TY - JOUR A1 - Sharan, Malvika A1 - Förstner, Konrad U. A1 - Eulalio, Ana A1 - Vogel, Jörg T1 - APRICOT: an integrated computational pipeline for the sequence-based identification and characterization of RNA-binding proteins JF - Nucleic Acids Research N2 - RNA-binding proteins (RBPs) have been established as core components of several post-transcriptional gene regulation mechanisms. Experimental techniques such as cross-linking and co-immunoprecipitation have enabled the identification of RBPs, RNA-binding domains (RBDs) and their regulatory roles in the eukaryotic species such as human and yeast in large-scale. In contrast, our knowledge of the number and potential diversity of RBPs in bacteria is poorer due to the technical challenges associated with the existing global screening approaches. We introduce APRICOT, a computational pipeline for the sequence-based identification and characterization of proteins using RBDs known from experimental studies. The pipeline identifies functional motifs in protein sequences using position-specific scoring matrices and Hidden Markov Models of the functional domains and statistically scores them based on a series of sequence-based features. Subsequently, APRICOT identifies putative RBPs and characterizes them by several biological properties. Here we demonstrate the application and adaptability of the pipeline on large-scale protein sets, including the bacterial proteome of Escherichia coli. APRICOT showed better performance on various datasets compared to other existing tools for the sequence-based prediction of RBPs by achieving an average sensitivity and specificity of 0.90 and 0.91 respectively. The command-line tool and its documentation are available at https://pypi.python.org/pypi/bio-apricot. KW - RNA-binding proteins KW - identification KW - characterization Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-157963 VL - 45 IS - 11 ER - TY - JOUR A1 - Stepniak, Beata A1 - Kästner, Anne A1 - Poggi, Giulia A1 - Mitjans, Marina A1 - Begemann, Martin A1 - Hartmann, Annette A1 - Van der Auwera, Sandra A1 - Sananbenesi, Farahnaz A1 - Krüger-Burg, Dilja A1 - Matuszko, Gabriela A1 - Brosi, Cornelia A1 - Homuth, Georg A1 - Völzke, Henry A1 - Benseler, Fritz A1 - Bagni, Claudia A1 - Fischer, Utz A1 - Dityatev, Alexander A1 - Grabe, Hans-Jörgen A1 - Rujescu, Dan A1 - Fischer, Andre A1 - Ehrenreich, Hannelore T1 - Accumulated common variants in the broader fragile X gene family modulate autistic phenotypes JF - EMBO Molecular Medicine N2 - Fragile X syndrome (FXS) is mostly caused by a CGG triplet expansion in the fragile X mental retardation 1 gene (FMR1). Up to 60% of affected males fulfill criteria for autism spectrum disorder (ASD), making FXS the most frequent monogenetic cause of syndromic ASD. It is unknown, however, whether normal variants (independent of mutations) in the fragile X gene family (FMR1, FXR1, FXR2) and in FMR2 modulate autistic features. Here, we report an accumulation model of 8 SNPs in these genes, associated with autistic traits in a discovery sample of male patients with schizophrenia (N = 692) and three independent replicate samples: patients with schizophrenia (N = 626), patients with other psychiatric diagnoses (N = 111) and a general population sample (N = 2005). For first mechanistic insight, we contrasted microRNA expression in peripheral blood mononuclear cells of selected extreme group subjects with high-versus low-risk constellation regarding the accumulation model. Thereby, the brain-expressed miR-181 species emerged as potential "umbrella regulator", with several seed matches across the fragile X gene family and FMR2. To conclude, normal variation in these genes contributes to the continuum of autistic phenotypes. KW - permutation KW - miR-181 KW - PGAS KW - FXR2 KW - FXR1 KW - FMR2 KW - FMR1 KW - identification KW - protein KW - fraxe mental retardation KW - CGG repeat KW - CPG Island KW - schizophrenia KW - expression KW - males Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-136893 VL - 7 IS - 12 ER - TY - JOUR A1 - van Koolwijk, Leonieke M. E. A1 - Ramdas, Wishal D. A1 - Ikram, M. Kamran A1 - Jansonius, Nomdo M. A1 - Pasutto, Francesca A1 - Hys, Pirro G. A1 - Macgregor, Stuart A1 - Janssen, Sarah F. A1 - Hewitt, Alex W. A1 - Viswanathan, Ananth C. A1 - ten Brink, Jacoline B. A1 - Hosseini, S. Mohsen A1 - Amin, Najaf A1 - Despriet, Dominiek D. G. A1 - Willemse-Assink, Jacqueline J. M. A1 - Kramer, Rogier A1 - Rivadeneira, Fernando A1 - Struchalin, Maksim A1 - Aulchenko, Yurii S. A1 - Weisschuh, Nicole A1 - Zenkel, Matthias A1 - Mardin, Christian Y. A1 - Gramer, Eugen A1 - Welge-Lüssen, Ulrich A1 - Montgomery, Grant W. A1 - Carbonaro, Francis A1 - Young, Terri L. A1 - Bellenguez, Céline A1 - McGuffin, Peter A1 - Foster, Paul J. A1 - Topouzis, Fotis A1 - Mitchell, Paul A1 - Wang, Jie Jin A1 - Wong, Tien Y. A1 - Czudowska, Monika A. A1 - Hofman, Albert A1 - Uitterlinden, Andre G. A1 - Wolfs, Roger C. W. A1 - de Jong, Paulus T. V. M. A1 - Oostra, Ben A. A1 - Paterson, Andrew D. A1 - Mackey, David A. A1 - Bergen, Arthur A. B. A1 - Reis, Andre A1 - Hammond, Christopher J. A1 - Vingerling, Johannes R. A1 - Lemij, Hans G. A1 - Klaver, Caroline C. W. A1 - van Duijn, Cornelia M. T1 - Common Genetic Determinants of Intraocular Pressure and Primary Open-Angle Glaucoma JF - PLoS Genetics N2 - Intraocular pressure (IOP) is a highly heritable risk factor for primary open-angle glaucoma and is the only target for current glaucoma therapy. The genetic factors which determine IOP are largely unknown. We performed a genome-wide association study for IOP in 11,972 participants from 4 independent population-based studies in The Netherlands. We replicated our findings in 7,482 participants from 4 additional cohorts from the UK, Australia, Canada, and the Wellcome Trust Case-Control Consortium 2/Blue Mountains Eye Study. IOP was significantly associated with rs11656696, located in GAS7 at 17p13.1 (p = 1.4 x 10\(^{-8}\)), and with rs7555523, located in TMCO1 at 1q24.1 (p = 1.6 x 10\(^{-8}\)). In a meta-analysis of 4 case-control studies (total N = 1,432 glaucoma cases), both variants also showed evidence for association with glaucoma (p = 2.4 x 10\(^{-2}\) for rs11656696 and p = 9.1 x 10\(^{-4}\) for rs7555523). GAS7 and TMCO1 are highly expressed in the ciliary body and trabecular meshwork as well as in the lamina cribrosa, optic nerve, and retina. Both genes functionally interact with known glaucoma disease genes. These data suggest that we have identified two clinically relevant genes involved in IOP regulation. KW - expression KW - goldmann applanation tonometer KW - central corneal thickness KW - genome-wide scan KW - beaver-dam eye KW - to-disc ratio KW - onset KW - association KW - identification KW - population Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131378 VL - 8 IS - 5 ER - TY - JOUR A1 - Wagner, Ines A1 - Volkmer, Michael A1 - Sharan, Malvika A1 - Villaveces, Jose M. A1 - Oswald, Felix A1 - Surendranath, Vineeth A1 - Habermann, Bianca H. T1 - morFeus: a web-based program to detect remotely conserved orthologs using symmetrical best hits and orthology network scoring JF - BMC Bioinformatics N2 - Background: Searching the orthologs of a given protein or DNA sequence is one of the most important and most commonly used Bioinformatics methods in Biology. Programs like BLAST or the orthology search engine Inparanoid can be used to find orthologs when the similarity between two sequences is sufficiently high. They however fail when the level of conservation is low. The detection of remotely conserved proteins oftentimes involves sophisticated manual intervention that is difficult to automate. Results: Here, we introduce morFeus, a search program to find remotely conserved orthologs. Based on relaxed sequence similarity searches, morFeus selects sequences based on the similarity of their alignments to the query, tests for orthology by iterative reciprocal BLAST searches and calculates a network score for the resulting network of orthologs that is a measure of orthology independent of the E-value. Detecting remotely conserved orthologs of a protein using morFeus thus requires no manual intervention. We demonstrate the performance of morFeus by comparing it to state-of-the-art orthology resources and methods. We provide an example of remotely conserved orthologs, which were experimentally shown to be functionally equivalent in the respective organisms and therefore meet the criteria of the orthology-function conjecture. Conclusions: Based on our results, we conclude that morFeus is a powerful and specific search method for detecting remotely conserved orthologs. KW - reciprocal best hit KW - finder using symmetrical best hits KW - sequences KW - annotation KW - identification KW - database KW - genomes KW - proteins KW - homologs KW - hidden markov-models KW - phylogenetic trees KW - PSI-blast KW - eigenvector centrality KW - meta-analysis based orthology KW - orthology KW - remote sequence conservation KW - alignment clustering KW - orthology network Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-115590 VL - 15 IS - 263 ER - TY - JOUR A1 - Walther, Grit A1 - Wagner, Lysett A1 - Kurzai, Oliver T1 - Updates on the taxonomy of Mucorales with an emphasis on clinically important taxa JF - Journal of Fungi N2 - Fungi of the order Mucorales colonize all kinds of wet, organic materials and represent a permanent part of the human environment. They are economically important as fermenting agents of soybean products and producers of enzymes, but also as plant parasites and spoilage organisms. Several taxa cause life-threatening infections, predominantly in patients with impaired immunity. The order Mucorales has now been assigned to the phylum Mucoromycota and is comprised of 261 species in 55 genera. Of these accepted species, 38 have been reported to cause infections in humans, as a clinical entity known as mucormycosis. Due to molecular phylogenetic studies, the taxonomy of the order has changed widely during the last years. Characteristics such as homothallism, the shape of the suspensors, or the formation of sporangiola are shown to be not taxonomically relevant. Several genera including Absidia, Backusella, Circinella, Mucor, and Rhizomucor have been amended and their revisions are summarized in this review. Medically important species that have been affected by recent changes include Lichtheimia corymbifera, Mucor circinelloides, and Rhizopus microsporus. The species concept of Rhizopus arrhizus (syn. R. oryzae) is still a matter of debate. Currently, species identification of the Mucorales is best performed by sequencing of the internal transcribed spacer (ITS) region. Ecologically, the Mucorales represent a diverse group but for the majority of taxa, the ecological role and the geographic distribution remain unknown. Understanding the biology of these opportunistic fungal pathogens is a prerequisite for the prevention of infections, and, consequently, studies on the ecology of the Mucorales are urgently needed. KW - Mucorales KW - taxonomy KW - pathogens KW - identification KW - ecology KW - Circinella KW - Lichtheimia KW - Mucor KW - Rhizomucor KW - Rhizopus Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193081 SN - 2309-608X VL - 5 IS - 4 ER - TY - JOUR A1 - Wang, Huiqiang A1 - Chen, Nanhai G. A1 - Minev, Boris R. A1 - Szalay, Aladar A. T1 - Oncolytic vaccinia virus GLV-1h68 strain shows enhanced replication in human breast cancer stem-like cells in comparison to breast cancer cells JF - Journal of Translational Medicine N2 - Background: Recent data suggest that cancer stem cells (CSCs) play an important role in cancer, as these cells possess enhanced tumor-forming capabilities and are responsible for relapses after apparently curative therapies have been undertaken. Hence, novel cancer therapies will be needed to test for both tumor regression and CSC targeting. The use of oncolytic vaccinia virus (VACV) represents an attractive anti-tumor approach and is currently under evaluation in clinical trials. The purpose of this study was to demonstrate whether VACV does kill CSCs that are resistant to irradiation and chemotherapy. Methods: Cancer stem-like cells were identified and separated from the human breast cancer cell line GI-101A by virtue of increased aldehyde dehydrogenase 1 (ALDH1) activity as assessed by the ALDEFLUOR assay and cancer stem cell-like features such as chemo-resistance, irradiation-resistance and tumor-initiating were confirmed in cell culture and in animal models. VACV treatments were applied to both ALDEFLUOR-positive cells in cell culture and in xenograft tumors derived from these cells. Moreover, we identified and isolated CD44\(^+\)CD24\(^+\)ESA\(^+\) cells from GI-101A upon an epithelial-mesenchymal transition (EMT). These cells were similarly characterized both in cell culture and in animal models. Results: We demonstrated for the first time that the oncolytic VACV GLV-1h68 strain replicated more efficiently in cells with higher ALDH1 activity that possessed stem cell-like features than in cells with lower ALDH1 activity. GLV-1h68 selectively colonized and eventually eradicated xenograft tumors originating from cells with higher ALDH1 activity. Furthermore, GLV-1h68 also showed preferential replication in CD44\(^+\)CD24\(^+\)ESA\(^+\) cells derived from GI-101A upon an EMT induction as well as in xenograft tumors originating from these cells that were more tumorigenic than CD44\(^+\)CD24\(^-\)ESA\(^+\) cells. Conclusions: Taken together, our findings indicate that GLV-1h68 efficiently replicates and kills cancer stem-like cells. Thus, GLV-1h68 may become a promising agent for eradicating both primary and metastatic tumors, especially tumors harboring cancer stem-like cells that are resistant to chemo and/or radiotherapy and may be responsible for recurrence of tumors. KW - tumors KW - therapy KW - metastasis KW - identification KW - lines KW - gene expression KW - in-vitro propagation KW - acute myeloid leukemia KW - epithelial-mesenchymal transition KW - subpopulation Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130019 VL - 10 IS - 167 ER - TY - JOUR A1 - Whisnant, Adam W. A1 - Jürges, Christopher S. A1 - Hennig, Thomas A1 - Wyler, Emanuel A1 - Prusty, Bhupesh A1 - Rutkowski, Andrzej J. A1 - L'hernault, Anne A1 - Djakovic, Lara A1 - Göbel, Margarete A1 - Döring, Kristina A1 - Menegatti, Jennifer A1 - Antrobus, Robin A1 - Matheson, Nicholas J. A1 - Künzig, Florian W. H. A1 - Mastrobuoni, Guido A1 - Bielow, Chris A1 - Kempa, Stefan A1 - Liang, Chunguang A1 - Dandekar, Thomas A1 - Zimmer, Ralf A1 - Landthaler, Markus A1 - Grässer, Friedrich A1 - Lehner, Paul J. A1 - Friedel, Caroline C. A1 - Erhard, Florian A1 - Dölken, Lars T1 - Integrative functional genomics decodes herpes simplex virus 1 JF - Nature Communications N2 - The predicted 80 open reading frames (ORFs) of herpes simplex virus 1 (HSV-1) have been intensively studied for decades. Here, we unravel the complete viral transcriptome and translatome during lytic infection with base-pair resolution by computational integration of multi-omics data. We identify a total of 201 transcripts and 284 ORFs including all known and 46 novel large ORFs. This includes a so far unknown ORF in the locus deleted in the FDA-approved oncolytic virus Imlygic. Multiple transcript isoforms expressed from individual gene loci explain translation of the vast majority of ORFs as well as N-terminal extensions (NTEs) and truncations. We show that NTEs with non-canonical start codons govern the subcellular protein localization and packaging of key viral regulators and structural proteins. We extend the current nomenclature to include all viral gene products and provide a genome browser that visualizes all the obtained data from whole genome to single-nucleotide resolution. Here, using computational integration of multi-omics data, the authors provide a detailed transcriptome and translatome of herpes simplex virus 1 (HSV-1), including previously unidentified ORFs and N-terminal extensions. The study also provides a HSV-1 genome browser and should be a valuable resource for further research. KW - infected-cell protein KW - messenger RNA KW - binding protein KW - type 1 KW - identification KW - ICP27 KW - translation KW - expression KW - sequence KW - domain Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229884 VL - 11 ER -