of the data and automatically generates warnings to notify the user of potential outliers, low-quality chips, or low statistical power. The results are generated in a standard format that allows ready use with both specialized analysis tools like MapMan and PageMan and generic spreadsheet applications. To further improve user friendliness, Robin includes both integrated help and comprehensive external documentation. To demonstrate the statistical power and ease of use of the workflows in Robin, we present a case study in which we apply Robin to analyze a two-color microarray experiment comparing gene expression in tomato (Solanum lycopersicum) leaves, flowers, and roots.
Publisher: Frontiers Media SA
Date: 2011
Publisher: Springer Science and Business Media LLC
Date: 04-09-2021
DOI: 10.1007/S00109-021-02131-W
Abstract: Human sterile α motif and HD domain-containing protein 1 (SAMHD1), originally described as the major cellular deoxyribonucleoside triphosphate triphosphohydrolase (dNTPase) balancing the intracellular deoxynucleotide (dNTP) pool, has come recently into focus of cancer research. As outlined in this review, SAMHD1 has been reported to be mutated in a variety of cancer types and the expression of SAMHD1 is dysregulated in many cancers. Therefore, SAMHD1 is regarded as a tumor suppressor in certain tumors. Moreover, it has been proposed that SAMHD1 might fulfill the requirements of a driver gene in tumor development or might promote a so-called mutator phenotype. Besides its role as a dNTPase, several novel cellular functions of SAMHD1 have come to light only recently, including a role as negative regulator of innate immune responses and as facilitator of DNA end resection during DNA replication and repair. Therefore, SAMHD1 can be placed at the crossroads of various cellular processes. The present review summarizes the negative role of SAMHD1 in chemotherapy sensitivity, highlights reported SAMHD1 mutations found in various cancer types, and aims to discuss functional consequences as well as underlying mechanisms of SAMHD1 dysregulation potentially involved in cancer development.
Publisher: Oxford University Press (OUP)
Date: 13-11-2017
DOI: 10.1105/TPC.17.00524
Publisher: Oxford University Press (OUP)
Date: 04-2009
DOI: 10.1093/NAR/GKP206
Publisher: Oxford University Press (OUP)
Date: 30-12-2021
Abstract: Hepatitis E virus (HEV) is a major cause of acute viral hepatitis. Better understanding of HEV subtypes involved in hepatitis E infections is essential. Investigation of sources and routes of transmission and the identification of potential clusters/outbreaks rely upon molecular typing of viral strains. A study was carried out to evaluate the ability of laboratories to undertake molecular typing with genotype and subtype determination. A blinded panel of 11 different Orthohepevirus A strains was distributed to 28 laboratories performing HEV sequence analysis. Laboratories used their routine HEV sequencing and genotyping methods. Results were returned by 25 laboratories. Overall, 93% s les were assigned to the correct genotype and 81% were assigned to the correct subtype. Fragments lified for typing ranged in size and the sequencing assays targeted both the structural and non-structural protein-coding regions. There was good agreement between the reported sequences where methods targeted overlapping fragments. In some cases, incorrect genotypes/subtypes were reported, including those not contained in the panel, and in one case, a genotype was reported for a blinded control s le containing Zika virus collectively these data indicate contamination problems. In general, identification of genotypes was good however, in a small number of cases, there was a failure to generate sequences from some of the s les. There was generally broad agreement between the use of online typing tools such as the one provided by HEVnet and curated lists of published HEV reference sequences however, going forward harmonization between these resources is essential.
Publisher: Public Library of Science (PLoS)
Date: 23-06-2011
Publisher: Cold Spring Harbor Laboratory
Date: 27-08-2018
DOI: 10.1101/397935
Abstract: An increasing number of bioinformatics tools are developed in JavaScript to provide an interactive visual interface to users. However, there are no tools yet that enable fast client-side analysis of large, high-throughput sequencing file formats, such as BAM and VCF files. We present HTSlib-js, an asm.js-based JavaScript wrapper for HTSlib, the de facto standard for processing BAM and VCF files. HTSlib-js exploits recent technological advances in web browser engines that dramatically increase the performance of browser-based tools to enable swift processing of files in the aforementioned formats. HTSlib-js enables quick development of JavaScript-based applications that include processing of aligned sequence reads and variant calling data. HTSlib-js constitutes a toolkit for developers to easily write fast, accessible, browser-based applications that place an emphasis on data visualization, interactivity and privacy. Real-world ex les demonstrate the capabilities of HTSlib-js and serve as guide for own developments.
Publisher: Wiley
Date: 17-07-2012
Publisher: Springer Science and Business Media LLC
Date: 2010
Publisher: Oxford University Press (OUP)
Date: 13-05-2016
DOI: 10.1093/BIOINFORMATICS/BTW302
Abstract: Motivation: Integrating heterogeneous datasets from several sources is a common bioinformatics task that often requires implementing a complex workflow intermixing database access, data filtering, format conversions, identifier mapping, among further erse operations. Data integration is especially important when annotating next generation sequencing data, where a multitude of erse tools and heterogeneous databases can be used to provide a large variety of annotation for genomic locations, such a single nucleotide variants or genes. Each tool and data source is potentially useful for a given project and often more than one are used in parallel for the same purpose. However, software that always produces all available data is difficult to maintain and quickly leads to an excess of data, creating an information overload rather than the desired goal-oriented and integrated result. Results: We present SoFIA, a framework for workflow-driven data integration with a focus on genomic annotation. SoFIA conceptualizes workflow templates as comprehensive workflows that cover as many data integration operations as possible in a given domain. However, these templates are not intended to be executed as a whole instead, when given an integration task consisting of a set of input data and a set of desired output data, SoFIA derives a minimal workflow that completes the task. These workflows are typically fast and create exactly the information a user wants without requiring them to do any implementation work. Using a comprehensive genome annotation template, we highlight the flexibility, extensibility and power of the framework using real-life case studies. Availability and Implementation: hildsish/sofia/releases/latest under the GNU General Public License Contact: liam.childs@hu-berlin.de Supplementary information: Supplementary data are available at Bioinformatics online.
Publisher: Springer Science and Business Media LLC
Date: 03-2022
DOI: 10.1186/S13073-022-01018-W
Abstract: Pancreatic neuroendocrine neoplasms (PanNENs) fall into two subclasses: the well-differentiated, low- to high-grade pancreatic neuroendocrine tumors (PanNETs), and the poorly-differentiated, high-grade pancreatic neuroendocrine carcinomas (PanNECs). While recent studies suggest an endocrine descent of PanNETs, the origin of PanNECs remains unknown. We performed DNA methylation analysis for 57 PanNEN s les and found that distinct methylation profiles separated PanNENs into two major groups, clearly distinguishing high-grade PanNECs from other PanNETs including high-grade NETG3. DNA alterations and immunohistochemistry of cell-type markers PDX1, ARX, and SOX9 were utilized to further characterize PanNECs and their cell of origin in the pancreas. Phylo-epigenetic and cell-type signature features derived from alpha, beta, acinar, and ductal adult cells suggest an exocrine cell of origin for PanNECs, thus separating them in cell lineage from other PanNENs of endocrine origin. Our study provides a robust and clinically applicable method to clearly distinguish PanNECs from G3 PanNETs, improving patient stratification.
Publisher: Wiley
Date: 10-05-2012
DOI: 10.1111/J.1365-3040.2012.02522.X
Abstract: Arabidopsis thaliana is a geographically widely spread species consisting of local accessions differing both genetically and phenotypically. These differences may constitute environmental adaptations and a latitudinal cline in freezing tolerance has been shown previously. Many plants, including Arabidopsis, exhibit increased freezing tolerance after cold exposure (cold acclimation). Here we present evidence for geographical clines (both latitudinal and longitudinal) in acclimated (ACC) and non-acclimated (NA) freezing tolerance, estimated from electrolyte leakage measurements on 54 accessions. Leaf Pro contents were not correlated with freezing tolerance, while sugar contents (Glc, Fru, Suc, Raf) were in the ACC, but not the NA state. Expression levels of 14 cold-induced genes were investigated before and after 2 weeks of cold acclimation by quantitative RT-PCR. Expression of the CBF1, 2 and 3 genes was not correlated with freezing tolerance. The expression of some CBF-regulated (COR) genes, however, was correlated specifically with ACC freezing tolerance. A tight correlation between CBF and COR gene expression was only observed under non-acclimating conditions, where CBF and COR expression were also correlated with the expression of PRR5, a component of the circadian clock. Collectively, this study sheds new light on the molecular determinants of plant-freezing tolerance and cold acclimation and their geographical dependence.
Publisher: Springer Science and Business Media LLC
Date: 25-01-2017
DOI: 10.1038/NCOMMS14093
Abstract: Genetic heterogeneity between and within tumours is a major factor determining cancer progression and therapy response. Here we examined DNA sequence and DNA copy-number heterogeneity in colorectal cancer (CRC) by targeted high-depth sequencing of 100 most frequently altered genes. In 97 s les, with primary tumours and matched metastases from 27 patients, we observe inter-tumour concordance for coding mutations in contrast, gene copy numbers are highly discordant between primary tumours and metastases as validated by fluorescent in situ hybridization. To further investigate intra-tumour heterogeneity, we dissected a single tumour into 68 spatially defined s les and sequenced them separately. We identify evenly distributed coding mutations in APC and TP5 3 in all tumour areas, yet highly variable gene copy numbers in numerous genes. 3D morpho-molecular reconstruction reveals two clusters with ergent copy number aberrations along the proximal–distal axis indicating that DNA copy number variations are a major source of tumour heterogeneity in CRC.
Publisher: Springer Science and Business Media LLC
Date: 30-05-2017
DOI: 10.1038/NMETH.4262
Location: Germany
No related grants have been discovered for Liam Childs.