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Modelling viruses to kill cancer
17 November 2009
Computational studies of virus behaviour in tumours could lead to more effective cancer treatments
Molecular BioSystems Board member wins EMBO Young Investigator Award
06 November 2009
Madan Babu was one of 17 scientists chosen this year as winners of the EMBO Young Investigators award
Contents list for Molecular BioSystems, issue 12, 2009
Front cover
Mol. BioSyst., 2009, 5, 1373
DOI: 10.1039/b922400a
Inside front cover
Mol. BioSyst., 2009, 5, 1374
DOI: 10.1039/b922401g
Contents and Highlights in Chemical Biology
Mol. BioSyst., 2009, 5, 1375
DOI: 10.1039/B922402P
Editorial
Computational and Systems Biology
Mol. BioSyst., 2009, 5, 1391
DOI: 10.1039/b921381n
M. Madan Babu and Hirotada Mori introduce this themed issue of Molecular BioSystems focusing on Computational and systems biology
Reviews
The potential of microfluidic water-in-oil droplets in experimental biology
Yolanda Schaerli and Florian Hollfelder,
Mol. BioSyst., 2009, 5, 1392
DOI: 10.1039/b907578j
Droplets with femto- to nanolitre volumes, handled in microfluidic devices, are an increasingly popular platform for high-throughput experiments that can be carried out under controlled conditions with a quantitative readout.
Signal initiation in biological systems: the properties and detection of transient extracellular protein interactions
Gavin J. Wright,
Mol. BioSyst., 2009, 5, 1405
DOI: 10.1039/b903580j
Enhanced HTML article available
Extracellular glycoprotein interactions are not detected by most high throughput assays creating 
blind-spots
in protein interaction maps. This review examines this problem and discusses recent advances that have begun to address it.
From genes to cells to tissues—modelling the haematopoietic system
Samuel D. Foster, S. Helen Oram, Nicola K. Wilson and Berthold Göttgens,
Mol. BioSyst., 2009, 5, 1413
DOI: 10.1039/b907225j Enhanced HTML article available
Many important questions in the haematopoietic system remain unanswered or even unanswerable with current experimental tools. Scientists have therefore increasingly turned to modelling to tackle complexity at multiple levels ranging from networks of genes to the behaviour of cells and tissues.
ChIPing away at the genome: the new frontier travel guide
Jelena Aleksic and Steven Russell,
Mol. BioSyst., 2009, 5, 1421
DOI: 10.1039/b906179g Enhanced HTML article available
Mapping protein–DNA interactions in vivo via chromatin immunoprecipitation and microarrays or sequencing provides powerful insights into genome organisation and transcriptional regulation.
Scoring overlapping and adjacent signals from genome-wide ChIP and DamID assays
Audrey Qiuyan Fu and Boris Adryan,
Mol. BioSyst., 2009, 5, 1429
DOI: 10.1039/b906880e Enhanced HTML article available
We review existing quantitative methods to score overlaps, and to cluster binding events in ChIP and DamID profiles. We provide a simple guide to some of the statistical tools used by these methods.
Systems-level approaches for identifying and analyzing genetic interaction networks in Escherichia coli and extensions to other prokaryotes
Mohan Babu, Gabriel Musso, J. Javier Díaz-Mejía, Gareth Butland, Jack F. Greenblatt and Andrew Emili,
Mol. BioSyst., 2009, 5, 1439
DOI: 10.1039/b907407d Enhanced HTML article available
Escherichia coli may hold the key to understanding the unique biomolecular properties of prokaryotic cells. Recent advances in high-throughput screening techniques and subsequent results are discussed here.
Structural interactomics: informatics approaches to aid the interpretation of genetic variation and the development of novel therapeutics
Semin Lee, Alan Brown, William Ross Pitt, Alicia Perez Higueruelo, Sungsam Gong, George Richard Bickerton, Adrian Schreyer, Duangrudee Tanramluk, Alison Baylay and Tom Leon Blundell,
Mol. BioSyst., 2009, 5, 1456
DOI: 10.1039/b906402h Enhanced HTML article available
This review focuses on the use of structural interactomics in the development of novel therapeutics.
Explorations in topology–delving underneath the surface of genetic interaction maps
Michal Breker and Maya Schuldiner,
Mol. BioSyst., 2009, 5, 1473
DOI: 10.1039/b907076c Enhanced HTML article available
This review focuses on the methodologies currently available for using and interpreting large datasets of genetic interactions for functional gene groups, elaborates on the challenges ahead and highlights the need for comprehensive integrative analysis to extract the wealth of information found.
The powerful law of the power law and other myths in network biology
Gipsi Lima-Mendez and Jacques van Helden,
Mol. BioSyst., 2009, 5, 1482
DOI: 10.1039/b908681a Enhanced HTML article available
Topological properties such as the power law, small world and scale-freeness have been claimed as universal laws for biological and other complex networks. However these properties are contradicted by statistical or even by visual comparison of the observed distribution (green) with the power law (blue). We review and discuss the field of network biology and its relevance in terms of function and evolution.
Scaling relationship in the gene content of transcriptional machinery in bacteria
Ernesto Pérez-Rueda, Sarath Chandra Janga and Agustino Martínez-Antonio,
Mol. BioSyst., 2009, 5, 1494
DOI: 10.1039/b907384a Enhanced HTML article available
The metabolic, defensive, communicative and pathogenic capabilities of eubacteria depend on their repertoire of genes and ability to regulate the expression of them. Sigma and transcription factors have fundamental roles in controlling these processes.
Systems analyses of circadian networks
Katharine E. Hubbard, Fiona C. Robertson, Neil Dalchau and Alex A. R. Webb,
Mol. BioSyst., 2009, 5, 1502
DOI: 10.1039/b907714f Enhanced HTML article available
We review the contribution that systems approaches have made to the understanding of the circadian clock in Arabidopsis thaliana and compare this to systems analyses of mammalian circadian clocks.
Global signatures of protein and mRNA expression levels
Raquel de Sousa Abreu, Luiz O. Penalva, Edward M. Marcotte and Christine Vogel,
Mol. BioSyst., 2009, 5, 1512
DOI: 10.1039/b908315d Enhanced HTML article available
Large-scale technology has enabled us to measure and compare protein and mRNA expression in different organisms. From these data we gain insights on the underlying regulation of translation and protein degradation.
Theoretical models of spontaneous activity generation and propagation in the developing retina
Keith B. Godfrey and Stephen J. Eglen,
Mol. BioSyst., 2009, 5, 1527
DOI: 10.1039/b907213f Enhanced HTML article available
In the developing retina, nearby neurons are spontaneously active, producing progagating patterns of activity, known as retinal waves. In this article we review several computational models used to help evaluate the mechanisms that might be responsible for the generation of retinal waves.
Structure and organization of drug-target networks: insights from genomic approaches for drug discovery
Sarath Chandra Janga and Andreas Tzakos,
Mol. BioSyst., 2009, 5, 1536
DOI: 10.1039/b908147j Enhanced HTML article available
Recent explosion in the amount of omics data opens new ways of predicting novel drugs and drug targets using network-based approaches.
Modelling the Drosophila embryo
Johannes Jaeger,
Mol. BioSyst., 2009, 5, 1549
DOI: 10.1039/b904722k
This historical overview on modelling pattern formation in the early Drosophila embryo shows how experimental and theoretical approaches have converged over the past decades to create a powerful new methodology for the systems-level study of developmental gene regulatory networks.
Logical modelling of cell cycle control in eukaryotes: a comparative study
Adrien Fauré and Denis Thieffry,
Mol. BioSyst., 2009, 5, 1569
DOI: 10.1039/b907562n Enhanced HTML article available
The use of qualitative approaches for modelling the cell cycle is presented and discussed.
Nucleosome positioning—what do we really know?
Andrew Travers, Micaela Caserta, Mark Churcher, Edwige Hiriart and Ernesto Di Mauro,
Mol. BioSyst., 2009, 5, 1582
DOI: 10.1039/b907227f
This review addresses whether a genomic code for nucleosome positioning exists and how nucleosome arrays are organised in vivo.
Supervised learning with decision tree-based methods in computational and systems biology
Pierre Geurts, Alexandre Irrthum and Louis Wehenkel,
Mol. BioSyst., 2009, 5, 1593
DOI: 10.1039/b907946g
An accessible and comprehensive introduction to decision tree-based methods for supervised learning in computational and systems biology.
Conformational averaging in structural biology: issues, challenges and computational solutions
Daniela Kruschel and Bojan Zagrovic,
Mol. BioSyst., 2009, 5, 1606
DOI: 10.1039/b917186j
The authors review different aspects of the problem of conformational averaging in structural biology experiments, discuss the pitfalls of the associated single-structure paradigm and describe different computational solutions to address the problem.
Papers
On the basic computational structure of gene regulatory networks
Carlos Rodríguez-Caso, Bernat Corominas-Murtra and Ricard V. Solé,
Mol. BioSyst., 2009, 5, 1617
DOI: 10.1039/b904960f Enhanced HTML article available
We extract the minimal core of causal relations, uncovering the hierarchical and modular organisation from a novel dynamical/causal perspective in a comparative study for Escherichia coli, Bacillus subtilis and Saccharomyces cerevisiae gene regulatory networks.
Prediction of protein–protein interactions between Helicobacter pylori and a human host
Nidhi Tyagi, Oruganty Krishnadev and Narayanaswamy Srinivasan,
Mol. BioSyst., 2009, 5, 1630
DOI: 10.1039/b906543c Enhanced HTML article available
Interactions of extracellular protein domains in H. pylori with human proteins have been predicted. Analysis of some of the examples reveals that the interactions are consistent with the structural compatibility of binding partners. Examples of interactions with discernible biological relevance are discussed.
Amidoligases with ATP-grasp, glutamine synthetase-like and acetyltransferase-like domains: synthesis of novel metabolites and peptide modifications of proteins
Lakshminarayan M. Iyer, Saraswathi Abhiman, A. Maxwell Burroughs and L. Aravind,
Mol. BioSyst., 2009, 5, 1636
DOI: 10.1039/b917682a
We present an evolutionary scenario for the multiple convergent origins of peptide ligases in various folds and clarify the bacterial origin of eukaryotic peptide-tagging enzymes of the TTL family.
Integration of signals from the B-cell antigen receptor and the IL-4 receptor leads to a cooperative shift in the cellular response axis
Nooshin Aflakian, Srikanth Ravichandran, Md. Sarwar Jamal, Henna Jarvenpaa, Riitta Lahesmaa and Kanury V. S. Rao,
Mol. BioSyst., 2009, 5, 1661
DOI: 10.1039/b901992h Enhanced HTML article available
Crosstalk between signals emanating from two distinct cell surface receptors resulted in an additive effect on gene expression. Products of these genes then counteracted to fine-tune the cellular phenotypic response.
Predicting essential genes based on network and sequence analysis
Yih-Chii Hwang, Chen-Ching Lin, Jen-Yun Chang, Hirotada Mori, Hsueh-Fen Juan and Hsuan-Cheng Huang,
Mol. BioSyst., 2009, 5, 1672
DOI: 10.1039/b900611g Enhanced HTML article available
Integrating the topological characteristics of protein–protein interaction networks and the gene sequence properties, we present a machine learning approach for the prediction of essential genes.
Coding DNA repeated throughout intergenic regions of the Arabidopsis thaliana genome: evolutionary footprints of RNA silencing
Jian Feng, Daniel Q. Naiman and Bret Cooper,
Mol. BioSyst., 2009, 5, 1679
DOI: 10.1039/b903031j Enhanced HTML article available
Pyknons are non-random sequence patterns significantly repeated throughout non-coding genomic DNA. DNA sequence patterns from the Arabidopsis thaliana genome were detected using a probability-based method. We postulate that RNA-mediated gene silencing leads to the accumulation of gene sequences in non-coding DNA regions.
Analysis of structured and intrinsically disordered regions of transmembrane proteins
Bin Xue, Liwei Li, Samy O. Meroueh, Vladimir N. Uversky and A. Keith Dunker,
Mol. BioSyst., 2009, 5, 1688
DOI: 10.1039/b905913j Enhanced HTML article available
Intrinsically disordered regions (IDRs) of helical bundle and beta barrel integral transmembrane proteins as well as the IDRs of water soluble proteins all exhibit statistically distinct amino acid compositional biases. This suggested that developing new predictors can increase the accuracy of disorder prediction for integral transmembrane proteins.
Genome-wide analysis predicts DNA structural motifs as nucleosome exclusion signals
Kangkan Halder, Rashi Halder and Shantanu Chowdhury,
Mol. BioSyst., 2009, 5, 1703
DOI: 10.1039/b905132e Enhanced HTML article available
Several factors are known to determine chromatin organization. Recent observations indicate a widespread role of G-quadruplexes, or G4 motifs, in gene regulation. Our results show a structural motif as a possible nucleosome exclusion signal and predict an alternate/additional regulatory role of G4 motifs.
Stable G-quadruplexes are found outside nucleosome-bound regions
Han Min Wong and Julian Leon Huppert,
Mol. BioSyst., 2009, 5, 1713
DOI: 10.1039/b905848f Enhanced HTML article available
We show that regulatory G-quadruplexes found upstream of transcription start sites are located in a region depleted of nucleosomes. Generally in Caenorhabditis elegans and humans, stable G-quadruplexes are located outside nucleosome-bound regions, hence making it easier for them to form in vivo.
A dependency graph approach for the analysis of differential gene expression profiles
Andreas Bernthaler, Irmgard Mühlberger, Raul Fechete, Paul Perco, Arno Lukas and Bernd Mayer,
Mol. BioSyst., 2009, 5, 1720
DOI: 10.1039/b903109j Enhanced HTML article available
This paper describes the construction principles of a dependency network representing human protein coding genes integrating genomic, transcriptomic and proteomic profiles. We demonstrate the improved analysis of differential gene expression profiles at the level of this network.
A network-based method for predicting gene–nutrient interactions and its application to yeast amino-acid metabolism
Idit Diamant, Yonina C. Eldar, Oleg Rokhlenko, Eytan Ruppin and Tomer Shlomi,
Mol. BioSyst., 2009, 5, 1732
DOI: 10.1039/b823287n Enhanced HTML article available
We present a new computational method for predicting metabolic gene–nutrient interactions (GNI) that uncovers the dependence of gene essentiality on the presence or absence of nutrients in the growth medium.
Strategies for efficient disruption of metabolism in Mycobacterium tuberculosis from network analysis
Karthik Raman, Rohit Vashisht and Nagasuma Chandra,
Mol. BioSyst., 2009, 5, 1740
DOI: 10.1039/b905817f Enhanced HTML article available
Schematic illustration of metabolism in a mycobacterial cell. Network construction and graph analysis identifies strategic nodes for maximal and efficient disruption of metabolism, suggesting highly potent drug target combinations.
Unraveling the potential of intrinsically disordered proteins as drug targets: application to Mycobacterium tuberculosis
Meenakshi Anurag and Debasis Dash,
Mol. BioSyst., 2009, 5, 1752
DOI: 10.1039/b905518p Enhanced HTML article available
Tuberculosis remains a disease that causes havoc despite efforts to conquer the pathogen using structure-based rational drug design. We try to unravel thirteen intrinsically disordered essential proteins as potential drug targets with particular focus on GlmU, FtsW and Obg.
Relative stability of DNA as a generic criterion for promoter prediction: whole genome annotation of microbial genomes with varying nucleotide base composition
Vetriselvi Rangannan and Manju Bansal,
Mol. BioSyst., 2009, 5, 1758
DOI: 10.1039/b906535k Enhanced HTML article available
The relative lower stability of promoter regions as compared to neighboring genomic sequences has been used to develop an algorithm 
PromPredict' for promoter identification. It is found to be very reliable when applied to whole genome annotation for microbial genome sequences.
Towards inferring time dimensionality in protein–protein interaction networks by integrating structures: the p53 example
Nurcan Tuncbag, Gozde Kar, Attila Gursoy, Ozlem Keskin and Ruth Nussinov,
Mol. BioSyst., 2009, 5, 1770
DOI: 10.1039/b905661k Enhanced HTML article available
Structural data, efficient structural comparison algorithms and appropriate datasets and filters can assist in getting an insight into time dimensionality in interaction networks; in predicting which interactions can and cannot co-exist; and in obtaining concrete predictions consistent with experiment.
Energy based approach for understanding the recognition mechanism in protein–protein complexes
M. Michael Gromiha, Kiyonobu Yokota and Kazuhiko Fukui,
Mol. BioSyst., 2009, 5, 1779
DOI: 10.1039/b904161n Enhanced HTML article available
A novel energy based approach for identifying the binding site residues in protein–protein complexes showed the importance of cation–
, electrostatic and aromatic interactions with charged and aromatic residues at binding sites.
Modular logical modelling of the budding yeast cell cycle
Adrien Fauré, Aurélien Naldi, Fabrice Lopez, Claudine Chaouiya, Andrea Ciliberto and Denis Thieffry,
Mol. BioSyst., 2009, 5, 1787
DOI: 10.1039/b910101m Enhanced HTML article available
This manuscript presents a logical compositional modelling method and its application to the budding yeast cell cycle. The resulting model couples three regulatory modules: the core cycling engine, the morphogenetic checkpoint and mitotic exit, and qualitatively accounts for the wild-type and numerous mutant behaviours.
Dissection of USP catalytic domains reveals five common insertion points
Yu Ye, Hartmut Scheel, Kay Hofmann and David Komander,
Mol. BioSyst., 2009, 5, 1797
DOI: 10.1039/b907669g Enhanced HTML article available
This paper provides a detailed map of ubiquitin specific protease (USP) catalytic domains from human and yeast, revealing large insertions that intersperse the catalytic fold at five points.
Signaling network analysis of ubiquitin-mediated proteins suggests correlations between the 26S proteasome and tumor progression
Cong Fu, Jie Li and Edwin Wang,
Mol. BioSyst., 2009, 5, 1809
DOI: 10.1039/b905382d Enhanced HTML article available
We performed a comprehensive analysis of a literature-mined human signaling network by integrating data on ubiquitin-mediated protein half-lives. Our findings have implications for the development of cancer treatments and prognostic markers focused on the ubiquitination machinery.
Transcription regulatory networks in Caenorhabditis elegans inferred through reverse-engineering of gene expression profiles constitute biological hypotheses for metazoan development
Vanessa Vermeirssen, Anagha Joshi, Tom Michoel, Eric Bonnet, Tine Casneuf and Yves Van de Peer,
Mol. BioSyst., 2009, 5, 1817
DOI: 10.1039/b908108a Enhanced HTML article available
We illustrate the value of the reverse-engineering algorithm LeMoNe as a biological hypothesis generator for differential gene expression.
A c-Myc regulatory subnetwork from human transposable element sequences
Jianrong Wang, Nathan J. Bowen, Leonardo Mariño-Ramírez and I. King Jordan,
Mol. BioSyst., 2009, 5, 1831
DOI: 10.1039/b908494k Enhanced HTML article available
We evaluated the contribution of transposable elements (TEs) to the c-Myc regulatory network by searching for c-Myc binding sites derived from TEs and by analyzing the expression and function of target genes with nearby TE-derived c-Myc binding sites.
Inferring the transcriptional network of Bacillus subtilis
Abeer Fadda, Ana Carolina Fierro, Karen Lemmens, Pieter Monsieurs, Kristof Engelen and Kathleen Marchal,
Mol. BioSyst., 2009, 5, 1840
DOI: 10.1039/b907310h Enhanced HTML article available
By integrating known and de novo predicted motifs with a comprehensive gene expression compendium, we expand the current Bacillus subtilis regulatory network and provide insight into its condition dependency.
Signal amplification in a lattice of coupled protein kinases
Jacki P. Goldman, Matthew D. Levin and Dennis Bray,
Mol. BioSyst., 2009, 5, 1853
DOI: 10.1039/b903397a Enhanced HTML article available
Bacteria such as Escherichia coli can detect remarkably low concentrations of nutrients such as amino acids. We explain this sensitivity by postulating an amplification step in the signal cascade due to cooperative interactions between molecules of the protein kinase CheA.
Ligand dependent intra and inter subunit communication in human tryptophanyl tRNA synthetase as deduced from the dynamics of structure networks
Priti Hansia, Amit Ghosh and Saraswathi Vishveshwara,
Mol. BioSyst., 2009, 5, 1860
DOI: 10.1039/b903807h Enhanced HTML article available
Homodimeric protein tryptophanyl tRNA synthetase (TrpRS) has a Rossmann fold domain and belongs to the 1c subclass of aminoacyl tRNA synthetases. In this study, we have modeled the structure of human TrpRS bound to the activated ligand and the cognate tRNA.
Correlation between mRNA expression levels and protein aggregation propensities in subcellular localisations
Gian Gaetano Tartaglia and Michele Vendruscolo,
Mol. BioSyst., 2009, 5, 1873
DOI: 10.1039/b913099n Enhanced HTML article available
We investigate the relationship between mRNA expression levels and protein aggregation propensities at the proteomic level, and find that these quantities exhibit a significant correlation when they are averaged across subcellular localisations.
Molecular modeling and docking studies of human 5-hydroxytryptamine 2A (5-HT2A) receptor for the identification of hotspots for ligand binding
Karuppiah Kanagarajadurai, Manoharan Malini, Aditi Bhattacharya, Mitradas M. Panicker and Ramanathan Sowdhamini,
Mol. BioSyst., 2009, 5, 1877
DOI: 10.1039/b906391a Enhanced HTML article available
We have performed sequence analysis and molecular modeling of 5-HT2A that has revealed a set of conserved residues and motifs considered to play an important role in maintaining structural integrity and function of the receptor.
An integrative approach towards completing genome-scale metabolic networks
Nils Christian, Patrick May, Stefan Kempa, Thomas Handorf and Oliver Ebenhöh,
Mol. BioSyst., 2009, 5, 1889
DOI: 10.1039/b915913b Enhanced HTML article available
We propose a strategy that incorporates genomic sequence data and metabolite profiles into modelling approaches to arrive at improved gene annotations and more complete genome-scale metabolic networks.
DNA supercoiling regulates the stress-inducible expression of genes in the cyanobacterium Synechocystis
Jogadhenu S. S. Prakash, Maria Sinetova, Anna Zorina, Elena Kupriyanova, Iwane Suzuki, Norio Murata and Dmitry A. Los,
Mol. BioSyst., 2009, 5, 1904
DOI: 10.1039/b903022k Enhanced HTML article available
The genome-wide microarray analysis of stress-dependent gene expression due to changes in DNA supercoiling has been performed in the cyanobacterium Synechocystis. Gene expression profiles are presented for responses to cold, heat, and salt stresses.
A metabolomic and multivariate statistical process to assess the effects of genotoxins in Saccharomycescerevisiae
Christopher M. Titman, Jessica A. Downs, Stephen G. Oliver, Paul L. Carmichael, Andrew D. Scott and Julian L. Griffin,
Mol. BioSyst., 2009, 5, 1913
DOI: 10.1039/b907754e Enhanced HTML article available
A combined high resolution 1H NMR and gas chromatography mass spectrometry based metabolomic approach was used to monitor and distinguish different genotoxic compounds from other types of toxic lesion.
The ABC of reverse engineering biological signalling systems
Maria Secrier, Tina Toni and Michael P. H. Stumpf,
Mol. BioSyst., 2009, 5, 1925
DOI: 10.1039/b908951a
We discuss a statistical approach—approximate Bayesian computation (ABC)—which allows us to approximate the posterior distribution over model-parameters and show how this can add insights into our understanding of the system dynamics.
Prediction of conditional gene essentiality through graph theoretical analysis of genome-wide functional linkages
P. Manimaran, Shubhada R. Hegde and Shekhar C. Mande,
Mol. BioSyst., 2009, 5, 1936
DOI: 10.1039/b905264j Enhanced HTML article available
We demonstrate the efficacy of combined graph theoretical and machine learning approaches in ranking essential nodes from a large network of genome-wide functional linkages, which yields predictions with high accuracy. We therefore perceive such predictions as highly useful in applications such as defining and prioritizing drug targets.
A global view of Escherichia coli Rsd protein and its interactions
Sarah E. Piper, Jennie E. Mitchell, David J. Lee and Stephen J. W. Busby,
Mol. BioSyst., 2009, 5, 1943
DOI: 10.1039/b904955j Enhanced HTML article available
The Escherichia coli Rsd protein forms 1 : 1 complexes with 
70 protein, which is the major factor in determining promoter recognition by RNA polymerase. Here we describe measurements of the levels of Rsd, RNA polymerase, 70 and the alternative 38 factor.
Back matter
Mol. BioSyst., 2009, 5, 1948
DOI: 10.1039/B922403N
Back cover
Mol. BioSyst., 2009, 5, 1951
DOI: 10.1039/b922404c
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